CN116916934A

CN116916934A - Novel therapeutic regimens for the treatment of autoimmune disorders

Info

Publication number: CN116916934A
Application number: CN202180075970.6A
Authority: CN
Inventors: U·博舍特; U·维德曼
Original assignee: Merck Patent GmbH
Current assignee: Merck Patent GmbH
Priority date: 2020-09-10
Filing date: 2021-09-10
Publication date: 2023-10-20

Abstract

The present invention relates to novel therapeutic regimens for the treatment of autoimmune disorders. The novel treatment regimen preferably provides the patient with an effective treatment of autoimmune disorders with an advantageous safety profile and/or high quality of life. Preferably, the novel treatment regimen provides a beneficial benefit-risk ratio to patients at risk of infection.

Description

Novel therapeutic regimens for the treatment of autoimmune disorders

Technical Field

The present invention relates to novel therapeutic regimens for the treatment of autoimmune disorders. The novel treatment regimen preferably provides the patient with an effective treatment of autoimmune disorders with an advantageous safety profile and/or high quality of life. Preferably, the novel treatment regimen provides an advantageous benefit-risk ratio for patients at risk of infection. This is considered of particular importance because substantially all therapeutic options for the treatment of autoimmune disorders that provide effective treatment include active ingredients with immunosuppressive properties, which are generally of safety concern in the context of infectious disorders.

Background

In the treatment of autoimmune disorders, such as Multiple Sclerosis (MS), rheumatoid Arthritis (RA), systemic Lupus Erythematosus (SLE), neuromyelitis optica spectrum disease (NMOSD), and Myasthenia Gravis (MG), inhibition of at least a portion of the immune system of the afflicted body can result in an improvement in the clinical manifestations of the individual disorder, as autoimmune disorders are considered as the result of excessive activation of the body's autoimmune system.

Accordingly, various direct or indirect immunosuppressive drugs are widely used in the treatment of autoimmune disorders, including, but not limited to, corticosteroids such as cortisol, glucocorticoids such as prednisone, dexamethasone and hydrocortisone, cytostatics such as nitrogen mustard (e.g., cyclophosphamide), nitrosoureas, platinum compounds, antimetabolites such as methotrexate, azathioprine, mercaptopurine, fluorouracil and cladribine, antibodies to B-and/or T-cell receptors such as omuzumab, rituximab, oxcarbatozumab, orrituximab and moruzumab, drugs acting on immunoaffinins such as cyclosporine, tacrolimus, sirolimus and everolimus, and other immunosuppressive drugs such as interferons, opioids, TNF binding proteins such as infliximab, etanercept and adalimumab, and mycophenolic acid.

In the fields of Multiple Sclerosis (MS), rheumatoid Arthritis (RA), systemic Lupus Erythematosus (SLE), neuromyelitis optica spectrum disease (NMOSD) and Myasthenia Gravis (MG), the most widely used immunosuppressive drugs include injections such as natalizumabAlemtuzumab- >Orivizumab->RituximabAnd glatiramer acetate->Oral medications such as dimethyl fumarate +.>Fengomod->And cladribine tablet->

However, since autoimmune diseases are often incurable, but chronic lifelong conditions, continued administration of immunosuppressive drugs over years (if not decades) is also a clinical reality. Thus, their side effects can lead to serious consequences in many correspondingly treated subjects, sometimes even more severe than the underlying autoimmune disease itself. Under immunosuppressive therapy, either by bacteria, viruses or viruses and related pathogens (e.g., viroids, fungi or protozoans), each infection or even opportunistic infections can pose a serious clinical crisis to the subject.

The active ingredient cladribine has been developed in the eighties of the twentieth century as an active ingredient (API), which is an antimetabolite for the treatment of certain hematological cancers, and is subsequently approved for the treatment of Hairy Cell Leukemia (HCL). Its mode of action in HCL indications is based on the following findings: it is capable of enriching for certain blood cells, including lymphocytes, in the living body of the treated subject and depleting them, for example by apoptosis. As a result of treatment with cladribine, the amount of lymphocytes in the treated subject is considerably reduced, thereby affecting the immune system of the subject, since the immune system is largely dependent on lymphocytes normally provided by the living body. Thus, treatment of hairy cell leukemia with cladribine is known to be associated with potential side effects such as increased risk of infection, increased severity of infection and increased risk of long-term malignancy.

Despite these problems, the in vivo lymphopenia achieved by administering an API to a subject, and the resulting inhibition of the immune system of the treated body by it, is not necessarily initially negative, as the reduced activity of the immune system is beneficial in the treatment of certain disorders or conditions, such as host graft rejection and autoimmune diseases or autoimmune disorders in general. Various immunosuppressive drugs are the treatment options of choice in both host graft rejection and in the treatment or amelioration of autoimmune diseases.

However, to date, there is a high medical need for treatment regimens for treating autoimmune disorders with immunosuppressants having a positive benefit-risk ratio with respect to adverse events triggered by infections (especially viral and/or bacterial infections).

It is known that various types of bacteria, particularly various types of pathogenic bacteria, can potentially infect (more particularly pathologically infect) one or more host species, including warm-blooded animals, mammals and humans. In general, when the body of an organism (i.e. the body of a host) is invaded by one or more of said pathogenic bacteria and the body of the host is not able to control or sufficiently control the replication and spread of said pathogenic bacteria in the body of the host or parts or organs thereof and thus a bacterial disease or disorder, infection by (pathogenic) bacteria often results in a bacterial disease or infectious bacterial disease in said host.

Other bacteria are characterized as opportunistic pathogens and cause disease mainly in people suffering from immunosuppression or cystic fibrosis. Examples of these opportunistic pathogens include pseudomonas aeruginosa (Pseudomonas aeruginosa) (causing diseases such as hospital acquired infections, ventilator-associated pneumonia (a type of pulmonary infection occurring in people who use mechanical ventilators in hospitals), and various sepsis syndromes), new burkholderia cepacia (Burkholderia cenocepacia), and mycobacterium avium (Mycobacterium avium) (found in fresh water and saline, household dust and soil, causing diseases known as mycobacterium avium infection or mycobacterium avium complex infection in humans, typically only in immunocompromised subjects or subjects with severe lung disease).

Preferably, the bacterial infection, disease or condition includes, but is preferably not limited to, anthrax, cholera, diphtheria, haemophilus influenzae (Haemophilus influenzae), meningococcal meningitis, pertussis, plague, pneumococcal disease, streptococcus pneumoniae (Streptococcus pneumoniae), tetanus, tuberculosis and typhoid fever.

Various types of viruses are known which potentially can infect (more particularly pathologically infect) one or more host species, including warm-blooded animals, mammals and humans. In general, viral infections often result in viral diseases or infectious viral diseases when the body of an organism (i.e. the body of a host) is invaded by a pathogenic virus and infectious viral particles (e.g. viral particles) attach to and enter susceptible cells of the host or the body of a subject.

Basic structural features, such as genome type, virion shape and replication sites, generally share the same characteristics among viral species within the same family:

double-stranded DNA family: three are non-enveloped (Adenoviridae, papillomaviridae and Polyomaviridae) and two are enveloped (Herpesviridae and Poxviridae). All non-enveloped families have icosahedral capsids.

Partially double stranded DNA virus: hepadnaviridae (Hepadnaviridae). These viruses are enveloped.

One family of single-stranded DNA viruses infects humans: parvoviridae (Parvoviridae). These viruses are non-enveloped.

Positive single strand RNA family: three non-enveloped (Astroviridae, calicividae and Picornaviridae) and four enveloped (Coronaviridae, flavoviridae, retroviridae and Togaviridae). All non-enveloped families have icosahedral nucleocapsids.

Negative single stranded RNA family: arenaviridae (Arenaviridae), bunyaviridae (Bunyaviridae), filoviridae (Filoviridae), orthomyxoviridae (Orthomyxoviridae), paramyxoviridae (Paramyxoviridae), and Rhabdoviridae (Rhabdoviridae). All are surrounded by a helical core capsid.

Double-stranded RNA genome: reoviridae (Reoviridae).

Hepatitis b virus has not been classified into one family but is clearly different from other families where people are infected.

Viruses known to infect humans that have not been associated with disease: dactyloviridae (Anelloviridae) and dependoviridae (dependoviruses). Both taxonomies are non-enveloped single-stranded DNA viruses.

The virology of the infected person provides rules that may help doctors and medical microbiologists/virologists.

As a general rule, DNA viruses replicate in the nucleus, while RNA viruses replicate in the cytoplasm. The exceptions to this rule are known: poxviruses replicate in the cytoplasm, and orthomyxoviruses and hepatitis delta viruses (RNA viruses) replicate in the nucleus.

Segment genome: bunyaviridae, orthomyxoviridae, arenaviridae and reoviridae (acronym BOAR). All RNA viruses.

Viruses transmitted almost exclusively by arthropods: bunyavirus (Bunyavirus), flavivirus (flavovirus) and Togavirus (Togavirus). Some reoviruses are transmitted by arthropod vectors. All RNA viruses.

One family of enveloped viruses causes gastroenteritis (coronaviridae). All other viruses associated with gastroenteritis are non-enveloped.

The table [ table 1] given below summarizes some of the clinically most important pathogenic viruses known to afflict a variety of hosts (including humans), as well as the individual virus types, families, exemplary transmission pathways, and infections/diseases that are generally attributed. However, the clinical properties of viruses may vary significantly among different species within the same family.

Table 1:

preferably, in the context of the use according to the invention and/or the method of treatment according to the invention, all the viruses and/or viral disorders given above are regarded as clinically relevant viruses and/or viral disorders. More preferably, in MS, many vaccine-preventable infectious diseases are relevant, as the risk of infection or adverse outcome is increased by MS itself or its therapy. These mainly include Hepatitis B Virus (HBV) and Varicella Zoster Virus (VZV). Other infectious diseases may include hepatitis B, measles, influenza, poliovirus, pneumococcus, diphtheria, tetanus and bordetella pertussis (Bordetella pertussis), SARS-COVID-2 and/or SARS-COVID-19. Vaccines against SARS Covid-2 and/or SARS-COVID-19 are currently available, wherein further alternatives will soon become available.

Viral infections and/or resulting diseases can often be detected by clinical manifestations, signs and/or symptoms, including but not limited to severe muscle pain and joint pain or rash and lymphadenopathy prior to fever. Standard laboratory surveys may help detect viral infections. Laboratory surveys may also be used to diagnose bacterial infections associated with viral infections. Viral infections generally have a limited duration and treatments according to the prior art generally consist of alleviation of symptoms and often prescribe antipyretics and analgesics.

However, the best protection of a subject from the potentially serious and deleterious consequences of an infection is the amelioration or prevention of such an infection. The most advantageous mode of prevention or amelioration of the present invention is currently considered to be vaccination of subjects threatened by the infection.

However, preventive measures against infections (such as vaccination) generally require an appropriate immune response of the respective body and are therefore generally recommended to be done before serious medical interventions (i.e. surgery, chemotherapy, radiation therapy or immunosuppressive therapy is started) and/or after the end of each serious medical intervention.

Thus, precautions against infections (such as vaccination) that require an appropriate immune response of the respective body are generally recommended to be made before the start of each immunosuppressive treatment and/or after the end of each immunosuppressive treatment (if present).

In this context, vaccination is preferably administration of a vaccine to assist the immune system in developing a protection from disease (preferably infectious disease). Vaccines typically contain pathogens (preferably microorganisms or viruses) or proteins or toxins from individual organisms in attenuated, live or killed/dead states for the individual disease. They help prevent diseases from infectious diseases when stimulating adaptive immunity of the body. Vaccination is the most effective method of preventing infectious diseases, so infectious disease prevention in people with reduced immunity due to immunosuppressive therapy is generally regarded as important and advantageous/desirable.

Infectious conditions for which a vaccine is available or at least desirable include, but are not limited to, influenza and influenza-like diseases, such as parainfluenza virus (causing croup, pneumonia, bronchiolitis and/or common cold) and coronavirus-induced infections, such as epidemics or pandemics caused by SARS-CoV, HCoV NL63, HCoV HKU1, MERS-CoV and SARS-CoV-2/covd-19 and/or mutants or successor viruses thereof.

More specifically, coronaviruses preferably constitute the orthocoronaviridae subfamily (orthoroonavirinae), the coronaviridae family, the order of the reticuloviridae (Nidovirales), and the ribovirodomain (riboviroia). They are considered enveloped viruses with a positive-sense single-stranded RNA genome and/or a helically symmetric nucleocapsid. The latter is typically enclosed in an icosahedral protein shell. Coronaviruses are considered to have genome sizes ranging from about 26 to 32 kilobases, one of the largest genomes in RNA viruses. Furthermore, they often have characteristic rod-like spikes protruding from their surface, which in electron micrographs produce images reminiscent of coronaries, the name of which is believed to be derived therefrom.

Human coronaviruses were found in the sixties of the twentieth century, including viruses tagged with B814, 229E, IBV (infectious bronchitis virus) and OC 43. This new group of viruses is called coronaviruses because of their unique morphological appearance. Thereafter, a variety of other human coronaviruses have been identified, including SARS-CoV in 2003, HCoV NL63 in 2004, HCoV HKU1 in 2005, MERS-CoV in 2012, and SARS-CoV-2 in 2019. However, there have also been a large number of animal coronaviruses identified since the sixties of the twentieth century.

Influenza, commonly referred to as "influenza," is an infectious disease caused by influenza viruses. Symptoms may be mild to severe. The most common symptoms include: high fever, runny nose, sore throat, muscle and joint pain, headache, cough and tiredness. These symptoms usually begin two days after exposure to the virus and most last for less than one week. However, cough may last for more than two weeks. Diarrhea and vomiting may be present in children, but these are not common in adults. Complications of influenza may include viral pneumonia, secondary bacterial pneumonia, sinus infections, and exacerbation of previous health problems such as asthma or heart failure.

In general, three of four classes of influenza viruses affect humans: type a, type b and type c. Butyl has heretofore not been known to infect humans, but is believed to have the potential to do so.

There are 4 classes of influenza viruses: type a, type b, type c and type d. Only influenza a and b cause seasonal epidemics of respiratory illness that occur annually. Influenza a viruses are further divided into different subgroups based on two proteins found on the surface of the virus-Hemagglutinin (HA) and Neuraminidase (NA). There are 18 different HA subtypes (H1-18) and 11 different NA subtypes (N1-11).

Each year, once a year influenza vaccines protect against 3 or 4 influenza strains. H1N1, H1N2 and H3N2 are currently the only known influenza a virus subtypes that are transmitted in humans and are included in trivalent vaccines, while additional influenza b strains are included in tetravalent vaccines.

H1N1 influenza is also known as swine influenza. It is called swine influenza because in the past, people who have infected it had direct contact with pigs. This changed a few years ago, when a new virus spread in people who were not close to pigs was presented. In 2009, H1N1 rapidly spread worldwide, so the world health organization (World Health Organization) called pandemic.

H3N2 virus continues to spread worldwide as seasonal influenza a virus. Seasonal H3N2 viruses associated with severe disease in the elderly experience regular antigen drift. In the years where H3N2 predominated strains, there are more hospitalizations, especially in high risk groups such as elderly and young children.

All northern hemisphere 2018-2019 influenza vaccines contained a/michigan/45/2015-like (H1N 1) pdm09 virus and B/Colorado/06/2017-like Victoria lineage virus. Tetravalent vaccines contained n additional B/phukey/3073/2013-like Yamagata lineage viruses. Genetic characterization of the virus indicated that most of the a (H3N 2) viruses transmitted in the united states were antigenically distinct or drifted from 2018-19 northern hemisphere vaccine strains, while the a (H1N 1) pdm9 viruses transmitted were well matched.

Influenza b virus is known to infect only humans and seals. This limited host range clearly leads to a lack of related influenza pandemics, in contrast to morphologically similar influenza a virus-induced influenza pandemics, as both mutate by both antigen drift and reassortment. Based on the antigenic properties of the surface glycoprotein hemagglutinin, there are two known transmission lineages of influenza b virus. These lineages were designated B/Yamagata/16/88-like and B/Victoria/2/87-like viruses. CDC licensed tetravalent influenza vaccines are currently designed to protect against both co-transmitted lineages and have been shown to be more effective than previous trivalent vaccines in preventing influenza caused by influenza b virus. Further narrowing the impact of this virus, "in humans, influenza b virus evolves slower than type a virus but faster than type c virus. The mutation rate of influenza B virus is 1/3 to 1/2 of that of type A.

Trivalent inactivated influenza vaccines for injection are most commonly used worldwide.

Tetravalent inactivated influenza vaccine available from 2014/2015 season for use in Magnify study

In 2011, attenuated live influenza vaccine (LAIV) for intranasal use was approved in EU/EEA for children and adolescents (2-17 years). According to WHO recommendations, all live attenuated influenza vaccines currently available are tetravalent combination vaccines, containing two influenza a strains (H1N 1 and H3N2 subtypes) and two influenza b strains (Victoria and Yamagata lineages).

Since seasonal influenza vaccines are generally recommended for some susceptible populations of immune responders that are weaker due to age or disease, several attempts to improve the vaccine have been explored over the past 10-15 years, for example: the antigen dose administered is increased, intradermal administration to activate the other arms of the immune system, and an immunostimulatory compound, such as an adjuvant, is added.

Products utilizing these new technologies are currently licensed and available in some EU/EEA countries. See the table below. For influenza vaccines, MF59 (squalene) and AS03 (squalene and α -tocopherol) have been approved AS adjuvants by regulatory bodies in the european union, canada and the united states. Data from several observational studies, indicating improved performance against influenza disease and hospitalization and reduced hospitalization in the elderly, have been included in the label for adjuvanted trivalent influenza vaccines.

Most influenza vaccines (both inactivated and live attenuated) are produced in eggs of fertilized hens based on influenza virus/antigen. Thus, these vaccines cannot be administered to egg-allergic individuals who develop severe symptoms after exposure to egg proteins. Thus, some manufacturers have developed cell-based influenza vaccines.

In Mavenclad-related clinical trials, the following influenza strains were used: H1N1 (Brisbanea), H3N2 (Kansas A), H1N1 (Michigana A), H3N2 (Singapore A), victoria (Colorado/B), yamagata (Phuket/B).

Influenza a virus subtype H1N2 (a/H1N 2) is a subtype of influenza a virus species (sometimes referred to as avian influenza virus). It is currently popular in both the human and swine populations. H1N1, H1N2 and H3N2 are the only known influenza a virus subtypes currently transmitted in humans. The virus does not generally cause a more severe disease than other influenza viruses, and the abnormal increase in influenza activity is not related to it.

H3N2 virus continues to spread worldwide as seasonal influenza a virus. Seasonal H3N2 viruses associated with severe disease in the elderly experience regular antigen drift.

Typical influenza vaccine compositions for general use or to be used in 2018-2021 are listed in FIG. 16

Trivalent inactivated influenza vaccines for injection are most commonly used worldwide. Influenza antigen formulations vary between manufacturers. Inactivated influenza vaccines available at EU/EEA may contain split virion influenza virus products or subunit influenza products. Adjuvanted inactivated subunit influenza vaccines for the elderly are available in some EU/EEA member countries.

Tetravalent inactivated influenza vaccines for injection available from season 2014/2015 in some EU/EEA countries are expected to replace trivalent vaccines over time. Although available in private markets in some european countries, vaccine authorization, vaccine availability, observed vaccine availability and cost may affect the speed of such replacement.

The popular pediatric program of finland and uk organizations provides tetravalent LAIV to infants between 2 and 3 years or between 2 and 11 years, respectively.

Since seasonal influenza vaccines are generally recommended for some susceptible populations of immune responders that are weaker due to age or disease, several attempts to improve the vaccine have been explored over the past 10-15 years, for example: the dose of antigen administered is increased, intradermal administration to activate the other arms of the immune system, and an immunostimulatory compound such as an adjuvant is added (see references 1-4).

Most influenza vaccines (both inactivated and live attenuated) are produced in eggs of fertilized hens based on influenza virus/antigen. Thus, these vaccines cannot be administered to egg-allergic individuals who develop severe symptoms after exposure to egg proteins. Thus, some manufacturers have developed cell-based influenza vaccines that can be administered to individuals with severe egg allergy. The use of cell-based products may have improved matching to transmitted influenza strains, as they avoid egg adaptation problems.

Table 2: seasonal influenza vaccine overview available for EU/EEA (2019/20 seasons)

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Table 3: seasonal influenza vaccine available to UK (season 2020/2021) all influenza vaccines available to UK in season 2020 to 2021

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Infectious conditions for which a vaccine is available or at least desirable include, but are preferably not limited to, hepatitis B Virus (HBV) and Varicella Zoster Virus (VZV). Other infectious diseases may include hepatitis b, measles, influenza vaccine, poliovirus, pneumococcus, diphtheria, tetanus and bordetella pertussis, and SARS-Covid 2. Vaccines against SARS Covid-2 are currently available, wherein further alternatives will soon become available.

Other diseases, including smallpox, varicella, poliomyelitis, tetanus, measles, mumps, rubella, pertussis and/or influenza-like conditions may also be relevant.

Vaccination with a vaccine is one way to artificially activate the immune system to protect against infectious diseases. Activation occurs by priming the immune system with an immunogen. Stimulating an immune response with an infectious agent is known as vaccination. Vaccination includes various ways of administering an immunogen.

Various routes for administering vaccines are known to the skilled artisan. Typically, vaccine administration may be oral, by injection (intramuscular, intradermal, subcutaneous), by puncture, transdermal or intranasal. Several recent clinical trials aim at delivering vaccines via mucosal surfaces to be absorbed by the general mucosal immune system, thus avoiding the need for injection.

Most vaccines are administered before the patient has been infected with the disease to help increase future protection. However, some vaccines are administered after the patient has been infected with the disease. Vaccines administered after smallpox exposure are reported to provide some protection from disease or may reduce the severity of disease.

Most vaccines are administered by injection because they are not reliably absorbed through the intestinal tract. Attenuated live polio vaccines, rotavirus vaccines, some typhoid vaccines and some cholera vaccines are administered orally to generate immunity in the intestines. Although vaccination provides a durable effect, it typically takes several weeks to develop and requires an immune system capable of generating an appropriate immune response.

Vaccine type

There are several different types of vaccines. Each type is designed to teach your immune system how to combat certain types of pathogens and the severe diseases they cause. When scientists prepare vaccines, they consider: how your immune system responds to the pathogen, which people need to vaccinate against the pathogen, and the best technique or method to prepare the vaccine. Based on some of these factors, scientists decide what type of vaccine they will make. There are several main types of vaccines, such as attenuated live vaccines, inactivated vaccines, subunit vaccines, recombinant vaccines, polysaccharide vaccines and conjugate vaccines, toxoid vaccines.

The most relevant vaccine types are described in more detail below:

attenuated live vaccine: live vaccines use attenuated (or attenuated) forms of disease causing pathogens. Because these vaccines are so similar to natural infections that they help prevent, they produce a strong and durable immune response. Only 1 or 2 doses of most live vaccines can give you life-long protection from pathogens and their resulting diseases. However, live vaccines also have some limitations. For example: because they contain a small amount of attenuated live virus, some people should consult their healthcare provider prior to receiving them, such as those with an attenuated immune system, those with long-term health problems, or those with organ transplants. They need to be cooled down and therefore they are not suitable for long distance transport. This means that they cannot be used in countries where refrigerator use is limited. Live vaccines are used to protect against the following: measles, mumps, rubella (MMR combination vaccine), rotavirus, smallpox, varicella, yellow fever, nasal influenza vaccine;

inactivated vaccine: inactivated vaccines use a killed form of disease causing pathogens. Inactivated vaccines generally do not provide as strong immunity (protection) as live vaccines. Thus, you may need several doses over a period of time in order to obtain a sustained immunity against the disease. Inactivated vaccines are used to protect against the following: hepatitis a, influenza (injection only), poliomyelitis (injection only), rabies;

Subunit vaccines, recombinant vaccines, polysaccharide vaccines and conjugate vaccines: these vaccines use specific fragments of the pathogen-such as its protein, sugar or capsid (the outer shell around the pathogen). Because these vaccines use only specific fragments of the pathogen, they give a very strong immune response targeting a critical part of the pathogen. They can also be used in almost everyone in need thereof, including those with a weakened immune system and long-term health problems. One limitation of these vaccines is that you may need to boost the injection to obtain sustained protection against the disease. These vaccines are used to protect against the following: hib (haemophilus influenzae type b) disease, hepatitis B, HPV (human papilloma virus), pertussis (part of a DTaP combination vaccine), pneumococcosis, meningococcal disease, shingles,

Toxoid vaccine: toxoid vaccines use toxins (deleterious products) produced by disease causing pathogens. They produce part of immunity against disease causing pathogens, not pathogens themselves. This means that the immune response targets the toxin rather than the whole pathogen. Like some other types of vaccines, you may need to boost injections to obtain sustained protection against disease. Toxoid vaccines are used to protect against the following: diphtheria, tetanus;

DNA plasmid vaccine: comprising small circular DNA fragments called plasmids, which carry genes encoding proteins from the pathogen of interest. The manufacturing process for DNA plasmid vaccines is well established, allowing rapid development of experimental vaccines to cope with emerging or reappeared infectious diseases. The vaccine research center (Vaccine Research Center) of NIAID has developed candidate DNA vaccines to address several viral disease threats during outbreaks, including SARS coronavirus in 2003 (SARS-CoV), H5N1 avian influenza in 2005, H1N1 pandemic influenza in 2009, and zika virus in 2016. The time from selection of the viral genes to be included in the vaccine to initiation of clinical studies in humans was shortened from 20 months for SARS-CoV to a few 3 months more for zika virus.

mRNA vaccine: vaccines based on messenger RNA (mRNA), which is an intermediate stage between DNA and protein, are also under development. Recent technological advances have largely overcome the problems of mRNA instability and difficulty in delivering it into cells, and some mRNA vaccines have demonstrated encouraging early results. For example, NIAID-supported researchers developed an experimental mRNA vaccine that protected mice and monkeys from pick-up virus infection after a single dose.

Recombinant vector vaccine (platform-based vaccine): some vaccines do not deliver DNA or mRNA directly to cells, but rather use harmless viruses or bacteria as vectors or carriers to introduce genetic material into cells. Several such recombinant vector vaccines are approved to protect animals from infectious diseases, including rabies and canine distemper. Many of these veterinary vaccines are based on a technology developed by NIAID researchers in the eighties of the twentieth century that uses attenuated forms of poxviruses to deliver genetic material of pathogens. Today, NIAID-supported scientists are developing and evaluating recombinant vectorized vaccines to protect humans from viral effects such as HIV, zika virus, and ebola virus.

However, vaccination may lead to a serious clinical crisis in the vaccinated body, e.g. due to vaccine failure. Generally, failure of a vaccine is suggested when an organism infects a disease despite vaccination against it. Primary vaccine failure occurs when the immune system of the organism does not produce antibodies at the time of the first vaccination. Vaccines may fail when given several series and fail to generate an immune response. The term "vaccine failure" does not necessarily imply that the vaccine is defective. Most vaccine failures are due solely to individual differences in immune response, but also occur in immunosuppressive bodies, for example under immunosuppressive therapy in patients suffering from autoimmune diseases.

Historically, the term "vaccination" is often used interchangeably with "vaccination". However, these terms are not synonyms. Vaccination is a more general term that initially consists of: relatively 'safe' injections of samples taken from (viral) diseased bodies, such as cattle with vaccinia. Vaccination is a very likely, almost as old practice as the disease itself, and smallpox virus obtained from pustules or crusts of smallpox infected subjects is injected into the superficial layer of the skin, typically on the upper arm of the subject. Inoculation is often done 'arm to arm', or less efficiently 'crusting to arm'. Vaccination often encourages patients to infect smallpox and, in some cases, the infection is transformed into a severe disease.

In one aspect of the invention, the term vaccination is preferably intended to also include the meaning of the term "vaccination". However, since the reliability and safety aspects of vaccination are often questioned, the term "vaccination" is preferably intended to exclude "vaccination".

Vaccination with individual vaccines has led to a substantial reduction in the prevalence of a variety of infectious diseases in countries with higher development. Previous studies on the effectiveness of vaccination/vaccine on mortality or morbidity of those exposed to various diseases have shown a nearly 100% reduction in mortality and an approximately 90% reduction in exposure.

However, with the development of anti-vaccine exercise, even the most developed countries can see the reburning of dead ashes of certain vaccine-preventable diseases. For example, as the number of measles cases has increased continuously in recent years, measles virus has now lost its state of elimination in US. As a result, even infectious diseases that were previously considered "extinct" can now endanger subjects whose body is in an immunosuppressive state again.

As a result, a subject suffering from an autoimmune disease that is prone to treatment with an immunosuppressant or has received treatment with an immunosuppressant would be highly desirable as a prophylactic measure (preferably vaccination) against infection. However, as outlined above and/or below, vaccination requires an appropriate immune response of the vaccinated body and is therefore generally advisable to do so before the start of each immunosuppressive treatment and/or after the end of each immunosuppressive treatment. Typically, a gap or interval of duration of at least six weeks to several months is maintained between the initiation and/or termination of vaccination and immunosuppressive therapy so as to have a safe margin.

Unfortunately, because of the severity and unpredictability of certain autoimmune disorders that can cause severe outbreaks, episodes, or recurrence of disease activity to any subject at essentially any given time, and the primarily chronic nature of the autoimmune disorder requires prolonged (if not sustained) immunosuppressive treatment over years or even decades, maintaining the gap or interval that is expected to be a safe boundary is a big task for both subjects in need of treatment and vaccination, as well as for the attending physician.

Detailed Description

Over the past two decades, treatment options for patients with autoimmune diseases, including but not limited to Multiple Sclerosis (MS), have grown as many highly effective active ingredients (APIs) have been found, developed and/or approved for marketing. Examples of such APIs include, but are not limited to, injectables/monoclonal antibodies, such as natalizumab, orelizumab and alemtuzumab, and oral/small molecule drugs, such as dimethyl fumarate, fingolimod, teriflunomide and cladribine tablets. All of the above modes of action of the API are believed to be based on their effect on lymphocytes and/or lymphocyte subsets, including but not limited to, reducing the number of circulating lymphocytes, e.g., by depletion and/or apoptosis of lymphocytes or subsets thereof, inhibiting migration of lymphocytes in the body, e.g., by engraftment inhibition of sequestered lymphocytes or subtypes thereof, or other functional modulation of lymphocytes or subtypes thereof.

However, since lymphocytes are a very important part of the immune system, a reduction in the number of circulating lymphocytes and/or subtypes thereof is believed to affect the body's ability to mount an immune response, for example, against an infection and/or a vaccine against such an infection. Thus, tracking of adverse events with respect to the API and other APIs with similar modes of action generally shows an increase in infection-related adverse events caused by a new infection or by reactivation and/or chronic infection of persistent or even latent infection. One of the obvious options for reducing the risk of acquiring an infection, preventing the outbreak of an existing latent infection or preventing the exacerbation of an existing persistent infection includes vaccination strategies and strategies for vaccination such as immunization.

However, since both infection and vaccination/immunization against infection are considered to be particularly problematic in immunocompromised patients, including MS patients due to the disease itself, and in particular in MS patients under immunosuppressive therapy (including but not limited to immunosuppressive therapy with the API described above), the treatment of infection and its prophylaxis via vaccination/immunization is considered to be associated with a high risk for said immunocompromised patients. In particular, many infectious diseases that can be prevented by a vaccine in theory are of great importance in this respect, since the risk of infection itself or the adverse outcome of an infected patient increases due to MS itself and/or its therapy. Examples of such theoretical vaccine-preventable infectious diseases include, but are not limited to, hepatitis B Virus (HBV), varicella Zoster Virus (VZV), measles, mumps and rubella (MMR), hepatitis A, hepatitis B, human Papilloma Virus (HPV), diphtheria, tetanus, acellular pertussis, meningococcal and/or influenza,

However, the response to vaccines has also been shown to be impaired in MS patients receiving immunotherapy, especially lymphocyte depletion immunotherapy. For example, peripheral B cell depletion patients treated with orelizumab produced only a significantly reduced humoral response to clinically relevant vaccines. The humoral immune response against vaccination is significantly reduced compared to placebo, especially in patients receiving orelizumab. Similarly, the response to 23-valent pneumococcal polysaccharide vaccine is essentially compromised, with fewer patients producing positive responses to ≡12 strains.

Vaccination of MS patients on alemtuzumab therapy achieved adequate vaccination protection using recall antigens (tetanus, diphtheria, polio). In contrast, however, the response showed sub-optimally high individual variability after vaccination with pneumococcal polysaccharide vaccine.

The effectiveness of vaccination of MS patients with fingolimod is reduced compared to placebo-treated patients and may remain limited during and up to two months after fingolimod withdrawal. Although natalizumab treatment does not appear to affect the response to primary or secondary vaccination within clinically relevant limits, the response to H1N1 influenza vaccine is significantly reduced similarly to that found for glatiramer acetate.

Cladribine is a known immunosuppressant (ATC codes L01BB04 and L04AA 40). In view of this, it was previously considered inappropriate to administer a vaccine during treatment with this agent. According to the major regulatory authorities (e.g. FDA, EMA), administration of the vaccine must be avoided during treatment with cladribine as a prophylactic measure against infectious complications and their sequelae in immunosuppressive patients. In addition, administration of such vaccines may lead to unexpected adverse effects. In view of the immunosuppressive properties of cladribine, patients treated with this product are not expected to generate a sufficient or effective immune response in any case.

Cladribine tabletSafe and effective treatment of Multiple Sclerosis (MS), preferably in adults, and in particular treatment of relapsing Multiple Sclerosis (MS), including Relapsing Remitting MS (RRMS) and active Secondary Progressive MS (SPMS), is provided. Due to its safety profile cladribine tablet +.>Is generally recommended for patients who already have an inadequate response to or are not tolerant of alternative drugs indicated for the treatment of MS. In addition, gram (g)Ledrobine tablet>Preferably indicated for the treatment of adult patients with highly active relapsing Multiple Sclerosis (MS) as defined by clinical or imaging features. Cladribine tabletPreferably 3.5mg/kg body weight over 2 years, preferably as 1 course of 1.75mg/kg per year. Each course of treatment preferably consists of 2 weeks of treatment, one preferably at the beginning of the first month of each treatment year and one preferably at the beginning of the second month. Each treatment week preferably consists of 4 or 5 days during which the patient preferably receives 10mg or 20mg (one or two) depending on body weight, preferably as a single daily dose. Preferably, no further cladribine treatment is required at year 3 and/or at year 4 after completion of 2 courses of treatment (see section 5.1). The restart of therapy after year 4 has not been formally studied, but is clearly still an option as the case may be. In the context of risk management of infection under treatment and/or opportunistic infections, unique dosing regimens, unique dosimetry, defined substantially two years of treatment length, and sustained efficacy well beyond two years up to 4 years and possibly longer of treatment regimens, present special challenges to physicians. More specifically, in patients that seem to be threatened by such infections and/or opportunistic infections, doctors tend to hesitate to enable treatment with oral cladribine, especially during periods in which the outbreak of the infection is high, such as the influenza season, and more particularly during periods when the new infection spreads worldwide, such as the current covd-19 pandemic.

However, even the most preferred protection strategy against infection in the context of actual or potential immunosuppressive therapy, vaccination/immunization presents significant challenges to the attending physician due to the complexity of the immune system (which makes vaccine-mediated protection a complex immunological challenge), especially in the context of potential immunosuppressive therapy and/or potentially immunocompromised subjects suffering from autoimmune disorders such as MS.

With respect toEuropean product profile outline (European Summary of Product Characteristics) (EU SmPC) of (cladribine tablet) states that treatment with MAVENCLAD should not be initiated within 4 to 6 weeks after vaccination with live or attenuated live vaccine due to the risk of active vaccine infection. Vaccination with live or attenuated live vaccine during and after cladribine treatment should be avoided as long as the patient's white blood cell count is not within normal limits. In this respect (I)>(cladribine tablet) tag information (EU SmPC) statement (extract):

MAVENCLAD indicates an adult patient for the treatment of highly active relapsing Multiple Sclerosis (MS) as defined by clinical or imaging features.

Live or attenuated live vaccine

Treatment with MAVENCLAD should not be initiated within 4 to 6 weeks after vaccination with live or attenuated live vaccine, due to the risk of active vaccine infection. Vaccination with live or attenuated live vaccine during and after cladribine treatment should be avoided as long as the patient's white blood cell count is not within normal limits.

Further vaccine information statement (as advice):

the cladribine tablet should not start within 4-6 weeks after vaccination with live or attenuated live vaccine.

O any live attenuated vaccine should be avoided during treatment with cladribine tablets. The user should wait as much as possible for the lymphocyte/leukocyte to return to normal.

If an inactivated component vaccination is necessary for the patient, the clinician should wait for lymphocyte levels to return to within normal range.

For some multi-dose vaccinations, the clinician may consider the first dose of vaccine administered 4-6 weeks prior to initiation of treatment with cladribine tablets. Subsequent vaccine doses should be administered at a later date after priming with cladribine tablets, once lymphocyte counts have recovered.

Furthermore, according to Giovannoni (Giovannoni G. Cladribine to treat relapsing forms of multiple sclerosis. NeurotherAN_SNutincs. 2017;14:874-87. (https:// doi. Org/10.1007/s 13311-017-0573-4), in RMS patients receiving sustained immunosuppressive therapy (maintenance therapy) the use of live or attenuated live vaccines is contraindicated.

The american society of neurology (American Academy of Neurology) cooperates with the immune panel of the committee of clinical practice guidelines for MS (Immunization Panel of the MS Council for Clinical Practice Guidelines) to issue evidence and advice summaries regarding immunization and MS. Advice statement:

"use in youWithin 4 to 6 weeks prior to treatment, you should not receive live or attenuated live vaccines. During your treatment with MAVENCLAD, and until your healthcare provider tells you that your immune system is no longer weakened, you should not receive these types of vaccines.

"live and attenuated live vaccines are generally not recommended for persons with MS who receive Disease Modifying Therapy (DMT).

However, during the clarithromycin study, cladribine tablet treated Multiple Sclerosis (MS) patients received a vaccine (mainly against influenza virus). Adverse Events (AEs) associated with vaccine administration were not reported in these subjects.

Furthermore, we have newly found evidence in a small retrospective survey of blood samples from patients enrolled in a MAGNIFY study: in the case of recurrent MSVarious time points before and during cladribine treatment, e.g., for seasonal influenza (hemagglutination inhibition [ HAI ]]Not less than 40) and varicella zoster virus (VZV; 100 IU/L), the antibody titer after vaccination of patients treated with cladribine tablets remains above the clinically accepted seroprotection limit. In addition, we have recently found evidence in detailed blood sample analysis: this finding is a result of the general principle caused by the temporal behaviour of certain lymphocyte subtypes and their impact on their immune environment that have been newly discovered, and is therefore considered suitable for a wide variety of vaccines and/or vaccine types (if not all vaccines and/or vaccine types). In EU and 80 more than one country around the world,(cladribine tablets) are indicated for the treatment of adult patients suffering from relapsing Multiple Sclerosis (MS), preferably highly active relapsing Multiple Sclerosis (MS) as defined by clinical or imaging features. Is 3.5mg/kg body weight over 2 years as 1 course of 1.75mg/kg per year. In US->(cladribine tablet)/(cladribine tablet)>The (cladribine) tablet is indicated for use in the treatment of relapsing Multiple Sclerosis (MS) in adults, including relapsing-remitting disease and active secondary progressive disease. MAVENCLAD is administered in 2 courses spaced about 1 year apart, with a recommended cumulative dose of MAVENCLAD of 3.5mg/kg body weight, which is administered orally and divided into 2 courses once per year (1.75 mg/kg per course), preferably as follows:

treatment course 1:

first cycle (month 1): starting at any time.

Second cycle (month 2): starting 23-27 days after the last dose (about 1 month after the start of the first cycle).

Treatment course of 2 nd year:

first cycle (month 1): approximately 1 year after the beginning of the first session, at least 43 weeks after the last dose.

Each treatment cycle consisted of 4 or 5 consecutive days; the periodic dose as 1 or 2 tablets is administered once daily for 4 or 5 consecutive days.

In this context of the treatment of MS with cladribine (preferably oral cladribine and especially a cladribine tablet), we have surprisingly found that in the context of said treatment, preferably of said treatment regimen as described above/below, various vaccinations can be safely and/or effectively performed at essentially any time (preferably any time) during said treatment, including the 1 st and/or 2 nd year course of treatment as described above/below in more detail, in spite of the fact that: the mode of action of cladribine, preferably oral cladribine and especially cladribine tablets, is associated with an extended period of moderate to severe lymphopenia in both the 1 st year course of treatment and the 2 nd year course of treatment, as indicated by low Absolute Lymphocyte Count (ALC). Furthermore, this has been found to be particularly surprisingly applicable to the 2 nd year course, since at the beginning of the 2 nd year course, ALC does not return to normal levels in most if not all cases, and thus the grade of lymphopenia is even more pronounced during the extended period of the 2 nd year course, as shown by the further and prolonged decline in ALC. Surprisingly, the detailed analysis of blood samples of unvaccinated patients under the MS treatment, as well as of patients vaccinated (preferably including vaccination during the 1 st year course of treatment and/or the 2 nd year course of treatment) immediately before and during the MS treatment clearly shows that, contrary to what was considered before, the immune response to vaccination under treatment with cladribine (preferably oral cladribine and especially cladribine tablets) is preferably not correlated or not significantly correlated with ALC levels, e.g. a low ALC value indicates a low probability for safe and/or effective vaccination. In contrast, the patient is vaccinated directly before beginning the 1 st year course of treatment and/or directly before beginning the 2 nd year course of treatment, the patient is vaccinated during the 1 st year course of treatment and/or during the 2 nd year course of treatment, preferably comprising vaccination during the first cycle (month 1) and/or the second cycle (month 2) of the 1 st year course of treatment and preferably comprising vaccination during the first cycle (month 1) and/or the second cycle (month 2) of the 2 nd year course of treatment, preferably the data presented herein show safety and/or efficacy, especially for patients suffering from grade 0 to grade 3 lymphopenia, more preferably grade 1 to grade 3 lymphopenia, and especially grade 1 to grade 2 lymphopenia or grade 2 to grade 3 lymphopenia when vaccination is to be performed. This is preferably 4 vaccines selected from live, attenuated live and non-live vaccines, preferably as described herein. By "immediately before beginning the 1 st and/or 2 nd year course of treatment" is preferably meant that the patient is vaccinated less than 4 weeks, more preferably less than 3 weeks, even more preferably less than 2 weeks and especially less than one week before beginning the 1 st and/or 2 nd year course of treatment, in particular the patient is vaccinated at 3 weeks, 2 weeks and/or 1 st week before beginning the 1 st and/or 2 nd year course of treatment, preferably comprising vaccinating the patient at the last day before beginning the 1 st and/or 2 nd year course of treatment. Vaccination of a patient during the 1 st year course of treatment preferably means vaccinating the patient on the first day of the first cycle (month 1) in the 1 st year course of treatment, on which day cladribine, preferably oral cladribine and especially a cladribine tablet, is administered to the patient, and at all times between the last day of the 1 st year course of treatment. Typically, the last day of the 1 st year course of therapy is also the day before the beginning of the first cycle of the 2 nd year course of therapy (month 1). Vaccination of a patient during the 2 nd year course of treatment preferably means vaccinating the patient at all times between the first day of the first cycle (month 1) in the 2 nd year course of treatment, when cladribine, preferably oral cladribine and especially a cladribine tablet, is administered to the patient, and the last day of the 2 nd year course of treatment. Typically, the last day of the 2 nd year course is preferably about one year apart, preferably 45 to 55 weeks apart, more preferably 47 to 53 weeks apart, and especially 48 to 52 weeks apart from the beginning of the first cycle of the 2 nd year course (month 1). Vaccination of patients during the 1 st and/or 2 nd year course of treatment is preferably in patients suffering from grade 0 to grade 3 lymphopenia, more preferably grade 1 to grade 3 lymphopenia, and especially grade 1 to grade 2 lymphopenia or grade 2 to grade 3 lymphopenia. Surprisingly, we have found that in contrast to what has been previously discussed, there is preferably no or at least no significant reduction in the immune response to vaccination at the nadir of Absolute Lymphocyte Count (ALC), immediately before the nadir of ALC, and during an extended period in which slow recovery of ALC occurs. Typically, ALC in a patient during a 1 st year course and/or a 2 nd year course is calculated from the beginning (i.e., day 1) of the respective first period (i.e., month 1) of the 1 st year course and/or the 2 nd year course, and the ALC nadir is reached at or at least relatively sharply decreased within weeks 7 to 9 from the beginning (i.e., day 1) of the respective first period (i.e., month 1) of the 1 st year course and/or the 2 nd year course, then at or at 12-16 weeks (e.g., in a CLARITY study), weeks 10 to 14, or weeks 8 to 14, e.g., during weeks 9 to 12, weeks 8 to 10, or weeks 9 to 11. The ALC nadir is then typically followed by a very slow recovery of ALC, and thus a period of very low ALC levels from 10-36 weeks, more preferably 9-24 weeks or 8-24 weeks counted from the beginning (i.e., day 1) of the corresponding first cycle (month 1) of the 1-year course of therapy and/or 2-year course of therapy. Vaccination during the 10-36 week period or the 9-24 week period has not previously been suggested, as safe and/or effective vaccination during these periods is considered to be impossible. However, according to the present invention it is preferably recommended that the patient is actually vaccinated at the 8 th-36 th or 9 th-24 th week period (preferably counted starting (i.e. day 1) from the respective first period (month 1) of the 1 st and/or 2 nd year course of treatment, respectively), as it was recently found that safe and/or effective vaccination, preferably with a vaccine as described herein, is possible. Surprisingly, we have newly found that if there is a period of reduced immune activity or capacity to generate a basic immune response, which may be considered as relevant for patients with a special risk profile under treatment with cladribine, oral cladribine, cladribine tablets, it is a period of 4 to 9 weeks, preferably 5 to 9 weeks, more preferably 5 to 8 weeks, even more preferably 5 to 7 weeks, and especially 6 to 8 or 6 to 7 weeks, preferably counted starting (i.e. day 1) from the corresponding first cycle (1 st month) of the 1 st and/or 2 nd year course, respectively.

It is therefore recommended that the vaccine is preferably vaccinated at any point in time of the actual or planned treatment with cladribine, oral cladribine or cladribine tablet, preferably comprising one or more options selected from the group consisting of

i) Vaccination of the patient directly prior to the beginning of the 1 st and/or 2 nd year course, preferably vaccination of the patient directly prior to the 1 st and/or 2 nd year course as described above and/or below, and in particular vaccination of the patient directly prior to the beginning of the 1 st year course, preferably as described above and/or below,

ii) vaccinating the patient during the 1 st year course and/or vaccinating the patient during the 2 nd year course, preferably comprising vaccinating during the first period (month 1) and/or the second period (month 2) of the 1 st year course, and preferably comprising vaccinating during the first period (month 1) and/or the second period (month 2) of the 2 nd year course, preferably as described above and/or below;

iii) Vaccinating the patient at any time between

a) A first day of administration of cladribine, oral cladribine or a tablet of cladribine to a patient during a first period of a 1 st year treatment session (month 1), and

b) At the end of the period of 5 to 11 months, preferably 4 to 10 months, more preferably 4 to 8 months or 3 to 5 months from the last day of administration of cladribine, oral cladribine or cladribine tablet to a patient in the 1 st course of treatment or the second cycle of the 2 nd course of treatment (month 2);

iv) vaccinating the patient at any time between

a) In the first cycle of the 1 st year course of treatment (month 1), the first day of administration of cladribine, oral cladribine or cladribine tablet to the patient, and

b) In the second cycle of the 1 st year course of treatment (month 2), cladribine, oral cladribine or cladribine tablet is administered to the patient at the end of the period of 5 to 11 months, preferably 4 to 10 months, more preferably 4 to 8 months or 3 to 5 months from the last day;

v) vaccinating the patient at any time between

a) In the first cycle of the 2 nd year course of treatment (month 1), the first day of administration of cladribine, oral cladribine or cladribine tablet to the patient, and

b) In the second cycle of the 2 nd year course of treatment (month 2), cladribine, oral cladribine or cladribine tablet is administered to the patient at the end of the period of 5 to 11 months, preferably 4 to 10 months, more preferably 4 to 8 months or 3 to 5 months from the last day;

vi) vaccinating the patient at any time between

a) In the first cycle of the 1 st year course of treatment (month 1), cladribine, oral cladribine or cladribine tablet is administered to the patient from the first day, at the end of the period of 2 to 3 months, and

b) In the first cycle of the 1 st year course of treatment (month 1), the first day of administration of cladribine, oral cladribine or a tablet of cladribine to a patient is at the end of a period of 4 to 8 months, preferably 5 to 7 months, more preferably 5 to 6 months, still more preferably 6 months;

vii) vaccinating the patient at any time between

b) In the first cycle of the 1 st year course of treatment (month 1), the first day of administration of cladribine, oral cladribine or cladribine tablet to the patient is at the end of a period of 2 to 5 months, preferably 2 to 3 months;

viii) vaccinating the patient at any time between

a) In the first cycle of the 2 nd year course of treatment (month 1), cladribine, oral cladribine or cladribine tablet is administered to the patient from the first day, at the end of the period of 2 to 3 months, and

b) In the first cycle of the 2 nd course of treatment (month 1), the first day of administration of cladribine, oral cladribine or a cladribine tablet to a patient is at the end of a period of 4 to 8 months, preferably 5 to 7 months, more preferably 5 to 6 months, still more preferably 6 months;

ix) vaccinating the patient at any time between

b) In the first cycle of the 2 nd year course of treatment (month 1), the first day of administration of cladribine, oral cladribine or cladribine tablet to the patient is at the end of a period of 2 to 5 months, preferably 2 to 3 months.

Preferably, it is recommended that the vaccine is vaccinated at any point in time of the actual treatment with cladribine, oral cladribine or cladribine tablet, preferably as described above and/or below, and more preferably as described in one or more options selected from options ii), iii), iv) or v),

except for a time period selected from the following

A) the time of the second cycle of the year 1 treatment (month 2),

beta) the time of the second cycle of the year 2 treatment (month 2),

γ) the time of the second cycle of the 1 st year treatment (month 2), and 1, 2 or 3 weeks thereafter, preferably 1 or 2 weeks thereafter,

and/or

δ) the time of the second cycle of the 2 nd year treatment (month 2), and 1, 2 or 3 weeks thereafter, preferably 1 or 2 weeks thereafter.

Alternatively, it is suggested to vaccinate at any point in time of the actual treatment with cladribine, oral cladribine or cladribine tablet, preferably as described above and/or below, and more preferably as described in one or more options selected from options ii), iii), iv) or v),

a) Except for a period of time, preferably 4 to 9 weeks, preferably 5 to 9 weeks, more preferably 5 to 8 weeks, even more preferably 5 to 7 weeks, and especially 6 to 8 or 6 to 7 weeks, counted preferably from the beginning of the corresponding first cycle (month 1) of the 1 st course of treatment, i.e. day 1, and/or

B) Except for a period of time preferably from 4 to 9 weeks, preferably from 5 to 9 weeks, more preferably from 5 to 8 weeks, even more preferably from 5 to 7 weeks, and especially from 6 to 8 or 6 to 7 weeks counted from the beginning of the corresponding first cycle (month 1) of the 2 nd course of therapy, i.e. day 1.

The advice given above is preferably used for vaccination/vaccination of patients with a vaccine selected from live and/or non-live vaccines. More preferably, they are selected from live vaccines, attenuated live vaccines and/or non-live vaccines.

The suggestions given above are more preferably used for vaccination of patients using a vaccine selected from the group consisting of live attenuated vaccines, inactivated vaccines, subunit vaccines, recombinant vaccines, polysaccharide vaccines, conjugate vaccines and toxoid vaccines and/or combinations thereof.

Preferred in this respect are influenza vaccines and/or varicella zoster virus vaccines, preferably as described herein.

Also preferred in this respect are (anti) Corona vaccines, (anti) COVID-19 vaccines, (anti) SARS-COVID-19 vaccines and/or (anti) SARS-CoV-2 vaccines, more preferably (anti) SARS-CoV-2 vaccines and/or (anti) COVID-19 vaccines, and preferably vaccines against mutants thereof.

With respect to varicella zoster virus vaccines, live vaccines or attenuated live vaccines are preferred, e.g(live herpes zoster vaccine) which can be used to prevent herpes zoster virus (shingles) in humans 50 years and older. Also preferred in this regard are Varicella Zoster Virus (VZV) non-live vaccines, preferably including but not limited to inactivated VZV vaccines and recombinant VZV vaccines, e.g.>Or shintrix->

Shingles is caused by the same virus that causes varicella in children (varicella). When this virus becomes active again in adults, it can cause shingles (heres zoster) or shingles (shingles). (live herpes zoster vaccine) is a live vaccine that helps prevent herpes zoster, such as a preferably inactivated or recombinant VZV vaccine e.gOr shintrix->As is.

Shingles (HZ) often occur after reactivation of latent Varicella Zoster Virus (VZV) in sensory and autonomic neurons. The incidence of HZ varies from 6-8 cases/1000 persons-year at age 50-59 years to >11 cases/1000 persons-year at age 70 years. The severity of HZ and its complications also increases with age, closely corresponding to age-related decline in VZV-specific T cell-mediated immunity (CMI), which is thought to be important in preventing reactivation of latent VZV and preventing transmission of reactivating virus. The HZ vaccine is believed to boost VZV-specific memory T cells, preventing them from falling below the threshold required for protection from HZ, which is currently unknown.

A VZV attenuated live vaccine (Zostovax, merck Sharpe & Dohme Corp, hereinafter referred to as herpes zoster live vaccine [ ZVL ]) may be used to prevent HZ in individuals older than 50 years. ZVL, however, has some limitations. Clinical trials indicated that vaccine efficacy against HZ was 70% in adults 50-59 years of age and decreased with age from 64% in people 60-69 years of age to 18% in people ≡80 years of age. Furthermore, ZVL efficacy against HZ decreases over time from 62% in the first year after vaccination to about 40% in the fifth year after vaccination.

Recombinant glycoprotein E (gE) subunit vaccines (HZ/su) were developed to overcome the unmet medical need for better vaccines. HZ/su consists of recombinant VZV gE and AS01B adjuvant systems. gE was chosen as the vaccine antigen because it is the most abundant glycoprotein expressed by VZV-infected cells and it induces both neutralizing antibodies and CD 4T cell responses. AS01B contained Quillaja saponaria (Quillaja saponaria Molina) fraction 21 (QS-21; licensed by GSK from anti LLC, agenus Inc., a Delaware, a full resource company of US corporation) and 3-O-deacyl-4' -monophosphoryl lipid A (MPL). AS01B stimulates local and transient activation of the innate response, leading to recruitment and activation of antigen presenting dendritic cells. QS-21 is an adjuvant that induces transient local cytokine responses in muscle and draining lymph nodes and activation of dendritic cells and macrophages in animal models. the toll-like receptor type 4 agonist MPL acts synergistically with QS-21 to enhance the immune response to co-administered antigens by producing interferon-gamma (IFN-gamma).

Phase I and phase II trials confirm that a single HZ/su dose elicits a basal humoral and CMI response that is further increased after the second dose.

The treatment regimens, vaccination regimens and recommendations given above are preferably safe and/or effective, preferably safe and/or effective as described herein, preferably in patients, and especially in patients suffering from grade 0 to grade 3 lymphopenia, more preferably grade 1 to grade 3 lymphopenia, and especially grade 1 to grade 2 lymphopenia or grade 2 to grade 3 lymphopenia, and even more preferably in patients with an age >30 years, >40 years, >50 years, >60 years or >70 years, preferably with an age >50 years, >60 years or >70 years, and especially with an age >50 years, at the time of administration or to be administered vaccination.

Further preferred methods of treatment, vaccination methods and/or vaccination under treatment are described in one or more of the sections selected from section [1] to section [36], and preferably in the section associated therewith and/or immediately adjacent thereto.

Further background and insight underlying the mechanism of the present invention are preferably described below.

Vaccine response and effector mechanisms

Vaccines were found to induce effector mechanisms (cells or molecules) that could rapidly control replication of pathogens or inactivate toxic components thereof. Early protective efficacy is conferred primarily by the induction of immune effectors (antigen-specific antibodies) produced by B cells that are capable of binding to pathogens or toxins. Long-term protection requires vaccine antibodies to stay above a protection threshold and/or maintain immune memory that enables rapid and efficient reactivation. Antigen-specific antibodies have been formally demonstrated to confer vaccine-induced protection against a number of diseases. The dominant role of B cells in the efficacy of current vaccines should not mask the importance of T cell responses. Most antigens and vaccines trigger B-cell responses (humoral immunity) and T-cell responses (cellular immunity).

Cd4+ T cells are required for most antibody responses, and antibodies exert a significant effect on T cell responses against intracellular pathogens. T cells are necessary for the induction of high affinity antibodies and immune memory. Cytotoxic cd8+ T lymphocytes are additional effectors that limit the spread of infectious agents by recognizing and killing infected cells or secreting specific antiviral cytokines. Cd4+ T helper cells (Th) provide support for the generation and maintenance of B-cell and CD8 responses and contribute to protection by cytokine production (e.g., IFN- γ expressing Th1 cells). Other additional Th subtype effector cells are follicular Th cells (Tfh), supporting efficient B cell activation and differentiation of antibody secreting cells or TH17 cells.

Table 4: mechanism of effect triggered by vaccine

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The nature of the vaccine exerts a direct influence on the type of immune effector elicited that mediates protective activity

The hallmark of T-dependent responses (caused by toxoids, proteins, inactivated or attenuated live virus vaccines) is the induction of higher affinity antibodies and immunological memory. In addition, attenuated live vaccines/vectors typically produce CD8 cytotoxic T cells. Most current vaccines mediate their protective efficacy through induction of vaccine antibodies, while vaccine-induced cd4+ T cells contribute to macrophage activation and control of mycobacterium tuberculosis. Current vaccines mediate protection mainly by inducing highly specific IgG serum antibodies. Live vaccines induce serum IgA and secretory IgA levels, which help limit viral shedding at mucosal surfaces. There is definitive evidence that T cells are the major effector of BCG in BCG-vaccinated infants or shingles-vaccinated adults. There is indirect evidence that vaccine-induced T cells contribute to the protection provided by other vaccines.

Table 5: t cell response to vaccine

Innate immunity and vaccination

Upon exposure to pathogens in the tissue or injection site, immature dendritic cells mature and migrate to the secondary lymph nodes where induction of B and T cell responses occurs. The central role of mature DCs (dc=dendritic cells) in the induction of vaccine responses is to provide sufficient danger signals through vaccine antigens or adjuvants to trigger inflammatory effects. When DCs, monocytes and neutrophils encounter pathogens and are activated, they express pattern recognition receptors (e.g., toll-like receptors, TLRs) that sense potential hazards. They regulate the expression of cell surface proteins and produce pro-inflammatory cytokines and chemokines. The inflammatory environment drives the differentiation of monocytes into macrophages and DC maturation. In the absence of dangerous signals, DCs remain immature and in contact with naive cells, and cd4+ cells do not differentiate into effector cells. Live vaccines trigger the innate immune system most effectively in time and space via TLRs. Non-live vaccines (e.g., proteins, glycoconjugates, inactivated microorganisms) may still contain pathogen recognition receptors, however, vaccine-induced activation stays more limited at the injection site. Upon activation, DCs alter their homing receptors and migrate to draining lymph nodes where B and T cell responses occur.

Primary AB response

In response to a protein antigen, B cells capable of binding to the antigen through their surface immunoglobulins undergo rapid activation. Initial antigen exposure primingFollicular external responseIn which B cells differentiate rapidly into plasma cells that produce low affinity antibodies (IgM +/-IgG isotype), which results in the rapid appearance of low Ig titers in serum within days after immunization. Antigen-specific T helper cells that have been activated by antigen-loaded DCs trigger antigen-specific B cells to migrate toward follicular DCs, initiating a Germinal Center (GC) reaction. In GC, B cells receive additional signals from T follicular helper (Tfh) cells, undergo extensive clonal proliferation and transition from IgM toward IgG, igA, or IgE. As B cells proliferate in the center of development, igG antibody titers increase up to peak, which is usually reached 4 weeks after immunization. The short lifetime of these plasma cells results in a rapid decrease in antibody titer. The minimum 3 week interval between 2 primary doses allowed undisturbed development of successive waves of Ag-specific primary responses.

Secondary AB responses

In the course of the secondary immune response,enhanced exposureReactivating immune memory at the antigen and resulting in a rapid increase in IgG titer. The short-lived plasma cells maintain peak levels for several weeks until long-lived plasma cells that have reached a viable niche in the bone marrow continue to produce antigen-specific antibodies, which then decline with slower kinetics. The minimum interval of 4 months between priming and boosting allows affinity maturation of memory B cells and thus higher secondary responses. This general mode may not be suitable for live vaccines that trigger long-term IgG antibodies for extended periods of time.

Table 6: determinants of the duration of vaccine antibody responses in healthy humans

Vaccine-induced B-cell memory

Memory B cells are generated during the primary response to T-dependent vaccines. They persist in the absence of antigen-re-exposure to antigen drives their differentiation into antibody-producing plasma cells. This reactivation is rapid, without the aid of T cells, so that the potentiated response is characterized by a rapid increase to higher titers of antibodies, which have a higher affinity for the antigen than the antibodies generated during the initial response.

Vaccine-induced T cell memory

Table 9: in the elderly

In addition, there is a recent shift in peak age-specific prevalence of MS from 40 to around 60 in europe and north america, and aging of the MS population may be associated with serious disability. Biological aging or immune aging of the immune system is affected by both genetic and environmental factors and is associated with a reduced ability to fight infection and develop immune memory. Lymphocyte levels are also generally lower in older MS patients than in younger patients, and the use of Disease Modifying Drugs (DMD) that further reduce lymphocyte function can potentially place older patients at greater risk of chronic infection and malignancy. Meta-analysis of clinical studies involving 13 classes of immunomodulatory drugs in 28,000 more MS patients suggests that the efficacy of DMD decreases with age. Opportunistic infections such as cryptococcosis meningitis are common for some DMDs, and this risk increases with patient age. The risk of Varicella Zoster Virus (VZV) reactivation is higher in the elderly, and the use of DMD may further increase the risk of virus reactivation in older MS patients. In particular, low lymphocyte levels in the Central Nervous System (CNS) are also associated with increased risk of Progressive Multifocal Leukoencephalopathy (PML), and aging appears to contribute to this risk. In view of these observations, it is important to understand the immunological impact of DMD on older MS patients relative to younger MS patients.

Cladribine (especially cladribine tablets) was found to result in a preferential decrease in circulating T and B lymphocytes, which play a central role in the pathogenesis of MS. Consistent with its mechanism of action, lymphopenia (. Gtoreq.1 grade) has been reported in 90% of patients treated with cladribine tablets at 3.5mg/kg (two years of treatment). Analysis of the summary data from stage 3 CLARITY and CLARITY Extension trials and PREMIERE registration showed that treatment with cladribine tablet 3.5mg/kg resulted in a transient decrease in ALC and depletion of cd19+ B, CD4+t and cd8+t lymphocyte subsets. This is followed by a recovery phase within weeks of the nadir, in which lymphocyte levels gradually reach normal or threshold levels. Cladribine is thought to reset the immune system in a way that it promotes a longer treatment-free period through selective and transient reduction of lymphocyte subpopulations.

In the experimental section herein, post hoc analysis of phase 3 clinical data is provided which is further explored and characterized in comprehensive safety analysis for the effect of age (+.50 years relative to >50 years) on the properties of lymphopenia experienced by patients treated with cladribine tablets at 3.5 mg/kg.

Because the immune system undergoes significant remodeling during aging due to immune aging, the effect and efficacy of DMD on older MS patients is unknown. The results from this post hoc exploratory analysis confirm that the incidence of grade 3 lymphopenia of cladribine tablets is not significantly different in both younger and older MS patients. Although cladribine tablets had no significantly different effect on ALC and/or lymphocyte subpopulations in older and younger patients during the two years of treatment, ALC decreased within weeks after administration in both treatment years and gradually increased to normal levels, largely independent of patient age. The overall incidence of grade 3 lymphopenia and the time to return to grade 1/2 lymphopenia were not significantly different across the two age groups.

In MS patients treated with DMD such as interferon, dimethyl fumarate (DMF) and alemtuzumab, a decrease in ALC and lymphocyte subpopulations has been observed. In the comprehensive analysis of 2470 MS patients treated with DMF, grade 3 lymphopenia lasting more than or equal to 6 months was observed in 2.2% of patients treated with DMF. Following infusion of the anti-CD 52 monoclonal antibody alemtuzumab, depletion of lymphocyte subpopulations has been observed, with near complete depletion of ALC, cd19+ B, CD4+t and cd8+t lymphocytes observed. However, recovery to LLN range after alemtuzumab infusion may take 8 months (B lymphocytes) to nearly 3 years (T lymphocytes). Because of its mechanism of action, lymphopenia is the expected effect of cladribine tablets. However, recovery of ALC and lymphocyte subpopulations (cd19+b and cd4+t) occurred shortly after nadir following depletion with cladribine tablets and reached normal levels within 30-43 weeks after the last dose of treatment of year 2; cd8+ T lymphocytes did not drop below LLN. The results from this post hoc analysis show similar trends in both ALC and lymphocyte subpopulation levels regardless of age, and restoration of both age groups to normal levels occurs at the end of the study year.

The pathogenesis of MS is found to be driven by autoreactive immune cells, mainly T and B lymphocytes infiltrating into the CNS. Thus, various DMDs utilized in MS therapies lead to immunomodulation or lymphocyte depletion. A potential risk of DMD in elderly people is the risk of opportunistic infections such as PML caused by JC virus (JCV). In the multinational cohort of MS patients, the seropositive rate of JCV increased from 49.5% in patients <30 years old to 66.5% in patients over 60 years old. MS patients over 50 years of age have been reported to be at greater risk of developing PML after treatment with DMD, such as fingolimod and dimethyl fumarate. In elderly MS patients, treatment with natalizumab is associated with an earlier onset of PML; the additive effects of immunosenescence and natalizumab-induced T lymphocyte reservoir restriction are attributed to this increased risk. In a previous post hoc analysis of patients treated with cladribine tablet 3.5mg/kg in monotherapy oral cohorts (median age-36 years), an increase in the frequency of infection was observed during ≡3 grade lymphopenia; the type of infection events occurring in grade 3/4 lymphopenia patients are not different from those occurring outside of these periods. However, the incidence and type of infection is not analyzed by patient age. Current studies explore the incidence and nature of TEAE of viral and bacterial infections by patient age in patients treated with cladribine tablets at 3.5mg/kg who reported grade 3 lymphopenia. The incidence of these TEAEs is generally similar between younger and older patients with grade 3 lymphopenia. While most (> 50%) of these TEAEs were mild to moderate in severity in both age groups, severe TEAEs were reported in the age >50 year old group. In elderly patients with grade 3 lymphopenia or more, higher frequencies of bronchitis, shingles, respiratory tract infections and pneumonia are reported; this group also has a higher incidence of these TEAEs occurring during the onset of grade 1 ≡3 lymphopenia. The higher incidence of herpes reactivation observed in the group >50 years of age was consistent with previous studies in which viral reactivation was reported as patients increased in age. In summary, the results from this post hoc analysis show that treatment with cladribine tablets has an age-dependent effect on TEAE, whereby TEAE is slightly higher in older MS patients and slightly lower in younger MS patients, but still supports its use also in patients with an aging immune system.

Current analysis has some limitations. First, analysis is limited by its post hoc nature. Second, fewer patients are in the group aged >50 years compared to the group aged 50 years. Finally, circulating lymphocytes reflect only a portion of the total lymphocyte population, and thus, only partially reflect changes occurring within the CNS. Although cladribine has been reported to cross the blood brain barrier and enter the CNS, the effect of cladribine tablets on CNS resident lymphocytes has not been fully understood so far.

This post hoc analysis of data from phase 3 studies (CLARITY, CLARITY Extension and ORACLE-MS) and PREMIERE registration of cladribine tablets 3.5mg/kg demonstrated that cladribine tablets had a relatively small but different effect on ALC and lymphocyte subpopulations in older patients relative to younger patients during the 2 year treatment period. Further, in patients reporting ≡3 grade lymphopenia using cladribine tablets, the incidence of TEAE for viral and bacterial infections was slightly higher in older groups. However, these results still strongly support the use of cladribine tablets at 3.5mg/kg in both younger and older MS patients.

The covd-19 pandemic has caused unprecedented disruption to normal social and economic life worldwide. By the end of month 6 of 2020, over 1000 thousands of cases have occurred worldwide, about 500,000 deaths (https:// www.who.int/emergences/diseases/novel-coronavir-2019). The disease is caused by a novel human and animal co-patient coronavirus SARS-CoV-2, which infects cells via the angiotensin converting enzyme receptor type 2 expressed on cells of the respiratory tract as well as critical tissues such as the brain.

Two observations of the proposed covd-19 pathogenesis may be related to the treatment of Multiple Sclerosis (MS) patients. Coronaviruses that resulted in the prior outbreaks of SARS and MERS were shown to suppress the natural Interferon (IFN) response. Evidence from patients with the most severe form of covd-19 also shows significant downregulation of IFN-stimulated gene expression. (Park and Iwasaki, 2020) in addition, lymphopenia is very commonly observed in patients with covd-19. (Guan et al 2020; huang et al 2020) severe lymphopenia has been associated with poorer outcome compared to patients with higher lymphocyte counts at admission. (Onder et al 2020; zhou et al 2020)

These observations are relevant because recombinant IFNbeta has been approved for treatment of relapsing MS for more than 20 years (Jakimovski et al, 2018), and many recently approved agents have reduced Absolute Lymphocyte Counts (ALC) or certain lymphocyte subpopulations. The recent data (Reich et al, 2018) provide some confirmation as to the severity of COVID-19 in MS patients, whether or not the patients were treated with disease modifying drugs (Louapre et al, 2020; sormani, 2020). However, more data is required.

Here we report the use of cladribine tablets in the Merck KGaA global patient safety databaseCovd-19 cases occurred in the MS patients treated. While such voluntary medication alert data may be incomplete, (Hughes et al 2020), they may provide additional corresponding levels of detail regarding individual medications for information presented in national and international registries regarding covd-19 occurring in MS patients. (Louapre et al 2020; sormani, 2020).

By day 29 of 6 months, approximately 19,000 patients with recurrent MS have been treated with cladribine tablets. At this date, 46 diagnosed or suspected COVID-19 patients were present in the secure database. Patient ages of 35 patients were available, in the range of 22-67 years. There were 26 females, 12 males and 8 patients with unreported gender. If the confirmed diagnostic test reports positive, the case is defined as diagnosed. If no validation test is performed or reported, the case is described as suspected. Because of the well-documented problem of false negative rates with respect to Polymerase Chain Reaction (PCR) testing techniques of COVID-19, (Woloshin et al 2020), suspected cases meeting the world health organization diagnostic criteria are included in our analysis even if a negative PCR test is reported. Cases are designated as severe if they meet criteria for hospitalization, are considered life threatening or medically significant. Consistent with usual drug alertness practices, the results are classified as recovered, in-recovery, not recovered, fatal or unreported.

Of the 46 cases in total, 18 cases were diagnosed. The 3 case confirmation included a report of positive immunoglobulin G detection after the onset of the covd-19 symptom. The 4 of the diagnosed cases were classified as severe (since 3 cases required hospitalization, while doctors reported a classification of "medically significant" 1 case). Of the suspected covd-19 cases, 2 were classified as severe (1 was hospitalized and 1 was classified as "medically significant" by the physician).

Most patients with suspected or confirmed diagnosis of covd-19 have mild to moderate respiratory symptoms. Two diagnosed cases were not reported to experience any symptoms of covd-19. None of the cases (suspected or confirmed) received mechanical ventilation and no death occurred. There is no indication of the relevant involvement of other organ systems, in particular no reporting of ischemic complications.

Cladribine tablets were taken during the short dosing period at the beginning of treatment years 1 and 2. Each dosing period consisted of 2 weeks of treatment (up to 5 days) separated by 1 month. The ALC nadir occurs (or more precisely begins) from month 2 to 3 after the beginning of each treatment year, preferably from 1 to 3 months, and the remaining time count in the next year is gradually increased. Accordingly, for many patients treated with cladribine, oral cladribine and especially cladribine tablets, the lowest point of ALC was found to occur at months 4-6 or 5-6. This preferably applies to the 1 st and/or 2 nd year of treatment. The median ALC for the first year remained above the lower normal limit (LLN). In the second year, median ALC remained above 800 cells/mL and recovered above LLN before the end of the treatment year. (Giovannoni et al, 2010) the time from the last dose of cladribine tablet to the onset of COVID-19 was available for 21/46 patients with a median of 180 days (i.e., about 6 months after the last dose; range 3-559 days). Two patients experienced a covd-19 episode between weeks of treatment 1 or 2 with the second treatment Zhou Yanchi until symptoms resolved. Another patient who had not experienced the onset of covd-19 until the beginning of year 2 also delayed the treatment until the symptoms resolved.

Consistent with immunosuppressive drug use under other conditions during a covd-19 pandemic, (Russell et al 2020), our data does not suggest that MS patients treated with cladribine tablets and infected with covd-19 are at higher risk for serious outcome.

Advantageously, cladribine (preferably oral cladribine and especially cladribine tablets) was found to appear to have a unique effect on the biology of the immune system (preferably including but not limited to the humoral (humiral), innate and/or adaptive immune system), which allows for a surprisingly advantageous risk/benefit profile in the management of infectious disorders and in particular in the management of vaccination as a protective measure against infectious disorders.

Surprisingly, it has also been found that cladribine (preferably oral cladribine and especially cladribine tablets) appears to have a further unique effect on the biology of the immune system, preferably including but not limited to the adaptive immune system (B and T cells) and/or the innate immune system (NK cells, myeloid cells) driving both humoral and cellular vaccination responses.

Even more surprising, it was found that cladribine (preferably oral cladribine and especially cladribine tablets) appears to have a unique effect on the biology of the adaptive immune system. The innate immune system is less affected. Cladribine affects the temporal pattern of CD19+ B cell subtypes and CD4+, CD8+ T cell subtypes in a very specific manner. The unique pattern of cell subtype specific depletion and re-proliferation allows for a surprisingly advantageous risk/benefit profile in the management of infectious disorders, and in particular vaccination.

More specifically, we have advantageously found that, depending on the temporal pattern of lymphocyte numbers observed in blood samples obtained from clinical trials (CLARITY, ORACLE, post hoc analysis), an improved time window appears to be advantageously sufficient for vaccination, said time window comprising a period of time starting 2 to 4 months after the last dose of the treatment cycle of year 1 (4-6 months after the first cladribine dose) and ending 4-6 weeks before the next treatment cycle (e.g. the treatment cycle of year 2). Similarly for year 2, we have found that the experimental immunization window preferably begins 2 to 4 months after the last dose (4-6 months after the first cladribine dose), but continues indefinitely or until 4-6 weeks before any subsequent or further disease modifying treatment is initiated. However, the core of the present invention provides an even more free and/or much more flexible approach with regard to infection prevention, and in particular the timelines and opportunities for infection prevention via vaccination and/or immunization.

Even more specifically, we have advantageously found that, depending on the temporal pattern of lymphocyte numbers observed in blood samples obtained from clinical trials (CLARITY and ORACLE analysis and MAGNIFY 4 phase study), an improved time window appears to be advantageously sufficient for vaccination, said time window comprising a period of time starting 1-2 months after the last dose of the treatment cycle of year 1 (3-5 months or preferably 3-4 months after the first cladribine dose) and ending 4-6 weeks before the next treatment cycle. Similarly for year 2, we have found that the experimental immunization window preferably begins 1 to 2 months after the last dose (3-5 months or preferably 3-4 months after the first cladribine dose) but continues indefinitely or until 4-6 weeks before any further disease modifying treatment is initiated. However, the core of the present invention provides an even more free and/or much more flexible approach with regard to infection prevention, and in particular the timelines and opportunities for infection prevention via vaccination and/or immunization.

Even more specifically, we have advantageously found that, depending on the temporal pattern of lymphocyte numbers observed in blood samples obtained from clinical trials (CLARITY and ORACLE analysis and MAGNIFY 4 phase study), an improved time window appears to be advantageously sufficient for vaccination, said time window comprising a period of time ending 0-4 weeks, preferably 1-3 weeks and especially 1 week, 2 weeks or 3 weeks (5-10 weeks, preferably 6-10 weeks and 6-8 weeks after the first cladribine dose), and preferably 0-4 weeks, preferably 1-3 weeks and especially 0, 1 week, 2 weeks or 3 weeks after the last dose of the treatment cycle starting at year 1. Similarly for year 2 we have found that the experimental vaccination window preferably starts 0-4 weeks, preferably 1-3 weeks and especially 1, 2 or 3 weeks (5-10 weeks, preferably 6-10 weeks and 6-8 weeks after the first cladribine dose) after the last dose of the treatment cycle of year 1, but preferably continues indefinitely or until 0-4 weeks, preferably 1-3 weeks and especially 0, 1, 2 or 3 weeks before any subsequent or further disease modifying treatment is initiated. However, the core of the present invention provides an even more free and/or much more flexible approach with regard to infection prevention, and in particular the timelines and opportunities for infection prevention via vaccination and/or immunization.

The key role of B cells in early and sustained humoral vaccine responses, e.g. in eliciting immune responses against neoantigens and immunoglobulin class switching from IgM to IgG and mucosal IgA, we found that the kinetics of B cell subpopulations counting after cladribine tablet cycle application was considered important. Deep immunophenotyping of blood samples from MAGNIFY-MS studies has provided more information and insight regarding the kinetics of, for example, B cell subsets, providing a broader theoretical basis for the timing and use of vaccines.

In the blood samples of our ongoing MAGNIFY-MS 4 phase biomarker score study, the B and T cell subtypes as well as immunoglobulins have been analyzed and longitudinal analysis will be performed for the remainder of the 2 year study duration. The results of 1 year have been fully analyzed and the temporal pattern of cell numbers we found is shown in tables a and B. All B cell subtypes have an early nadir at 2 months after initiation of cladribine treatment (especially after the last cladribine dose of month 2), and all other B cell subtypes, except memory B cells, then immediately begin to re-proliferate, with an increased number already shown at 3 months. Interestingly, the transitional and regulatory B cell numbers had again achieved positive increases (+35%, +216%) at month 3, and the levels remained high at month 6 (+19%, +202%) up to 12 months (+23%, +75%). The naive B cell numbers showed continued re-proliferation at month 3 (-69%) and month 6 (-35%) until full recovery of numbers and even a slight increase (+32%) was reached at month 12. Memory B cell counts showed a more durable decrease in blood compartments, but the number in lymphoid tissues may be less affected as shown in cladribine marmoset studies. In addition, the number of immunoglobulins did not decrease at various time points following cladribine treatment suggesting that tissue shortlived plasma cells or long lived plasma cells are not cladribine targets. Total cd4+ and cd8+ T cells showed moderate depletion and had reached the nadir (-60%, -50%) at month 6 with minor effects at month 1 (30% and 20%, respectively). Interestingly, central and effector memory T cells and/or TH1 and TH 17T cells also showed moderate decreases at month 3 (-56% and-37%, respectively) and further repopulation from this time point.

Interestingly, the innate immune system is less affected. Only NK cells showed a moderate decrease at month 1-2 and then proliferated to normal numbers.

These data support the following perspectives: sufficient B cells are available at even much earlier time points than would be expected from total lymphocyte counts, which is important for generating early and sustained immune or recall responses against the new antigen. The correlation of inter-patient variability of B cell recovery in peripheral compartments (i.e. in blood) with the effectiveness of vaccination in individual patients (if present) remains to be determined, but is considered to have little correlation. It is well envisioned that the B cell kinetics in the central compartment are more homogeneous. The consequences of variable recovery are believed to be further alleviated by the following findings: (i) innate immune cells, which are less affected by cladribine by providing sufficient centers for danger signal induction of vaccine responses, (ii) cladribine induces only moderate depletion of cd4+ and cd8+ T cells, (iii) B cells are less associated with immediate immune responses, and (iv) memory B cells begin to function late in the immune response process. These data are described in detail in fig. 2 and 3.

Advantageously, these findings allow for much higher applicability of vaccination in the context of cladribine treatment, as well as much greater flexibility in vaccinating in the context of cladribine treatment.

In the clinical trial program of cladribine tablets, the incidence of total infection (24.9 events per 100 patients-year (PY) versus 27.1 events for placebo) and the incidence of severe infection (0.8 versus 0.9/100 PY) were not more frequent than with placebo.

In vaccine-preventable diseases, shingles occurred more frequently with cladribine (0.83 episodes/100 PY versus 0.2 episodes/100 PY with placebo). The incidence was higher in cladribine treated patients with grade 3-4 lymphopenia (4.5/100 PY) than in patients with grade 0-2 lymphopenia (0.73/100 PY). Most shingles episodes occur 1-3 years after the initiation of treatment. Systemic, severe or disseminated herpes zoster episodes have not been reported to date.

Other vaccine-preventable diseases are limited to influenza, which does not show any different incidence relative to placebo (grade 0-2 for lymphopenia, 2.75 relative to 2.69 cases/100 PY; and grade 3-4 for lymphopenia, 3.35 relative to 2.69/100 PY).

However, also for cladribine tablets, the health authorities provide the following recommendations: all necessary vaccinations and/or immunizations should generally be well applied before starting the treatment with cladribine tablets. Although data from P-cell depleting antibody therapies cannot be extrapolated directly to oral cladribine, it has been generally suggested to date that vaccination programs be completed at least 4-6 weeks prior to initiation of cladribine therapy. In particular, vaccination or immunization with a live or attenuated live vaccine should be completed at least 4 to 6 weeks before starting treatment with cladribine tablets due to the high risk of active infection by the vaccine. Likewise, vaccination should be avoided after cladribine treatment, especially when considering live or attenuated live vaccines, as long as lymphocyte counts are below the normal range.

Surprisingly, it has been found that the depletion of lymphocytes induced by cladribine is particularly selective and affects the different subtypes of lymphocytes in a unique and distinct manner from other immunosuppressants or APIs, especially with respect to the onset of depletion, the amount of lymphocytes depleted, the duration of depletion of the respective lymphocyte subtype, rebound or increase of the respective lymphocyte subtype over time, the timing of said increase or rebound, etc. As a result, the potential negative impact of cladribine treatment on the parts of the immune system responsible for generating an immune response against vaccination, immunization and/or infection was found to be surprisingly low.

In contrast to the general recommendations to date, it has surprisingly been found that subjects suffering from autoimmune disorders can undergo a cladribine treatment, preferably a cladribine tablet treatment, at any time deemed to be in need of treatment, more preferably a cladribine tablet treatment approved by the health authorities in more than 75 countries worldwide, and that nevertheless, at any time where such vaccination and/or immunization is deemed necessary or desirable, the vaccination and/or immunization can be safely conducted against an infection, preferably a viral infection and/or bacterial infection, including but not limited to immediately before starting the cladribine treatment, during the cladribine treatment, preferably during a limited amount of months during the treatment period in which the cladribine or the cladribine tablet is actually administered to the subject, and during a few months of the cladribine period, which is generally after the cladribine treatment period and constitutes the largest part of about two treatment periods, preferably comprising 2 or more cycles, as it has been approved for the preferred health authorities.

Even more surprising, it has been found that a correspondingly cladribine treated subject, preferably a cladribine tablet treated subject, is still preferably capable of eliciting an immune response against vaccination, immunization and/or infection in at least a meaningful way or extent, preferably at least a sufficient way or extent, preferably at all times or at least almost all times during the two year treatment period or cycle approved and suggested by the health authorities. In this context, at least a meaningful way or extent preferably means that the subject vaccinated with cladribine treatment, preferably the subject vaccinated with cladribine treatment as described herein, has been shown to fulfill a seropositive standard hemagglutination inhibition [ HAI ] ([ HAI ]. Gtoreq.40) equal to or higher than 40 and/or a corresponding relevant antibody titer, e.g. at least a two-fold increase, preferably at least a four-fold increase (VZV;. Gtoreq.100 IU/L) in varicella zoster virus titer.

Accordingly, preferred aspects of the invention relate to:

[1] a method for treating an autoimmune disorder in a patient in need thereof, the method comprising:

(a) Orally administering cladribine to a patient, optionally during one or more courses of treatment, at a fixed dose per patient, per body weight and per course of treatment, wherein the fixed dose is selected from the range of 1.0mg/kg to 3.0mg/kg,

(b) Identifying a patient at risk of acquiring an infection,

(c) Vaccinating a patient at risk of acquiring an infection with a vaccine against said infection, and

d) Orally administering cladribine to a patient, optionally during one or more courses of treatment, at a fixed dose per patient, per body weight and per course of treatment, wherein the fixed dose is selected from the range of 1.0mg/kg to 3.0mg/kg,

provided that the method comprises one or more courses of treatment in which cladribine is administered, and

a further condition is that the fixed dose for each patient is approximately the same throughout the one or more courses of treatment in which cladribine is administered,

thereby treating the patient for the autoimmune disorder and limiting the risk of the patient acquiring the infection.

Accordingly, preferred is a method for treating an autoimmune disorder in a patient in need thereof, the method comprising:

(a) Preferably cladribine is not administered,

(b) Identifying a patient at risk of acquiring an infection,

(c) Vaccinating a patient at risk of acquiring an infection, preferably within a time frame of less than four weeks, preferably less than three weeks and especially less than three weeks prior to subsequent administration of cladribine, with a vaccine against said infection, preferably according to step d) as given below:

d) Administering cladribine during one or more, preferably one or two, and especially two, courses of treatment, comprising orally administering cladribine, preferably a cladribine tablet, to each patient, each body weight and each course of treatment at a fixed dose selected from the group consisting of 1.0mg/kg to 3.0mg/kg, and preferably about 1.75mg/kg, per course of treatment

Provided that the method comprises one or more, preferably two, courses of treatment in which cladribine is administered, and

Patients identified as being at risk of acquiring infection are vaccinated prior to the beginning of a first course of treatment comprising oral administration of cladribine, preferably occurring less than four weeks, less than three weeks or less than two weeks prior to the beginning of the first course of treatment. It is advantageous if the identification of the patient has taken place before the start of cladribine treatment according to the present invention, in particular if the identification has taken place shortly before the start of the first course of treatment (planned or required).

Alternatively, preferred is a method for treating an autoimmune disorder in a patient in need thereof, the method comprising:

(a) Orally administering cladribine to a patient during a course of treatment at a fixed dose per patient, per body weight and per course of treatment, wherein the fixed dose is selected from the range of 1.0mg/kg to 3.0mg/kg,

(b) Identifying a patient at risk of acquiring an infection,

(c) Vaccinating a patient at risk of acquiring an infection with a vaccine against said infection, wherein vaccination preferably occurs during the first month of said course of treatment and/or less than four weeks after the end of said course of treatment, and

d) Orally administering cladribine to a patient during one or more treatment periods at a fixed dose per patient, per body weight and per treatment period, wherein the fixed dose is selected from the range of 1.0mg/kg to 3.0mg/kg,

provided that the method comprises two or more courses of treatment in which cladribine is administered, and preferably

A method for treating an autoimmune disorder in a patient in need thereof, the method comprising:

(a) Orally administering cladribine to a patient, optionally during one or more courses of treatment, at a fixed dose per patient, per weight of said patient and per course of treatment, wherein said fixed dose is selected from the range of 1.0mg/kg to 3.0mg/kg of said patient,

(b) Identifying a patient at risk of acquiring an infection,

d) Orally administering cladribine to each patient, each patient's weight, and the fixed dose per session, optionally during one or more sessions, wherein the fixed dose is selected from the range of 1.0mg/kg to 3.0mg/kg of body weight,

provided that the method comprises one or more, more preferably at least two, for example 2, 3, 4 or 5, and especially two courses of treatment, in which cladribine is administered, and

preferably further provided that the fixed dose per patient is approximately the same throughout the one or more courses of treatment in which cladribine is administered,

Thereby treating the patient for the autoimmune disorder and limiting the risk of the patient acquiring the infection. Preferably, there is a cladribine-free period of at least nine months, preferably 9-18 months and especially about 10 months between the first treatment course and the second or subsequent treatment course. Preferably, the fixed dose during the respective therapy session is about 1.75mg/kg body weight. Preferably, each course of treatment or treatment period consists of about two months, preferably referred to as "treatment months", in which cladribine (preferably oral cladribine and especially a cladribine tablet) is administered, preferably as described herein. Preferably, the month or treatment month each comprises one treatment week, wherein the treatment week is preferably initiated at the beginning of each month or treatment month. Preferably, each treatment week consists of 4 or 5 days (treatment day) during which the patient is preferably treated with cladribine, preferably independently selected from 10 mg/day or 20 mg/day per day. Preferably, 10 mg/day or 20 mg/day is administered as an oral dosage form, preferably a solid oral dosage form, and especially as a tablet, each containing 10mg of cladribine.

More preferably, there is a cladribine-free period of at least nine months, preferably 9-18 months and especially about 10 months between the first course of treatment and the second course of treatment, and also preferably between every two of any subsequent courses of treatment. Preferably, the fixed dose during the respective therapy session is about 1.75mg/kg body weight. Preferably, each course of treatment consists of about two months.

[2] The method as described herein and in particular as described above and/or below, wherein the duration of each course of treatment in step (a) is independently selected from about 1 to about 3 months, and/or wherein the duration of each course of treatment in step (d) is independently selected from about 1 to about 3 months.

Particularly preferably, the duration of each treatment session is about two months, preferably two months.

[3] As described herein and in particular as described above and/or below,

i) Wherein the method comprises two or more courses of treatment wherein cladribine is administered, each course of treatment having a duration of about 1 to about 3 months,

ii) wherein each of the two or more courses is separated by a period in which cladribine is not administered to the patient, and

iii) Wherein the periods during which cladribine is not administered to the patient each have a duration of at least 9 months.

[4] The method as described herein and in particular as described above and/or below, wherein at least one of the periods in which cladribine is not administered to the patient has a duration of 9 to 18 months. Preferably, there is a cladribine-free period of at least nine months, preferably 9-18 months and especially about 10 months between the first treatment course and the second or subsequent treatment course. More preferably, there is a cladribine-free period of at least nine months, preferably 9-18 months and especially about 10 months between the (first) course of treatment and the subsequent course of treatment.

Preferably, the period in which cladribine is not administered to the patient is also referred to as the "cladribine free period". Preferably, each cladribine-free period after one treatment course and before the next treatment course has a duration of about 10 months, preferably 10 months. However, if the subject's medical condition does not allow for the next course of treatment after a course of treatment followed by 10 months or about 10 months of the cladribine-free period, the next course of treatment may be delayed by extending the cladribine-free period, for example, up to 12 months, up to 14 months, up to 16 months, or even up to 18 months.

[5] A method as described herein and in particular as described above and/or below, comprising:

(a) Orally administering cladribine to a patient during 1 or 2 courses of treatment at a fixed dose per patient, per body weight and per course of treatment, wherein the fixed dose is selected from the range of 1.0mg/kg to 3.0mg/kg,

(b) Identifying a patient at risk of acquiring an infection,

d) Cladribine is orally administered to a patient during 0 or 1 course of treatment at a fixed dose per patient, per body weight and per course of treatment, wherein the fixed dose is selected from the range of 1.0mg/kg to 3.0 mg/kg. According to this method, the vaccination of the patient preferably takes place within a time frame set by the last oral administration of cladribine of the last course of treatment and ends at the beginning of the second treatment month in the subsequent course of treatment. Alternatively, preferably, vaccination of the patient occurs within a time frame of less than four weeks, less than three weeks and especially less than two weeks after the end of the last course of treatment, or less than four weeks, less than three weeks and especially less than two weeks before the beginning of the first treatment month or the second treatment month of the subsequent course of treatment.

Preferably, each course is separated from the next by a cladribine-free period as described herein, preferably at least 9 months, more preferably 9 to 18 months, more preferably 9 to 16 months, and especially preferably 9 to 14 months. More preferably, each course is separated from the next by a cladribine-free period of 10 to 18 months, more preferably 10 to 16 months, even more preferably 10 to 14 months and especially 10 to 12 months.

[6] A method as described herein and in particular as described above and/or below, comprising:

(a) Orally administering cladribine to a patient during 0 or 1 course of treatment at a fixed dose per patient, per body weight and per course of treatment, wherein the fixed dose is selected from the range of 1.0mg/kg to 3.0mg/kg,

(b) Identifying a patient at risk of acquiring an infection,

d) Cladribine is orally administered to a patient during 1 or 2 courses of treatment at a fixed dose per patient, per body weight and per course of treatment, wherein the fixed dose is selected from the range of 1.0mg/kg to 3.0 mg/kg.

If no course of treatment is present prior to step (b) and/or (c), the patient is vaccinated prior to the beginning of a first course of treatment comprising oral administration of cladribine, preferably less than four weeks, less than three weeks, less than two weeks or less than one week prior to the beginning of the first course of treatment, preferably comprising a course of treatment comprising administration of cladribine as described herein. It is advantageous if the identification of the patient has taken place before the start of cladribine treatment according to the present invention or the method of treatment as described herein. If no course of treatment is present prior to step (b) and/or (c), the patient is vaccinated prior to the beginning of the first course of treatment comprising oral administration of cladribine, preferably less than four weeks, less than three weeks or less than two weeks prior to the beginning of the first course of treatment. It is advantageous if the identification of the patient has taken place before the start of cladribine treatment according to the present invention.

If cladribine is administered once during step (a), the vaccination of the patient preferably occurs within a time frame set by the last oral administration of cladribine for the last course of treatment and ends at the beginning of the second treatment month in the subsequent course of treatment. Alternatively, preferably, vaccination of the patient occurs within a time frame of less than four weeks, less than three weeks and especially less than two weeks after the end of the last course of treatment, or less than four weeks, less than three weeks and especially less than two weeks before the beginning of the first treatment month or the second treatment month of the subsequent course of treatment.

[7] The method as described herein and in particular as described above and/or below, wherein a course of treatment of cladribine administered to said patient is separated from each other by at least 9 months wherein cladribine is not administered to said patient. Preferably, the courses of treatment are separated from each other by 9 to 18 months, preferably 9 to 16 months, more preferably 9 to 14 months and especially 9 to 12 months, wherein cladribine is not administered to the patient. More preferably, the courses of treatment are separated from each other by 10 to 18 months, preferably 10 to 16 months, more preferably 10 to 14 months and especially 10 to 12 months, wherein cladribine is not administered to the patient.

[8] A method as described herein and in particular as described above and/or below, wherein

i) Identifying a patient at risk of acquiring an infection according to step (b), and/or

ii) vaccinating said patient according to step (c) at any of the following times

a) Within a time frame of about 4 weeks prior to a course of treatment in which cladribine is orally administered to the patient, and/or

Any of the following occurs

b) Within a time frame of about 4 weeks after a course of treatment in which cladribine is orally administered to the patient.

[9] The method as described herein and in particular as described above and/or below, wherein the method comprises at least 2 courses of treatment wherein cladribine is orally administered to the patient, and wherein vaccinating the patient according to step (c) occurs within about 4 weeks prior to the first course of treatment wherein cladribine is orally administered to the patient, or at any time within about 4 weeks after the last course of treatment wherein cladribine is orally administered to the patient.

[10] The method as described herein and in particular as described above and/or below, wherein the method comprises at least 2 courses of treatment wherein cladribine is orally administered to the patient, and wherein vaccinating the patient according to step (c) occurs at any time within a time frame beginning about 2 weeks before the beginning of the first course of treatment wherein cladribine is orally administered to the patient, and ending within about 2 weeks after the end of the last course of treatment wherein cladribine is orally administered to the patient.

[11] A method as described herein and in particular as described above and/or below, wherein

a) Within a time frame of about 1 or 2 weeks prior to a course of treatment in which cladribine is orally administered to the patient, and/or

Any of the following occurs

b) Within a time frame of about 4 or about 5 weeks from the beginning of each course of treatment in which cladribine is orally administered to the patient.

[12] The method as described herein and in particular as described above and/or below, wherein vaccinating the patient according to step (c) occurs at any time within the time frame of

i) Beginning at the beginning of a first course of treatment in which cladribine is orally administered to the patient, and

ii) terminates at the end of the last course of treatment in which cladribine is orally administered to the patient.

The method as described herein and in particular as described above and/or below, wherein the patient is vaccinated, preferably according to step (c), during a first treatment month of a course of treatment as described herein, during a second month of the course of treatment as described herein and/or during a cladribine-free period after the course of treatment as described herein.

The method as described herein and in particular as described above and/or below, wherein the patient is vaccinated, preferably according to step (c), during a first treatment month of a course of treatment as described herein, during a second month of the course of treatment as described herein and/or during a cladribine-free period after the course of treatment as described herein. If vaccination of the patient occurs during the cladribine-free period following the course of treatment as described herein, it preferably occurs within the first 9 months of the cladribine-free period, preferably within the first 6 months of the cladribine-free period, more preferably within the first 4 months of the cladribine-free period and especially within the first 3 months of the cladribine-free period.

The method as described herein and in particular as described above and/or below, wherein the patient is vaccinated, preferably according to step (c), during a first treatment month of a course of treatment as described herein, during a second month of the course of treatment as described herein and/or during a cladribine-free period after the course of treatment as described herein. If vaccination of the patient occurs during the cladribine-free period following the course of treatment as described herein, it preferably occurs within the last 6 months of the cladribine-free period, preferably within the first 4 months of the cladribine-free period, more preferably within the first 2 months of the cladribine-free period and especially within the last month of the cladribine-free period.

[13] The method as described herein and in particular as described above and/or below, wherein the method comprises two courses of treatment wherein cladribine is orally administered to the patient, and wherein vaccinating the patient according to step (c) occurs at any time within a time frame beginning about 2 weeks before the beginning of a first course of treatment wherein cladribine is orally administered to the patient, and ending within about 2 weeks after the end of a second course of treatment wherein cladribine is orally administered to the patient.

[14] The method as described herein and in particular as described above and/or below, wherein vaccinating the patient according to step (c) occurs at any time as specified in one or more of the segments above and/or below, except for about 4 weeks before and/or about 4 weeks after the lowest B cell count determined in the blood of the individual subject during a time frame set by the start of two adjacent courses of treatment in which cladribine is orally administered to the patient.

The method as described herein and in particular as described above and/or below, wherein vaccinating the patient, preferably vaccinating the patient according to step (c), occurs at any time as specified in one or more of the above and/or below, except during a time frame set by the start of two adjacent courses of treatment in which cladribine is orally administered to the patient, about 2 weeks before and/or about 2 weeks after the lowest B cell count determined in the blood of the respective subject.

[15] The method as described herein and in particular as described above and/or below, wherein vaccinating the patient, preferably according to step (c), occurs at any time as specified in one or more of the above and/or below, except for a period of time of 5 to 13 weeks or 6 to 14 weeks after the start of each course of treatment in which cladribine is orally administered to the patient.

[16] The method as described herein and in particular as described above and/or below, wherein said vaccination, preferably said vaccination as described in step (c), comprises administering a vaccine to said patient in 1 to 6 separate doses, preferably if more than 1 dose of vaccine is to be administered, preferably at different days.

[17] The method as described herein and in particular as described above and/or below, wherein the vaccination, preferably the vaccination as described in step (c), comprises administering a vaccine to the patient in 2 to 6 divided doses, wherein the 2 to 6 divided doses are administered to the patient at different days within a time frame of about 1 to 12 weeks, preferably 1 to 8 weeks, still preferably 1 to 6 weeks and in particular 2 to 4 weeks.

[17b] The method as described herein and in particular as described above and/or below, wherein the vaccination, preferably the vaccination as described in step (c), comprises administering a vaccine to the patient in 2 to 6 divided doses, preferably 2 to 5 divided doses, more preferably 2 to 4 divided doses and in particular 2 or 3 divided doses, wherein each of the divided doses is preferably administered to the patient at different days within a time frame of about 1 to 12 weeks, preferably 1 to 8 weeks, still preferably 1 to 6 weeks and in particular 2 to 4 weeks.

[18] A method of treating an autoimmune disorder and reducing the risk of infection in a subject in need thereof, the method comprising

a) Orally administering cladribine to said subject within a course of about 2 months, wherein said course of treatment is followed by a cladribine-free period of at least 9 months wherein cladribine is not administered to said patient, and orally administering a fixed dose of cladribine to each patient selected from the group consisting of 1.0mg/kg to 3.0mg/kg to said patient, and

b) Vaccinating or immunizing the subject against the infection within a time frame of

i) Beginning less than 4 weeks, preferably less than 3 weeks and especially less than 2 weeks prior to the course of about 2 months wherein cladribine is orally administered to the patient, and ending at the beginning of the second treatment month in each course wherein cladribine is orally administered to the patient, and/or

ii) starts at the end of the second treatment month in said course of treatment in which cladribine is orally administered to the patient and ends at the end of the cladribine-free period of at least 9 months immediately after the course of treatment.

[19] A method of treating an autoimmune disorder and reducing the risk of infection in a subject in need thereof, the method comprising

a) At least 2 courses of treatment each of about 2 months in duration, wherein cladribine is orally administered to the subject at a fixed dose per patient and per course of treatment, wherein the fixed dose is selected from the range of 1.0mg/kg and 3.0mg/kg, preferably 1.5mg/kg and 2.0mg/kg, and wherein each course of treatment is followed by a cladribine-free period of at least 9 months wherein cladribine is not administered to the subject, and

b) At least one vaccination period of up to 4 weeks, preferably up to 2 weeks, wherein the subject is vaccinated or immunized against the infection one or more times,

wherein the vaccination period starts with

i) Less than 4 weeks, preferably less than 3 weeks and especially less than 2 weeks before the beginning of the treatment session,

ii) within the first week or second week of the course of treatment, and/or

iii) The cladribine-free period is preferably immediately after the course of treatment by a time frame set at the end of the course of treatment in which cladribine is orally administered to the patient and ending at the end of a subsequent cladribine-free period of at least 9 months in which cladribine is not administered to the subject.

A method of treating an autoimmune disorder and reducing the risk of infection in a subject in need thereof, preferably as described above and/or below, comprising

a) At least 2 treatment periods of about 2 months each, wherein cladribine is orally administered to the subject at a fixed dose per patient and per treatment period, wherein the fixed dose is selected from the range of 1.0mg/kg to 3.0mg/kg, preferably 1.5mg/kg to 2.0mg/kg, and wherein each treatment period is followed by a cladribine-free period of at least 9 months wherein cladribine is not administered to the subject, and

b) At least one vaccination period, preferably one or two vaccination periods, of up to 4 weeks, preferably up to 2 weeks, wherein the subject is vaccinated or immunized against the infection one or more times,

wherein the vaccination period starts with

i) Less than 4 weeks, preferably less than 3 weeks and especially less than 2 weeks before the beginning of the treatment period,

ii) within the first, second, third or fourth week of the treatment period, preferably within 1 to 4, 1 to 3, 2 to 4 or 3 to 4 weeks, and/or

iii) The cladribine-free period preferably immediately follows the treatment period by a time frame set at the end of the treatment period in which cladribine is orally administered to the patient and ending at the end of a subsequent cladribine-free period of at least 9 months in which cladribine is not administered to the subject.

[20] A method of treating an autoimmune disorder and reducing the risk of infection in a subject in need thereof, preferably as described above and/or below, comprising

a) 2 courses of treatment each of about 2 months in duration, wherein cladribine is orally administered to the subject at a fixed dose per patient and per course of treatment, wherein the fixed dose is selected from the range of 1.5mg/kg and 2.0mg/kg, and wherein each course of treatment is followed by a cladribine-free period of at least 9 months, preferably at least 10 months, wherein cladribine is not administered to the subject, and

b) One or two vaccination periods of up to 4 weeks, preferably up to 2 weeks, wherein the subject is vaccinated or immunized one or more times against the infection,

wherein the vaccination periods each begin with

ii) within the first week or second week of the course of treatment, and/or

iii) By any time within a time frame set as follows: wherein the cladribine-free period preferably immediately follows the course of treatment at the end of the course of oral administration of cladribine to the patient, and wherein a subsequent cladribine-free period of at least 9 months or preferably 10 months without cladribine administration to the subject ends.

[21] A method of treating an autoimmune disorder and reducing the risk of infection in a subject in need thereof, preferably as described above and/or below, comprising

wherein each of said vaccination periods is independent of each other,

i) Starting less than 4 weeks, preferably less than 3 weeks and especially less than 2 weeks before the beginning of the treatment session and ending 6 weeks, preferably 4 weeks and especially 2 weeks after the beginning of the treatment session, or

ii) starts at the end of the course of treatment, starts 1 week after the end of the course of treatment, or starts two weeks after the end of the course of treatment.

[21b] Preferably, the fixed dose for each patient and each course of therapy is the same or about the same for at least 2 courses, preferably at least 2 adjacent courses. Preferably, the fixed dose is fixed for each patient, the weight of each of the patients, and each course of treatment.

[22] The method according to one or more of the preceding claims, preferably as described above and/or below, wherein the subject

i) One or more, preferably one or two vaccination sessions are performed within a time frame starting two weeks before the start of the session and ending four weeks after the start of the session,

and/or

ii) vaccination is carried out one or more times, preferably one or two times, within a time frame starting at the end of the course of treatment and ending two, three or four weeks after the end of the course of treatment.

[23b] The method according to one or more of the above and/or below paragraphs, wherein each course of treatment consists of 2 months of treatment. Preferably, the treatment months each comprise one treatment week, wherein the treatment week is preferably initiated at the beginning of each treatment month.

[23] The method according to one or more of the preceding and/or following paragraphs, wherein each course of treatment consists of 2 treatment months, wherein each treatment month comprises one treatment week, wherein the treatment week preferably starts at the beginning of the respective treatment month.

[24] As described herein and in particular as described above and/or below, wherein each treatment week consists of 4 or 5 days (treatment day) during which the patient is preferably receiving cladribine treatment, preferably independently selected from 10 mg/day or 20 mg/day per day.

[25] A method as described herein and in particular as described above and/or below, wherein

i) The vaccination period comprises two to four weeks,

ii) one or more vaccinations are preferably administered to the subject during the first week and/or the last week of the vaccination period, and/or

iii) At least one vaccination is administered to the subject on one of the first, second, third, fifth, sixth, or seventh days of the first week and/or on one of the first, second, third, fifth, sixth, or seventh days of the last week.

[26] The method as described herein and in particular as described above and/or below, wherein at the beginning of the vaccination period or during the vaccination period the subject to be vaccinated or immunized has a lymphopenia grade No. 1, lymphopenia grade No. 2 or lymphopenia grade No. 3.

[26b] The method as described herein and in particular as described above and/or below, wherein the subject is vaccinated with one or more vaccines, preferably a vaccine as described herein and in particular as described above and/or below, selected from the group consisting of live and/or non-live vaccines. More preferably, they are selected from live vaccines, attenuated live vaccines and/or non-live vaccines.

[26c] The method as described herein and in particular as described above and/or below, wherein the subject is vaccinated with one or more vaccines selected from the group consisting of attenuated live vaccines, inactivated vaccines, subunit vaccines, recombinant vaccines, polysaccharide vaccines, conjugate vaccines and toxoid vaccines and/or combinations thereof.

[27] The method as described herein and in particular as described above and/or below, wherein the subject is vaccinated with one or more vaccines selected from the group consisting of inactivated vaccines, subunit vaccines, recombinant vaccines, polysaccharide vaccines, conjugate vaccines and toxoid vaccines and/or combinations thereof.

[27b] The method as described herein and in particular as described above and/or below, wherein the subject is vaccinated with one or more vaccines, preferably a vaccine as described herein and in particular as described above and/or below, which is not a live vaccine and/or an attenuated live vaccine and/or a combination thereof.

[28] A method as described herein and in particular as described above and/or below, wherein the infection is a viral infection, preferably selected from hepatitis, preferably hepatitis a and/or hepatitis b, more preferably hepatitis b, varicella zoster (shingles), or if not exposed: varicella, measles, influenza, poliovirus, pneumococcal pneumonia, diphtheria, tetanus, pertussis, human Papilloma Virus (HPV) and other papilloma virus related diseases, covid-19, as vaccines have become available today, as well as any other viral disease according to immunization schedules recommended based on age, travel or geographical exposure related risk or other factors.

[29] The method as described herein and in particular as described above and/or below, wherein the infection is a bacterial infection, preferably selected from anthrax, cholera, diphtheria, haemophilus influenzae, meningococcal meningitis, pertussis, plague, pneumococcal disease, streptococcus pneumoniae, tetanus, tuberculosis and typhoid.

[30] A method as described herein and in particular as described above and/or below, wherein the vaccination is performed with a vaccine selected from the group consisting of: anthrax, cholera, diphtheria, haemophilus influenzae, meningococcal, pertussis, plague, pneumococcal, streptococcus pneumoniae, tetanus, tuberculosis, typhoid.

[31] The method as described herein and in particular as described above and/or below, wherein the autoimmune disorder is selected from Multiple Sclerosis (MS), rheumatoid Arthritis (RA), systemic Lupus Erythematosus (SLE), neuromyelitis optica spectrum disease (NMOSD) and Myasthenia Gravis (MG), preferably Multiple Sclerosis (MS), neuromyelitis optica spectrum disease (NMOSD) and Myasthenia Gravis (MG).

[32] The method as described herein and in particular as described above and/or below, wherein the autoimmune disorder is Multiple Sclerosis (MS).

[33] A method as described herein and in particular as described above and/or below, wherein the autoimmune disorder is Multiple Sclerosis (MS) comprising one or more indications selected from the group consisting of: relapsing Multiple Sclerosis (RMS), relapsing Remitting Multiple Sclerosis (RRMS), secondary Progressive Multiple Sclerosis (SPMS), and Primary Progressive Multiple Sclerosis (PPMS).

[34] A method as described herein and in particular as described above and/or below, the method comprising:

orally administering cladribine to a patient during one or more courses of treatment at a fixed dose per patient, per body weight and per course of treatment, wherein the fixed dose is selected from the range of about 1.0mg/kg to about 3.0mg/kg, and wherein cladribine is administered to the patient in such a manner that an effective or bioavailable amount of cladribine in the patient is a fixed dose per patient, per body weight and per course of treatment selected from the range of about 0.5mg/kg to about 1.6mg/kg, preferably 0.8+/-0.2 mg/kg.

[35] The method as described herein and in particular as described above and/or below, wherein said effective or bioavailable amount of cladribine in said patient is achieved by administration of an oral dosage form providing a bioavailability of cladribine in said patient in a range selected from the range of about 30% to about 100%, preferably about 40% to 50%, at a fixed dose per patient, per body weight and per course of treatment in a range of about 0.3mg/kg to about 2.0 mg/kg.

The fixed dose for each patient, each body weight, and each course of therapy is preferably the same or about the same for at least two of the courses of therapy. The fixed dose per patient, per body weight, and per course of treatment is more preferably the same or about the same throughout the course of treatment. Even more preferably, the fixed dose per patient, per body weight and per course of treatment is preferably the same throughout all of the courses for the respective patient or is approximately the same throughout all of the courses for the respective patient. Particularly preferably, the fixed dose per patient, per body weight and per course of treatment is preferably the same throughout all of the courses of treatment for all patients or is approximately the same throughout all of the courses of treatment for all patients. Preferably, "substantially the same" in this respect means interchangeability of +/-15% of the fixed dose, preferably +/-10% of the fixed dose, and especially +/-5% of the fixed dose per patient and/or per course of treatment.

[36] The method according to one or more of the preceding claims, wherein the autoimmune disorder to be treated is Multiple Sclerosis (MS), preferably Relapsing MS (RMS), more preferably Relapsing Remitting MS (RRMS), secondary Progressive MS (SPMS) and Primary Progressive MS (PPMS), and the subject to be treated has a High Disease Activity (HDA), preferably a high disease activity as defined according to HDA 1, HDA 2, HDA 3 or HDA 4.

The method as described herein and in particular as described above and/or below, wherein the subject to be treated is aged >30 years, >40 years, >50 years, >60 years or >70 years, preferably aged >50 years, >60 years or >70 years, and in particular >50 years.

A method as described herein and in particular as described above and/or below, wherein the vaccination of the patient occurs at any time except for the following time periods: 5 to 10 weeks, 6 to 11 weeks, 5 to 13 weeks, or 6 to 14 weeks after the start of each treatment period or course in which cladribine is orally administered to the patient.

A method as described herein and in particular as described above and/or below, wherein the vaccination of the patient occurs at any time except for the following time periods: 5 to 9 weeks, 6 to 10 weeks, 5 to 12 weeks, or 6 to 13 weeks after the start of each treatment period or course in which cladribine is orally administered to the patient.

Advantageously, in the context of the present invention, vaccination of a subject during and after cladribine treatment, preferably cladribine tablet treatment, is preferably recommended and may preferably be administered less than 6 weeks before the start of cladribine therapy, and in particular less than 4 weeks before the start of cladribine therapy, even if the patient's white blood cell count is not within normal limits, but preferably is closer to normal than grade 4 lymphopenia, more preferably is closer to normal than grade 3 lymphopenia, and in particular is equal to grade 2 lymphopenia. The type of vaccine considered suitable in this connection is preferably selected from the group consisting of attenuated live vaccines, inactivated vaccines, subunit vaccines, recombinant vaccines, polysaccharide vaccines, conjugate vaccines and toxoid vaccines and/or combinations thereof.

Thus, the subject of the present invention is preferably a method of treating an autoimmune disorder, and in particular multiple sclerosis, in a patient by administering cladribine, preferably a cladribine tablet, preferably as defined herein, comprising vaccination of the subject during and after said cladribine treatment, preferably a cladribine tablet treatment, in which patient the white blood cell count is not within normal limits, but preferably is closer to normal than grade 4 lymphopenia, more preferably is closer to normal than grade 3 lymphopenia, and in particular is equal to grade 2 lymphopenia, wherein said vaccination is also preferably administered less than 6 weeks before the start of cladribine therapy, and in particular less than 4 weeks before the start of cladribine therapy. The type of vaccine considered suitable in this connection is preferably selected from the group consisting of attenuated live vaccines, inactivated vaccines, subunit vaccines, recombinant vaccines, polysaccharide vaccines, conjugate vaccines and toxoid vaccines and/or combinations thereof.

Thus, the subject of the present invention is especially preferably a method of treating an autoimmune disorder, especially multiple sclerosis, in a patient, preferably as defined herein, by administering cladribine (preferably oral cladribine and especially a cladribine tablet), comprising treating, preferably oral cladribine and especially multiple sclerosis, at said cladribine The subject is vaccinated during and after cladribine tablet treatment, with grade 1-2 lymphopenia, grade 1-3 lymphopenia, or grade 1-4 lymphopenia, more preferably with grade 2-3 lymphopenia or grade 2-4 lymphopenia. Preferably, the vaccination is also administered less than 6 weeks, preferably less than 4 weeks, more preferably less than 2 weeks and especially less than one week before the start of cladribine therapy, preferably applicable at the start of the first course of treatment, the second course of treatment and/or each subsequent course of treatment. The type of vaccine considered suitable in this connection is preferably selected from the group consisting of attenuated live vaccines, inactivated vaccines, subunit vaccines, recombinant vaccines, polysaccharide vaccines, conjugate vaccines and toxoid vaccines and/or combinations thereof. According to cladribine tabletsThe recommended cumulative dose of cladribine, which is administered orally and divided into 2 courses once per year (about 1.75mg/kg per course) is about 3.5mg/kg body weight (see table 1). Each course of treatment was divided into 2 treatment cycles:

administration of the first course of treatment

First procedure/first period: beginning at any time.

First procedure/second cycle: applied 23 to 27 days after the last dose of the first procedure/first cycle.

Administration of the second course of treatment

Second procedure/first cycle: at least 43 weeks after the last dose of the first procedure/second cycle.

Second procedure/second cycle: the administration was 23 to 27 days after the last dose of the second procedure/first cycle.

Table 10: the Mavenclad dose per cycle of patient body weight per course of treatment

* The use of MAVENCLAD in patients weighing less than 40kg was not investigated.

Preferably, the periodic dose is administered as 1 or 2 tablets once per day over 4 or 5 consecutive days.

Accordingly, preferred within the context of the present invention is a method of treating an autoimmune disorder and reducing the risk of infection in a subject in need thereof, the method comprising

a) Orally administering cladribine in a cumulative dose divided into 2 courses of about once per year, about 3.5mg/kg body weight, wherein in each course of about once per year about 1.75mg/kg is administered per course, and wherein each course of treatment is divided into two treatment cycles wherein cladribine is orally administered, each cycle preferably consisting of four or five consecutive days,

wherein said

i) First procedure/first period: oral cladribine administration may begin at any time,

ii) first process/second cycle: oral clara Qu Binshi begins 23 to 27 days after the last dose administered in the first course/cycle

iii) Second procedure/first cycle: oral clar Qu Binshi starts at least 43 weeks after the last dose of the first process/second cycle, and

iv) second procedure/second cycle: oral clara Qu Binshi starts 23 to 27 days after the last dose administered in the second procedure/first cycle, and

b) Wherein the subject is vaccinated within the following first time frame

Starting four weeks before the first process/first cycle, and

terminating at the start of the second process/second cycle, and/or

The subject was vaccinated within the following second time frame,

starting at the end of the second procedure/second cycle, and

end of the second year (preferably 96-104 weeks after the start of the first procedure/first cycle).

Further preferred is a method of treating an autoimmune disorder and reducing the risk of infection in a subject in need thereof, the method comprising

Wherein said

iv) second procedure/second cycle: oral clara Qu Binshi starts 23 to 27 days after the last dose used in the second procedure/first cycle administration, and

b) Wherein the subject is vaccinated

1) Within the following first time frame

Starting less than four weeks before the first process/first cycle, and

terminating at the beginning of the first process/second cycle,

2) In the following second time frame,

starting 2 to 3 weeks after the end of the first process/second cycle and ending 4 to 6 weeks after the end,

3) In the following third time frame,

starting less than four weeks before the second process/first cycle, and

terminating at the beginning of the second process/second cycle,

and/or

4) Fourth time frame

Starting 2 to 3 weeks after the end of the second process/second cycle and ending 4 to 6 weeks after the end. A method as described herein and in particular as described above and/or below, wherein the vaccination of the patient occurs at any time except for the following time periods: 5 to 10 weeks, 6 to 11 weeks, 5 to 13 weeks, or 6 to 14 weeks after the start of each treatment period or course in which cladribine is orally administered to the patient.

The method as described herein and in particular as described above and/or below, wherein the vaccination comprises administering a vaccine to the patient in 1 to 6 separate doses administered at different days.

The method as described herein and in particular as described above and/or below, wherein the vaccination comprises administering the vaccine to the patient in 2 to 6 divided doses, wherein the 2 to 6 divided doses are administered to the patient at different days within a time frame of about 1 to 12 weeks, preferably 1 to 8 weeks, still preferably 1 to 6 weeks and in particular 2 to 4 weeks.

The method as described herein and in particular as described above and/or below, wherein at the beginning of the vaccination period or during the vaccination period the subject to be vaccinated or immunized has a lymphopenia grade No. 1, lymphopenia grade No. 2, or lymphopenia grade No. 3.

The method as described herein and in particular as described above and/or below, wherein the subject is vaccinated with one or more vaccines selected from the group consisting of attenuated live vaccines, inactivated vaccines, subunit vaccines, recombinant vaccines, polysaccharide vaccines, conjugate vaccines and toxoid vaccines and/or combinations thereof.

The method as described herein and in particular as described above and/or below, wherein the subject is vaccinated with one or more vaccines selected from the group consisting of inactivated vaccines, subunit vaccines, recombinant vaccines, polysaccharide vaccines, conjugate vaccines and toxoid vaccines and/or combinations thereof.

The method as described herein and in particular as described above and/or below, wherein the subject is vaccinated with one or more vaccines, preferably a vaccine as described herein and in particular as described above and/or below, which is not a live vaccine and/or an attenuated live vaccine and/or a combination thereof.

A method as described herein and in particular as described above and/or below, wherein the infection is a viral infection, preferably selected from hepatitis, preferably hepatitis a and/or hepatitis b, more preferably hepatitis b, varicella zoster (shingles), or if not exposed: varicella, measles, influenza, poliovirus, pneumococcal pneumonia, diphtheria, tetanus, pertussis, human Papilloma Virus (HPV) and other papilloma virus related diseases, covid-19, as vaccines are now becoming available, as well as any other viral disease according to immunization schedules recommended based on age, travel or geographic exposure related risk or other factors.

The method as described herein and in particular as described above and/or below, wherein the infection is a bacterial infection, preferably selected from anthrax, cholera, diphtheria, haemophilus influenzae, meningococcal meningitis, pertussis, plague, pneumococcal disease, streptococcus pneumoniae, tetanus, tuberculosis and typhoid.

A method as described herein and in particular as described above and/or below, wherein the vaccination is performed with a vaccine selected from the group consisting of: anthrax, cholera, diphtheria, haemophilus influenzae, meningococcal, pertussis, plague, pneumococcal, streptococcus pneumoniae, tetanus, tuberculosis, typhoid.

The method as described herein and in particular as described above and/or below, wherein the autoimmune disorder is selected from Multiple Sclerosis (MS), rheumatoid Arthritis (RA), systemic Lupus Erythematosus (SLE), neuromyelitis optica spectrum disease (NMOSD) and Myasthenia Gravis (MG), preferably Multiple Sclerosis (MS), neuromyelitis optica spectrum disease (NMOSD) and Myasthenia Gravis (MG).

The method as described herein and in particular as described above and/or below, wherein the autoimmune disorder is Multiple Sclerosis (MS).

A method as described herein and in particular as described above and/or below, wherein the autoimmune disorder is Multiple Sclerosis (MS) comprising one or more indications selected from the group consisting of: relapsing Multiple Sclerosis (RMS), relapsing Remitting Multiple Sclerosis (RRMS), secondary Progressive Multiple Sclerosis (SPMS), and Primary Progressive Multiple Sclerosis (PPMS).

For use according to the invention, the following vaccine types and/or vaccine platforms are generally preferred and are selected from the following: live attenuated viruses, recombinant viral vectorized vaccines, preferably those that are biologically engineered to express target pathogen antigens in vivo, inactivated or killed viruses, protein subunit vaccines, virus-like particles (VLPs) and nucleic acid (DNA or mRNA) based vaccines.

The method as described herein and in particular as described above and/or below, wherein the vaccination is against herpes zoster, varicella zoster, influenza, SARS-CoV-2/covd-19 or a combination and/or mutant thereof.

In view of oral cladribine and in particular cladribine tabletsParticularly preferred are methods for treating an autoimmune disorder in a patient in need thereof, the method comprising: (a) 3.5mg, preferably +/-0.5mg, of cladribine per kilogram of said patient is orally administered to said patient during a treatment period of about 2 years, i.e., 2 treatment yearsA heavy cumulative dose, wherein the cladribine is orally administered to the patient as 1 course of 1.75mg, preferably +/-0.25mg, per kilogram of body weight of the patient and per treatment year, wherein each course of treatment comprises two weeks of treatment, one at the beginning of the first month of the respective treatment year and one at the beginning of the second month, and wherein each treatment week comprises 4 or 5 days during which the patient orally receives as daily dose about 10mg or about 20mg of cladribine;

(b1) At least one vaccine is vaccinated to the patient during the first treatment year and/or during two weeks before the first treatment year begins,

And/or

(b2) At least one vaccine is vaccinated to the patient during the second treatment year and/or during two weeks before the beginning of the second treatment year,

one or more vaccines selected from the group consisting of antiviral vaccines and antibacterial vaccines are used. Preferably, the autoimmune disorder is selected from Multiple Sclerosis (MS), rheumatoid Arthritis (RA), systemic Lupus Erythematosus (SLE), neuromyelitis spectrum disease (NMOSD) and Myasthenia Gravis (MG), preferably Multiple Sclerosis (MS), neuromyelitis spectrum disease (NMOSD) and Myasthenia Gravis (MG), and in particular from Multiple Sclerosis (MS), relapsing MS (RMS), relapsing Remitting Multiple Sclerosis (RRMS) and Secondary Progressive Multiple Sclerosis (SPMS), preferably in High Disease Activity (HDA) patients, even more preferably in HDA patients as defined herein.

[45] Thus, particularly preferred is a method for treating an autoimmune disorder in a patient in need thereof, preferably as described above and/or below, the method comprising:

(i1) Orally administering to said patient a cumulative dose (mg/kg) of cladribine of 3.5mg, preferably +/-0.5mg, per kilogram body weight of said patient, wherein

(i2) The cumulative dose is divided into 2 yearly courses of 1.75mg, preferably +/-0.25mg, of cladribine per kilogram of body weight of the patient and per course of treatment, wherein

(i3) Each course of treatment is divided into 2 treatment cycles, wherein

(i4) Each treatment cycle dose is about 10mg or about 20mg per day, depending on the body weight, orally administered once per day for 4 or 5 days in total, and preferably the treatment cycle dose is administered during the first week of each treatment cycle, wherein

(ii 1) the first treatment session/first treatment cycle may be initiated at any time, and

(ii 2) then administering the first course of treatment/second course of treatment or the first course of treatment/second course of treatment dose, preferably as described in section (i 4),

(iii 1) orally administering to said patient a second course of treatment/first course of treatment or a second course of treatment/first course of treatment dose at least 43 weeks after the last dose of the first course of treatment/second course of treatment, preferably as described in section (i 4), and

(iii 2) orally administering to said patient a second course of treatment/second treatment cycle, preferably as described in section (i 4), about 23 to 27 days after the last dose of the second course of treatment/first treatment cycle, and

iv) vaccinating said patient, preferably

(ivl) at least once between the beginning of the first course of treatment and the end of the first course of treatment, or during two weeks before the beginning of the first course of treatment, and/or

iv 2) at least once between the beginning of the second treatment session/first treatment session and the end of the second treatment session, or during two weeks prior to the beginning of said second treatment session/first treatment session,

one or more vaccines selected from the group consisting of antiviral vaccines and antibacterial vaccines are used.

[46] A method as described herein and in particular as described above, wherein the patient is vaccinated

(iv 1) at least once between the beginning of the first treatment year/session and the end of the first treatment year, or during a week prior to the beginning of the first treatment year/session,

and/or

iv 2) at least once between the beginning of the second course of treatment/the first course of treatment and the end of the second course of treatment, or during a week prior to the beginning of said second course of treatment/the first course of treatment.

[47] A method as described herein and in particular as described above, wherein the patient is vaccinated

(iv 1) occurs at least once during one week of the first treatment year/beginning of the first course of treatment and the end of month 10 or 11 of the first treatment year, and/or during two weeks prior to the beginning of the first treatment year/first course of treatment, preferably during the last week;

And/or

iv 2) at least once between the beginning of the second treatment year/first treatment period and the end of said second treatment year, preferably between the beginning of the second treatment year/first treatment period and the end of the 7 th month, 8 th month, 9 th month or 10 th month of said second treatment year, and/or at least once during one week of the two weeks before the beginning of the second treatment year/first treatment period, preferably during the last week.

[48] A method as described herein and in particular as described above, wherein the patient is vaccinated

(ivl) within one or more months of the first treatment year, wherein the one or more months are selected from month 1 of the first treatment year and month 3-12 of the first treatment year, preferably month 3-11 and especially month 4-10, and/or occur at least once, preferably once or twice during one week, preferably during the last week, of two weeks before the first treatment year/first treatment session is started;

and/or

iv 2) during one or more months of the first treatment year, wherein the month is selected from month 1 of the first treatment year and month 3-12 of the second treatment year, preferably month 3-11, more preferably month 4-10 and especially month 4-18, and/or during one of the two weeks before the beginning of the second treatment year/first treatment session, preferably at least once, preferably once or twice during the last week.

[49] A method as described herein and in particular as described above, wherein the patient is vaccinated

(ivl) within one or more months of the first treatment year, wherein the one or more months are selected from month 1 of the first treatment year, month 3 of the first treatment year and month 4-12 of the first treatment year, preferably month 5-11 and especially month 6-10, and/or occur at least once, preferably once or twice, during one week of two weeks before the first treatment year/first treatment cycle begins, preferably during the last week;

and/or

iv 2) within one or more months of the first treatment year, wherein the month is selected from month 1 of the first treatment year, month 3 of the first treatment year and month 4-12 of the second treatment year, preferably month 5-11 and especially month 6-10, and/or during one week of two weeks before the beginning of the second treatment year/first treatment course, preferably at least once, preferably once or twice during the last week.

[50] A method as described herein and in particular as described above, wherein the patient is vaccinated

At least one occurrence between weeks 6 and 52 of the first treatment year, preferably between weeks 8 and 52 of the first treatment year, more preferably between weeks 9 and 52 of the first treatment year, even more preferably between weeks 10 and 48 of the first treatment year, and in particular between weeks 12 and 42 of the first treatment year.

[51] A method as described herein and in particular as described above, and in particular as described in section [48], wherein the patient is vaccinated

At least one occurrence during one of the weeks between week 6 and week 52 of the second treatment year, preferably between week 8 and week 52 of the second treatment year, more preferably between week 9 and week 52 of the second treatment year, even more preferably between week 10 and week 48 of the second treatment year, and especially between week 12 and week 42 of the second treatment year, and/or during one of the two weeks before the beginning of the second treatment year/first treatment session, preferably during the last week.

The method as described herein and in particular as described above, wherein said vaccinating said patient occurs at least once during weeks 1 to 5 of said first treatment year and/or said second treatment year, preferably during weeks 1 to 4, more preferably during weeks 2 to 4, and in particular during weeks 1 to 2, weeks 2 to 3 or weeks 3 to 4.

The method as described herein and in particular as described above, wherein said vaccinating said patient preferably occurs at least once during weeks 6 to 18, preferably weeks 6 to 16, more preferably weeks 7 to 15, and in particular weeks 8 to 12, in particular weeks 7 to 9, 9 to 12 or 13 to 15 of said first and/or said second treatment year.

Preferred is a method as described herein and especially as described above, wherein said vaccinating said patient occurs at least once within one or two weeks after the last oral cladribine dose in said first course of treatment in said first treatment year and/or second treatment year, i.e. week 2 or week 3, or preferably week 3 or week 4 of said treatment year.

Preferred is a method as described herein and in particular as described above, wherein said vaccinating said patient occurs at least once within week 3 or week 4 of said treatment year after the last oral cladribine dose in said second course of treatment in said first and/or second treatment year.

Even more preferred is a method as described herein and especially as described above, wherein said vaccinating said patient occurs at least once within one or two weeks after the last oral cladribine dose in said first course of treatment in said first treatment year, i.e. week 2 or week 3 of said first treatment year. During the course of the number of weeks, the patient preferably receives one or more injections of the vaccine, preferably one injection of the vaccine.

Even more preferred is a method as described herein and especially as described above, wherein said vaccinating said patient occurs at least once within one or two weeks after the last oral cladribine dose in said second course of treatment in said first treatment year, i.e. week 3 or week 4 of said first treatment year. During the course of the number of weeks, the patient preferably receives one or more injections of the vaccine, preferably one injection of the vaccine. Preferably, the same applies for the second year of treatment.

The method as described herein and in particular as described above, wherein the patient will receive more than one injection of the vaccine, e.g. two or three injections of the vaccine, then the first injection of the vaccine is preferably administered within weeks as outlined herein and in particular as outlined directly above. If the patient is to receive two or more injections of the vaccine, preferably two injections of the vaccine, then the second of the two or more injections is preferably administered during weeks 6 to 16, more preferably weeks 7 to 14, even more preferably weeks 8 to 12, and especially weeks 9 to 11 of the (first or second, preferably first) treatment year. Particularly preferably, the second of said two or more injected amounts of vaccine is administered preferably 7 to 15 weeks, more preferably 7 to 12 weeks, and especially 7 weeks, 8 weeks or 9 weeks after the administration day of said first injected amount of said vaccination, said first injected amount preferably being administered as described above, and particularly preferably within one week of 1 to 4 weeks counted from the first day in which cladribine is orally administered in each treatment year. Alternatively, the second of said two or more injected amounts of vaccine is preferably administered 5 to 12 weeks, more preferably 6 to 10 weeks, and especially 6 weeks, 7 weeks or 8 weeks after the administration day of said first injected amount of said vaccination, which is preferably administered as described above, and especially preferably within one week of 2 to 5 weeks, and especially within one week of 2, 3 or 4 weeks, counted from the first day in which cladribine is orally administered in the respective treatment year. This is preferred for a vaccine to be administered at least twice, more preferably for a vaccine to be administered 2 times, preferably as 2 separate injections, which are preferably administered separately over a period of at least 2 weeks and at most 8 months, preferably at least 3 weeks and at most 6 months, and especially at least 4 weeks and at most 6 months or so. Preferably, the 2 separate injections are preferably separated by 3 to 9 weeks, preferably about 4 to 8 weeks, e.g. about 4 weeks or about 8 weeks, or 4 to 7 months, preferably 5 to 6 months, e.g. about 6 months.

A method as described herein and in particular as described above, wherein

i) The patient will receive more than one dose or shot of the vaccine, preferably two or three doses or shots of the vaccine,

ii) a first dose or injection of said vaccine, or of said first dose or injection, preferably administered according to one or more of claims 54 to 58, and

iii) A second dose or injection of said more than one dose or injection, or the second dose or injection, is administered at least 1 to 8 weeks after said first dose or injection, preferably about 1 week, about 2 weeks, about 4 weeks or about 4 to 6 months after said first dose or injection.

The method as described herein and in particular as described above, wherein the second of said two or more vaccine doses or injections is administered 7 to 15 weeks, preferably 7 to 12 weeks, and in particular 7 weeks, 8 weeks or 9 weeks after the administration day of said first dose or injection of said vaccination, said first dose or injection preferably being administered as described herein and in particular as described above, and in particular preferably being administered within one week of 1 to 4 weeks, one week of 1 to 2 weeks, one week of 2 to 3 weeks, one week of 2 to 4 weeks or one week of 3 to 4 weeks counted from the first day in which cladribine is orally administered in the respective course of treatment.

Such vaccine packages are typically to be administered 2 times (i.e., as two separate injections)Including but not limited to varicella zoster virus vaccines or varicella zoster vaccine and (anti) zoster virus vaccines. Preferably, the terms "(anti) herpes zoster virus" or "(anti) herpes zoster" and "(anti) varicella zoster virus" or "(anti) varicella zoster" are considered as synonyms, respectively. Preferred (anti) varicella zoster virus vaccines include, but are not limited to, live (anti) varicella zoster virus vaccines, (anti) live attenuated varicella zoster virus vaccines, (anti) inactivated varicella zoster virus vaccines. Preferred examples include, but are not limited to(live herpes zoster vaccine) and inactivated or recombinant VZV vaccines, e.g. +.>Or shintrix->Inactivated or recombinant VZV vaccines, e.g.>Or shintrix->Particularly preferred in this regard. However, repeated vaccinations are common, i.e. a second (or subsequent) injection of the same vaccine is administered in order to optimise the vaccination achieved or achievable by said vaccine. This applies both to vaccines intended for single use, such as (anti) influenza vaccines, and to vaccines intended for repeated use, such as one repeated use of the vaccine, or as 2 separate injections of the vaccine, as is typical for (anti) varicella zoster virus vaccines. Preferably, the live (anti) varicella zoster virus vaccine and/or the attenuated live (anti) varicella zoster virus vaccine is administered only once, preferably as one injection. This applies generally to +. >(live herpes zoster vaccine). However, in this case as well, repeated vaccination is possible, i.e. a second (or even further subsequent) injection of the same vaccine is administered in order to optimize the vaccination achieved or achievable by said vaccine.

In the above method, all recommendations and timelines given in relation to the first treatment year for vaccinating and/or using the vaccine for the patient are preferably also applicable to the second treatment year and, if applicable, to any subsequent treatment year.

Can be regarded as a disorder (in particular a viral disorder), against which a subject (preferably a patient and more preferably a patient in need thereof) can be vaccinated in the context of the present invention, and against which a vaccine is preferably present (preferably a viral disease), preferably comprising one or more of the disorders given below, but preferably not limited to the disorders given below, preferably the viral disorders given below:

cholera, dengue fever, diphtheria, hepatitis a, hepatitis b, hepatitis e, haemophilus influenzae type b (Hib), human Papilloma Virus (HPV), influenza, japanese encephalitis, malaria, measles, meningococcal meningitis, mumps, pertussis, pneumococcosis, poliomyelitis, rabies, rotavirus, rubella, tetanus, tick-borne encephalitis, tuberculosis, typhoid fever, varicella and/or yellow fever.

Vaccines against covd-19 and/or mutants thereof are highly desirable for use according to the invention. Several vaccines against the covd-19 virus (SARS-COV-2) are currently available and several are under development, i.e. approved by health authorities. Practical and/or alternative methods include subunit vaccines comprising viral proteins, particularly surface membrane spike proteins that mediate receptor attachment; a nucleic acid-based vaccine that enables a host cell to produce a viral antigen, i.e., a spike protein or immunogenic portion thereof; all microbial methods such as attenuated live vaccines, inactivated vaccines or viral vector vaccines.

Preferred vaccines for use according to the present invention, preferably antiviral vaccines include one or more of the vaccines given below, but are preferably not limited to the vaccines given below:

influenza virus vaccines, inactivated, e.g., afluria or Afluria (Pro),

influenza virus vaccines, inactivated, e.g., fluarix Quadrivalent or Fluarix Quadrivalent (Pro),

influenza virus vaccines, inactivated, e.g., flublok Quadrivalent or Flublok Quadrivalent (Pro),

influenza virus vaccines, inactivated, e.g. Fluvin or Fluvin (Pro),

Adult hepatitis B vaccines, such as Engerix-B,

influenza virus vaccines, inactivated, e.g., flublok or Flublok (Pro),

live herpes zoster vaccines, such as Zostavax or Zostavax (Pro),

human papillomavirus vaccines, such as Gardasil 9 or Gardasil 9 (Pro),

influenza virus vaccines, inactivated, e.g., flucelvax Quadrivalent or Flucelvax Quadrivalent (Pro),

herpes zoster vaccines, inactivated, e.g., shintrix or shintrix (Pro),

influenza virus vaccines, live, trivalent, e.g., fluMist or FluMist (Pro),

influenza virus vaccines, inactivated, e.g. Fluzone,

influenza virus vaccines, inactivated, e.g., fluzone High-Dose or Fluzone High-Dose (Pro),

influenza virus vaccines, inactivated, e.g., fluad or Fluad (Pro),

influenza virus vaccines, live, trivalent, e.g. FluMist Quadrivalent,

yellow fever vaccines, e.g. Stamaril or Stamaril (Pro)

Smallpox vaccines, such as ACAM2000 or ACAM2000 (Pro),

influenza virus vaccines, inactivated, e.g., afluria Quadrivalent or Afluria Quadrivalent (Pro),

influenza virus vaccines, inactivated, e.g. Agriflu,

measles virus vaccines, such as attreuvax,

human papillomavirus vaccines, such as Cervarix or Cervarix (Pro),

Smallpox vaccines, such as Dryvax,

hepatitis B Pediatric vaccines, such as Engerix-B Pediatric,

influenza virus vaccines, inactivated, e.g., fluarix or Fluarix (Pro),

influenza virus vaccines, inactivated, e.g. Flucelvax,

influenza virus vaccines, inactivated, e.g. FluLaval or FluLaval (Pro),

influenza virus vaccines, inactivated, e.g., fluLaval Preservative-Free Quadrivalent,

influenza virus vaccines, inactivated, e.g., fluLaval Quadrivalent or FluLaval Quadrivalent (Pro),

influenza virus vaccines, inactivated, e.g., fluzone High-Dose Quadrivalent,

influenza virus vaccines, inactivated, e.g., fluzone Intradermal Quadrivalent,

influenza virus vaccines, inactivated, e.g., fluzone Quadrivalent or Fluzone Quadrivalent (Pro),

adult hepatitis A vaccines, such as Havrix or Havrix (Pro),

a Pediatric hepatitis A vaccine, such as Havrix Pediatric,

rabies vaccine, human diploid cells, such as Imovax Rabies or Imovax Rabies (Pro),

poliovirus vaccine, inactivated, e.g. Ipol or Ipol (Pro),

japanese brain vaccine sa14-14-2, inactivated, e.g., ixiaro or Ixiaro (Pro),

rubella virus vaccines, such as Meruvax II,

Mumps virus vaccines, such as Mumpsvax,

rabies vaccine, purified chicken embryo cells, such as RabAvert or RabAvert (Pro),

adult vaccines for hepatitis b, such as Recombivax HB Adult,

adult vaccines for hepatitis b, such as Recombivax HB Dialysis Formulation,

a hepatitis b pediatric vaccine, such as Recombivax HB Pediatric/Adolescent,

rotavirus vaccines, such as Rotarix or Rotarix (Pro),

rotavirus vaccines, such as RotaTeq or RotaTeq (Pro),

adult hepatitis A vaccines, such as Vaqta or Vaqta (Pro),

a Pediatric hepatitis A vaccine, such as Vaqta Pediatric,

varicella virus vaccines, such as Varivax or Varivax (Pro),

and/or

Yellow fever vaccines, such as YF-Vax or YF-Vax (Pro).

Can be regarded as a disorder (in particular a viral disorder), against which a subject (preferably a patient and more preferably a patient in need thereof) can be vaccinated in the context of the present invention, and against which a vaccine is preferably present (preferably a bacterial disorder), preferably comprising one or more of the disorders given below, but preferably not limited to the disorders given below, preferably the bacterial disorder given below:

anthrax (prophylaxis), cholera (prophylaxis), diphtheria (prophylaxis), haemophilus influenzae (prophylaxis), meningitis, meningococcus, meningococcal meningitis (prophylaxis), pertussis (prophylaxis), plague (prophylaxis), pneumococcal disease (prophylaxis), streptococcus pneumoniae (prophylaxis), tetanus (prophylaxis), tuberculosis (prophylaxis) and/or

Typhoid (prevention).

Preferred vaccines for use according to the present invention, preferably antibacterial vaccines include one or more of the vaccines given below, but are preferably not limited to the vaccines given below:

pneumococcal 23 multivalent vaccines such as pneumocandx 23 or pneumocandx 23 (Pro),

pneumococcal 13-valent vaccine such as Prevnar 13 or Prevnar 13 (Pro),

meningococcal conjugate vaccines, for example Menactra or Menactra (Pro),

haemophilus type b binding (prp-t) vaccines, such as ActHIB or ActHIB (Pro),

meningococcal vaccines of group B, e.g. Bexservo or Bexservo (Pro),

adsorbing anthrax vaccine, such as Biothrax or Biothrax (Pro),

haemophilus type b binding (prp-t) vaccines, such as Hiberix or Hiberix (Pro),

type b haemophilus binding (prp-omp) vaccines, such as Liquid PedvaxHIB or Liquid PedvaxHIB (Pro),

haemophilus type b binding (prp-t) vaccine/meningococcal conjugate vaccine, e.g. MenHibrix,

meningococcal polysaccharide vaccines, e.g. Menomune A/C/Y/W-135,

meningococcal conjugate vaccines, for example Menveo or Menveo (Pro),

pneumococcal 7-valent vaccine, such as Prevnar or Prevnar (Pro),

tetanus toxoid, such as Te Anatoxal Berna,

Tetanus toxoid, such as Tetanus Toxoid Adsorbed,

meningococcal group B vaccines, e.g. Trumenba or Trumenba (Pro)

Typhoid vaccines, inactivated, e.g. Typhim Vi or Typhim Vi (Pro)

Cholera vaccine, live, e.g. Vaxchora or Vaxchora (Pro), and/or

Typhoid vaccines, live, e.g. Vivotif Berna.

Particularly preferred for use as vaccine in the context of the present invention are inactivated and/or recombinant herpes zoster vaccines or varicella zoster vaccines, preferably vaccines with the European drug administration (European Medicines Agency) (EMA) product code EMEA/H/C/004336, wherein the active substance comprises recombinant varicella zoster virus glycoprotein E, with the international nonpatent designation (INN) or the generic designation "herpes zoster vaccine" or "herpes zoster vaccine (recombinant, adjuvanted)", the therapeutic area (MeSH) in respect of which comprises herpes zosterAnd/or an Anatomic Therapeutic Chemical (ATC) code relating thereto is J07BK03. Such vaccines are under the trade nameIs known. Preferably, the inactivated and/or recombinant herpes zoster vaccine or varicella zoster vaccine is available as a powder and suspension, preferably mixed together, for example by a doctor or nurse, before administration to the patient, preferably by injection, for example by intramuscular injection into the patient's upper arm. Vaccination in this regard preferably comprises 2 separate vaccinations, 2 separate injections or 2 separate injections, preferably administered about 3 weeks to about 8 months apart, preferably about 4 weeks to about 6 months apart. Typically, in this regard, two separate vaccinations, two separate injections or two separate injections are administered to the patient or subject

(i) About 3 to 5 weeks or about one month apart

(ii) About 8 to 10 weeks or about 2 months apart,

(iii) About 24 to 28 weeks or about 6 months apart, or

iv) about 4 to 28 weeks apart, about 6 to 26 weeks apart, or about 8 to 25 weeks apart, or substantially up to 6 months apart.

Accordingly, if desired or necessary in this regard, the second vaccination, dose, injection or injection amount may be spaced from 3 to 10 weeks apart, but is preferably administered within 6 months after the first vaccination, dose injection or injection amount. A person whose immune system is not working properly, under immunosuppressive therapy and/or being treated or treated according to the treatment methods of the present invention, and thus who benefits from a shorter vaccination schedule, may have a second dose one to two months after the first dose, preferably within a vaccination period as outlined herein. This is particularly preferred for inactivated or recombinant herpes zoster vaccine (zoster vaccinee), herpes zoster vaccine (herpes zoster vaccine), varicella zoster vaccine and/or VZV vaccine, especially such vaccines, which are typically administered 2 times to the subject or patient in order to achieve optimal protection for the subject or patient Protect or immunize. Administration is typically accomplished by 2 separate vaccinations, 2 separate injections, or 2 separate injection volumes, preferably as known in the art and particularly as described herein. Preferred examples of such vaccines are adjuvanted recombinant herpes zoster vaccines, for example under the trade nameCommercially available vaccines. Such vaccines are preferably indicated for use in the prophylaxis of shingles (shingles), more preferably in the prophylaxis of shingles (shingles) in adults 50 years and older. The vaccine is also preferred for use as a vaccine according to the invention. The two doses of the vaccine are preferably administered via injection, preferably intramuscularly, and preferably according to the following schedule:

at any time during the vaccination period described herein, preferably the first dose during the early vaccination period described herein,

followed by a second dose administered as follows

a) Any time between 1 and 6 months after the first dose, or

b) At any time between 2 and 6 months after the first dose,

preferably during the post vaccination period described herein.

Preferably, if used in accordance with the methods of the invention, an adjuvanted recombinant herpes zoster vaccine, e.g Shows a potentiation of the VZV-specific immune response, said potentiation being believed to be the mechanism by which it protects the subject or patient from the varicella zoster and/or shingles disease.

Also particularly preferred for use as vaccine in the context of the present invention are live herpes zoster vaccines, which are preferably live attenuated virus vaccines, e.g(live herpes zoster vaccine), and is preferably indicated for prophylaxis of shingles (shingles), more preferably for prophylaxis of shingles (shingles) in individuals 50 years and older. Live vaccines for herpes zoster, e.g.>Preferred are lyophilized formulations of live, attenuated Varicella Zoster Virus (VZV) strains, for example, the Oka/Merck strain of live attenuated Varicella Zoster Virus (VZV). When the reconstruction is performed as shown, +.>Is a sterile suspension for subcutaneous administration. Typically, such live herpes zoster vaccines are for single administration, and therefore, in accordance with the invention, they are typically administered only once (i.e. as a single dose) to a subject or patient. However, one repeated administration may be recommended or prescribed by the attending physician. In any case, it is generally administered subcutaneously, preferably in the deltoid region of the upper arm of the subject or patient. Herpes Zoster (HZ), commonly known as shingles (shingles) or shingles (zoster), preferably Varicella Zoster Virus (VZV) which produces varicella (varicella) as a primary infection. After initial infection, the virus remains dormant in the dorsal root or cranial sensory ganglion until it is reactivated, producing shingles. Shingles is characterized by unilateral, painful, vesicular rash with a distribution of skin nodes. The risk of developing Shingles (Zoster) and/or Shingles (shinles) appears to be associated with a decrease in VZV-specific immunity. (anti) herpes zoster virus vaccine (or (anti) herpes zoster vaccine), (anti) varicella zoster virus vaccine (or (anti) varicella zoster vaccine), preferably live herpes zoster vaccine and in particular +. >Shows a boost of VZV-specific immunity, which is considered to be its protection from shingles and its concurrenceMechanisms of the symptomatic influence. In general, it is not recommended to use live herpes zoster vaccines such as +.>Is administered to an individual who is immunodeficiency or immunosuppressed by disease or therapy because of the possibility of developing severe or fatal disseminated vaccine strain varicella zoster virus disease. The cause of immunodeficiency or immunosuppression may include, but is not limited to, primary or acquired immunodeficiency status, AIDS or other clinical manifestations of infection with human immunodeficiency virus, leukemia, lymphoma or other malignant neoplasm affecting the bone marrow or lymphatic system, and immunosuppressive therapy. However, in the context of the present invention, this is considered to be different, as the results underlying the present invention clearly show that, due to the fact that cladribine (preferably oral cladribine and especially cladribine tablets (e.g.)>) With cladribine (preferably oral cladribine and especially cladribine tablets (e.g.)>) A) surprisingly advantageous interaction of the immune system of a subject or patient treated as described herein and/or as approved tags, preferably approved EMA and/or FDA tags, is less inhibitory than expected and/or described in the prior art. Thus, the results underlying the present invention clearly demonstrate that when a dose of cladribine (preferably oral cladribine and especially cladribine tablet (e.g.: a >) In the context of treating autoimmune disorders, several vaccines and/or vaccine types (if not all vaccines and/or vaccine types) can be safely and/or effectively administered to a subject or patient.

Suitable (anti) influenza (virus) vaccines include, but are not limited to:

mutagrip may contain minor amounts of eggs such as ovalbumin, as well as neomycin, formaldehyde and octoxynol-9 (according to the Spanish tag) used during the manufacturing process. The vaccine was used in subjects-70056800227010005 and 70056800227010013 from spanish.

Tetravalent inactivated influenza vaccine (Vaxigripttetra) ^TM )

VaxigripTetra ^TM (IIV 4; sanofi Pasteur) is a tetravalent split virion influenza vaccine approved in Europe in 2016 for individuals older than or equal to 3 years. IIV4 builds on trivalent split virion influenza vaccineIs above a good record of (a). Coverage area: this document reviews the rationale for developing tetravalent influenza vaccines and discusses the results of phase III clinical trials supporting immunogenicity, safety, and tolerability of IIV 4. Expert comments: IIV4 is immunogenic and well tolerated. The addition of a second strain of b to a trivalent split virion influenza vaccine provides an excellent immune response to the other strain, but does not reduce the immune response with respect to the other three strains or negatively impact the safety profile. By providing broader protection against the co-transmitted influenza b lineage, IIV4 has the potential to further reduce influenza-related morbidity and mortality beyond that achieved with trivalent vaccines.

Vagigrip tetra contains a buffer solution of sodium chloride, potassium chloride, disodium phosphate dihydrate, potassium dihydrogen phosphate and water for injection. Certain components such as egg (ovalbumin, chicken protein), neomycin, formaldehyde or octoxynol-9 may be present in very small amounts. The vaccine was used in subjects-70056800221620002, 70056800221620004, 70056800221620006 (all from finland).

Alfuria quad-0.5 mL single dose AFLURIA QUADRIVALENT contains sodium chloride (4.1 mg), sodium dihydrogen phosphate (80 mcg), disodium hydrogen phosphate (300 mcg), potassium dihydrogen phosphate (20 mcg), potassium chloride (20 mcg) and calcium chloride (0.5 mcg). It is also possible to contain residual amounts of sodium taurodeoxycholate (.ltoreq.10 ppm), ovalbumin (< 1 mcg), sucrose (< 10 mcg), neomycin sulfate (.ltoreq.81.8 nanograms [ ng ]), polymyxin B (.ltoreq.14 ng), beta-propiolactone (.ltoreq.1.5 ng) and hydrocortisone (.ltoreq.0.56 ng) per 0.5mL dose from the manufacturing process. The vaccine was used in subject-70056800221220003 (from australia).

Trivalent inactivated influenza virus vaccines and tetravalent inactivated influenza vaccines are preferred (anti) influenza (virus) vaccines for use according to the invention.

Particularly preferred for use as a vaccine in the context of the present invention is a tetravalent influenza vaccine (split virions, inactivated), which is indicated for the prevention of influenza diseases caused by two influenza a virus subtypes and two influenza b virus types comprised in the vaccine. Tetravalent influenza vaccines (split virions, inactivated) are vaccines administered to protect a subject or patient from influenza (influenza). Tetravalent influenza vaccines (split virions, inactivated) or similar types of vaccines are indicated for the prevention of influenza diseases caused by two influenza a virus subtypes and two influenza b virus types contained in the vaccine. Typically, such influenza vaccines are administered only once a year, preferably before or during the influenza season. Preferably, the influenza vaccine is administered once a year or in combination with the influenza season, but preferably is administered in accordance with the vaccination period of the present invention.

However, such influenza vaccines may also be administered more than once, preferably 2 or 3 times, more preferably 2 times, per year or per influenza season, for example in order to boost or optimise the vaccination achieved or achievable by the vaccine. If such a vaccine is to be administered 2 times, the first dose is preferably administered at any time during the vaccination period described herein, preferably during the early vaccination period described herein,

followed by a second dose administered within 1-3 weeks after the first administration, preferably within 1-3 weeks of the same early vaccination period, or within 4 weeks to 3 months after the first dose, preferably within a late or subsequent vaccination period as described herein.

Particularly preferred for use as vaccines in the context of the present invention are (anti) Corona vaccines, (anti) COVID-19 vaccines, (anti) SARS-COVID-19 vaccines and/or (anti) SARS-CoV-2 vaccines, including but not limited to

Vaccines based on mRNA technology, for example:

mRNA-1273 (Moderna/NIAID vaccine),

BNT162b2 (Pfizer/BioNTech vaccine);

vector-based vaccines, preferably adenovirus/vector-based vaccines, such as:

the ad26.cov2.s (Johnson & Johnson/Janssen Pharmaceuticals vaccine),

AZD1222 (ChAdOx 1-S) (AstraZeneca/University of Oxford vaccine),

Gam-COVID-Vac/Sputnik V(Gamaleya Institute)，

Ad5-nCoV(CanSino Biologics)；

vaccines based on virus-like particles (VLPs), for example:

CVnCoV(CureVac)，

CoVLP(Medicago)；

DNA-based vaccines, for example:

INO-4800(Inovio Pharmaceuticals/International Vaccine Institute)；

protein-based vaccines, for example:

ZF2001 (Anhui Zhifei Longcom Biopharmaceutical), preferably with an adjuvant,

NVX-CoV2373 (Novavax), preferably with the addition of an adjuvant;

inactivated virus-based or dead virus-based vaccines, for example:

Covaxin/BBV152(Bharat Biotech/Indian Council of Medical Research(ICMR)/National Institute for Virology(NIV)，

CoronaVac(Sinovac)，

Sinopharm/Wuhan Institute of Biological Products，

BBIBP-CorV(Sinopharm/Beijing Institute of Biological Products)；

etc.

The same applies preferably to further (anti) Corona vaccines, (anti) COVID-19 vaccines, (anti) SARS-COVID-19 vaccines and/or (anti) SARS-CoV-2 vaccines.

Vaccines based on mRNA technology, such as mRNA-1273 (Moderna/NIAID vaccine), and BNT162b2 (Pfizer/BioNTech vaccine), and/or protein-based vaccines, such as ZF2001 (Anhui Zhifei Longcom Biopharmaceutical), preferably with the addition of an adjuvant, and NVX-CoV2373 (Novavax), preferably with the addition of an adjuvant, are particularly preferred.

Varicella zoster virus infection, including but not limited to herpes zoster infection and/or shingles, is an identified risk with respect to patients suffering from autoimmune disorders, including but not limited to Multiple Sclerosis (MS), recurrent MS (RRMS) and/or Secondary Progressive MS (SPMS), and treated or treated with cladribine, preferably oral cladribine and particularly cladribine tablets. Accordingly, vaccination of patients who are antibody negative for varicella zoster virus suggests at least 4 to 6 weeks prior to initiation of treatment with cladribine (preferably oral cladribine and especially cladribine tablets) for attenuated live or live vaccines, and during Mavenclad treatment for non-live vaccines.

However, in the context of treatment with cladribine (preferably oral cladribine and especially a cladribine tablet), especially in a cladribine tablet as approved according to EMA SmPC and/or FDA USPIIn the context of the dosimetry of (a), there is a high need for more flexibility and/or options for vaccinating patients. Surprisingly and advantageously, by studying the effect of treatment of a patient with cladribine tablets according to SmPC and/or USPI, it was newly found that the effect of said treatment with cladribine tablets on the immune system of said patient was different from originally expected, i.e. less severe and strongly dependent on the point in time within said treatment. Even more surprising and advantageous, it has recently been found that vaccination can be handled much more freely in the context of treatment with cladribine tablets.

Accordingly, the subject of the present invention is to provide improved options for vaccinating patients in the context of treatment with cladribine tablets, preferably in view of current vaccination or vaccination guidelines.

Thus, a preferred subject matter is to provide improved options to vaccinate patients with (anti) varicella zoster virus vaccine or (anti) zoster virus vaccine (collectively "VZV-vaccine") in the context of treatment with cladribine tablets, preferably taking into account current vaccination or vaccination guidelines, and as for example USPI and/or SmPC with respect to cladribine tablets The cladribine tablet is in a dosage form

Preferred VZV vaccines in this respect comprise recombinant varicella zoster virus glycoprotein E, preferably a vaccine having the International Nonpatent Name (INN) or the generic name "shingles vaccine" or "shingles vaccine (recombinant, adjuvanted)", e.g.

Thus, a preferred subject of the present invention is a method of vaccinating a patient in the context of cladribine tablet therapy, wherein the method is performed in accordance with the method described in relation to cladribine tabletsAt least one vaccine, preferably as further defined and/or described herein, is administered to the patient at any time during cladribine tablet treatment of USPI and/or SmPC. Even more preferred is a method of vaccinating a patient with said herpes zoster vaccine (recombinant, adjuvanted), wherein said vaccine is administered 2 times to said patient, and wherein the first administration of said vaccine to said patient is in accordance with USPI and/or SmPC with respect to cladribine tablets +>Any time during the treatment of the cladribine tablet, preferably as further defined and/or described herein, and the second administration of the vaccine follows the first administration of the vaccineOccurs after about one month, within about 2 months, or within 2 to 6 months.

Even more preferred is a method of vaccinating a patient with said herpes zoster vaccine (recombinant, adjuvanted), wherein said vaccine is administered 2 times to said patient, and wherein the first administration of said vaccine to said patient is in accordance with USPI and/or SmPC with respect to cladribine tabletsThe cladribine tablet treatment is initiated within weeks 1 to 4 and preferably 2 to 4, preferably as further defined and/or described herein, and the second administration of the vaccine

a) In relation to cladribine tablets according to USPI and/or SmPCThe cladribine tablet treatment occurs within weeks 8 to 14 and preferably 10 to 12 after initiation of treatment, preferably as further defined and/or described herein, or

b) May be delayed until month 6 after the first administration of the vaccine to the patient.

It has recently been found that when cladribine (preferably oral cladribine and especially cladribine tablets) is used) In the context of treating a patient, it is advantageously possible to vaccinate the patient safely and/or effectively,

the patient is preferably one who is negative for varicella zoster virus, more preferably one who is treated with cladribine, oral cladribine or cladribine tablet Patients who are antibody negative for varicella zoster virus prior to or during treatment,

using varicella zoster vaccine, preferably varicella zoster non-live vaccine,

in the presence of cladribine, warpOral cladribine or cladribine tabletAt any point during the treatment with cladribine, oral cladribine or cladribine tablet is preferred>Any point in time during the course of 2 years that is typically required for such treatment. Preferably, cladribine (preferably oral cladribine and especially cladribine tablet +.>) Said treatment of a patient as described herein and in particular as described in relation to cladribine tablets +.>The disclosure of which is incorporated by reference into this patent application, preferably in accordance with the state of SmPC and/or USPI by month 11 of 2020, is described in SmPC approved by European health authorities (European Health Authority) (EMA) and/or USPI approved by the United states food and drug administration (US Food and Drug Administration) (FDA). Suitable varicella zoster vaccines are known in the art. Preferred varicella zoster vaccines are described herein. Particularly preferred in this respect are vaccines comprising recombinant varicella zoster virus glycoprotein E, preferably vaccines with the International Nonpatent Name (INN) or the generic name "shingles vaccine" or "shingles vaccine (recombinant, adjuvanted)", e.g.) >Preferably, the treatment of a patient with cladribine is the treatment of an autoimmune disorder as described herein, and in particular the treatment of Multiple Sclerosis (MS), preferably Relapsing MS (RMS), more preferably Relapsing Remitting MS (RRMS) and/or Secondary Progressive MS (SPMS).

In addition, it has been recently discovered that when cladribine (preferably oral cladribine and especially cladribine tablets are used)) In the context of treating a patient, it is advantageously possible to vaccinate the patient safely and/or effectively,

the patient is preferably one who is negative for varicella zoster virus, more preferably one who is treated with cladribine, oral cladribine or cladribine tabletPatients who are antibody negative for varicella zoster virus prior to or at the beginning of treatment,

using varicella zoster vaccine, preferably varicella zoster non-live vaccine,

in the form of cladribine, oral cladribine or cladribine tabletsDuring the treatment period given below, the preferred time period is:

a) In cladribine, oral cladribine or cladribine tabletAfter (or: counted by) the first dose of the vaccine within 2 to 4 weeks (e.g. the first dose of the vaccine or the only dose of the vaccine) and/or within 10 to 12 weeks (alternatively, e.g. the second dose of the vaccine or the only dose), there is the possibility of delaying the administration of the second dose of the vaccine until month 6 after the first dose of the vaccine. Preferably, this applies to the administration of cladribine, oral cladribine or cladribine tablets +. >Is usually required for the first and/or second of the 2 years. Preferably, cladribine (preferably oral cladribine and especially cladribine tablet)) The treatment of patients as described herein and in particular as for cladribine tabletsThe disclosure of which is incorporated by reference into the present application, preferably in accordance with the state of SmPC and/or USPI by month 11 of 2020, is described in European health authorities (EMA) approved SmPC and/or United states Food and Drug Administration (FDA) approved USPI. Suitable varicella zoster vaccines are known in the art. Preferred varicella zoster vaccines are described herein. Particularly preferred in this respect are vaccines comprising recombinant varicella zoster virus glycoprotein E, preferably vaccines with the International Nonpatent Name (INN) or the generic name "shingles vaccine" or "shingles vaccine (recombinant, adjuvanted)", e.g.)>Preferably, the treatment of a patient with cladribine is the treatment of an autoimmune disorder as described herein, and in particular the treatment of Multiple Sclerosis (MS), preferably Relapsing MS (RMS), more preferably Relapsing Remitting MS (RRMS) and/or Secondary Progressive MS (SPMS).

Preferably, the pharmaceutical composition is formulated with cladribine (preferably oral cladribine and especially cladribine tablets) In the context of treating a patient, it is advantageously possible to vaccinate the patient safely and/or effectively,

using varicella zoster vaccine, preferably varicella zoster non-live vaccine,

in-use ClaraTablet of cladribine, oral cladribine or cladribineDuring the treatment period given below, the preferred time period is:

a) In cladribine, oral cladribine or cladribine tabletAfter (or: counted by) the first dose of the vaccine within weeks 2 to 4 (first dose of the vaccine) and/or within weeks 10 to 12 (second dose of the vaccine), there is a possibility of delaying the administration of said second dose of the vaccine until month 6 after the first dose of the vaccine. Preferably, this applies to the administration of cladribine, oral cladribine or cladribine tablets +.>Is usually required for the first and/or second of the 2 years. Preferably, cladribine (preferably oral cladribine and especially cladribine tablet +. >) Said treatment of a patient as described herein and in particular as described in relation to cladribine tablets +.>The implementations described in SmPC approved by European health authorities (EMA) and/or USPI approved by the United states Food and Drug Administration (FDA), the disclosures of which are incorporated by reference into the present application, preferably in accordance with the state of SmPC and/or USPI by month 11 of 2020. Suitable varicella zoster vaccines are known in the art. Preferred varicella zoster vaccines are described herein. Particularly preferred in this respect are vaccines comprising recombinant varicella zoster virus glycoprotein E, preferably vaccines with the International Nonpatent Name (INN) or the generic name "shingles vaccine" or "shingles vaccine (recombinant, adjuvanted)", e.g.)>Preferably, the treatment of a patient with cladribine is the treatment of an autoimmune disorder as described herein, and in particular the treatment of Multiple Sclerosis (MS), preferably Relapsing MS (RMS), more preferably Relapsing Remitting MS (RRMS) and/or Secondary Progressive MS (SPMS).

Alternatively, in the case of a tablet with cladribine (preferably oral cladribine and especially cladribine tablet) In the context of treating a patient, it is advantageously possible to vaccinate the patient safely and/or effectively,

The patient is preferably one who is negative for varicella zoster virus, more preferably one who is treated with cladribine, oral cladribine or cladribine tabletPatients who are antibody negative for varicella zoster virus prior to or during treatment,

using varicella zoster vaccine, preferably varicella zoster non-live vaccine,

in the form of cladribine, oral cladribine or cladribine tabletsAt any point during the treatment with cladribine, oral cladribine or cladribine tablet is preferred>At any point during the course of 2 years that is typically required for such treatment,

except for the administration of cladribine, oral cladribine or cladribine tablet @Preferably outside the first 3 months after the first dose of (a)

a) Except for the use of cladribine, oral cladribine or cladribine tabletsWithin the first treatment year of 2 years of the need for such treatment, outside the first 3 months after administration of the first dose of cladribine, oral cladribine or cladribine tablet,

and/or

b) Except for the use of cladribine, oral cladribine or cladribine tabletsWithin the second of the 2 years typically required for such treatment, outside the first 3 months after the first dose of cladribine, oral cladribine or cladribine tablet is administered. Preferably, cladribine (preferably oral cladribine and especially cladribine tablet +. >) The treatment of patients as described herein and in particular as for cladribine tabletsThe implementations described in SmPC approved by European health authorities (EMA) and/or USPI approved by the United states Food and Drug Administration (FDA), the disclosures of which are incorporated by reference into the present application, preferably in accordance with the state of SmPC and/or USPI by month 11 of 2020. Suitable varicella zoster vaccines are known in the art. Preferred varicella zoster vaccines are described herein. Particularly preferred in this respect are vaccines comprising recombinant varicella zoster virus glycoprotein E, preferably vaccines with the International Nonpatent Name (INN) or the generic name "shingles vaccine" or "shingles vaccine (recombinant, adjuvanted)", e.g.)>Preferably, treatment of a patient with cladribine is treatment of an autoimmune disorder as described herein, and in particularMultiple Sclerosis (MS), preferably Relapsing MS (RMS), more preferably Relapsing Remitting MS (RRMS) and/or Secondary Progressive MS (SPMS), is treated.

Thus, the treatment methods found in accordance with the foregoing are the preferred subjects of the present invention.

Therefore, it is preferable that:

a method of treatment, preferably as hereinbefore and/or hereinafter described, comprising

a) Treatment of patients with cladribine tablets, preferably as described herein and in particular as described in relation to USPI or EU SmPCThe sum is that

b) Varicella zoster vaccine the patient is vaccinated once or twice, preferably as described herein with respect to vaccination with varicella zoster vaccine, at any point during the treatment with cladribine tablets, preferably at any point during treatment 1 out of 2 years and/or treatment 2 that is typically required for the treatment with cladribine tablets.

b) Varicella zoster vaccine the patient is vaccinated once or twice, preferably as described herein with respect to vaccination with varicella zoster vaccine, at any point in time during the year calculated from the first administration of the cladribine tablet to the patient, preferably during the 1 st of the 2 years of treatment normally required for said treatment with cladribine tablet.

a) Treatment of patients with cladribine tablets, preferably as described herein and in particular as USPI orEU SmPC concernsThe sum is that

b) Varicella zoster vaccine the patient is vaccinated once or twice, preferably as described herein with respect to vaccination with varicella zoster vaccine, at any point in time during the year calculated from the first administration of the cladribine tablet to the patient, preferably the 1 st of the 2 years of treatment normally required for said treatment with a cladribine tablet.

b) Varicella zoster vaccine the patient was vaccinated twice,

wherein within 2 to 4 weeks (first dose) and within 10 to 12 weeks (second dose) after administration of the first dose of the cladribine tablet, the patient vaccinates once with the varicella zoster vaccine with the possibility of delaying administration of the vaccinated second dose until the 6 th month after the first dose of the vaccination.

b) The patient was vaccinated twice with varicella zoster non-live vaccine,

wherein within weeks 2 to 4 (first dose) and 10 to 12 (second dose) after the first administration of the cladribine tablet, the patient, preferably a patient who is antibody negative for varicella zoster virus, is vaccinated once with the varicella zoster non-live vaccine with the possibility of delaying the administration of the second dose of the vaccination until month 6 after the first dose of the vaccination.

b) The patient was vaccinated twice with varicella zoster non-live vaccine,

wherein within 2 to 4 weeks (first dose) and within 10 to 12 weeks (second dose) after the first administration of the cladribine tablet (or calculated from the first administration of the cladribine tablet), the patient, preferably a patient who is antibody negative for varicella zoster virus prior to the first vaccination and/or prior to the first administration of the cladribine tablet, is vaccinated once with the varicella zoster non-live vaccine with the possibility of delaying the administration of the second dose of the vaccination until the 6 th month after the first dose of the vaccination.

b) Varicella zoster vaccine the patient is vaccinated once or twice, preferably as described herein with respect to vaccination with varicella zoster vaccine, at any point during the treatment with cladribine tablets, preferably at any point during treatment 1 of 2 years and/or treatment 2 of the years normally required for the treatment with cladribine tablets,

except for the first 3 months following the first dose of cladribine tablet administered to the patient, preferably within each of the 2 years (treatment 1 and/or treatment 2 years) typically required for the treatment with a cladribine tablet.

b) Varicella zoster vaccine the patient is vaccinated once or twice, preferably as described herein with respect to vaccination with varicella zoster vaccine, at any point in time during the year calculated from the first administration of the cladribine tablet to the patient, preferably during the 2 nd year of treatment of the patient typically required for said treatment with the cladribine tablet, except for the first 3 months after the first dose of the cladribine tablet administered to the patient, preferably within the first treatment year (treatment 1 st year) of the 2 years typically required for said treatment with the cladribine tablet, outside the first 3 months after the first dose of the cladribine tablet administered to the patient.

b) Varicella zoster vaccine the patient is vaccinated once or twice, preferably as described herein with respect to vaccination with varicella zoster vaccine, at any point in time during the year from the first administration of the cladribine tablet to the patient, preferably the 1 st of the 2 years of treatment normally required for said treatment with a cladribine tablet,

except for the first 3 months after the first dose of cladribine tablet is administered to the patient, preferably within the second treatment year (treatment year 2), preferably the second treatment year (treatment year 2) of the 2 years typically required for such treatment with cladribine tablet.

The first administration of the cladribine tablet preferably refers to the first administration of the cladribine tablet within a first treatment year (treatment year 1 or first course of treatment) and/or a second treatment year (treatment year 2 or second course of treatment) of the treatment with the cladribine tablet, preferably the treatment with the cladribine tablet as described herein, which is typically required for the treatment.

Preferably, the treatment of a patient with a cladribine tablet is treatment of an autoimmune disorder as described herein, and in particular treatment of Multiple Sclerosis (MS), preferably Relapsing MS (RMS), more preferably Relapsing Remitting MS (RRMS) and/or Secondary Progressive MS (SPMS).

A tablet preferably as described herein with cladribine, preferably oral cladribine and especially cladribineA method of treating a patient, the method further comprising

The patient is vaccinated with a vaccine,

the varicella zoster vaccine is used and the vaccine,

preferably a varicella zoster non-live vaccine,

in the form of cladribine, oral cladribine or cladribine tabletsAt any point during the treatment with cladribine, oral cladribine or cladribine tablet is preferred>Any point in time during the course of 2 years that is typically required for such treatment. Preferably, cladribine, preferably oral cladribine and especially cladribine tablets are used +. >Said treatment of a patient as described herein and in particular as described in relation to cladribine tablets +.>The implementations described in SmPC approved by European health authorities (EMA) and/or USPI approved by the United states Food and Drug Administration (FDA), the disclosures of which are incorporated by reference into the present application, preferably in accordance with the state of SmPC and/or USPI by month 11 of 2020. Suitable varicella zoster vaccines are known in the art. Preferred varicella zoster vaccines are described herein. Particularly preferred in this respect are vaccines comprising recombinant varicella zoster virus glycoprotein E, preferably vaccines with the International Nonpatent Name (INN) or the generic name "shingles vaccine" or "shingles vaccine (recombinant, adjuvanted)", e.g.)>

A tablet preferably as described herein with cladribine, preferably oral cladribine and especially cladribineMethod of treating a patient, the method furtherThe steps include

The patient is vaccinated with a vaccine,

The varicella zoster vaccine is used and the vaccine,

preferably a varicella zoster non-live vaccine,

in the form of cladribine, oral cladribine or cladribine tabletsDuring the period given below, namely:

a) In cladribine, oral cladribine or cladribine tabletAfter (or: counted by) the first dose of vaccine, within 2 to 4 weeks (preferably with the first dose of vaccine or the only dose of vaccine) and/or within 10 to 12 weeks (alternatively, preferably with the second dose of vaccine or the only dose), the patient is vaccinated with the possibility of delaying the administration of the second dose of vaccine until the 6 th month after the first dose of vaccine. Preferably, this applies to the administration of cladribine, oral cladribine or cladribine tablets +.>Is usually required for the first and/or second of the 2 years. Preferably, cladribine, preferably oral cladribine and especially cladribine tablets are used +.>The treatment of patients as described herein and in particular asConcerning cladribine tablets->The implementations described in SmPC approved by European health authorities (EMA) and/or USPI approved by the United states Food and Drug Administration (FDA), the disclosures of which are incorporated by reference into the present application, preferably in accordance with the state of SmPC and/or USPI by month 11 of 2020. Suitable varicella zoster vaccines are known in the art. Preferred varicella zoster vaccines are described herein. Particularly preferred in this respect are vaccines comprising recombinant varicella zoster virus glycoprotein E, preferably vaccines with the International Nonpatent Name (INN) or the generic name "shingles vaccine" or "shingles vaccine (recombinant, adjuvanted)", e.g.) >

The patient is vaccinated with a vaccine,

using varicella zoster vaccine, preferably varicella zoster non-live vaccine,

in the form of cladribine, oral cladribine or cladribine tabletsDuring the course of the treatment, for the period of time given below,

a) In cladribine, oral cladribine or cladribine tabletAfter (or: counted by) the first dose of (a first dose of) 2 to 4 weeks (a first dose of vaccine) and/or 10 to 12 weeks (a second dose of vaccine), vaccinating the patient,

there is the possibility of delaying the administration of the second dose of the vaccine until month 6 after the first dose of the vaccine. Preferably, this applies to the use of cladribine, oral cladribine or cladribine tablets Is usually required for the first and/or second of the 2 years. Preferably, cladribine, preferably oral cladribine and especially cladribine tablets are used +.>Said treatment of a patient as described herein and in particular as described in relation to cladribine tablets +.>The implementations described in SmPC approved by European health authorities (EMA) and/or USPI approved by the United states Food and Drug Administration (FDA), the disclosures of which are incorporated by reference into the present application, preferably in accordance with the state of SmPC and/or USPI by month 11 of 2020. Suitable varicella zoster vaccines are known in the art. Preferred varicella zoster vaccines are described herein. Particularly preferred in this respect are vaccines comprising recombinant varicella zoster virus glycoprotein E, preferably vaccines with the International Nonpatent Name (INN) or the generic name "shingles vaccine" or "shingles vaccine (recombinant, adjuvanted)", e.g.)>

Preferably as described herein with respect to use of caratDronabine, preferably oral cladribine and especially cladribine tabletA method of treating a patient, the method further comprising

The patient is vaccinated with a vaccine,

using varicella zoster vaccine, preferably varicella zoster non-live vaccine,

and/or

b) Except for the use of cladribine, oral cladribine or cladribine tabletsWithin the second of the 2 years typically required for such treatment, outside the first 3 months after the first dose of cladribine, oral cladribine or cladribine tablet is administered. Preferably, cladribine, preferably oral cladribine and especially cladribine tablets are used +. >The treatment of patients as described herein and in particular as for cladribine tabletsThe implementations described in SmPC approved by European health authorities (EMA) and/or USPI approved by the United states Food and Drug Administration (FDA), the disclosures of which are incorporated by reference into the present application, preferably in accordance with the state of SmPC and/or USPI by month 11 of 2020. Suitable varicella zoster vaccines are known in the art. Preferred varicella zoster vaccines are described herein. Particularly preferred in this respect are vaccines comprising recombinant varicella zoster virus glycoprotein E, preferably vaccines with the International Nonpatent Name (INN) or the generic name "shingles vaccine" or "shingles vaccine (recombinant, adjuvanted)", e.g.)>

Summarizing:

a particularly preferred subject of the invention relates to the use of cladribine tabletsA method of treating a patient, further comprising

Vaccinating a patient, preferably a patient that is antibody negative for varicella zoster virus prior to said treatment and/or said vaccination, with a varicella zoster vaccine, preferably a varicella zoster vaccine as described herein,

a) Wherein said vaccination takes place immediately prior to said treatment of the patient with said cladribine tablet, preferably immediately one or two weeks prior to the initiation of said treatment of the patient with said cladribine tablet,

And/or

b) Wherein said vaccination occurs at any time during said treatment of a patient with said cladribine tablet, preferably at any time during said treatment of a patient with said cladribine as described herein.

Preferably, said treatment of a patient with said cladribine tablet is treatment of an autoimmune disorder as described herein, and in particular treatment of Multiple Sclerosis (MS), preferably Relapsing MS (RMS), more preferably Relapsing Remitting MS (RRMS) and/or Secondary Progressive MS (SPMS). Preferred in this respect are vaccines comprising attenuated live varicella zoster virus, e.g(live herpes zoster vaccine). More preferably, the vaccine is administered prior to treatment with the cladribine tablet. Preferred are both before and during treatment with the cladribine tablet, in this connection especially preferred are vaccines comprising recombinant varicella zoster virus glycoprotein E, preferably vaccines with the International Nonpatent Name (INN) or the generic name "shingles vaccine" or "shingles vaccine (recombinant, adjuvanted)", e.g.)>

and/or

b) Wherein said vaccination takes place within 2 to 4 weeks after the first dose of the cladribine tablet (preferably with the first dose of the vaccine) and within 10 to 12 weeks (preferably with the second dose of the vaccine), with the possibility of delaying the administration of the second dose of saddle bags (saddlebags) until 6 months after this first dose of the vaccine.

or (b)

b) Wherein the vaccination takes place within 2 to 4 weeks after the first dose of the cladribine tablet (preferably with the first dose of the vaccine) and within 10 to 12 weeks (preferably with the second dose of the vaccine), with the possibility of delaying the administration of the second dose of saddle bag up to 6 months after this first dose of the vaccine;

or (b)

c) Wherein the vaccination takes place within 12 to 14 weeks after the first dose of the cladribine tablet (preferably with the first dose of the vaccine) and within 20 to 22 weeks (preferably with the second dose of the vaccine), with the possibility of delaying the administration of the second dose of saddle bag up to 6 months after this first dose of the vaccine;

preferably, said treatment of a patient with said cladribine tablet is treatment of an autoimmune disorder as described herein, and in particular treatment of Multiple Sclerosis (MS), preferably Relapsing MS (RMS), more preferably Relapsing Remitting MS (RRMS) and/or Secondary Progressive MS (SPMS). Preferred in this respect are vaccines comprising attenuated live varicella zoster virus, e.g (live herpes zoster vaccine). More preferably, the vaccine is administered prior to treatment with the cladribine tablet. Preferred are both before and during treatment with the cladribine tablet, in this connection especially preferred are vaccines comprising recombinant varicella zoster virus glycoprotein E, preferably vaccines with the International Nonpatent Name (INN) or the generic name "shingles vaccine" or "shingles vaccine (recombinant, adjuvanted)", e.g.)>

and/or

b) Wherein said vaccination occurs at any time during said treatment of the patient with said cladribine tablet, preferably at any time during said treatment of the patient with said cladribine as described herein, except for the first 3 months after administration of the first dose of said cladribine tablet, preferably except for the first 3 months after administration of the first dose of said cladribine tablet.

Therefore, it is preferable that

[85] A method for treating Multiple Sclerosis (MS), preferably as described above and/or below, in a patient in need thereof, the method comprising

a) With cladribine tabletsTreating said patient, preferably as described above and/or below, and in particular as +.>Described in USPI or EU SmPC, and

b) Non-live vaccine for varicella zoster The patient is vaccinated, wherein the patient is vaccinated with the vaccine once (first dose) within weeks 2 to 4 and then with the vaccine (second dose) within weeks 10 to 12, counted from the day the patient receives the first dose of the cladribine tablet, preferably from the day the patient receives the first dose of the cladribine tablet in each treatment period of about 1 year, each treatment year or (once a year) course, with the possibility of delaying the administration of the second dose of the vaccine until 6 months after the administration of the first dose of the vaccine.

[85b] Also preferred is a method for treating Multiple Sclerosis (MS) in a patient in need thereof, preferably as described above and/or below, the method comprising

b) Non-live vaccine for varicella zosterVaccinating the patient, wherein the patient is vaccinated with the vaccine once within weeks 12 to 14 (first dose) and then with the vaccine (second dose) within weeks 20 to 22, counted from the day the patient receives the first dose of the cladribine tablet, preferably from the patient at about Counting from the day of receiving the first dose of the cladribine tablet during each treatment period of 1 year, each treatment year or (once per year) has the possibility of delaying the administration of the second dose of the vaccine until 6 months after the administration of the first dose of the vaccine.

[86] A method for treating Multiple Sclerosis (MS), preferably as described above and/or below, in a patient in need thereof, the method comprising

b) Non-live vaccine for varicella zosterThe patient is vaccinated, wherein the patient is vaccinated with the vaccine once within weeks 2 to 4 (first dose) and then with the vaccine (second dose) within weeks 10 to 12, counted from the day the patient receives the first dose of the cladribine tablet, preferably from the day the patient receives the first dose of the cladribine tablet in each treatment period of about 1 year, each treatment year or (yearly) course, with the possibility of delaying the administration of the second dose of the vaccine until 6 months after the administration of the first dose of the vaccine.

[86b] A method for treating Multiple Sclerosis (MS), preferably as described above and/or below, in a patient in need thereof, the method comprising

b) Non-live vaccine for varicella zosterThe patient is vaccinated, wherein the patient is vaccinated with the vaccine once within weeks 12 to 14 (first dose) and then with the vaccine (second dose) within weeks 20 to 22, counted from the day the patient receives the first dose of the cladribine tablet, preferably from the day the patient receives the first dose of the cladribine tablet in each treatment period of about 1 year, each treatment year or (yearly) course, with the possibility of delaying the administration of the second dose of the vaccine until 6 months after the administration of the first dose of the vaccine.

[87] A method for treating Multiple Sclerosis (MS), preferably as described above and/or below, in a patient in need thereof, the method comprising

a) With cladribine tabletsTreating said patient, preferably as described above and/or below, and in particular as +.>Described in USPI or EU SmPC, and +.>

b) Non-live vaccine for varicella zosterVaccinating said patient, wherein said patient is vaccinated with said vaccine once within month 1 (first dose), then within months 3 to 8 and preferably 3 to 6The number of (second dose) is counted from the day the patient receives the first dose of the cladribine tablet, preferably from the day the patient receives the first dose of the cladribine tablet during each treatment period of about 1 year, each treatment year or course (once per year), and wherein the first dose of the vaccine and the second dose of the vaccine are preferably administered 1 to 7 months apart, more preferably 2 to 6 months apart, and especially 2 to 3 months or 3 to 6 months apart.

[88] A method for treating Multiple Sclerosis (MS), preferably as described above and/or below, in a patient in need thereof, the method comprising

a) With cladribine tablets Treating said patient, preferably as described above and/or below, and in particular as +.>Described in USPI or EU SmPC, and

b) Non-live vaccine for varicella zosterThe patient is vaccinated, wherein the patient is vaccinated with the vaccine twice, preferably by administering a first dose and a second dose that are 2 to 6 months apart, and preferably about two months or about three months apart, wherein the first dose of the vaccine is administered within 4 to 10 months, and especially 5 to 8 months, counted from the day the patient receives the first dose of the cladribine tablet, preferably from the day the patient receives the first dose of the cladribine tablet in each treatment period of about 1 year, each treatment year or (yearly) course of treatment.

[89] A method for treating Multiple Sclerosis (MS) in a patient in need thereof, preferably as described above and/or below, and in particular as described in section [85], wherein the patient is antibody negative for varicella zoster virus, preferably before vaccination with the vaccine of the varicella zoster non-live vaccine and/or before receiving the first dose of the cladribine tablet.

[90] A method for treating Multiple Sclerosis (MS), preferably as described above and/or below, in a patient in need thereof, the method comprising

b) The patient is vaccinated with at least one vaccine, wherein the at least one vaccination occurs during months 3 to 8 and especially during months 3 to 6, the months being counted from the day the patient receives the first dose of the cladribine tablet, preferably from the day the patient receives the first dose of the cladribine tablet in each treatment period of about 1 year, each treatment year or (yearly) course.

[91] A method for treating Multiple Sclerosis (MS), preferably as described above and/or below, in a patient in need thereof, the method comprising

b) Vaccinating said patient at least once, preferably at least twice and especially twice with a vaccine,

b1 Wherein a first vaccination occurs 1 or 2 weeks before or 1 or 2 weeks after the day of the patient receiving the first dose of the cladribine tablet, and optionally wherein at least one subsequent vaccination occurs 2 to 4 weeks or 3 to 10 weeks after the first vaccination occurs.

[92] A method for treating Multiple Sclerosis (MS), preferably as described above and/or below, in a patient in need thereof, the method comprising

b1 Wherein the first vaccination occurs 1 or 2 weeks before the day of the patient receiving the first dose of the cladribine tablet, or 1 to 4 weeks, preferably 2 to 4 weeks, and especially 1 or 2 weeks, 2 or 3 weeks or 3 or 4 weeks after the day of the patient receiving the first dose of the cladribine tablet, and optionally wherein at least one subsequent vaccination occurs 2 to 8 months or 2 to 6 months after the first vaccination.

[93] A method for treating Multiple Sclerosis (MS), preferably as described above and/or below, in a patient in need thereof, the method comprising

a) With cladribine tabletsTreating said patient, preferably as described above and/or below, and in particular as/>Described in USPI or EU SmPC, and

b1 Wherein the first vaccination occurs 1 or 2 weeks before the day of the patient receiving the first dose of the cladribine tablet, or 1 to 4 weeks, preferably 2 to 4 weeks, and especially 1 or 2 weeks, 2 or 3 weeks or 3 or 4 weeks after the day of the patient receiving the first dose of the cladribine tablet, and optionally

Wherein at least one subsequent vaccination occurs within months 2 to 12, preferably 2 to 10 and especially 3 to 9, the months being counted from the day the patient receives the first dose of the cladribine tablet, preferably from the day the patient receives the first dose of the cladribine tablet in each treatment period of about 1 year, each treatment year or (yearly) course.

[94] A method for treating Multiple Sclerosis (MS), preferably as described above and/or below, and in particular according to one or more of paragraphs [90] to [93], in a patient in need thereof, wherein the vaccine is selected from the group consisting of

a) Selected from: (anti) varicella zoster virus vaccine, (anti) zoster virus vaccine, live attenuated (anti) varicella zoster virus vaccine, inactivated and/or recombinant (anti) varicella zoster virus vaccine, and inactivated and/or recombinant (anti) varicella zoster virus vaccine;

b) Selected from: mRNA-based (anti) SARS-CoV-2/COVID-19 virus vaccine, vector-based (anti) SARS-CoV-2/COVID-19 virus vaccine, adenovirus/vector-based (anti) SARS-CoV-2/COVID-19 virus vaccine, virus-like particle (VLP) -based (anti) SARS-CoV-2/COVID-19 virus vaccine, DNA-based (anti) SARS-CoV-2/COVID-19 virus vaccine,

protein-based (anti) SARS-CoV-2/COVID-19 virus vaccine,

inactivated virus-based (anti) SARS-CoV-2/COVID-19 virus vaccine and killed virus-based (anti) SARS-CoV-2/COVID-19 virus vaccine,

and/or

c) Consists of a (anti) influenza virus vaccine selected from the group consisting of: monovalent (anti) influenza virus vaccines, bivalent (anti) influenza virus vaccines, trivalent (anti) influenza virus vaccines, tetravalent (anti) influenza virus vaccines, and multivalent (anti) influenza virus vaccines.

[95] A method for treating Multiple Sclerosis (MS), preferably as described above and/or below, in a patient in need thereof, the method comprising

b) Vaccinating said patient at least once, preferably at least twice and especially twice with a vaccine, wherein said vaccine is a (anti) SARS-CoV-2/COVID-19 viral vaccine, preferably a (anti) SARS-CoV-2/COVID-19 viral vaccine as described above and/or below and especially as described in section [94],

b1 Wherein a first vaccination occurs 1 or 2 weeks before the day of the patient receiving the first dose of the cladribine tablet, or 1 to 4 weeks, preferably 2 to 4 weeks, and especially 1 or 2 weeks, 2 or 3 weeks or 3 or 4 weeks after the day of the patient receiving the first dose of the cladribine tablet, and optionally a second vaccination occurs 2 to 6 weeks, preferably 3 to 5 weeks, and especially 3 to 4 weeks after the first vaccination, optionally followed by one or more subsequent vaccinations after at least 3 weeks, at least 6 weeks or at least 12 weeks;

b2 Wherein a first vaccination occurs 1 or 2 weeks, 2 or 3 weeks or 3 or 4 weeks after the day of receiving the first dose of cladribine tablet by the patient, preferably the day of receiving the first dose of cladribine tablet by the patient in each treatment period of about 1 year, each treatment year or course (once per year), and optionally a second vaccination occurs 2 to 6 weeks, preferably 3 to 5 weeks and especially 3 to 4 weeks after the first vaccination, optionally followed by one or more subsequent vaccinations after at least 3 weeks, at least 6 weeks or at least 12 weeks;

and/or

b3 Wherein the first vaccination occurs 3 to 11 months, preferably 4 to 10 months and especially 3 to 6 or 4 to 8 months after the day on which the patient receives the first dose of the cladribine tablet, preferably the day on which the patient receives the first dose of the cladribine tablet in each treatment period of about 1 year, each treatment year or (once per year) course of treatment,

and optionally a second vaccination occurs 2 to 6 weeks, preferably 3 to 5 weeks and especially 3 to 4 weeks after said first vaccination, optionally followed by one or more subsequent vaccinations after at least 3 weeks, at least 6 weeks or at least 12 weeks.

[96] A method for treating Multiple Sclerosis (MS), preferably as described above and/or below, in a patient in need thereof, the method comprising

b) Vaccinating said patient at least once, preferably once or twice, with a vaccine, wherein said vaccine is an (anti) influenza virus vaccine, preferably an (anti) influenza virus vaccine as described above and/or below and in particular as described in section [94],

b1 Wherein a first vaccination occurs 1 or 2 weeks before the day of the patient receiving the first dose of the cladribine tablet, or 1 to 4 weeks, preferably 2 to 4 weeks, and especially 1 or 2 weeks, 2 or 3 weeks or 3 or 4 weeks after the day of the patient receiving the first dose of the cladribine tablet, and optionally a second vaccination occurs 1 to 6 weeks, preferably 2 to 5 weeks, and especially 1-2 or 3-4 weeks after the first vaccination, optionally followed by one or more subsequent vaccinations after at least 3 weeks, at least 6 weeks or at least 12 weeks;

b2 Wherein a first vaccination occurs 1 to 5 weeks, preferably 1 to 4 weeks and especially 2-3 or 3-4 weeks after the day of the patient receiving the first dose of the cladribine tablet, and optionally a second vaccination occurs 1 to 6 weeks, preferably 2 to 5 weeks and especially 1-2 or 3-4 weeks after the first vaccination, optionally followed by one or more subsequent vaccinations after at least 3 weeks, at least 6 weeks or at least 12 weeks;

And/or

b3 Wherein a first vaccination takes place 3 to 11 months, preferably 4 to 10 months and especially 3 to 6 or 4 to 8 months after the day of the patient receiving the first dose of cladribine tablet, and optionally a second vaccination takes place 2 to 6 weeks, preferably 3 to 5 weeks and especially 3 to 4 weeks after the first vaccination, optionally followed by one or more subsequent vaccinations after at least 3 weeks, at least 6 weeks or at least 12 weeks.

Preferably, the day on which the patient receives the first dose of the cladribine tablet means the day on which the patient receives the first dose of the cladribine tablet in each treatment period of about 1 year, each treatment year, or a course of treatment (once a year).

[97] A method for treating Multiple Sclerosis (MS) in a patient in need thereof, preferably as described above and/or below, and in particular according to one or more of paragraphs [84] to [96], wherein the day on which the patient receives the first dose of the cladribine tablet is

a) The first day of the first treatment year (treatment 1 st year or first course) with respect to cladribine treatment, preferably as described above and/or below, and in particular as described above Cladribine treatment as described in USPI or EU SmPC,

and/or

b) For the first day of the second treatment year (treatment year 2 or second course) of cladribine treatment, preferably cladribine treatment as described in one or more of the preceding claims.

[98] A method for treating Multiple Sclerosis (MS) in a patient in need thereof, preferably as described above and/or below, and in particular according to one or more of sections [85] to [97], wherein in the above method all recommendations and timelines given in relation to the first course of treatment, the first year of treatment and/or the year of treatment for vaccinating the patient and/or using said vaccine are preferably also applicable to the second course of treatment, the second year of treatment and/or the year of treatment, respectively, and if applicable to any subsequent course of treatment or year of treatment.

[99] A method for treating Multiple Sclerosis (MS) in a patient in need thereof, preferably as described above and/or below, and in particular according to one or more of sections [85] to [98], wherein each of said 2 once-a-year courses, preferably said first course and/or said second course, has a duration of about 1 year, preferably about 12 months, more preferably 46 to 54 weeks, more preferably 48-53 weeks and in particular about 48 or about 52 weeks, preferably independently selected for each course.

[100] A method for treating Multiple Sclerosis (MS), preferably as described above and/or below, and in particular according to one or more of paragraphs [85] to [99], in a patient in need thereof, wherein

i) The autoimmune disorder is selected from the group consisting of Multiple Sclerosis (MS), rheumatoid Arthritis (RA), systemic Lupus Erythematosus (SLE), neuromyelitis optica (NMOSD) and Myasthenia Gravis (MG), preferably Multiple Sclerosis (MS), neuromyelitis optica (NMOSD) and Myasthenia Gravis (MG), and is preferably Multiple Sclerosis (MS), more preferably multiple sclerosis selected from the group consisting of Relapsing Multiple Sclerosis (RMS), relapsing Remitting Multiple Sclerosis (RRMS), secondary Progressive Multiple Sclerosis (SPMS) and Primary Progressive Multiple Sclerosis (PPMS),

ii) the subject or patient has High Disease Activity (HDA), and/or

iii) Wherein the subject or patient is over 30 years old, over 40 years old, over 50 years old, over 60 years old or over 70 years old, preferably between 30 and 40 years old.

Preferably, the term "high disease activity" or the abbreviation "HDA" as used herein is known and understood in the art. However, the term "high disease activity" or abbreviated "HDA" as used in the context of the present invention preferably defines a subject, preferably a human subject, more preferably a patient, suffering from an autoimmune disorder as defined herein, and preferably suffering from Multiple Sclerosis (MS) as defined herein, and in particular Recurrent MS (RMS) of Recurrent Remitting MS (RRMS), and suffering from a higher than average disease load or burden. Suitable definitions have been developed as to how "HDA" can be characterized, preferably for use in relation to cladribine, more preferably cladribine tablets, and in particular In a similar manner as this is done for other therapeutic agents used in the field of autoimmune disorders, such as fingolimod and natalizumab, which are preferably used as a reference, in the tag description of the highly active disease form given above.

However, for specific reasons, it is not possible to reliably apply the exact definition for HAD (high disease activity).

For this reason, we consult the national institutes of health (National Health Agencies), review other recently approved documents for DMD for MS (european public assessment report (European Public Assessment Reports) [ EPAR ]), and solicit opinion of MS clinical specialists, and develop 3 additional HDA definitions:

HDA1：

o (a) the subject had at least 1 relapse in the previous year when on DMD therapy, and at least 1 t1gd+ lesions or 9T 2 lesions, or

o (b) subjects had 2 or more relapses in the previous year (no prior use of DMD or duration of prior DMD therapy less than 1 year at any time in the subject's history) and at least 1 t1gd+ lesions.

HDA2：

o subjects had 2 or more relapses in the previous year (regardless of previous treatment status).

HDA3：

o subjects had 2 or more relapses in the previous year (regardless of previous treatment status), and at least: 1 t1gd+ lesion or 9T 2 lesions.

HDA4：

o (b) subjects had 2 or more relapses in the previous year (regardless of previous treatment status).

In summary, the efficacy of cladribine 3.5mg/kg in subjects with HDA2, HDA4 and HDA4 largely supported the efficacy seen in the overall population (note the absence of HDA 1).

HDA1 is still less effective in selecting patients with high disease activity.

Note that HDA4 is indicated in the EMA tag.

These findings are further enhanced by the fact that: approximately 19,000 patients with recurrent MS have been treated with cladribine tablets. Wherein 46 diagnosed or suspected covd-19 patients are present in the secure database. Patient ages of 35 patients were available, ranging from 22-67 years of age. There were 26 females, 12 males and 8 patients with unreported gender. If the confirmed diagnostic test reports positive, the case is defined as diagnosed. If no validation test is performed or reported, the case is described as suspected. Because of the well-documented problem of false negative rates with respect to Polymerase Chain Reaction (PCR) testing techniques of COVID-19, (Woloshin et al 2020), suspected cases meeting the world health organization diagnostic criteria are included in our analysis even if a negative PCR test is reported. Cases are designated as severe if they meet criteria for hospitalization, are considered life threatening or medically significant. Consistent with usual drug alertness practices, the results are classified as recovered, in-recovery, not recovered, fatal or unreported.

Of the 46 cases in total, 18 cases were diagnosed. Confirmation in 3 cases included a report of positive immunoglobulin G detection after the onset of the covd-19 symptoms. The 4 of the diagnosed cases were classified as severe (since 3 cases required hospitalization, while doctors reported a classification of "medically significant" 1 case). Of the suspected covd-19 cases, 2 were classified as severe (1 was hospitalized and 1 was classified as "medically significant" by the physician).

Considering that the patient was able to test positive confirmation with covd-19 via IgG, it was suggested that the patient could be using cladribine tabletsSufficient IgG responses were generated during the immune-lowering phase of the treatment.

Definition of the definition

The step of "identifying a patient at risk of acquiring an infection" according to the present invention is a routine step for a person skilled in the art, preferably including but not limited to a skilled physician, preferably a skilled physician in the fields of general medicine, immunology and/or autoimmune disorders. It is particularly preferred that the "identification of the patient at risk of acquiring an infection" is at the discretion of the attending physician who may employ standard laboratory procedures, including for example determining antibody and/or Ig titers.

The term "mg/kg" as used herein preferably means "milligrams/kilogram body weight".

More preferably, the term "mg/kg" as used herein, and more preferably as used in connection with a fixed dose wherein cladribine is administered orally to a patient, preferably means "milligrams" of cladribine "administered per kilogram of body weight (orally) of said patient.

The "total dose" or "cumulative dose" preferably refers to the total dose of cladribine administered during the treatment, i.e. the dose reached at the end of the treatment calculated by summing the daily doses. For example, the total dose of cladribine corresponding to treatment with 0.7mg/kg cladribine per day during 5 days is 3.5mg/kg or the total dose of cladribine corresponding to treatment with 0.35mg/kg cladribine per day during 5 days is 1.7mg/kg.

"total effective dose" or "cumulative effective dose" preferably refers to the bioavailable dose of cladribine after a given administration period, i.e., the bioavailable dose reached at the end of treatment, calculated by summing the daily doses minus the bioavailability factor. For example, the total effective dose of cladribine corresponding to treatment of 0.7mg/kg of cladribine per day during 5 days in which the bioavailability of cladribine is about 40% is 1.4mg/kg, or the total effective dose of cladribine corresponding to treatment of 0.35mg/kg of cladribine per day during 5 days in which the bioavailability of cladribine is about 40% is 0.7mg/kg.

Generally, the bioavailability of cladribine or a formulation of cladribine used in the context of the present invention is from about 20% to about 90%, preferably from about 25% to about 80%, more preferably from about 30% to about 70%, even more preferably from about 35% to about 60%, and especially from about 40% to about 50%, such as about 35%, about 40%, about 45%, about 50% or about 55%. Particularly preferably, the bioavailability from the cladribine tablet is 45% +/-25%, more preferably 45% +/-20%, even more preferably 45% +/-15%, even more preferably 45% +/-10%, and especially 45% +/-5%, preferably based on the total content of cladribine (2-CdA) as active ingredient in the oral formulation preferably used in the method and/or treatment regimen according to the present invention.

The term "bioavailability" as used herein with respect to pharmaceutical dosage forms (including but not limited to tablets) is known and understood in the art. Additionally, methods and/or procedures for reliably determining the bioavailability are known, understood, and described in the art. Those known methods and/or procedures generally meet the requirements of good manufacturing practice (Good Manufacturing Practice) (GMP) and/or the requirements of good clinical practice (Good Clinical Practice) (GCP) to the extent such as by health authorities such as the FDA and/or EMA, among other requirements.

However, bioavailability may preferably be assessed using the following method:

bioavailability is conventionally defined as the fraction of dose reaching the systemic circulation, which has been evaluated after oral administration of a single 10mg tablet of Mavenclad and 3mg cladribine (leutatin 1 mg/mL) administered as a 1 hour IV infusion in randomized, two-phase, two-sequence crossover studies in multiple sclerosis patients, where cladribine plasma concentrations were measured using a validated LC/MS method. Bioavailability has been estimated by means of nonlinear mixed effect modeling (software nomem version VI [ higher version also applicable ]) which was developed by incorporating it in the form of a log transformation (to constrain it in the range of 0-1) as a parameter into a comprehensive pharmacokinetic model that would be developed by combining several studies using Mavenclad under various conditions (e.g. feeding/fasted) and different durations (see RM Savic 2017 (DOI 10.1007/s 40262-017-0516-6)). The modeling takes into account several covariates, such as food intake associated with drug administration. In addition to the parameter estimators, their accuracy and inter-subject variance are also included in the drug statistical model and calculated. After sequential model development, improvement and validation, cladribine bioavailability after administration of a Mavenclad 10mg tablet has been estimated to be 45.6%, preferably about 45.6%, more preferably with a precision of 7.03% and/or a variance of 22.3% (on the logistic scale).

However, other methods and methodologies may also be successfully applied, for example as described in the following: "Population Pharmacokinetics of Cladribine in Patients with Multiple Sclerosis", radojka m.savic, ana m.novakovic, marianne Ekblom, alain Munafo & Mats o.karlsson; clinical Pharmacokinetics, volume 56, pages 1245-1253 (2017), and/or "The Clinical Pharmacology of Cladribine Tablets for the Treatment of Relapsing Multiple Sclerosis", robert Hermann, mats O.Karlsson, ana M.Novakovic, nadia Terranova, markus Fluck & Alain Munafo; clinical Pharmacokinetics, volume 58, pages 283-297 (2019), which is incorporated herein by reference in its entirety.

More specifically, e.g. according to cladribine tabletsUse of approved tags and considering the bioavailability of cladribine tablet about 45% by administration of cladribine tablet +.>The recommended cumulative effective dose preferably achieved in the patient is preferably about 1.58mg/kg body weight over 2 years (e.g., by administering cladribine tablets in an amount of about 3.5mg/kg body weight based on about 45% bioavailability of the administered tablets as previously outlined) Achieved), preferably as 1 course of administration of 0.79mg/kg body weight per year ((e.g. about 45% bioavailability based on the administered tablet as outlined previously, by administering cladribine tablet +_ in an amount of about 1.75mg/kg body weight)>Implemented by. According to approved marksEach treatment session preferably consists of 2 weeks of treatment, one preferably at the beginning of the first month of each treatment year, and one preferably at the beginning of the second month. Each treatment week preferably consists of 4 or 5 days during which the patient preferably receives 10mg or 20mg (one or two tablets), preferably as a single daily dose, preferably depending on body weight.

The term "U.S. prescription information (United States Prescribing Information)" abbreviated as "USPI" is known and understood in the art. Preferably, the USPI sets forth usage agreed upon by the health authorities, preferably by the federal drug administration (US Federal Drug Agency), and more particularly preferably by the federal drug administration, which is approved for use in the marketplace. It provides information about usage to healthcare professionals and is an inherent part of the new drug or drug marketing license (Marketing Authorisation) (MA) application in the united states. Preferably, the equivalent of USPI in the european union is the product property profile (SmPC).

Reference to USPI in the context of the present invention preferably refers to the trade name Or USPI of oral cladribine or cladribine tablet marketed by Mavenclad alone. Preferably, the USPI mentioned in connection with cladribine tablets in the context of the present invention means that cladribine tablets effective up to 2020 are mentioned +.Is provided in (C). Preferably, cladribine tablets/-are mentioned>Including all of the content of the USPI, except as to vaccination and/or vaccination against infection, preferably vaccination, vaccination and/or infection as described herein in the context of the present invention. Preferably, the present invention provides a method of treatment, whichThe content of the USPI with respect to said immunization and/or vaccination against infection is preferably advantageously improved. Particularly preferably, reference to USPI includes treatment regimens or schedules and/or dosimetry given in the USPI.

The term "European product characteristics profile" abbreviated as "EU SmPC" or "SmPC" is known and understood in the art. Preferably, it refers to a file describing the nature of the drug and the official approved conditions of use. The product profile forms the basis of information about how the healthcare professional can safely and effectively use the drug. More specifically, smPC preferably sets forth usage agreed upon by health authorities, preferably European health authorities (or authorities), and more specifically, european drug administration (EMA) marketing approved drug usage. It provides information about usage to healthcare professionals and is an inherent part of new drugs or drug marketing licensing (MA) applications within the european union. Preferably, the equivalent of SmPC in the United states of America is "United states prescription information" or abbreviated as "USPI".

Mention of EU SmPC or preferably SmPC in the context of the present invention preferably refers to the use of the trade nameOr EU SmPC or preferably SmPC, of oral cladribine or cladribine tablets marketed by Mavenclad alone. Preferably, in the context of the present invention reference to EU or preferably SmPC in relation to cladribine tablets means reference to cladribine tablets/-a valid as of 2020>Or preferably SmPC. Preferably, cladribine tablets/-are mentioned>The EU or preferably SmPC of (a) includes all of the contents of the EU or preferably SmPC except as regards vaccination and/or vaccination against infection, preferably in the context of the present invention vaccination, vaccination and/or infection as described herein. Preferably, the present inventionIt is clear that a method of treatment is provided which preferably advantageously improves the content of EU SmPC or preferably SmPC in relation to said vaccination and/or vaccination against infection. Particularly preferably, reference to EU SmPC or preferably SmPC includes the treatment regimen or schedule and/or dosing given in said EU SmPC or preferably SmPC.

The terms "vaccination" and "immunization" are preferably used interchangeably in the context of the present invention, if not explicitly stated otherwise.

"one week" preferably refers to a period of time of either 5, about 6 or about 7 days.

"one month" preferably refers to or a period of about 28, about 29, about 30, or about 31 days.

The term "treatment" is known and understood in the art. In particular, the term may also preferably mean or include sequential succession of "induction therapy" and at least "maintenance therapy". In this particular context, a treatment may comprise "induction treatment" as well as about one or about two or about three maintenance treatments.

Typically, the treatment according to the invention is about 2 years (about 24 months) or about 3 years (about 36 months) or about 4 years (about 48 months), preferably about two years.

Preferably, the treatment according to the invention is about two years (about 24 months) or about three years (about 36 months) or about four years (about 48 months), preferably about two years (about 24 months). If the treatment according to the invention is about two years (about 24 months), it preferably comprises two treatment periods or courses. If the treatment according to the invention is about three years (about 36 months) or about four years (about 48 months), it preferably comprises three treatment periods/courses or four treatment periods/courses.

Preferably, the treatment period or course according to the invention comprises one month, two months or three months, wherein cladribine or preferably a cladribine tablet is administered to a subject, preferably a subject in need thereof. Preferably, the treatment period or course according to the invention comprises two months, wherein cladribine, preferably a cladribine tablet, is administered to the subject. Particularly preferably, each course of treatment consists of two weeks of treatment, one preferably at the beginning of the first month of the course of treatment and one preferably at the beginning of the second month of the course of treatment. Preferably, the same applies to the treatment period, since these terms are preferably interchangeable in the context of the present invention.

Preferably, each of said weeks of treatment comprises four or five days during which the subject receives cladribine, preferably cladribine tablet, preferably in a daily dose of 10 or 20mg, depending on the weight of the patient, so as to achieve administration of cladribine in mg/kg body weight as described herein.

The "cladribine free period" is preferably a period in which cladribine is not administered to a subject or patient. During the cladribine-free period, the patient may not have any administration or be administered with a placebo pill or another drug. The cladribine-free period preferably lasts at least 9 months or at least 10 months, and preferably at most about 10 months, at most 12 months, at most 14 months, at most 16 months, or at most about 18 months. For example, the cladribine-free period lasts for about 9 to about 12 months, about 10 months to about 14 months, or about 10 months to about 18 months, such as about 9 months, about 10 months, about 11 months, about 12 months, about 14 months, about 16 months, or about 18 months, but is typically about 10 months, about 14 months, or about 18 months. Particularly preferably, the cladribine-free period lasts for about 10 months. This is particularly preferred if a further treatment period follows. If the cladribine has no treatment period following the cladribine-free period, it preferably may in principle have any length or duration.

In the context of the present invention, beneficial effects can be seen to include, but are not limited to, a reduction, decrease or curtailment of pathological progression after onset of disease, after one or more "treatments", after one or more "treatment periods" or "courses", after one or more "treatment years", or during one or more cladribine-free periods.

"daily dose" preferably refers to the total dose of cladribine orally administered to a patient at the time of daily administration. Daily doses may be achieved by single or several administrations per day, for example once, twice or three times per day.

Preferably, the dose administered to an individual as a single dose or multiple doses will vary depending on a variety of factors including pharmacokinetic properties, patient condition and characteristics (sex, age, weight, health, size), symptom severity, concurrent therapy, frequency of treatment, and desired effect.

Patients suffering from MS may be defined as suffering from clinically or laboratory-defined MS, for example, according to the Schumacher or Poser criteria (Schumacher et al 1965,Ann.NY Acad.Sci.1965;122:552-568; poser et al 1983, ann. Neurol.13 (3): 227-31).

"recurrence" preferably involves a neurological problem that occurs over a short period of time, typically days, but sometimes as short as hours or even minutes. These episodes most often involve motor, sensory, visual or coordination problems early in the disease. Thereafter, bladder, intestinal, sexual and cognitive problems may be revealed. Sometimes attacks occur within weeks. Typical MS relapse involves a period of exacerbation with progression of neurological deficit followed by a plateau in which the patient is not improved but also is free of any exacerbations, followed by a recovery period. Recovery typically begins within a few weeks.

The "efficacy" of a treatment according to the invention may preferably be measured on the basis of a change in course of disease in response to a use according to the invention. For example, efficacy of MS treatment can be measured by the frequency of recurrence of RRMS and the presence or absence of new lesions in the CNS, as detected using methods such as MRI techniques (Miller et al, 1996, neurology,47 (Suppl 4): S217; evans et al, 1997, ann. Neurology,41: 125-132).

Preferably, observations of reduction and/or depression of MRI T1 gadolinium-enhanced lesions (believed to represent areas of active inflammation) give major efficacy variables.

The secondary efficacy variables preferably include MRI T1 enhanced brain lesion volume, MRI T1 enhanced lesion number, MRI T2 lesion volume (believed to represent total disease burden, i.e., demyelination, gliosis, inflammation, and axonal loss), MRI T1 enhanced low signal lesion volume (believed to represent primarily demyelination and axonal loss), time of progression of MS, frequency and severity of exacerbation, and time of exacerbation, extended disability status scale (Expanded Disability Status Scale) score and staripple neurological rating scale (Scripps Neurologic Rating Scale) (SNRS) score (cope et al, 1984, neurology,34, 1368-1372). Methods for early and accurate diagnosis of multiple sclerosis and tracking disease progression are described in Mattson,2002,Expert Rev.Neurotherapeutics,319-328.

The degree of disability in MS patients can be measured, for example, by Kurtzke Expanded Disability Status Scale (EDSS) score (Kurtzke, 1983, neurology,33, 1444-1452). Typically, a decrease in EDSS score corresponds to an improvement in disease, and conversely, an increase in EDSS score corresponds to a worsening of disease.

Cladribine (2-CdA)

2-CdA and its pharmacologically acceptable salts can be used in the practice of the invention.

Cladribine may be formulated into any pharmaceutical formulation suitable for oral administration. Representative oral formulations of 2-CdA are described in (WO 96/19230; WO 96/19229;US 6,194,395;US 5,506,214;WO 2004/087100; WO 2004/087101), the contents of which are incorporated herein by reference. Examples of ingredients for oral formulations are given below.

Methods for preparing 2-CdA are well known in the art. For example, the preparation of 2-CdA is described in (EP 173,059; WO 04/028462; WO 04/028462;US 5,208,327;WO 00/64918) and Robins et al, J.Am.chem.Soc.,1984, 106:6379. Alternatively, pharmaceutical formulations of 2-CdA are available from Bedford Laboratories, bedford, ohio.

Oral administration of cladribine may be in the form of a capsule, tablet, oral suspension or syrup. The tablet or capsule may contain about 3 to 500mg of cladribine. Preferably, they may contain from about 3 to about 10mg of cladribine, more preferably about 3, about 5 or about 10mg of cladribine. The capsule may be a gelatin capsule and may contain a small amount, for example less than 5% by weight of magnesium stearate or other excipients, in addition to the above indicated amounts of cladribine. The tablets may contain the aforementioned amounts of the compound and a binder, which may be gelatin solution, aqueous starch paste solution, aqueous polyethylene polyvinyl alcohol solution, etc., with usual sugar coating.

Preferably, the term "cladribine", as used in the context of the present invention, preferably means "oral cladribine", i.e. the active ingredient cladribine to be administered orally according to the present invention, if not otherwise explicitly defined. Preferably, the cladribine to be orally administered according to the present invention is administered in the form of an oral dosage form, e.g. a capsule filled with a cladribine solution, a capsule filled with a cladribine powder, a tablet containing cladribine and especially a tablet containing a cladribine-cyclodextrin complex, as it isIs marketed under the name of (c).

Composition and method for producing the same

The composition may further comprise one or more pharmaceutically acceptable additional ingredients, such as alum, stabilizers, antimicrobial agents, buffers, colorants, flavors, adjuvants, and the like.

The composition may be in the form of a tablet or lozenge formulated in a conventional manner. For example, tablets and capsules for oral administration may contain conventional excipients including, but not limited to, binding agents, fillers, lubricants, disintegrants, and wetting agents. Binding agents include, but are not limited to, syrup, acacia (accacia), gelatin, sorbitol, tragacanth, starch cement and polyvinylpyrrolidone. Fillers include, but are not limited to, lactose, sugar, microcrystalline cellulose, corn starch, calcium phosphate, and sorbitol. Lubricants include, but are not limited to, magnesium stearate, stearic acid, talc, polyethylene glycol, and silica. Disintegrants include, but are not limited to, potato starch and sodium starch glycolate. Wetting agents include, but are not limited to, sodium lauryl sulfate). The tablets may be coated according to methods well known in the art.

The compositions may also be liquid preparations including, but not limited to, aqueous or oily suspensions, solutions, emulsions, syrups and elixirs. The composition may also be formulated as a dry product for constitution with water or other suitable vehicle before use. Such liquid formulations may contain additives including, but not limited to, suspending agents, emulsifying agents, non-aqueous vehicles, and preservatives. Suspending agents include, but are not limited to, sorbitol syrup, methylcellulose, dextrose/syrup, gelatin, hydroxyethylcellulose, carboxymethylcellulose, aluminum stearate gel, and hydrogenated edible fats. Emulsifying agents include, but are not limited to, lecithin, sorbitan monooleate, and acacia. Non-aqueous vehicles include, but are not limited to, edible oils, almond oil, fractionated coconut oil, oily esters, propylene glycol, and ethyl alcohol. Preservatives include, but are not limited to, methyl or propyl parahydroxybenzoates and sorbic acid.

Particularly preferably, the cladribine or oral cladribine for use according to the present invention is to be administered orally as a tablet comprising 10mg of cladribine in the form of a mixture of cladribine, 2-hydroxypropyl-beta-cyclodextrin and cladribine-2-hydroxypropyl-beta-cyclodextrin complex, wherein the weight ratio of cladribine to 2-hydroxypropyl-beta-cyclodextrin is from about 1:10 to about 1:16, preferably from 1:13 to 1:15

Preferred oral dosage forms in tablet form are described directly below:

preferred compositions for oral use according to the application are tablets containing 10mg of cladribine (2-CdA), containing hydroxypropyl- β -cyclodextrin, preferably as cladribine-cyclodextrin complex, and the amount of excipient given in Table 11 below:

table 11:

* As described in WO 2004/087101, the disclosure of which is incorporated herein by reference in its entirety, cladribine is complexed with 2-hydroxypropyl-beta-cyclodextrin and lyophilized in a separate process.

However, it is also preferred according to the application to use a similar composition, which preferably contains cladribine-cyclodextrin complex and which preferably has the same or very similar bioavailability.

The naming of an active ingredient, active ingredient (API), medicament or international non-patent name (INN) thereof preferably includes all prodrugs, salts and solvates thereof, especially those that are functionally equivalent and/or deemed suitable substitutes from a clinical point of view, if not explicitly defined otherwise.

The terms human, human patient or patient are preferably used herein as interchangeable or synonymous if not otherwise explicitly defined.

The terms human (class), human patient or patient (only) are preferably used herein as interchangeable or synonymous if not otherwise explicitly defined.

Particularly preferred according to the present invention is the subject matter as described herein wherein two or more preferred, more preferred and/or particularly preferred embodiments, aspects and/or features of the subject matter are combined into one embodiment, aspect and/or subject matter. Preferably, preferred subject matter or embodiments can be combined with other preferred subject matter or embodiments in accordance with the present invention; more preferred subject matter or embodiments may be combined with other less preferred or even more preferred subject matter or embodiments; particularly preferred subject matter or embodiments can be combined with other preferred or even more preferred subject matter or embodiments alone, and the like.

Preferably in accordance with the terms in the label/marketing permit approved by the health authorities, as herein referred to with respect to cladribine, preferably cladribine tablets, more preferablyThe term "treatment period" as used in the time frame of administration to a subject, preferably a human subject, more preferably a patient and especially a patient in need thereof, may also be interchangeably referred to as a "course of treatment" and/or a "treatment period". Accordingly, the terms "treatment period", "course of treatment" and And/or "treatment cycle" may preferably be used interchangeably in the context of the present invention. The same preferably applies to the terms "treatment period", "course of treatment" and/or "treatment cycle". Preferably, the terms "treatment period", "course of treatment" and/or "treatment period" may also be used in abbreviated form of "period", "procedure" and/or "period", respectively, according to the invention, if not explicitly defined otherwise. However, in accordance with USPI, the term "first period" preferably means "month 1" in "year 1 course of treatment" and/or "year 2 course of treatment"; likewise, the term "second cycle" preferably means "month 2" in "first year course of treatment" and/or "second year course of treatment".

However, in the methods of treatment described herein, wherein administration of cladribine, preferably oral cladribine, and especially administration of a cladribine tablet (e.g., mavenclad) occurs according to or substantially according to a dosimetry as described in the EU SmPC/certified european label, two or more of said cladribine, oral cladribine or cladribine tablet are administered at their beginning for a period of about one year (also referred to as about 12 months, 46-54 weeks, 48-52 weeks, 48 weeks or 52 weeks, etc.), preferably referred to as "treatment years", e.g. "first treatment year", "second treatment year" or "subsequent treatment year". Also in this context, cladribine, oral cladribine or a tablet of cladribine is administered to a patient within each month, preferably each of two months, at the beginning of a "treatment year", preferably referred to as a "course of treatment", e.g. "first course", "second course" or "subsequent course".

In contrast, in the methods of treatment described herein, wherein administration of cladribine, preferably oral cladribine, and particularly of a cladribine tablet (e.g., mavenclad) occurs according to or substantially according to the dosimetry as described in the US PI/approved US label, two or more of said cladribine, oral cladribine or cladribine tablet are administered at the beginning thereof for a period of about one year (also referred to as about 12 months, 46-54 weeks, 48-52 weeks, 48 weeks or 52 weeks, etc.), preferably referred to as a "course of treatment", e.g., a "first course of treatment", "second course of treatment" or "subsequent course of treatment". Also in this context, cladribine, oral cladribine or a tablet of cladribine is administered to a patient for a period of about one month, preferably 2 periods of about one month, at the beginning of a "course of treatment", preferably referred to as "treatment periods", e.g. "first treatment period", "second treatment period" or "subsequent treatment period".

The terms "live attenuated vaccine (attenuated live vaccine (s))", "live attenuated vaccine (live attenuated vaccine (s))" and/or "live attenuated vaccine (live-attenuated vaccine (s))" are preferably used herein as interchangeable or synonymous if not otherwise explicitly defined.

The term "about" as used herein with respect to numbers, ranges and/or amounts preferably means "about (circumca)" and/or "about (appurtenant)". The meaning of these terms is well known in the art and preferably includes a variance, deviation and/or variability of +/-15% and especially +/-10% of the individual numbers, ranges and/or amounts.

In any event, the term "about" as used herein with respect to numbers, ranges and/or amounts preferably means "about (circumca)" and/or "about (appurtenant)". The meaning of these terms is well known in the art and preferably includes a variance, deviation and/or variability of at least +/-5% of the individual numbers, ranges and/or amounts.

Preferably, any range mentioned herein below includes all values and sub-values between the minimum and maximum limits of the range.

Preferably, in the context of the present invention, the terms "(anti) herpes zoster virus" or "(anti) herpes zoster" and "(anti) varicella zoster virus" or "(anti) varicella zoster" are considered as synonyms, respectively.

The terms "disorder" and "disease" as used herein are well known and understood in the art. In the context of the present invention, they are preferably used as synonyms, and are therefore preferably interchangeable, if the context in which they are used does not have other strong implications.

In medical contexts, including but not limited to treatment regimens, dosing schedules, and clinical trial designs, the terms "week"/"one week", "month"/"one month" and/or "year"/"one year" may be used with slight deviations from the definition of the calendar for convenience and/or ease of use by the patient, medical personnel, and/or doctor, as well as reliability and/or repeatability of the results, etc. For example, in the medical setting, a menstrual cycle is often referred to as 28 days, and a year is often referred to as 48 weeks.

Thus, in the context of the present invention, the term "week" or "one week" preferably refers to a period of about 5, about 6 or about 7 days, more preferably about 7 days.

In the medical context, the term "month" or "one month" preferably refers to a period of about 28, about 29, about 30 or about 31 days, more preferably about 28, about 30 or about 31 days.

In the medical context, the term "year" or "one year" preferably refers to a period of about 12 months, or about 48, about 50 or about 52 weeks, more preferably a period of 12 months or about 48 weeks or about 52 weeks.

Regarding the treatment of autoimmune diseases with cladribine, in particular cladribine tablets, thereby reducing the risk of serious infections in patients suffering from autoimmune diseases by means of the improved vaccination options according to the invention, the positive results reported in example 3 of the specific embodiment, in particular cladribine tablets, according to the surprisingly advantageous dosing regimen of the invention, are further confirmed by the positive results of most of the large number of infection cases, in particular of the cases of covd 19 The case appears under treatment and does not show any signs of impairment of the patient's immune system due to cladribine/cladribine tablet treatment in a manner that results in worse or more serious results due to the infection.

The invention is described in more detail below with the aid of examples. The invention may preferably be carried out within the scope of the claims and is not limited to the embodiments presented herein.

Furthermore, the following examples are given to aid the skilled person in a better understanding of the present invention by way of illustration. These examples are not intended to limit the scope of protection afforded by the claims. Features, properties and advantages illustrated for the methods, compounds, compositions and/or uses defined in the examples may be allocated to other methods, compounds, compositions and/or uses not specifically described and/or defined in the examples but falling within the scope of the claims.

The following examples therefore describe the invention in more detail, but do not limit the scope of the invention and the claims thereto.

Drawings

Fig. 1: a data set of suspected or confirmed diagnosis of covd-19 patients treated with MAVENCLAD (by month 29 of 2020).

Fig. 2: evolution of B cell subtypes and immunoglobulins during the first year of cladribine treatment course as tracked in the MAGNIFY-MS phase IV clinical trial.

Fig. 3: evolution of T cell subtypes, immunoglobulins and NK cell subtypes during the first year of cladribine treatment course as tracked in the MAGNIFY-MS phase IV clinical trial.

Fig. 4: patients under treatment with Mavenclad according to the inventionGraphical representation of vaccination schedule

Fig. 5: patients under treatment with Mavenclad according to the inventionGraphical representation of vaccination schedule

Fig. 6: patients under treatment with Mavenclad according to the inventionGraphical representation of vaccination schedule

Fig. 7: blood ALC results for patients spanish 2 and spanish 3 of example 4 summarised

Fig. 8: blood ALC results for patients Canadian 1 and Spain 1 of example 4 summarised

Fig. 9: summary of blood ALC results for patients Finnish 1 and French 1 of example 4

Fig. 10: example 4 summary of blood ALC results for patients in Australia 1 and Finland 2

Fig. 11: example 4 summary of blood ALC results for patients German 1 and British 2

Fig. 12: example 4 summary of blood ALC results for patients British 1 and French 2

Fig. 13: example 4 blood ALC results of patient Canadian VZV and Finnish VZV summarised

Fig. 14: example 4 summary of blood ALC results for patient Australian VZV

Fig. 15: antibody titres and ALC results for 8 Influenza/1 Sringrix treated patients discussed in example 4 are summarized

Fig. 16: typical influenza vaccine composition for general use or to be used in 2018-2021

Fig. 17:timing of covd-19 vaccination in treated MS patients: from last +.>Time to covd-19 vaccination (n=32)

Fig. 18: at the position ofFollow-up after covd-19 vaccination in treated MS patients: covd-19 vaccination follow-up time (n=32)

Fig. 19: COV-2IgG antibody titre after vaccination for high efficacy IMD treatment, violin plot

Fig. 20: post-vaccination COV-2IgG antibody titres for high efficacy IMD treatment, box plot

Fig. 21: igG antibody titer, violin profile following high-potency IMD-treated covd-19 vaccination

Fig. 22: igG antibody titer after high-potency IMD-treated covd-19 vaccination, box plot

Fig. 23: generation of B cell memory responses. Memory B cells are produced in response to T-dependent antigen (1) during a hair-center (GC) reaction (2), parallel to plasma cells. As they leave GC, these B cells do not differentiate into antibody-separating plasma cells, but rather into memory B cells (3) that migrate transiently through the blood (4) toward the extrafollicular region of the spleen and lymph node (5). They persist as resting cells until re-exposure to their specific antigen (6). Upon secondary antigen exposure, memory B cells proliferate and differentiate readily into plasma cells that secrete large amounts of high affinity antibodies (7) that can be detected in serum (8) within days after boosting. Ag: an antigen; BM: bone marrow; FDC: follicular dendritic cells; igG: immunoglobulin G; th: and T is assisted.

Fig. 24: according to the invention in usePatients under treatment (group 1 and group 2)Graphical representation of vaccination schedule, with cladribine tablets according to which they were effective in the year 2020Is compared to the EU SmPC or preferably SmPC vaccination schedule. Abbreviations: ep=endpoint, eoT =end of treatment, smpc=summary of product properties, w=week.

Detailed Description

Example 1

Lymphocyte counts from 12 subjects who were approved within two yearsCladribine tablet for labelTreatment (cladribine tablet>Dosing as 3.5mg/kg body weight is performed within 2 years, as 1 course of 1.75mg/kg per year, each course consisting of 2 weeks of treatment, one at the beginning of the first month of each treatment year and one at the beginning of the second month, each week of treatment consisting of 4 or 5 days, during which the patient receives 10mg or 20mg (one or two tablets) as a single daily dose, depending on body weight, and is preferably vaccinated with a vaccine selected from influenza vaccine or shingles vaccine.

At baseline (i.e. directly at cladribine tabletPrior to initiation of treatment) and at various time points (i.e., month 1, month 2, month 3, month 6, and month 12) blood samples from the subjects were obtained.

Analysis of the blood sample showed the following results:

all samples at baseline were defined as starting point, i.e. 0% difference at baseline. Since we are interested in potential vaccine responses, preferably B and T cell dependent vaccine responses, use of cladribine tabletsWe considered mainly the use of cladribine tablets +.>Effects of treatment and/or vaccination on B-cells, AB and T-cell effector cells. In addition, deviations from baseline (0%) were also obtained at some time points with respect to IgG and IgM levels.

The following results were obtained:

table 12: lymphocyte subpopulations (B cells) and immunoglobulins (IgG and IgM)

/>

Table 13: t-cells (CD 4 and CD 8)

Table 12 shows the B cell subpopulations.

The cd19+ total B cell number decreased with a steep slope at treatment month 1 and reached a minimum during or near the end of treatment month 2, with a decrease in cd19+ B cells to-76% and-90%, respectively. However, at month 3, month 6 and month 12 (which are the first part without cladribine), cd19+ B cells increased to-76%, -57% and-11%, respectively. However, the behavior of certain B cell subtypes is strongly different compared to it. For example, transitional B cells did not drop more than-61% at treatment month 1 and treatment month 2, and were above baseline from month 3. More specifically, at 10 months of cladribine-free period following the first treatment period, transitional B cell levels were +35% at month 3 (i.e., the first month of cladribine-free period), +19% at month 6 (i.e., the fourth month of cladribine-free period), and at month 12 (i.e., the last month of cladribine-free period of 10 months, and thus also the cladribine tablet of treatment of year 2 The last month before the beginning of the treatment period) was +23%. More abrupt and even more rapid is the effect of the first cladribine treatment period on naive B cells, with a decrease of-79% and-92% during the first month of treatment and the second month of treatment, respectively, followed by a rapid increase during the cladribine free period of 10 months, i.e., to-69% (3 months/1 month of cladribine free period), -35% (6 months/4 months of cladribine free period), and +35% (12 months/last month of cladribine free period of 10 months).Although memory B cells that developed into AB-producing plasma cells reached the lowest point of count (-93%) at treatment month 2 and showed a sustained decrease (-89%) in blood compartments up to 12 months, it must be noted that IgG immunoglobulin levels measured at all time points (months 1, 2, 3, 6 and 12) were comparable to baseline. IgM levels only slightly decreased at month 12, but were still within normal range, suggesting that a humoral response and even a recall response may be elicited following cladribine treatment.

Because B cells and antibodies play a key role in early and sustained humoral vaccine responses, our findings support the following evidence: due to the rapid recovery profile of naive and transitional B cells following cladribine treatment, vaccination responses (extrafollicular and germinal center responses) can be elicited at most time points, with the most likely decrease in antibody titers at month 2 being expected. The same applies to the second treatment year, since the total lymphocyte longitudinal profile after cladribine treatment shows a very similar pattern for 2 years, namely treatment 1 and treatment 2 years, preferably as for cladribine tablets The first year of treatment and the year of treatment given in the approval label of (c).

The heart of the induction of vaccine responses is the innate immune cells (less or not affected by cladribine) which provide a danger signal to activate the immune system and drive a successful Germinal Center (GC) response along with T cell helper cells (which are only moderately affected by cladribine at all time points). Surprisingly, the T cell subpopulation is also preferably affected in a very unique way by the treatment period with cladribine. Although also by use of cladribine tabletsBut they showed very different time-dependent behavior compared to B cells, only slightly decreased during the first five months from cladribine treatment, slightly the most around month 6 from treatment initiationLow point, and a slow increase towards the end of the cladribine-free period at month 12. However, since the T cell population preferably does not drop more than-50% to-60%, preferably there is sufficient T cell activity in both treatment 1 and treatment 2, so that activated antigen-specific T helper cells can trigger migration of specific B cells towards follicular Dendritic Cells (DCs), thereby preferably initiating a Germinal Center (GC) response. In the center of development, B cells preferably receive additional signaling from T follicular helper cells (Tfh), undergo extensive clonal proliferation, and shift antibody production from the IgM phenotype toward the IgG, igA, or IgE phenotype. As B cells proliferate in the center of development, igG antibody titers increase up to peak, which is typically reached around 4 weeks after vaccination/immunization.

As a result, cladribine tabletsThe selective effect on the time-dependent level of a specific subtype of the B-cell population and the T-cell population appears to be possible at essentially all times, directly in cladribine tablets->Treatment is started before or directly before the administration of cladribine tablet +.>After the end of the two year treatment schedule of (a) or preferably also within the first 12 months/1 st treatment year (preferably both from the point of view of patient safety), there may be a slight decrease in efficacy or quality of the immune response when vaccinated during the second treatment month, and possibly days before or after the month, preferably days after the second treatment month. However, even in the case of cladribine tablets +.>There may be a slight decrease in the immune response to vaccination, which may also be achieved by determining the antibody titer of interest and/or againVaccination and/or administration of the second dose within a suitable timeframe after the first vaccination, e.g. within 1 to 6 weeks, preferably within 3 to 6 weeks or 1 to 4 weeks, and especially within 2 or 3 weeks after the first vaccination. In general, a minimum interval of 2 or 3 weeks between 2 primary doses is considered sufficient to allow undisturbed development of successive waves of Ag or Ab specific primary responses. Optionally, the booster needle may also be administered after one or more vaccinations and/or one or more re-vaccinations.

Example 2:

this is a post hoc analysis aimed at further exploring and characterizing the effect of age (.ltoreq.50 years relative to >50 years) on the lymphopenia properties experienced by patients treated with cladribine tablets at 3.5mg/kg in a comprehensive safety analysis.

Method

Test design

CLARITY and ORACLE-MS are phase 3, double blind, randomized, placebo controlled 96 week studies of cladribine tablets in RRMS and First Clinical Demyelinating Event (FCDE) patients, respectively. Details concerning these studies have been previously disclosed; briefly, both CLARITY and ORACLE-MS studies evaluate the efficacy and safety of cladribine tablets at 3.5mg/kg (cumulative dose over 2 years) versus placebo. For this dosage regimen, cladribine 10mg tablet is administered at 0.875 mg/kg/week for more than two weeks over 4-5 consecutive days beginning at day 1 of week 1 and week 5 of year 1; this is followed by two weeks of treatment of year 2 (at 48 and 52 weeks from the beginning of the study, or preferably 49 and 53 weeks from the beginning of the study, respectively, since in these studies one year is preferably defined as consisting of 48 weeks and one month/month is defined as consisting of four weeks or 28 days). CLARITY Extension is a 120 week study that investigated the long-term safety and efficacy of cladribine tablets 3.5mg/kg versus placebo in qualified patients who completed claritey and then re-randomized to placebo or additional cladribine tablet 3.5mg/kg treatment. PREMIERE registration is a long-term observational safety study of patients who participated in a phase 3 study of cladribine tablets.

Post hoc analysis

This post-hoc analysis was performed to examine the effect of age (. Ltoreq.50 years and >50 years) at baseline and after treatment with placebo or cladribine tablets (3.5 mg/kg; cumulative dose over 2 years) on Absolute Lymphocyte Counts (ALC) and levels of specific B and T lymphocyte subsets. The analysis period was between weeks 0-288 of treatment with cladribine tablets 3.5mg/kg and the analysis population was cladribine tablets 3.5mg/kg monotherapy oral cohort (stage 3 CLARITY of MS, CLARITY Extension and safe population of ORACLE-MS study, and long-term follow-up in PREMIERE registration). The evaluation includes the incidence and severity of grade 3 lymphopenia; based on the NCI CTCAE v3.0 toxicity ranking system, the severity of grade 3 lymphopenia was defined as ALC levels <500 cells/. Mu.L. The time to recover from grade 3 or more lymphopenia to grade 2 or less (ALC 500 cells/. Mu.L) and grade 1 or less (ALC 800 cells/. Mu.L) was also evaluated. In addition, the effect of 3.5mg/kg cladribine tablet on the level of lymphocyte subpopulations, principally CD19+ B, CD4+T and CD8+T lymphocytes, was measured. All evaluations were performed for each baseline age group (.ltoreq.50 years and >50 years).

The incidence of adverse events (TEAE) occurring during the treatment of viral and bacterial infections was determined in patients with grade 3 lymphopenia attacks in both age groups. TEAE was evaluated at either year 1 (weeks 0-48) or year 2 (weeks 48-96) of cladribine tablet treatment, and by periods before, during and after grade 3 lymphopenia, respectively. Before, during and after lymphopenia are defined as: before (before the start date of the first lymphopenia ≡3), during (at or after the start date of the first lymphopenia up to and including the last date of the last lymphopenia), and after (after the end date of the last lymphopenia). The incidence of TEAE is summarized by the Preferred Term (Preferred Term) (PT) and is encoded according to version 20.0 of the MedDRA dictionary. All analyses used statisticsAnalysis software9.4 or higher.

Results

Patient(s)

A total of 1564 patients were included in this post hoc analysis. Of these 1379 were ∈50 years old (placebo: n=566; cladribine tablet 3.5mg/kg: n=813), and 185 were >50 years old (placebo: n=75; cladribine tablet 3.5mg/kg: n=110). Baseline data between age groups is generally well balanced, although groups aged >50 years have a higher proportion of females (73.6-76% versus 65.3-64.8%), longer disease duration (average-14.4 versus 7.9 years), a greater proportion of patients with one relapse at baseline (52.7-69.3% versus 37.5-44.9%), and a higher Extended Disability Status Scale (EDSS) at baseline (average-3.5 versus 2.4) (fig. 1) than groups aged 50 years.

ALC changes during two years of active treatment with cladribine tablet 3.5mg/kg

Following treatment with cladribine tablets, the 1 st year nadir of ALC appeared at week 9 (which is 4 weeks after completion of the 1 st year dosing) and the true nadir appeared at week 55 from the start of the study (at week 3 after completion of the 2 nd year dosing) for both age groups (fig. 1). For age less than or equal to 50 years of age and>the median (range) ALC at week 9 was 1.05 (0.2-6.7) x10 for the 50 year old group, respectively ⁹ Individual cells/L and 0.9 (0.3-2.5) x10 ⁹ Individual cells/L, corresponding to a decrease of 43.5% and 52.4% from baseline. ALC was restored to the normal range by the end of the study year (week 48; table 14) in the group at age > 50 years>1.02x10 ⁹ Individual cells/L). For group sums with age less than or equal to 50 years old>Group 50 years old, median of 2 nd year [ range ]]0.83[0.2-2.8 respectively]x10 ⁹ Individual cells/L and 0.79[0.1-1.7 ]]x10 ⁹ Individual cells/L, corresponding to 55.4% and 58.2% decrease from baseline. This was followed by gradual recovery of ALC to within normal range at the end of the second year of study (week 96).

Effect of cladribine tablet 3.5mg/kg on lymphocyte subpopulation

In both treatment years, a decrease in the respective levels of lymphocyte subpopulations (cd19+ B, CD4+t and cd8+t) was observed in both age groups following treatment with cladribine tablets; lymphocyte levels return to normal range by the end of the corresponding treatment year.

Cd19+b lymphocytes: for both age groups, the true nadir of cd19+ B lymphocyte levels occurred at week 9 (4 weeks from the second dose of year 1) and was below the lower normal limit (LLN) following treatment with cladribine tablets. The median (range) of the groups aged 50 years and >50 years was 20[4-239] and 13.0[2-121] cells/μl, respectively, corresponding to a decrease of 90.2% and 93.8% from baseline. Cd19+ B cells returned to normal range by week 36

Cd4+ T lymphocytes: for the age ∈50 and >50 year old groups, the true nadir of cd4+ T lymphocytes occurred at week 60 (8 weeks from the second dose of year 2) and week 72 (20 weeks from the second dose of year 2) after the 2 nd year dosing, respectively, and was lower than LLN for the two age groups. The median values (ranges) for the age of < 50 years and >50 years were 281[29-980] and 250[68-944] cells/uL, respectively, corresponding to 66.4% and 73.7% reduction from baseline. Median levels returned to normal range by week 96 (end of study year 2).

Cd8+ T lymphocytes: the true nadir of the group aged 50 years or less appears at week 72 (20 weeks after the second dose of year 2) after the 2 nd year of administration; median [ range ] was 232.5[43-1212] cells/μl, corresponding to a 41.8% decrease from baseline, and remained within normal range until week 96 (end of study year 2). For the age >50 year old group, the true nadir of CD8+ T lymphocyte levels was lower than LLN after treatment with cladribine tablets, and appeared at week 9 (median [ range ]:191[86-731] cells/. Mu.L, corresponding to 43.4% decrease from baseline), returning to normal range by week 13.

Severity of lymphopenia

Treatment with cladribine tablets at 3.5mg/kg correlated with grade 3 lymphopenia or more in both treatment years, with similar incidence in groups of age 50 and >50 years. In treatment year 1, 8.3% and 10.0% of patients reported grade 3 lymphopenia or more in groups of ages less than or equal to 50 years and >50 years, respectively; this increased to 18.7% and 20.0% by 2 nd year. Grade 4 lymphopenia onset was not reported in patients treated with cladribine tablet 3.5mg/kg at year 1; in year 2, it was reported in 2 (0.3%) patients with an age of less than or equal to 50 years and 1 (1.0%) patient with an age >50 years.

Recovery time from grade 3 or more lymphopenia

Between weeks 0 and 96, the incidence of grade 3 lymphopenia was similar in both age groups (age.ltoreq.50 years: 205/813[25.2% ]; age >50 years: 30/110[27.2% ]) in patients treated with cladribine tablets at 3.5 mg/kg. The average number of (SD) episodes per patient recovered from grade 3 or more lymphopenia to grade 2 or less was also similar between the two age groups (age 50 years: 1.6[1.1]; age >50 years: 1.9[1.0 ]). The median (range) time from the first grade-3 or more lymphopenia to grade-2 or less was 1.18 (range: 0.2-22.3) and 1.54 (range: 0.2-29.9) months in the age of 50 years or less and >50 years of age, respectively. Similarly, the average number of (SD) episodes per patient that return from grade 3 lymphopenia to grade 1 is 1.2 (0.5) and 1.3 (0.5), respectively, in the age group of 50 years and >50 years. The median (range) time from the first grade-3 or more lymphopenia to grade-1 or less was 5.49 (range: 0.2-88.4) and 6.06 (range: 0.2-46.5) months, respectively, in the age of 50 years or less and >50 years of age group.

Bacterial and viral infections according to age, treatment and lymphopenia status

TEAE incidence of viral and bacterial infections was analyzed in patients treated with cladribine tablets at 3.5mg/kg who reported grade 3 lymphopenia (age ∈50 years: N=205; age >50 years: N=309). The overall incidence of TEAE for viral and bacterial infections in these patients at treatment years 1 and 2 (weeks 0-96) is generally similar between the two age groups: age less than or equal to 50 years old: 105/205 (51.2%) relative to age >50 years: 17/30 (56.7%). The most commonly reported TEAEs across two age groups in > 5% of > 3 grade lymphopenia patients are viral upper respiratory infections, and influenza. Higher incidence of bronchitis (10% versus 5.9%), shingles (13.3% versus 3.4%), respiratory infections (6.7% versus 1.5%) and pneumonia (6.7% versus 1.0%) were noted in grade 3 lymphopenia patients in the age >50 group (age >50 versus 50). In the group of age less than or equal to 50 years, 103 (50.2%) patients receiving 3.5mg/kg cladribine tablets reported TEAE, all of which were mild to moderate in severity. In the group >50 years of age, 16 (53.3%) patients receiving 3.5mg/kg cladribine tablets reported TEAE that was mild to moderate in intensity, and 1 (3.3%) patient reported TEAE that was severe in both intensity.

In both age groups TEAE was similarly distributed with respect to lymphopenia episodes. However, during the onset of grade 1. Gtoreq.3 lymphopenia in the group with an age >50 years, more TEAE for viral and bacterial infections was reported (age. Ltoreq.50 years: 21.5%; age >50 years: 30%). Upper respiratory tract infections are commonly reported in two age groups during the lymphopenia phase, mostly mild to moderate in severity.

Discussion of the invention

Because the immune system undergoes significant remodeling during aging due to immune aging, the effect and efficacy of DMD on older MS patients is unknown. The results from this post hoc exploratory analysis confirm that the incidence of grade 3 lymphopenia of cladribine tablets is not significantly different in both younger and older MS patients. Furthermore, cladribine tablets had no significantly different effect on ALC and/or lymphocyte subpopulations in older and younger patients during the two years of treatment. ALC decreases within weeks after administration in both treatment years and gradually increases to normal levels, largely independent of patient age. The overall incidence of grade 3 lymphopenia and the time to return to grade 1/2 lymphopenia were not significantly different across the two age groups.

In MS patients treated with DMD such as interferon, dimethyl fumarate (DMF) and alemtuzumab, a decrease in ALC and lymphocyte subpopulations has been observed. In the comprehensive analysis of 2470 MS patients treated with DMF, grade 3 lymphopenia lasting more than or equal to 6 months was observed in 2.2% of patients treated with DMF. Following infusion of the anti-CD 52 monoclonal antibody alemtuzumab, depletion of lymphocyte subpopulations has been observed, with near complete depletion of ALC, cd19+ B, CD4+t and cd8+t lymphocytes observed. However, recovery to LLN range after alemtuzumab infusion may take 8 months (B lymphocytes) to nearly 3 years (T lymphocytes). Because of its mechanism of action, lymphopenia is the expected effect of cladribine tablets. However, recovery of ALC and lymphocyte subpopulations (cd19+b and cd4+t) occurred shortly after nadir following depletion with cladribine tablets and reached normal levels within 30-43 weeks after the last dose of treatment of year 2; cd8+ T lymphocytes did not drop below LLN. The results from this post hoc analysis show that the trends in both ALC and lymphocyte subpopulation levels are similar regardless of age and return to normal levels by the end of the study year in both age groups.

The pathogenesis of MS is found to be driven by autoreactive immune cells, mainly T and B lymphocytes infiltrating into the CNS. Thus, various DMDs utilized in MS therapies lead to immunomodulation or lymphocyte depletion. A potential risk of DMD in elderly people is the risk of opportunistic infections such as PML caused by JC virus (JCV). In the multinational cohort of MS patients, the seropositive rate of JCV increased from 49.5% in patients <30 years old to 66.5% in patients over 60 years old. MS patients over 50 years of age have been reported to be at greater risk of developing PML after treatment with DMD, such as fingolimod and dimethyl fumarate. In elderly MS patients, treatment with natalizumab is associated with an earlier onset of PML; the additive effects of immunosenescence and natalizumab-induced T lymphocyte reservoir restriction are attributed to this increased risk. In a previous post hoc analysis of patients treated with cladribine tablets at 3.5mg/kg in monotherapy oral cohorts (median age-36 years), an increase in the frequency of infection was observed during ≡3 grade lymphopenia; the type of infection events occurring in grade 3/4 lymphopenia patients are not different from those occurring outside of these periods. However, the incidence and type of infection is not analyzed by patient age. Current studies explore the incidence and nature of TEAE of viral and bacterial infections by patient age in patients treated with cladribine tablets at 3.5mg/kg who reported grade 3 lymphopenia. The incidence of these TEAEs is generally similar between younger and older patients with grade 3 lymphopenia. While most (> 50%) of these TEAEs were mild to moderate in severity in both age groups, severe TEAEs were reported in the age >50 year old group. In elderly patients with grade 3 lymphopenia or more, higher frequencies of bronchitis, shingles, respiratory tract infections and pneumonia are reported; this group also has a higher incidence of these TEAEs occurring during the onset of grade 1 ≡3 lymphopenia. The higher incidence of herpes reactivation observed in the group >50 years of age was consistent with previous studies in which viral reactivation was reported as patients increased in age. In summary, the results from this post hoc analysis show that treatment with cladribine tablets has an age-dependent effect on TEAE, whereby TEAE is slightly higher in older MS patients and slightly lower in younger MS patients, but still supports its use also in patients with an aging immune system.

Current analysis has some limitations. First, analysis is limited by its post hoc nature. Second, fewer patients are in the group with age >50 years old than in the group with age less than or equal to 50 years old. Finally, circulating lymphocytes reflect only a portion of the total lymphocyte population, and thus, only partially reflect changes occurring within the CNS. Although cladribine has been reported to cross the blood brain barrier and enter the CNS, the effect of cladribine tablets on CNS resident lymphocytes has not been fully understood so far.

Conclusion(s)

Example 3

Covd-19 case report

We report that cladribine tablets are undergoing administration46 of the treated patients with covd-19 had confirmed or suspected cases. 46 patients in the "Updated Post-Approval Safety of Cladribine Tablets in the Treatment of Multiple Sclerosis, with Particular Reference to Respiratory Viral Infections" (case report abstract 1) by Giovannoni et al also included 3 patients from MAGNIFY-MS and CLARIFY-MS who did diagnosis of COVID-19, as also reported in the "Clinical Outcomes in Patients with COVID-19Infection During Phase IV Studies of Cladribine Tablets for Treatment of Multiple Sclerosis" (case report abstract 2) by Karan, roy and Alexandri.

Reported data:

case report abstract 1

Details include summaries of confirmed (n=18) and suspected (n=28) cases, which report:

severity (defined as medically significant [ confirmed case n=1; suspected case n=1 ] or need hospitalization [ confirmed case n=3; suspected case n=1 ])

Results:

o recovered (confirmed case n=8; suspected case n=6),

o rehabilitation (confirmed case n=2; suspected case n=5)

O does not resolve (confirmed case n=1)

O unreported (confirmed case n=7; suspected case n=17)

Based on the availability of these data for 21 out of 46 patients (7 confirmations; 14 suspected), the dosage form of cladribine tablet was reportedTo the median time to the onset of covd-19 (180 days, ranging from 3 to 559 days).

For as more detailed data as possible, please refer to fig. 1 and table 14 relating to the part of the patient with the most complete data.

The age of onset of covd-19 (median 41 years; minimum: 22 years; maximum: 67 years) in 35/46 patients reported in archived posters (post). Cladribine tablet for 31/46 patients is retainedAnd the date of the last course of treatment was retained for 23/46 patients. The database also maintained the latest lymphocyte count for 9/46 patients (median 0.7G/L; minimum: 0.24, maximum: 1.2), and date of the latest lymphocyte count for 4/9 patients. To be taken from the group consisting of cladribine tablets->The time counted from the last course of treatment to the exact days of the COVID-19 episode is known for 20/46 patients and the recovery date for 3 patients is known.

Although we reported whether the case was diagnosed or suspected, we did not provide details of the diagnosis of covd-19 (i.e., PCR or antibody testing). We did have data on the number of patients tested for positive antibodies that required some degree of IgG response (table 14).

TABLE 14 patient with antibody-diagnosed COVID-19 (29 th month by 2020)

^a. The patient is included in fig. 1.

F, female; m, male; n, none; NR, not reported

This included one patient from the netherlands with a positive PCR test followed by a subsequent negative PCR test, but a positive IgG test (fig. 1 and table 14). The patient also had cladribine tabletsData of the time between the last course of treatment and the onset of covd-19 (104 days), and in cladribine tablets +.>Lymphocyte count (0.87G/L) measured between the most recent course of therapy and the onset of COVID-19.

These data suggest that the patient is able to use cladribine tablets given that the patient is able to test positive confirmation with COVID-19 via IgGSufficient IgG responses were generated during the immune-lowering phase of the treatment.

Case report summary 2

Details include sex, age, associated medical history, recent disability score (EDSS), and initial cladribine tablet of each of the 3 patientsIs a lymphocyte count prior to treatment. 3 patients in cladribine tablet->The time between the last dose of (c) and the onset of covd-19 is provided in months. From the graphic representation it is clear that 2/3 of the patients are receiving the cladribine tablet +. >Following the second year of treatment of (2) develop COVID-19, wherein patient 3 begins to use cladribine tablet +.>And develop covd-19 the next year prior to treatment. The course of the disease was reported by each of the 3 patients in terms of severity of symptoms, confirmation status of covd-19, need for hospitalization, and rehabilitation status.

In addition to the overall results from each of the 3 patients in phase IV studies of CLARIFY-MS and MAGNIFY-MS, the archived data included some details regarding the extent and nature of the symptoms of COVID-19 and concomitant diseases and medications (Table 15).

TABLE 15 use of cladribine tablets in either CLARIFY-MS or MAGNIFY-MSDemographic, medical history and COVID-19 Process in treated patients infected with COVID-19>

/>

AB, antibiotics; BL, baseline; DVT, deep vein thrombosis; EBV, EB virus; EDSS, expanding the disability status scale;

HTN, hypertension; inj, injecting; iv, intravenous; m2/6/12/14, month 2/6/12/14; SAE, serious adverse events; un v, unscheduled visit; y1/2 treatment initiation of treatment with year 1/2 of MAVENCLAD

Patients 1 and 2 had cladribine tablets on study schedule in addition to baseline lymphocyte levelsLymphocyte count values at months 2, 6 and 12 after the 1 st year of treatment. Patient 1 had month 14 (with cladribine tablet +. >After 2 nd year of treatment). Patient 2 had a drug composition at 3 months 2020 (in the case of cladribine tablets +.>One month after the last dose of the 2 nd year treatment). Patients 1 and 2 each had a report of potentially related adverse eventsPatient 1: asthmatic bronchitis at 10 months 2018, 12 months 2018 and 10 months 2019; angina pectoris at 10 months 2019.Patient 2: tachycardia of month 1 in 2019; left gland swelling and possible reactivation of epstein barr virus at month 1 in 2020). Patient 3 has not yet started to use cladribine tablet->Thus, according to the study schedule, there is a dose of cladribine in the form of a tablet +.>Lymphocyte counts at month 2 and month 6 following the 1 st year of treatment. In addition to the covd-19,patient 3 did not report other adverse events or associated concomitant diseases and medications.

Example 4

Vaccination study:

cladribine tablets were used at various time points before, during and after treatment with cladribine at years 1 and 2 for recurrent MSPost-vaccination antibody titers in 15 patients treated (MAGNIFY study) were maintained at levels that provided protective immunity against seasonal influenza and varicella zoster virus vaccines

(cladribine tablets) indicated for the treatment of adult patients with highly active relapsing Multiple Sclerosis (MS) as defined by clinical or imaging features. />The recommended cumulative dose of (cladribine tablet) was 3.5mg/kg body weight over 2 years, administered as 1 course of 1.75mg/kg per year.

European product characteristics outline (EU SmPC) statement of (cladribine tablet) due to risk of active vaccine infection with +.>Should not be initiated within 4 to 6 weeks after vaccination with live or attenuated live vaccine. Vaccination with live or attenuated live vaccines during and after cladribine treatment should be avoided as long as the patient's white blood cell count is not within normal limits.

There is a lack of data available to determine whether CT affects the antibody response to vaccination in patients with recurrent MS. The Merck internal data search retrieves the following information.

During the CLARITY clinical trial with cladribine tablets, some MS patients received vaccine (data shown in table 1) while being treated with 3.5mg/kg cladribine tablet during the placebo-controlled period. The most frequent vaccines accepted by these patients are influenza virus vaccines and tetanus vaccines. Information on the timing of vaccination associated with cladribine administration is not available. In patients treated with cladribine tablets, there was no AE report associated with the administration of the vaccine.

Table 15 vaccine-intent-to-treat (ITT) populations received in cladribine treatment groups during the CLARITY study.

	Cladribine tablet 3.5mg/kg (n=433) n (%)
		Vaccine ^*	20(4.6)

* Including influenza vaccine, tetanus vaccine, imudon (mixture of bacterial lysates), tick-borne encephalitis (TBE) vaccine, TBE virus antigen, hepatitis B vaccine, hepatitis vaccine, diphtheria vaccine, pertussis vaccine, tetanus vaccine, polio vaccine, encephalitis vaccine, rubella virus

In a small retrospective survey of blood samples from patients enrolled in the MAGNIFY study, at various time points (before, during or after) treatment of recurrent MS patients with cladribine tablets, antibody titers after vaccination remained above the seroprotection limit for seasonal influenza (hemagglutination inhibition [ HAI ]. Gtoreq.40) and varicella zoster virus (VZV;. Gtoreq.100 IU/L)). To investigate the antibody response against seasonal influenza and Varicella Zoster Virus (VZV) vaccination in Relapsing Multiple Sclerosis (RMS) patients treated with cladribine tablets (CT; 3.5mg/kg over 2 years). Absolute Lymphocyte Counts (ALC), B cell subpopulation counts and immunoglobulin (IgG and IgM) levels were measured longitudinally in the study and time points correlated with vaccination response are presented in the graph.

During the MAGNIFY-MS study (NCT 03364036), blood samples collected from 15 recurrent MS patients receiving seasonal influenza (n=12) or VZV vaccination (n=1 shaingrix, n=2 Zostavax) for CT treatment as standard of care were retrospectively analyzed. Two control blood samples (baseline sample before starting CT, closest sample available just before vaccination) and two post-vaccination blood samples (closest sample available after vaccination) were examined. Quantitative antibody titers against seasonal influenza and VZV vaccines were measured by hemagglutination inhibition (HAI) assay and enzyme-linked immunosorbent assay (ELISA), respectively. Longitudinal assessment of ALC (absolute lymphocyte count) and peripheral blood immune cells at various time points before and after vaccination was analyzed in vaccinated patients. Absolute cell counts and% change from baseline were evaluated and immunoglobulins G and M (IgG and IgM) were reported.

VZV vaccine: in post-vaccination samples from patients receiving VZV vaccine (Table 2: shangrix: 7005680022253003 or Zostavax:70056800221620004, 70056800221260001), antibody titers were above the level of protective titers (100 IU/L) at all time points examined, and at all times The treatment was maintained throughout. Although at->Lymphocytes were reduced to 800 cells/ml after the first course of treatment, but VZV titers were maintained in shintrix cases for up to 6 months. For Zostavax treatment, although cladribineGrade 2 and grade 1 lymphopenia was induced, as well as low mature B cell counts, but serum positive was maintained for 4.5 or 5.25 months (fig. 15).

Influenza: during years 1 or 2 of cladribine tablets, antibody titers were above the seroprotection limit (HAI > 40) for all strains present in the vaccine in post-vaccination blood samples from patients vaccinated against influenza a and b. Regardless of the time of vaccination (at 1 st and 2 nd years of cladribine treatment), lymphocyte count or B cell subtype (examples: cd19+ and cd20+ mature B cells) count, all vaccinated patients were able to develop an immune response (figure 15). Post-vaccination data for all patients vaccinated with different influenza strains showed 92-100% seroprotection. Influenza a strains (H1N 1/H3N 2) and influenza b strains (Victoria) showed 4-fold increases in antibody titers after vaccination of 11%, 13% and 8%. A2-fold change in AB titer was seen at 17-67% rate in all strains.

Table 16:

8 pieces ofInfluenza/1 shintrix treatmentPatient antibody titres and ALC results are summarized (FIG. 15)

Despite the differences in vaccination time points and absolute lymphocyte counts, all patients vaccinated against influenza a and influenza b during year 1 or 2 of CT treatment maintained a seroprotection titer of ≡40 across all strains present in the administered vaccine in the samples after vaccination. Patients with positive prior serum responses (HAI. Gtoreq.40) with 4-fold and 2-fold increases for at least 1 strain in post-vaccination titers were 37.5% (3/8) and 87.5% (7/8), respectively. Antibody effectThe total lymphocyte count in samples taken from 8 patients analyzed at available adjacent time points of vaccination should be compared. ALC counts at vaccination covered a broad range of severity from grade 3, 2, 1 to normal levels. Baseline or at all time points for shintrix-treated patientsAt month 3 and 6 after treatment, the antibody titer after vaccination increased 40-fold (titer)>4748IU/L)。

In summary, in this small retrospective survey, despite the fact that vaccination was done at various time points before or after cladribine treatment, the antibody titer following vaccination with CT treated recurrent MS patients remained at a level that provided protective immunity against seasonal influenza and shintrix vaccines.

Detailed description of some vaccination cases:

immunophenotyping results

We also examined the single vaccinated patient in more detail (figure 15) to better understand the potential immunological changes and potential vaccination responses associated with cladribine treatment. We were primarily interested in blood ALC, cd20+ mature B cells and memory B cell counts to define time and short-lived plasmablasts and CD38 for vaccination ^bright The potential nadir value of plasma cell number in order to see if we can detect vaccination response.

Most interestingly, we seen short-lived plasma cells and CD38 in 3 patients (FIG. 15: patients 70056800222530003, 70056800221620004, 70056800227010005) ^bright Transient increases in plasma cells indicate vaccination response. As reviewed by Finke et al 2012, the presence of PB in blood is transient after vaccination-the magnitude of PB response at day 7 predicts antibody titer at day 28.

Activated B cells proliferate and differentiate into antibody-producing cells, short-lived plasma cells and long-lived plasma cells (SLPC and LLPC) after immunization, and memory B cells (B _mem ). SLPC is found in the outer positions of follicles such as the red marrow of the spleen and the medullary cords of lymph nodes, while LLPC is located in other organs such as Bone Marrow (BM) and gut-associated lymphoid tissue (GALT), where it produces antibodies for a long period of time.

What is the phenotype and source of plasmablasts in the context of viral infection or vaccination, and whether plasmablasts can predict long-term immunity? Several studies have analyzed the kinetics and phenotypic changes of B cell subtypes in blood of vaccinated or infected individuals (reviewed in Finke 2012). Differentiation into Plasmablasts (PB) is most commonly monitored with the surface markers CD19, CD20, CD27, CD38 and CD138 and the intracellular marker Ki-67. The term acute plasmablasts is used in various papers to correlate CD19lowCD20-CD27highCD38highCD138 +/-cells, which appear after infection and vaccination, with the acute phase of the immune response and to distinguish them from steady state plasmablasts. The timing of acute PB appearance in blood surprisingly coincides after immunization or infection: flow cytometry analysis or ELISPOT performed ex vivo with human PBMCs sampled once daily after vaccination with yellow fever attenuated strain YF-17D, inactivated influenza vaccine, tetanus vaccine, and after infection with respiratory syncytial virus or dengue virus showed that the number of plasmablasts peaked consistently on day 6 or day 7. Thus, the response appears to be independent of the adjuvant used, and independent of the route of immunization. The presence of PB in the blood is transient after vaccination (Odensahl et al 2005; lee et al 2011), while the duration of the response depends on the persistence of the virus after natural infection.

A recent study on HIV-infected individuals under antiretroviral therapy, vaccinated with H1N1 vaccine and grouped into responder and non-responder groups, showed establishment of PB response predictive memory at day 7 and specific antibody titres at day 28. The study further showed that induction of PB and memory populations correlated with B-cell up-regulation of IL-21 receptor, which was different in the responder and non-responder groups (Palikkuth et al, 2011). In view of these lines of evidence that early PB responses might predict later immunity, it is critical to understand the origin of plasmablasts in a given antigen and adjuvant context in order to specifically generate a subpopulation of B cells that can trigger during repeated infections. Early in vitro experiments with human naive and memory B cells from tonsils demonstrated that memory B cells differentiated into plasmablasts more rapidly and more efficiently than naive B cells after nonspecific activation with CD40L and in the presence of IL-2 and IL-10 (Arpin et al, 1997). More recent studies using Ig sequencing of single plasmablasts and memory B cells to analyze their relationship in the context of tetanus vaccination indicate that a given memory B cell precursor can produce both plasmablasts and memory cells (Frolich et al, 2010).

All these data indicate that PB circulating in the blood (acute PB) is memory B cell derived at day 6-7 after infection or immunization. At least in the context of viral infection, similar timing of the appearance of acute PB following primary and booster immunization suggests that memory B cells may be the source of such PB in both cases.

In our MAGNIFY sub-study, which also covers vaccinated patients, we have used the following plasma cell markers to study both plasma cell populations:

short-lived plasma cells: CD45bright, SSClow, CD-, CD14-, CD56-, CD19dim, CD20-/dim, CD27bright

·CD38 ^bright Plasma cell: CD45bright, SSClow, CD-, CD14-, CD56-, CD19dim, CD20-, CD38brigh

Influenza-treated MAGNIFY patient (fig. 15):

patient 70056800227010005: the patient is at the firstThree half months (3.5M) after the procedure were vaccinated. It can be seen that the titer against the 2 Influenca strains increased by a factor of 4 or more, in the other 2 strains the titer was maintained at a protective level (i.e.not<40). ALC and CD20 ⁺ Both mature B cell numbers (fig. 3) were near nadir levels at the time of vaccination. Such asALC at the time of vaccination was grade 2 (600 cells/ml), measured at the end of the 3 month time point. At month 6 (M6), absolute lymphocyte levels increased to 900 cells/mL.

Although CD20 ⁺ The fact that B cells reached a-72% decrease (65 cells/mL) at month 3 (M3), but an increase and maintenance of titer was seen 2 weeks prior to vaccination, for another 4.5 months after vaccination. CD20 ⁺ B cells increased cells (135 cells/ml) at month 6 and reached normal levels (230 cells/ml) at month 12 (M12).

Consistent with the PB/PC increase described by Finke (2012) after viral infection or vaccination. 2 weeks after vaccination, CD38 ^bright Plasma cells increased 3.3-fold (from 822 cells/ml at month 2 (M2) to 2716 cells/ml at the end of month 3 (M3)) and the count decreased thereafter. Short-lived PC (CD 27) ^bright ) Increased by a factor of 3.3 (from 831 cells/ml at month 2 (M2) to 2762 cells/ml at the end of month 3 (M3) after cladribine treatment, 2 weeks after vaccination). IgG immunoglobulin levels were not affected at any time point after Mavenclad treatment.

Patient 70056800222520001: the patient vaccinated with the Influenza vaccine at month 4 (M4) confirmed the previous findings with patient 70056800227010005. It can be seen that the titer against 2 Influnza strains increased by a factor of > 2, the titers in the other 2 strains were maintained at a protective level (i.e., not <40). ALC counts were near nadir levels at vaccination and therefore should be below 600 cells/mL measured at month 2. Despite these low levels at vaccination, the antibody response is still protective. Because we lack CD20 ⁺ Count data for month 3 and 4 of mature B cells, we only state that the nadir of cd20+ B cells has been described as around 2-3 months in the MAGNIFY study. Although atA-80% decrease in memory B cells was still seen at month 6 after treatment, but IgG levels were notInfluence.

Patient: 70056800222010002: the patient is beginning the second yearVaccination was performed 33 days after the course of treatment. It can be seen that the titer against an Influenza strain increases by a factor of 4 or more. For the other 3 strains, titers were maintained at a protective level (i.e., not<40). At month 14, the absolute lymphocyte level at 1 month post-vaccination was 700 cells/ml.

In summary:

all MAGNIFY patients were able to respond regardless of vaccination time or lymphocyte count in 1 st year course (Y1)/2 nd year course (Y2)

In post-vaccination samples from patients receiving Varicella Zoster Virus (VZV) vaccine, antibody titers were above protective titer levels (. Gtoreq.100 IU/L) at all time points examined.

Antibody titers were above the seroprotection limit (HAI. Gtoreq.40) for all strains present in the vaccine in post-vaccination blood samples from patients vaccinated against influenza A and influenza B during years 1 or 2 of cladribine tablets.

Details about each patient in the vaccination study are given in the following table:

patient Spain 2-70056800227010013

Vaccination was performed against influenza strains H1N1 (MichiganA), H3N2 (Singapore A), victoria (Colorado/B) and Yamagata (Phuket/B) 49 days after the first dose of Mavenclad procedure 1

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Patient Spain 2-70056800227010013-expanded subject group ^#)

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Patient Spanish 3-70056800227050006

Vaccination was performed against influenza strains H1N1 (MichiganA), H3N2 (Singapore A), victoria (Colorado/B) and Yamagata (Phuket/B) 72 days after the first dose of Mavenclad procedure 1

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Patient spanish 3-70056800227050006-expanded subject group ^#)

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Patient Canadian 1-70056800222520001

Vaccination was performed 104 days after the first dose of Mavenclad procedure 1 against influenza strains H1N1 (Brisbanea), H3N2 (Kansasa), victoria (Colorado/B) and Yamagata (Phuket/B)

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Patient Canada 1-70056800222520001-expanded subject group ^#)

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Patient Spanish 1-70056800227010005

Vaccination was performed 113 days after the first dose of Mavenclad procedure 1 against influenza strains H1N1 (MichiganA), H3N2 (singapore a), victoria (Colorado/B) and Yamagata (phukey/B)

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Patient spanish 1-70056800227010005-extended subject group ^#)

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Patient Finnish 1-70056800221620004

At 187 days after the first dose of Mavenclad procedure 1, vaccinations were performed against influenza strains H1N1 (Brisbanea), H3N2 (Kansasa), victoria (Colorado/B) and Yamagata (Phuket/B) 1

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Patient Finnish 1-70056800221620004-extended subject group ^#)

Vaccination was performed on influenza strains H1N1 (Brisbanea), H3N2 (Kansasa), victoria (Colorado/B) and Yamagata (Phuket/B) 187 days after the first dose of Mavenclad procedure 1

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Patient French 1-70056800222010002

Vaccination was performed against influenza strains H1N1 (Brisbanea), H3N2 (Kansasa), victoria (Colorado/B) and Yamagata (Phuket/B) 33 days after the first dose of Mavenclad procedure 2

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Patient French 1-70056800222010002-extended subject group ^#)

/>

Patient Australia 1-70056800221220003

Vaccination was performed against influenza strains H1N1 (Brisbanea), victoria (Colorado/B) and Yamagata (Phuket/B) 133 days after the first dose of Mavenclad procedure 2

/>

Patient Australia 1-70056800221220003-extended subject group ^#)

/>

Patient Finnish 2-70056800221620002

Vaccination was performed 42 days prior to the first dose of Mavenclad procedure 2, against influenza strains H1N1 (Brisbanea), H3N2 (Kansasa), victoria (Colorado/B) and Yamagata (Phuket/B)

/>

Patient Finnish 2-70056800221620002-expanded subject group ^#)

/>

Patient German 1-70056800221100002

Vaccination was performed against influenza strains H1N1 (Brisbanea), H3N2 (Kansasa), victoria (Colorado/B) and Yamagata (Phuket/B) 43 days prior to the first dose of Mavenclad procedure 2

/>

Patient German 1-70056800221100002-extended subject group ^#)

/>

Patient England 2-70056800229010002

Vaccination was performed against influenza strains H1N1 (Brisbanea), H3N2 (Kansasa), victoria (Colorado/B) and Yamagata (Phuket/B) 81 days prior to the first dose of Mavenclad procedure 2

/>

Patient uk 2-70056800229010002-extended subject group ^#)

/>

Patient England 1-70056800229010001

Vaccination was performed on influenza strains H1N1 (Brisbanea), H3N2 (Kansasa), victoria (Colorado/B) and Yamagata (Phuket/B) 87 days prior to the first dose of Mavenclad procedure 2

/>

Patient uk 1-70056800229010001-expanded subject group ^#)

/>

Patient French 2-70056800222100003

Vaccination was performed against influenza strains H1N1 (Brisbanea), H3N2 (Kansasa), victoria (Colorado/B) and Yamagata (Phuket/B) 127 days prior to the first dose of Mavenclad procedure 2

/>

Patient French 2-70056800222100003-extended subject group ^#)

/>

Patient Canadian VZV-70056800222530003

68 days and 8 days before the first dose of Mavenclad procedure 1, withVaccination against varicella zoster virus>

Patient Canada VZV-70056800222530003-expanded subject group ^#)

/>

Patient Finnish VZV-70056800221620004

45 days before the first dose of Mavenclad procedure 1, withVaccination against varicella zoster virus

/>

Patient Finnish VZV-70056800221620004-expanded subject group ^#)

/>

Patient Australian VZV-70056800221260001

69 days before the first dose of Mavenclad procedure 1, withVaccination against varicella zoster virus

/>

Patient Australian VZV-70056800221260001-extended subject group ^#)

/>

# x): expansion of the subject group:

scr: screening; ending: end of the test (2 years); igG: immunoglobulin G; igM: immunoglobulin M; ALC: approximate lymphocyte count; TC: t cells; cent.mem.tc: a central memory T cell; eff mem TC: effector memory T cells; treg: regulatory T cells; term. Diff. Effector TC: terminally differentiated effector T cells; NKC: natural killer cells; LLOQ: lower limit of quantification

All lymphocyte cell values are in [ cells/. Mu.L ]

1: blood was collected at month 0 up to 6 days prior to the first Mavenclad dose

2: ALC measurement dates may differ from other measurements by up to 7 days

* Inoculated influenza strains

Example 5:

covd-19 vaccination recommendations and opportunities for sustained DMD/IMD efficacy and safety in your MS patients

MS patients are often treated with one or more immunomodulatory drugs (IMDs) or Disease Modifying Drugs (DMDs), which are the current gold standard in autoimmune disorders such as MS. Although IMDs preferably represent a subset of drugs in the DMD domain (through which the IMD provides efficacy depending on the mode of action), IMDs and DMDs are often used as synonyms. However, in this context, the terms "IMD" and "DMD" are preferably used interchangeably.

Previous covd-19 vaccination guidelines for MS patients suggest:

there were no vaccination restrictions for the following MS patients

-a non-therapeutic treatment of the patient,

-a therapeutic agent comprising IFN- β,

-a therapeutic treatment with glatiramer acetate,

therapeutic treatment with IV immunoglobulin, or

-treatment with natalizumab.

The treatment with DMD is initiated long enough from the last vaccination, i.e. at least 1 month after the last/second dose of covd-19 vaccine administered e.g. as described below,

Alzhuzumab

-

-orelobizumab, and

rituximab.

Table 16: clinical and demographic variables of multiple sclerosis patients vaccinated with pfizer bnt162b 2-covd-19

* Only 435 received the second vaccine dose at the date of data expiration; the inter-dose interval of 21 days was not completed for 109 patients; 3 patients were infected with SARS-COV-2 after the first vaccine dose, and 8 patients experienced acute MS relapse, and their second vaccine dose was delayed.

Table 17: clinical and demographic variables of multiple sclerosis patients vaccinated with pfizer bnt162b 2-covd-19

Table 18: clinical and demographic variables of multiple sclerosis patients vaccinated with pfizer bnt162b 2-covd-19

* Only 435 received the second vaccine dose at the date of data expiration; the inter-dose interval of 21 days was not completed for 109 patients; 3 patients were infected with SARS-COV-2 after the first vaccine dose, and 8 patients experienced acute MS recurrence, and their second vaccine dose was delayed

Table 19: adverse events in MS patients following BNT162b2 covd-19 vaccination

Table 20: MS-related adverse events following BNT162b2 covd-19 vaccination

The results are also presented in fig. 17 and 18.

Claims

1. A method for treating an autoimmune disorder in a patient in need thereof, the method comprising:

(a) Orally administering cladribine to a patient, optionally during one or more treatment periods, at a fixed dose per patient, per body weight and per treatment period, wherein the fixed dose is selected from the range of 1.0mg/kg to 3.0mg/kg,

(b) Identifying a patient at risk of acquiring an infection,

d) Orally administering cladribine to a patient, optionally during one or more treatment periods, at a fixed dose per patient, per body weight and per treatment period, wherein the fixed dose is selected from the range of 1.0mg/kg to 3.0mg/kg,

provided that the method comprises one or more treatment periods in which cladribine is administered, and

a further condition is that the fixed dose per patient is approximately the same throughout the one or more treatment periods in which cladribine is administered,

2. The method according to claim 1, wherein the duration of each treatment period in step (a) is independently selected from about 1 to about 3 months, and/or wherein the duration of each treatment period in step (d) is independently selected from about 1 to about 3 months.

3. A process according to claim 1 and/or 2,

i) Wherein the method comprises two or more treatment periods in which cladribine is administered, each having a duration of about 1 to about 3 months,

ii) wherein each of the two or more treatment periods are separated by a period in which cladribine is not administered to the patient, and

4. The method according to claim 1, 2 and/or 3, wherein at least one of the periods in which cladribine is not administered to the patient has a duration of 9 to 18 months.

5. The method according to one or more of the preceding claims, comprising:

(a) Orally administering cladribine to a patient during 1 or 2 treatment periods at a fixed dose per patient, per body weight and per treatment period, wherein the fixed dose is selected from the range of 1.0mg/kg to 3.0mg/kg,

(b) Identifying a patient at risk of acquiring an infection,

d) Cladribine is orally administered to a patient during 0 or 1 treatment period at a fixed dose per patient, per body weight and per treatment period, wherein the fixed dose is selected from the range of 1.0mg/kg to 3.0 mg/kg.

6. The method according to one or more of the preceding claims, comprising:

(a) Orally administering cladribine to a patient during 0 or 1 treatment period at a fixed dose per patient, per body weight and per treatment period, wherein the fixed dose is selected from the range of 1.0mg/kg to 3.0mg/kg,

(b) Identifying a patient at risk of acquiring an infection,

d) Cladribine is orally administered to a patient during 1 or 2 treatment periods at a fixed dose per patient, per body weight and per treatment period, wherein the fixed dose is selected from the range of 1.0mg/kg to 3.0 mg/kg.

7. The method according to claim 5 or claim 6, wherein the treatment periods in which cladribine is administered to the patient are separated from each other by at least 9 months in which cladribine is not administered to the patient.

8. A method according to one or more of the preceding claims, wherein

ii) vaccinating said patient according to step (c)

a) Occurs within a time frame of about 4 weeks prior to a treatment period in which cladribine is orally administered to the patient, and/or

b) Occurs within a time frame of about 4 weeks after a treatment period in which cladribine is orally administered to the patient.

9. The method according to one or more of the preceding claims, wherein the method comprises at least 2 treatment periods in which cladribine is orally administered to the patient, and wherein the vaccinating of the patient according to step (c) occurs within about 4 weeks before the first treatment period in which cladribine is orally administered to the patient, or within about 4 weeks after the last treatment period in which cladribine is orally administered to the patient.

10. The method according to one or more of the preceding claims, wherein the method comprises at least 2 treatment periods in which cladribine is orally administered to the patient, and wherein the vaccinating of the patient according to step (c) occurs within a time frame starting about 2 weeks before the beginning of the first treatment period in which cladribine is orally administered to the patient, and ending within about 2 weeks after the end of the last treatment period in which cladribine is orally administered to the patient.

11. A method according to one or more of the preceding claims, wherein

ii) vaccinating said patient according to step (c)

a) Occurs within a time frame of about 1 or 2 weeks prior to a treatment period in which cladribine is orally administered to the patient, and/or

b) Occurs within a time frame of about 4 or about 5 weeks from the beginning of each treatment period in which cladribine is orally administered to the patient.

12. The method according to one or more of the preceding claims, wherein the vaccinating of the patient according to step (c) occurs within a time frame of

i) Beginning at the beginning of a first treatment period in which cladribine is orally administered to the patient, and

ii) ends at the end of the last treatment period in which cladribine is orally administered to the patient.

13. The method according to one or more of the preceding claims, wherein the method comprises two treatment periods in which cladribine is orally administered to the patient, and wherein the vaccinating of the patient according to step (c) occurs within a time frame beginning about 2 weeks before the beginning of the first treatment period in which cladribine is orally administered to the patient, and ending within about 2 weeks after the end of the second treatment period in which cladribine is orally administered to the patient.

14. The method according to claim 9, 10, 11 or 12,

Wherein vaccinating the patient according to step (c) occurs at any time as specified in claim 9, 10, 11 or 12, except for about 4 weeks before and/or about 4 weeks after the lowest B cell count determined in the blood of the individual subject during a time frame set by the start of two adjacent treatment periods in which cladribine is orally administered to the patient.

15. The method according to claim 9, 10, 11, 12 or 13,

wherein vaccinating the patient according to step (c) occurs at any time as specified in claim 9, 10, 11 or 12, except for a period of time of 5 to 10 weeks, 6 to 11 weeks, 5 to 13 weeks or 6 to 14 weeks after the start of each treatment period in which cladribine is orally administered to the patient.

16. The method according to one or more of the preceding claims, wherein the vaccination in step (c) comprises administering a vaccine to the patient in 1 to 6 separate doses administered at different days.

17. The method according to one or more of the preceding claims, wherein the vaccination in step (c) comprises administering a vaccine to the patient in 2 to 6 divided doses, wherein the 2 to 6 divided doses are administered to the patient at different days within a time frame of about 1 to 12 weeks, preferably 1 to 6 weeks and especially 2-4 weeks.

18. A method of treating an autoimmune disorder and reducing the risk of infection in a subject in need thereof, the method comprising

a) Orally administering cladribine to said subject over a treatment period of about 2 months, wherein said treatment period is followed by a cladribine-free period of at least 9 months wherein cladribine is not administered to said patient, and orally administering a fixed dose of cladribine to each patient selected from the group consisting of 1.0mg/kg to 3.0mg/kg to said patient, and

i) Beginning less than 4 weeks, preferably less than 3 weeks and especially less than 2 weeks prior to the treatment period of about 2 months wherein cladribine is orally administered to the patient, and ending at the beginning of the second treatment month of each treatment period wherein cladribine is orally administered to the patient, and/or

ii) starts at the end of the second treatment month in said treatment period in which cladribine is orally administered to the patient and ends at the end of the cladribine-free period of at least 9 months immediately following the treatment period.

19. A method of treating an autoimmune disorder and reducing the risk of infection in a subject in need thereof, the method comprising

wherein the vaccination period starts with

ii) within the first week or second week of the treatment period, and/or

iii) The cladribine-free period is preferably immediately after the treatment period by a time frame set at the end of the treatment period in which cladribine is orally administered to the patient and ending at the end of a subsequent cladribine-free period of at least 9 months in which cladribine is not administered to the subject.

20. A method of treating an autoimmune disorder and reducing the risk of infection in a subject in need thereof, the method comprising

a) 2 treatment periods of duration of about 2 months each, wherein cladribine is orally administered to the subject at a fixed dose per patient and per treatment period, wherein the fixed dose is selected from the range of 1.5mg/kg to 2.0mg/kg, and wherein each treatment period is followed by a cladribine-free period of at least 9 months, preferably at least 10 months, wherein cladribine is not administered to the subject, and

wherein the vaccination periods each start from, preferably independently of each other, selected from

ii) within the first week or second week of the treatment period, and/or

iii) By any time within a time frame set as follows: wherein the end of the treatment period in which cladribine is orally administered to the patient, and wherein the end of a subsequent cladribine-free period of at least 9 months or preferably 10 months, preferably immediately following the treatment period, of cladribine is not administered to the subject.

21. A method of treating an autoimmune disorder and reducing the risk of infection in a subject in need thereof, the method comprising

wherein each of said vaccination periods is independent of the other

i) Starting less than 4 weeks, preferably less than 3 weeks and especially less than 2 weeks before the beginning of the treatment period and ending 6 weeks, preferably 4 weeks and especially 2 weeks after the beginning of the treatment period, or

ii) starts at the end of the treatment period, starts 1 week after the end of the treatment period, or starts two weeks after the end of the treatment period.

22. The method according to one or more of the preceding claims, wherein the subject

i) One or more, preferably one or two vaccination sessions are performed within a time frame beginning two weeks before the start of the treatment period and ending four weeks after the start of the treatment period,

and/or

ii) vaccination is carried out one or more times, preferably one or two times, within a time frame starting at the end of the treatment period and ending two, three or four weeks after the end of the treatment period.

23. The method according to one or more of the preceding claims, wherein each treatment period consists of 2 treatment months, wherein each treatment month comprises one treatment week, wherein the treatment week preferably starts at the beginning of the respective treatment month.

24. The method according to claim 23, wherein each treatment week consists of 4 or 5 days during which the patient is preferably treated with cladribine, preferably independently selected from 10 mg/day or 20 mg/day per day.

25. A method according to one or more of the preceding claims, wherein

i) The vaccination period comprises two weeks, four weeks or eight weeks,

ii) one or more vaccinations are administered to the subject during the first or last week of the vaccination period, and/or

26. The method according to one or more of the preceding claims, wherein at the beginning of the vaccination period or during the vaccination period the subject to be vaccinated or immunized has lymphopenia grade No. 1, lymphopenia grade No. 2 or lymphopenia grade No. 3.

27. The method according to one or more of the preceding claims, wherein the subject is vaccinated with one or more vaccines selected from the group consisting of inactivated vaccines, subunit vaccines, recombinant vaccines, polysaccharide vaccines, conjugate vaccines and toxoid vaccines and/or combinations thereof.

28. Method according to one or more of the preceding claims, wherein the infection is a viral infection, preferably selected from hepatitis, preferably hepatitis a and/or hepatitis b, more preferably hepatitis b, varicella zoster (shingles), or if not exposed: varicella, measles, influenza, poliovirus, pneumococcal pneumonia, diphtheria, tetanus, pertussis, human Papilloma Virus (HPV) and other papilloma virus related diseases, covid-19, preferably after the vaccine becomes available, and any other viral disease according to an immunization schedule recommended based on age, travel or geographical exposure related risk or other factors.

29. The method according to one or more of the preceding claims, wherein the infection is a bacterial infection, preferably selected from anthrax, cholera, diphtheria, haemophilus influenzae, meningococcal meningitis, pertussis, plague, pneumococcal disease, streptococcus pneumoniae, tetanus, tuberculosis and typhoid fever.

30. The method according to one or more of the preceding claims, wherein the vaccination is performed with a vaccine selected from the group consisting of: anthrax, cholera, diphtheria, haemophilus influenzae, meningococcal, pertussis, plague, pneumococcal, streptococcus pneumoniae, tetanus, tuberculosis, typhoid.

31. The method according to one or more of the preceding claims, wherein the autoimmune disorder is selected from the group consisting of Multiple Sclerosis (MS), rheumatoid Arthritis (RA), systemic Lupus Erythematosus (SLE), neuromyelitis spectrum disease (NMOSD) and Myasthenia Gravis (MG), preferably Multiple Sclerosis (MS), neuromyelitis spectrum disease (NMOSD) and Myasthenia Gravis (MG).

32. The method according to one or more of the preceding claims, wherein the autoimmune disorder is Multiple Sclerosis (MS).

33. The method according to one or more of the preceding claims, wherein the autoimmune disorder is Multiple Sclerosis (MS), comprising one or more indications selected from the group consisting of: relapsing Multiple Sclerosis (RMS), relapsing Remitting Multiple Sclerosis (RRMS), secondary Progressive Multiple Sclerosis (SPMS), and Primary Progressive Multiple Sclerosis (PPMS).

34. A method according to one or more of the preceding claims, the method comprising:

orally administering cladribine to a patient during one or more treatment periods at a fixed dose per patient, per body weight and per treatment period, wherein the fixed dose is selected from the range of about 1.0mg/kg to about 3.0mg/kg, and wherein cladribine is administered to the patient in such a manner that an effective or bioavailable amount of cladribine in the patient is a fixed dose per patient, per body weight and per treatment period selected from the range of about 0.5mg/kg to about 1.6mg/kg, preferably 0.8+/-0.2 mg/kg.

35. The method according to claim 34, wherein said effective or bioavailable amount of cladribine in said patient is achieved by administration of an oral dosage form providing a cladribine bioavailability in said patient in a range selected from the range of about 30% to about 100%, preferably about 40% to 50%, at a fixed dose of each patient, each body weight, and each treatment period in a range of about 0.3mg/kg to about 2.0 mg/kg.

36. The method according to one or more of the preceding claims, wherein the autoimmune disorder to be treated is Multiple Sclerosis (MS) and the subject to be treated has a High Disease Activity (HDA).

37. The method according to one or more of the preceding claims, wherein the subject to be treated is over 30 years old, over 40 years old, over 50 years old, over 60 years old or over 70 years old.

38. The method according to one or more of the preceding claims,

wherein the vaccination of the patient occurs at any time except for the following time periods: 5 to 10 weeks, 6 to 11 weeks, 5 to 13 weeks, or 6 to 14 weeks after the start of each treatment period or course in which cladribine is orally administered to the patient.

39. The method according to one or more of the preceding claims,

wherein the vaccination of the patient occurs at any time except for the following time periods: 4 to 9 weeks, 5 to 8 weeks, 5 to 7 weeks, 6 to 8 or 6 to 7 weeks after the start of each treatment period or course in which cladribine is orally administered to the patient.

40. The method according to one or more of the preceding claims, wherein the patient suffers from grade 0 to grade 3 lymphopenia, more preferably grade 1 to grade 3 lymphopenia, and in particular grade 1 to grade 2 lymphopenia or grade 2 to grade 3 lymphopenia, at the time of execution or to be subjected to vaccination.

41. The method according to one or more of the preceding claims, wherein the vaccination is or is to be performed at any time between

a) Cladribine, oral cladribine or a cladribine tablet is administered to a patient, preferably to the first day of the patient according to one or more of the preceding claims, and

b) The period of 5 to 11 months, preferably 4 to 10 months, more preferably 4 to 8 months or 3 to several months, from the last day of administration of cladribine, oral cladribine or a cladribine tablet to a patient, preferably according to one or more of the preceding claims, preferably wherein said last day of cladribine, oral cladribine or a cladribine tablet to a patient is the last day of administration of cladribine, oral cladribine or a cladribine tablet to a patient in a first or second course of treatment.

42. The method according to one or more of the preceding claims,

43. The method according to one or more of the preceding claims,

44. The method according to one or more of the preceding claims,

wherein the vaccination of the patient occurs on the day of or during a period of 4 weeks after the start of the respective treatment period or course in which cladribine is orally administered to the patient, preferably during a period of 5 to 9 weeks, 5 to 8 weeks, 5 to 7 weeks, 6 to 8 or 6 to 7 weeks after the start of the respective treatment period or course in which cladribine is orally administered to the patient.

45. A method for treating an autoimmune disorder in a patient in need thereof, the method comprising:

(i3) Each course of treatment is divided into 2 treatment cycles, wherein

(i4) Each treatment cycle dose is about 10mg or about 20mg per day, once daily orally, for 4 or 5 days depending on the body weight, and preferably the treatment cycle dose is administered during the first week of each treatment cycle, wherein

(ii 2) then administering the first course of treatment/the second course of treatment, or the first course of treatment/the second course of treatment dose, about 23 to 27 days after the last dose of the first course of treatment/the first treatment period, preferably as described in section (i 4),

(iii 1) orally administering to said patient a second course of treatment/first treatment cycle, or a second course of treatment/first treatment cycle dose, at least 43 weeks after the last dose of the first course of treatment/second treatment cycle, preferably as described in section (i 4), and

(iii 2) a second course of treatment/second treatment cycle of about 23 to 27 days after the last dose of the second course of treatment/first treatment cycle, preferably as described in section (i 4), and

iv) vaccinating said patient, preferably

(ivl) at least once between the beginning of the first course of therapy/first treatment cycle and the end of the first course of therapy, or during two weeks prior to the beginning of the first course of therapy/first treatment cycle,

And/or

iv 2) at least once between the beginning of the second treatment session/first treatment session and the end of the second treatment session, or during the two weeks prior to the beginning of said second treatment session/first treatment session,

46. Method according to one or more of the preceding claims, and in particular according to claim 45, wherein said patient is vaccinated

(iv 1) at least once during a week between the beginning of the first course of therapy and the end of the first course of therapy or prior to the beginning of the first course of therapy,

and/or

47. The method according to one or more of the preceding claims, wherein said patient is vaccinated

(iv 1) occurs at least once during one of the two weeks prior to the start of the first course of therapy/first treatment period and the end of the 10 th month or 11 th month of the first course of therapy, and/or during the last week;

And/or

iv 2) at least once between the beginning of the second course of treatment/first treatment cycle and the end of the second course of treatment, preferably at least once during one week of the two weeks before the beginning of the second course of treatment/first treatment cycle, preferably during the last week, between the beginning of the second course of treatment/first treatment cycle and the end of the 7 th month, 8 th month, 9 th month or 10 th month of the second course of treatment.

48. The method according to one or more of the preceding claims, wherein said patient is vaccinated

(ivl) during one or more months of said first course of treatment, wherein said one or more months are selected from month 1 of said first course of treatment and month 3-12 of said first course of treatment, preferably month 3-11 and especially month 4-10, and/or occur at least once, preferably once or twice, during one week of two weeks before the start of said first course of treatment/first treatment period, preferably during the last week;

and/or

iv 2) during one or more months of said first course of treatment, wherein said month is selected from month 1 of said first course of treatment and month 3-12 of said second course of treatment, preferably month 3-11, more preferably month 4-10 and especially month 4-8, and/or during one week of two weeks before the start of the second course of treatment/first treatment period, preferably at least once, preferably once or twice during the last week.

49. The method according to one or more of the preceding claims, wherein said patient is vaccinated

(ivl) within one or more months of said first course of treatment, wherein said one or more months are selected from month 1 of said first course of treatment, month 3 of said first course of treatment and month 4-12 of said first course of treatment, preferably month 5-11 and especially month 6-10, and/or occur at least once, preferably once or twice, during one week of two weeks prior to the start of said first course of treatment/first treatment period, preferably during the last week;

and/or

iv 2) during one or more months of said first course of treatment, wherein said month is selected from the 1 st month of said first course of treatment, the 3 rd month of said first course of treatment and the 4 th to 12 th months of said second course of treatment, preferably the 5 th to 11 th months and especially the 6 th to 10 th months, and/or during one week of the two weeks before the start of the second course of treatment/first treatment period, preferably at least once, preferably once or twice during the last week.

50. The method according to one or more of the preceding claims, wherein said patient is vaccinated

At least one occurrence between weeks 6 and 52 of the first course of treatment, preferably between weeks 8 and 52 of the first course of treatment, more preferably between weeks 9 and 52 of the first course of treatment, even more preferably between weeks 10 and 48 of the first course of treatment, and in particular between weeks 12 and 42 of the first course of treatment.

51. Method according to one or more of the preceding claims, and in particular according to claim 48, wherein said patient is vaccinated

Between weeks 6 and 52 of the second course of treatment, preferably between weeks 8 and 52 of the second course of treatment, more preferably between weeks 9 and 52 of the second course of treatment, even more preferably between weeks 10 and 48 of the second course of treatment, and in particular between weeks 12 and 42 of the second course of treatment,

and/or at least once during one of the two weeks prior to the start of the second course of therapy/first treatment cycle, preferably during the last week.

52. The method according to one or more of the preceding claims, wherein said patient is vaccinated

At least one occurrence between weeks 6 and 30 of the first course of treatment, preferably between weeks 7 and 28 of the first course of treatment, more preferably between weeks 8 and 26 of the first course of treatment, even more preferably between weeks 9 and 23 of the first course of treatment, and in particular between weeks 10 and 22 of the first course of treatment.

53. Method according to one or more of the preceding claims, and in particular according to claim 50, wherein said patient is vaccinated

At least one occurrence between weeks 6 and 30 of the second course of treatment, preferably between weeks 7 and 28 of the second course of treatment, more preferably between weeks 8 and 26 of the second course of treatment, even more preferably between weeks 9 and 23 of the second course of treatment, and in particular between weeks 10 and 22 of the second course of treatment.

54. The method according to one or more of the preceding claims, wherein said vaccinating said patient occurs at least once during weeks 1 to 5 of said first course of treatment and/or said second course of treatment, preferably during weeks 1 to 4, more preferably during weeks 2 to 4, and in particular during weeks 1 to 2, weeks 2 to 3 or weeks 3 to 4.

55. The method according to one or more of the preceding claims, wherein said vaccinating said patient preferably occurs at least once during weeks 6 to 18, preferably weeks 6 to 16, more preferably weeks 7 to 15, even more preferably weeks 8 to 14 or weeks 10 to 12, especially weeks 7 to 9, 10 to 12 or weeks 13 to 15 of said first and/or said second course of treatment.

56. The method according to one or more of the preceding claims, wherein said vaccinating said patient occurs at least once within one or two weeks, preferably immediately following one or two weeks, i.e. week 2 or week 3 of said course of treatment, after the last oral cladribine dose administered in said first course of treatment and/or in said first course of treatment in said second course of treatment.

57. The method according to one or more of the preceding claims, wherein said vaccinating said patient occurs at least once within one or two weeks, preferably immediately following one or two weeks, i.e. week 2 or week 3 of said first course of treatment, after the last oral cladribine dose administered in said first course of treatment.

58. The method according to one or more of the preceding claims, wherein the patient preferably receives one or more doses or injections of the vaccine, preferably one dose or injection of the vaccine, and in particular the first dose or injection of the vaccine or the first dose or injection.

59. A method according to one or more of the preceding claims, wherein

ii) a first dose or injection amount of said vaccine or of said first dose or injection amount, preferably administered according to one or more of claims 54 to 58, and

iii) A second dose or injection of said more than one dose or injection or the second dose or injection is administered at least 1 to 8 weeks after said first dose or injection.

60. The method according to one or more of the preceding claims, wherein said second dose or injection amount of said vaccine is administered during said first or second course of treatment, preferably from 6 to 16 weeks, more preferably from 7 to 14 weeks, even more preferably from 8 to 13 weeks, and especially from 9 to 11 weeks or from 10 to 12 weeks of said first course of treatment.

61. The method according to one or more of the preceding claims, wherein the second of said two or more vaccine doses or injections is administered 7 to 15 weeks, preferably 7 to 12 weeks, and especially 7 weeks, 8 weeks or 9 weeks after the administration day of said first dose or injection of said vaccination, preferably according to one or more of claims 54 to 58, and especially preferably within one week of 1 to 4 weeks, or one week of 2 to 3 weeks, counted from the first day wherein cladribine is orally administered in each course of treatment.

62. The method according to one or more of the preceding claims, wherein a second of said two or more vaccine doses or injections is administered 5 to 12 weeks, preferably 6 to 10 weeks, and especially 6 weeks, 7 weeks or 8 weeks after the administration day of said first dose or injection of said vaccination, preferably according to one or more of claims 54 to 58, and especially preferably within one week of 2 to 5 weeks, and especially one week of 2, 3 or 4 weeks, counted from the first day wherein cladribine is orally administered in each course of treatment.

63. The method according to one or more of the preceding claims, wherein the vaccine to be administered at least twice, preferably twice, more preferably as two or more separate doses or injections, is administered separately over a period of at least 2 weeks and up to 8 months, preferably at least 3 weeks and up to 6 months, and especially around at least 4 weeks and up to 6 months.

64. The method according to one or more of the preceding claims, wherein said at least two separate vaccinations, preferably said two vaccinations and/or said 2 separate doses or injections are separated

From 3 to 9 weeks, preferably from about 4 to 8 weeks, such as about 4 weeks or about 8 weeks, or

4 to 7 months, preferably 5 to 6 months, for example about 6 months.

65. The method according to one or more of the preceding claims, wherein said at least two separate vaccinations, preferably said two vaccinations and/or said 2 separate doses or injections are separated

a) From 3 to 9 weeks, preferably from about 4 to 8 weeks, such as about 4 weeks or about 8 weeks, or

b) From 4 to 7 months, preferably from 5 to 6 months, for example about 6 months,

and preferably

i) Wherein a first of said at least two separate vaccinations, preferably a first of said two vaccinations and/or a first of said 2 separate doses or injections, is administered within the first 2 weeks, the first 3 weeks, the first 4 weeks or the first 5 weeks of said first course of treatment or said second course of treatment, or

ii) wherein a first of said at least two separate vaccinations, preferably a first of said two vaccinations and/or a first of said 2 separate doses or injections, is administered before the start of said first course of treatment or during the last two weeks, preferably during the last week, before the start of said second course of treatment.

66. The method according to one or more of the preceding claims, wherein said at least two separate vaccinations, preferably said two vaccinations and/or said 2 separate doses or injections are separated

About 1 to 6 weeks, preferably about 2 to 5 weeks, and especially about 3 weeks or about 4 weeks.

67. The method according to one or more of the preceding claims, wherein the at least two separate vaccinations, preferably the two vaccinations and/or the 2 separate doses or injections are separated by about 1 to 6 weeks, preferably about 2 to 5 weeks, and especially about 3 weeks or about 4 weeks,

68. The method according to one or more of the preceding claims, wherein vaccinating the patient at least once comprises vaccinating the patient at least twice with a vaccine and/or using two or more separate doses or injections of a vaccine, wherein the target virus or target bacteria or target viruses of the vaccine are the same for each of the vaccinations and/or each of the doses or injections.

69. The method according to one or more of the preceding claims, wherein vaccinating the patient at least once comprises vaccinating the patient at least twice and/or using two or more separate doses or injections of vaccine, wherein the vaccine is very similar, identical or substantially identical for each vaccination and/or in each dose or injection of vaccine.

70. The method according to one or more of the preceding claims, wherein the patient is administered two vaccinations, and

a) Administering one of the two vaccinations to the patient

a1 Within the 1 st year/first course of treatment, or with oral administration of cladribine

a2 During the 2 nd year/second course of treatment in which cladribine is orally administered,

Time frames, preferably as given in one or more of the preceding claims, and

b) One vaccination is given below

b1 Outside of the 1 st year/first course of treatment, or in which cladribine is orally administered

b2 Outside of the 2 nd/second course of treatment in which cladribine is orally administered,

preferably within 1 to 3 weeks, more preferably 1 to 2 weeks and especially one week before each treatment year/each session is initiated.

71. The method according to one or more of the preceding claims, wherein two doses or two injection amounts of the same vaccine are administered to the patient, and

a) Administering a dose or injection of said vaccine to said patient

time frames, preferably as given in one or more of the preceding claims, and

b) One dose or injection of the vaccine is given below

72. The method according to one or more of the preceding claims, wherein the patient is administered two vaccinations, and wherein the patient is administered two vaccinations

a) Within the 1 st year/first course of treatment of oral administration of cladribine therein, or

b) During the 2 nd/second course of treatment in which cladribine is administered orally,

time frames as given in one or more of the preceding claims are preferred.

73. The method according to one or more of the preceding claims, wherein two doses or two injection amounts of the same vaccine are administered to the patient, and

administering two doses or injections of the vaccine to the patient

time frames as given in one or more of the preceding claims are preferred.

74. The method according to one or more of the preceding claims, wherein vaccinating the patient comprises vaccinating the patient twice with two separate doses or injections of vaccine, wherein the vaccine is very similar, identical or substantially identical for each vaccination and in each dose or injection of vaccine.

75. Method according to one or more of the preceding claims, and in particular according to one or more of the claims 58 to 74, wherein the vaccine

a) Selected from: (anti) varicella zoster virus vaccine, (anti) zoster virus vaccine, live attenuated (anti) varicella zoster virus vaccine, inactivated and/or recombinant (anti) varicella zoster virus vaccine and inactivated and/or recombinant (anti) varicella zoster virus vaccine;

and/or

protein-based (anti) SARS-CoV-2/COVID-19 virus vaccines, inactivated virus-based (anti) SARS-CoV-2/COVID-19 virus vaccines and dead virus-based (anti) SARS-CoV-2/COVID-19 virus vaccines.

76. Method according to one or more of the preceding claims, and in particular according to one or more of claims 58 to 75 or 59 to 75, wherein the vaccine is recombinant, adjuvanted Herpes zoster vaccine, preferably recombinant, adjuvanted herpes zoster vaccine comprising recombinant varicella zoster virus glycoprotein E, and in particular

77. The method according to one or more of the preceding claims, and in particular according to one or more of claims 58 to 74, wherein the vaccine is a (anti) influenza virus vaccine selected from the group consisting of a monovalent (anti) influenza virus vaccine, a bivalent (anti) influenza virus vaccine, a trivalent (anti) influenza virus vaccine, a tetravalent (anti) influenza virus vaccine and a multivalent (anti) influenza virus vaccine.

78. A method according to one or more of the preceding claims, and in particular according to one or more of claims 75 to 77, and in particular according to claim 76, wherein

1) Administering a first vaccination dose or injection to the patient during weeks 1 to 5, preferably weeks 1 to 4, even more preferably weeks 2 to 4 and especially weeks 2 to 3 of a treatment year 1/first course of treatment wherein cladribine is orally administered, and

2) A second vaccination dose or injection is administered to the patient during weeks 8 to 13, preferably weeks 9 to 12, more preferably weeks 9 to 11 and especially during weeks 10 to 12 of the treatment 1/first course of treatment wherein cladribine is orally administered.

79. A method according to one or more of the preceding claims, and in particular according to one or more of claims 75 to 77, and in particular according to claim 76, wherein

2) A second vaccination dose or injection is administered to the patient during weeks 9 to 12, preferably weeks 10 to 12, more preferably weeks 9 to 11 and especially during weeks 10 to 11 of the treatment 1/first course of treatment wherein cladribine is orally administered.

80. A method according to one or more of the preceding claims, and in particular according to one or more of claims 75 to 77, and in particular according to claim 76, wherein

1) Administering a first vaccination dose or injection to the patient during weeks 1 to 5, preferably weeks 1 to 4, even more preferably weeks 2 to 4 and especially weeks 2 to 3 or weeks 3 to 4 of a treatment 1 year/first course of treatment wherein cladribine is orally administered, and

2) A second vaccination dose or injection is administered to the patient during weeks 9 to 30, preferably weeks 12 to 28, more preferably weeks 13 to 26 and especially during weeks 15 to 26 of the treatment 1 year/first course of treatment wherein cladribine is orally administered.

81. A method according to one or more of the preceding claims, and in particular according to one or more of claims 75 to 77, and in particular according to claim 76, wherein

1) Administering a first vaccination dose or injection to the patient during weeks 1 to 5, preferably weeks 1 to 4, even more preferably weeks 2 to 4 and especially weeks 2 to 3 or weeks 3 to 4 of a 2 nd year/second course of treatment in which cladribine is orally administered, and

2) A second vaccination dose or injection is administered to the patient during weeks 8 to 13, preferably weeks 9 to 12, more preferably weeks 9 to 11 and especially during weeks 10 to 12 of the treatment 2/second course of treatment in which cladribine is orally administered.

82. A method according to one or more of the preceding claims, and in particular according to one or more of claims 75 to 77, and in particular according to claim 76, wherein

2) A second vaccination dose or injection is administered to the patient during weeks 9 to 12, preferably weeks 10 to 12, more preferably weeks 9 to 11 and especially during weeks 10 to 11 or weeks 11 to 12 of the treatment 2/second course of treatment wherein cladribine is orally administered.

83. A method according to one or more of the preceding claims, and in particular according to one or more of claims 75 to 77, and in particular according to claim 76, wherein

2) A second vaccination dose or injection is administered to the patient during weeks 9 to 30, preferably weeks 12 to 28, more preferably weeks 13 to 26 and especially during weeks 15 to 26 of the treatment 2/second course of treatment in which cladribine is orally administered.

84. The method according to one or more of the preceding claims, and in particular according to one or more of claims 58 to 75, 75 to 83 and/or claim 83, wherein the vaccine is a recombinant, adjuvanted herpes zoster vaccine, preferably a recombinant, adjuvanted herpes zoster vaccine comprising recombinant varicella zoster virus glycoprotein E, and in particularAnd wherein said first vaccination, said first dose and/or said first injected quantitySeparate from the second vaccination, the second dose and/or the second injection quantity

i) For a period of 2 to 6 weeks, preferably 3 to 5 weeks, and especially about 4 weeks or about one month,

ii) a period of 6 to 11 weeks, preferably 7 to 10 weeks, and especially about 8 to 9 weeks or about two months, or

iii) For a period of 2 to 8 months, preferably 2 to 7 months, and especially about 3 to 6 months.

85. A method for treating Multiple Sclerosis (MS) in a patient in need thereof, the method comprising

a) With cladribine tabletsTreating said patient, preferably as described in one or more of the preceding claims, and

b) Non-live vaccine for varicella zosterThe patient is vaccinated, wherein the vaccine is vaccinated once (first dose) within weeks 2 to 4, followed by 10 to 12 weeks (second dose), counted from the day the patient receives the first dose of the cladribine tablet, with the possibility of delaying the administration of the second dose of the vaccine until 6 months after the administration of the first dose of the vaccine.

86. A method for treating Multiple Sclerosis (MS) in a patient in need thereof, the method comprising

87. A method for treating Multiple Sclerosis (MS) in a patient in need thereof, the method comprising

b) Non-live vaccine for varicella zosterThe patient is vaccinated, wherein the vaccination is once (first dose) within month 1, followed by 3 to 8 months and preferably 3 to 6 months (second dose), counted from the day the patient receives the first dose of the cladribine tablet, and wherein the first dose of the vaccine and the second dose of the vaccine are preferably administered 1 to 7 months apart, more preferably 2 to 6 months apart, and especially 2 to 3 months or 3 to 6 months apart.

88. A method for treating Multiple Sclerosis (MS) in a patient in need thereof, the method comprising

b) Non-live vaccine for varicella zosterThe patient is vaccinated, wherein the patient is vaccinated with the vaccine twice, preferably by administering a first dose and a second dose that are 2 to 6 months apart, and preferably about two months or about three months apart, wherein the first dose of the vaccine is administered within 4 to 10 months, and especially 5 to 8 months, counted from the day the patient receives the first dose of the cladribine tablet.

89. The method according to claim 85, wherein said patient is antibody negative for varicella zoster virus, preferably antibody negative for varicella zoster virus prior to said vaccination with said varicella zoster non-live vaccine and/or prior to receiving the first dose of said cladribine tablet.

90. A method for treating Multiple Sclerosis (MS) in a patient in need thereof, the method comprising

b) At least one vaccine is vaccinated to the patient, wherein the at least one vaccination occurs during months 3 to 8 and especially during months 3 to 6, the months being counted from the day the patient receives the first dose of the cladribine tablet.

91. A method for treating Multiple Sclerosis (MS) in a patient in need thereof, the method comprising

b1 Wherein a first vaccination occurs 1 or 2 weeks before or 1 or 2 weeks after the day of the patient receiving the first dose of the cladribine tablet, and optionally

Wherein at least one subsequent vaccination occurs 2 to 4 weeks or 3 to 10 weeks after the first vaccination occurs.

92. A method for treating Multiple Sclerosis (MS) in a patient in need thereof, the method comprising

Wherein at least one subsequent vaccination occurs 2 to 8 months or 2 to 6 months after the first vaccination occurs.

93. A method for treating Multiple Sclerosis (MS) in a patient in need thereof, the method comprising

Wherein at least one subsequent vaccination occurs within months 2 to 12, preferably 2 to 10 and especially 3 to 9, the months being counted from the day the patient receives the first dose of the cladribine tablet.

94. The method according to one or more of claims 90 to 93, wherein the vaccine is selected from the group consisting of

protein-based (anti) SARS-CoV-2/COVID-19 virus vaccine, inactivated virus-based (anti) SARS-CoV-2/COVID-19 virus vaccine, and dead virus-based (anti) SARS-CoV-2/COVID-19 virus vaccine;

and/or

95. A method for treating Multiple Sclerosis (MS) in a patient in need thereof, the method comprising

b) Vaccinating said patient at least once, preferably at least twice and especially twice with a vaccine, wherein said vaccine is an (anti) SARS-CoV-2/COVID-19 viral vaccine, preferably an (anti) SARS-CoV-2/COVID-19 viral vaccine as described in claim 75 and/or claim 94,

b1 Wherein a first vaccination occurs 1 or 2 weeks before or 1 or 2 weeks after the day of the patient receiving the first dose of the cladribine tablet, and optionally a second vaccination occurs 2 to 6 weeks, preferably 3 to 5 weeks and especially 3 to 4 weeks after the first vaccination, optionally followed by one or more subsequent vaccinations after at least 3 weeks, at least 6 weeks or at least 12 weeks;

b2 Wherein a first vaccination occurs 1 or 2 weeks after the day of the patient receiving the first dose of the cladribine tablet, and optionally a second vaccination occurs 2 to 6 weeks, preferably 3 to 5 weeks and especially 3 to 4 weeks after the first vaccination, optionally followed by one or more subsequent vaccinations after at least 3 weeks, at least 6 weeks or at least 12 weeks;

And/or

96. A method for treating Multiple Sclerosis (MS) in a patient in need thereof, the method comprising

b) Vaccinating said patient with at least one vaccine, preferably one or two times, wherein said vaccine is an (anti) influenza virus vaccine, preferably an (anti) influenza virus vaccine as described in claim 76 and/or claim 94,

b1 Wherein a first vaccination occurs 1 or 2 weeks before or 1 or 2 weeks after the day of the patient receiving the first dose of the cladribine tablet, and optionally a second vaccination occurs 1 to 6 weeks, preferably 2 to 5 weeks and especially 1-2 or 3-4 weeks after the first vaccination, optionally followed by one or more subsequent vaccinations after at least 3 weeks, at least 6 weeks or at least 12 weeks;

and/or

97. The method according to one or more of the preceding claims, and in particular according to one or more of claims 84 to 96, wherein the day on which the patient receives the first dose of the cladribine tablet is

a) A first day of the first treatment year (treatment year 1 or first course) of cladribine treatment, preferably cladribine treatment as described in one or more of the preceding claims,

and/or

b) The first day of the second treatment year (treatment year 2 or second course) of cladribine treatment, preferably cladribine treatment as described in one or more of the preceding claims.

98. Method according to one or more of the preceding claims, wherein in the above method all suggestions and timelines for vaccinating a patient and/or administering said vaccine given in relation to the first course of treatment, the first year of treatment and/or the 1 st year of treatment are preferably also applicable to the second course of treatment, the second year of treatment and/or the 2 nd year of treatment, respectively, and, if applicable, to any subsequent course of treatment or year of treatment.

99. The method according to one or more of the preceding claims, wherein each of said 2 once-per-year courses, preferably said first course and/or said second course, has a duration of about 1 year, preferably about 12 months, more preferably 46 to 54 weeks, more preferably 48-53 weeks and especially about 48 or about 52 weeks, preferably is selected independently for each course of course.

100. The method according to one or more of the preceding claims, wherein the autoimmune disorder is selected from Multiple Sclerosis (MS), rheumatoid Arthritis (RA), systemic Lupus Erythematosus (SLE), neuromyelitis spectrum disease (NMOSD) and Myasthenia Gravis (MG), preferably Multiple Sclerosis (MS), neuromyelitis spectrum disease (NMOSD) and Myasthenia Gravis (MG), and preferably Multiple Sclerosis (MS), more preferably multiple sclerosis selected from Relapsing Multiple Sclerosis (RMS), relapsing Remitting Multiple Sclerosis (RRMS), secondary Progressive Multiple Sclerosis (SPMS) and Primary Progressive Multiple Sclerosis (PPMS), preferably in subjects or patients with High Disease Activity (HDA) and/or age above 30 years, above 40 years, above 50 years, above 60 years or above 70 years.