CN116568322A - New use of an immunogenic or vaccine composition against covd-19 - Google Patents
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Landscapes
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
Abstract
The present invention relates to an immunogenic or vaccine composition against SARS-CoV-2 for the treatment of Covid-19, characterized in that said composition is applied to the ocular mucosa and/or to the genitourinary mucosa.
Description
Background
In addition to the systemic immune system, our body also contains a mucosa-associated immune system (called MALT, mucosa-associated lymphoid tissue). The mucosa locally contains its own immune system, for example in the digestive tract (GALT, intestinal-related lymphoid tissue), in the nose (NALT, nasal-related lymphoid tissue) or even in the eye (GALT, conjunctival-related lymphoid tissue).
In fact, the site of entry of pathogens into the body is typically near the mucosa of the eye, nose, mouth or gastrointestinal tract. Thus, our body contains a large number of cellular and biochemical defense mechanisms directly on these mucous membranes, which are activated upon contact with pathogens. Typically, the mucosal immune system includes epithelial cells, innate immune cells, and dendritic cells, which are the interface between innate immunity and specific (acquired) immunity. Thus, the mucosa may contain innate immune cells, immunocompetent cells, memory cells and antibody producing cells.
After experiencing a primary infection by a pathogen, the body develops a systemic (serum) immunity against the pathogen. Furthermore, if the pathogen comes into contact with the mucosa of the body, mucosal immunity is generated in addition to systemic immunity.
Vaccines that can produce mucosal immunity are known. These vaccines are basically administered by the nasal or oral route. They present the unique advantage of inducing protective immune responses at mucosal and systemic levels. They also target the passage of mucous membranes blocking the pathways of most bacterial and viral pathogens (blocking crossing). For example, this is applied by nasal spraysInfluenza vaccine or even orally administered polio vaccine. Influenza virus (A virus) vaccination by ocular route in ferrets is also described in articles Eyedrop Vaccination Induced Systemic and Mucosal Immunity against Influenza Virus in Ferrets de Sangchul Yoon, eun-Do Kim, min-Suk Song, soo Jung Han, tae Kwann Park, kyoung Sub Choi, young-Ki Choi, and Kyoung Yul Seo; PLoS one.2016;11 In (6), e0157634 was studied. The teams of Kyoung Yul Seo, soo Jung Han, hye-Ran Cha, sang-Uk Seo, joo-Hye Song, so-Hyang Chung and Mi-Na Kwen have also studied ocular route vaccination in mice (Eye Mucosa: an Efficient Vaccine Delivery Route for Inducing Protective Immunity; J.Immunol 2010; 185:3610-3619), although mice are not a natural host for viruses.
In the case where the pathogen colonizes the mucosa and is highly infectious, the pathogen rapidly breeds after colonization of the mucosa, so that the infection of the mucosa and deeper layers progresses faster than the organism can establish effective immunity to eliminate the pathogen. This is typical of current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. In fact, covd-19 (or 2019 coronavirus disease) manifests itself mainly as mucosal infections and inflammations, with secondary severe systemic diseases, as well as influenza, herpes or poliomyelitis.
Current covd-19 pandemics have led to unprecedented research, particularly in order to develop vaccines, several covd-19 vaccines have now been approved for vaccinating the global population. Examples of such vaccines are: (1) Pfizer/BioNTech mRNA vaccine, commonly referred to as Bnt162b2 or(2) Moderna mRNA vaccine, commonly known as Moderna mRNA-1273, spikevax or Moderna COVID-19 vaccine; (3) Non-replicating viral vector vaccines of Alaslicon, commonly referred to as +.>ChAdOx1-S or Aoslercanic COVID-19 vaccine; (4) Janssen/Johnson&Johnson's non-replicating viral vector Vaccine, commonly referred to as ad26cov2.S, JMJ Vaccine or J &Jcovd-19; (5) Gamaleley a's non-replicating viral vector vaccine, commonly known as Sputnik V or Gam-COVID-Vac; (6) Sinovac R&D adjuvanted whole inactivated vaccine against covd-19, commonly known as CoronaVac; or (7) a recombinant nanoparticle subunit vaccine of Novavax with adjuvant (matrixM), commonly referred to as nuvaxoid or NVX-CoV2373。
All currently available covd-19 vaccines are administered by the intramuscular route. Thus, they produce good systemic immunity, limiting the severe progression of the disease, but they are not used to develop immunity in the mucosa. However, this immunity in the mucosa is critical for preventing new infections, otherwise the risk of SARS-CoV-2 infection will still be high.
In addition, the number of currently available vaccines remains too small, and the side effects that these vaccines may have (e.g., rare thrombosis) are also a concern for individuals who are therefore reluctant to vaccinate.
Thus, there remains a need to improve vaccination of the global population against covd-19 as a way to get rid of this pandemic crisis.
Disclosure of Invention
The present invention addresses this need by a new covd-19 vaccination modality that can improve immunity (dual immunity-systemic and mucosal immunity-actually yielding better protection against pathogens, thus contributing to the formation of collective immunity) while also reducing the risk of serious side effects associated with vaccination. Thus, the invention is useful for forming immunoglobulins of the IgM type, followed by immunoglobulins of the IgG type, in particular immunoglobulins of the secretory IgA type (sIgA on the mucosa). The present invention is also directed to providing a new most effective mode of covd-19 vaccination.
The present invention also aims to provide a new covd-19 vaccination pattern that is simpler and faster to implement, thereby increasing vaccination speed.
The invention is useful for developing mucosal immunity against SARS-CoV-2 by targeting the ocular mucosa and/or genitourinary mucosa. The present invention is also directed to the development of an immunity known as bactericidal (sterilizing). Indeed, it is an object of the present invention to target mucous membranes to form mainly IgA-type immunoglobulins (monomeric IgA, but also dimeric IgA and secretory IgA on mucous membranes), in particular in order to block the replication of the virus in the mucous membranes of the respiratory tract (this may be achieved by IgA-type rather than IgG-type immunoglobulins).
The present invention therefore relates to an immunogenic or vaccine composition against SARS-CoV-2 for the prevention and/or treatment of Covid-19, characterized in that it is administered on the ocular mucosa and/or on the urogenital mucosa.
The purpose of administering such a composition is to establish mucosal immunity and serum immunity against SARS-CoV-2. This dual immunity helps to better protect the organism from viruses and limit the risk of infection without serious systemic side effects (especially rare cases of thrombosis) that may currently be caused by some vaccines being injected intramuscularly. Indeed, in the case of the present invention, since serum immunity is indirectly obtained by mucosal immunity, no thrombotic event is expected to occur.
According to the present invention, the expression-immunogenic composition "and/or-vaccine composition" is understood to mean a composition that induces an immune response against SARS-CoV-2 after administration to a subject. Vaccine compositions are particularly useful for developing immunity, and more particularly protective and adaptive immune responses against SARS-CoV-2. Such immune response may be humoral and/or cellular. This immunity is also intended to be immune.
According to the present invention, the term SARS-CoV-2 is understood to mean viruses belonging to the family Coronaviridae, genus beta coronavirus and subgenera Sarbecovirus. It is an enveloped virus with a helical capsid whose genome consists of a single stranded RNA of about 30,000 nucleotides. The structure of SARS-CoV-2 virions comprises, inter alia, a helical capsid formed from the N protein, a matrix formed from the M protein and a lipid envelope comprising at least two protein types: s (glycoprotein) (spike) and small envelope protein (E) (and potentially Hemagglutinin Esterase (HE)). By producing neutralizing antibodies, S proteins and variants are the primary targets of immune responses. This surface protein binds to the ACE2 receptor (expressed in many tissues) and thus enables the virus to penetrate the cells of the contaminated organism. The S protein comprises two subunits, S1 and S2. S1 includes a Receptor Binding Domain (RBD) comprising a Receptor Binding Motif (RBM). The S2 subunit comprises a fusion peptide that allows the cell membrane of the cellular host (contaminated organism) to fuse with the viral envelope.
More specifically, according to the present invention, the term-SARS-CoV-2 "is understood to mean the virus whose sequence was originally described in GenBank under accession number MN908947, as well as all variants of the virus, in particular uk variants, south africa variants, indian variants and brazil/japan variants. In general, this is understood to mean in particular variants known as Alpha (B.1.1.7), beta (B.1.351), gamma (P.1), delta (B.1.617.2) and Omicron (B.1.1.529). This is also understood to mean variants B.1.640, B.1.427, B.1.429, B.1.616, B.1.525, P.3, B.1.617.2, B.1.620, B.1.617.3, B.1.214.2, A.23.1, A.27, A.28, C.16, B.1.351, B.1.526.1, B.1.526.2, P.2, B.1.1.519, AV.1, AT.1, C.36, B.1.621, C.37, AY.4.2, B.1.1.318, B.1.617.2, C.1.2 or BA.2. Information on SARS-CoV-2 sequences, mutations and variant sequences can be found, for example, in the following links: https:// www.ncbi.nlm.nih.gov/sars-cov-2/; https:// www.cdc.gov/corenavirus/2019-ncov/cases-updates/variant-survivin-cance/variant-info. https:// www.ecdc.europa.eu/en/covid-19/variants-content; https:// www.gisaid.org/.
According to the invention, the expression "prevention of Covid-19" is understood to mean prevention (prophlaxis). Administration of the immunogenic or vaccine composition according to the invention is particularly useful for blocking or reducing the risk of forming Covid-19 and/or reducing the risk of forming a form of the disease known as severe (meaning having severe symptoms, such as dyspnea and/or requiring hospitalization, typically in an intensive care unit) where applicable. Administration of the immunogenic or vaccine compositions according to the invention may also block or reduce the risk of viral transmission, typically from one person to another. According to a specific embodiment, the immunogenic or vaccine composition for preventing Covid-19 according to the invention is administered to a subject that is not contaminated, preferably not infected, with SARS-CoV-2.
According to the present invention, the expression-treatment Covid-19 "is understood as treatment. Administration of an immunogenic or vaccine composition according to the invention may in fact be considered to stimulate the natural defenses of the body even though the human is already minimally contaminated with viruses. According to a specific embodiment, the immunogenic or vaccine composition for the treatment of Covid-19 according to the invention is administered to a subject who has been contaminated and/or infected with SARS-CoV-2.
Preferably, the present invention relates to an immunogenic or vaccine composition against SARS-CoV-2 for the prevention of Covid-19, characterized in that it is administered on the ocular mucosa and/or on the urogenital mucosa.
According to the invention, the expression ocular mucosa is understood to mean conjunctiva and cornea. The conjunctiva is a transparent mucosa that covers the inner surfaces of the upper and lower eyelids and covers the anterior surface of the eyeball. Thus, ocular mucosa is more precisely understood to mean the palpebral conjunctiva and bulbar conjunctiva, as well as the conjunctival fornix.
According to the invention, the expression "urogenital mucosa" is understood to mean the mucosa of the urinary and/or reproductive system (male and female systems). Thus, rather, the urogenital mucosa is understood to mean the urogenital tract.
Targeting of the ocular and/or genitourinary mucosa serves to target the mucosa, which (i) is itself only weakly involved in the transmission of pathogens, but (ii) at the same time has very high immunological activity, which serves to immunize the body very rapidly, in particular prior to respiratory tract infections.
One of the non-limiting assumptions of the present inventors is that in fact, infection of the eye with SARS-CoV-2 results in a rapid build up of immunity, allowing the body to gain time so that when the contamination and/or infection progresses in the body to the nose, the body is already immunized. This progression of contamination and/or infection from eye to nose can be explained by the presence of the nasolacrimal duct connecting the nose and eyes. In cases of keratitis caused by APC virus (Adeno-paryngo conjunctivitis, epidemic keratitis type adenovirus), nasolacrimal duct infection has been described. The typical progression of this disease begins with infection of the conjunctiva by droplets and appears as severe conjunctivitis followed by pharyngitis. This can also explain why subjects, particularly medical personnel, develop systemic immunity against SARS-CoV-2 after onset of conjunctivitis positive for SARS-CoV-2.
Preferably, the immunogenic or vaccine composition is applied to the ocular mucosa.
According to another even more preferred embodiment, the invention thus relates to an immunogenic or vaccine composition against SARS-CoV-2 for use in the prevention of Covid-19, characterized in that it is applied to the ocular mucosa.
According to the invention, the immunogenic or vaccine composition may be administered in only one eye or in both eyes, preferably in both eyes. Unlike intramuscular administration of vaccines, which require increased organization and medical work (e.g., preparation of syringes, need for available resuscitation equipment in case of severe reaction to vaccination, etc.), injection onto the ocular mucosa (typically by eye drops) is simpler and faster to perform. In fact, the serious risks (such as the above-mentioned risk of thrombosis) are reduced, as are the risks of serious allergies, which are mainly manifested as stinging, tearing or even redeye eyes. Vaccination via eye drops can be further used for faster and larger scale vaccination.
According to one embodiment, the immunogenic or vaccine composition may be administered as a first dose of a vaccination program or as a booster in one or both eyes. According to one embodiment, the immunogenic or vaccine composition is applied to the ocular mucosa and/or the urogenital mucosa before or after at least one intramuscular administration of the immunogenic or vaccine composition. Preferably, the immunogenic or vaccine composition is applied to the ocular mucosa before or after at least one intramuscular administration of the immunogenic or vaccine composition. Preferably, the vaccine composition is applied to the ocular mucosa before or after at least one intramuscular administration of the vaccine composition. Typically, this means that the subject is vaccinated intramuscularly for the first time and then the enhancer is administered to the mucosa, particularly the ocular mucosa. This may also mean that the subject is vaccinated intramuscularly for the first time, one or more booster immunizations are also vaccinated intramuscularly, and then one or more additional booster immunizations are performed via mucosal, in particular ocular, administration. If a novel enhancer is required to target a particular variant of the SARS-CoV-2 virus, administration of an immunogenic or vaccine composition on the ocular mucosa and/or genitourinary mucosa after one or more intramuscular injections of the vaccine may be attractive. Typically, the immunogenic or vaccine composition according to the invention is administered on the ocular mucosa and/or the urogenital mucosa after at least one intramuscular administration, with the aim of enhancing the acquired immunity after the first intramuscular administration. This also means that the first administration of the immunogenic or vaccine composition can be performed on the ocular mucosa and/or the urogenital mucosa and that the boosting can be performed on the same mucosa or by the intramuscular route.
According to one embodiment, the immunogenic or vaccine composition comprises one or more substances for eliciting an immune response against SARS-CoV-2. Typically, the immunogenic or vaccine composition according to the invention comprises one or more SARS-CoV-2 antigen. Preferably, the antigen is specific for SARS-CoV-2.
According to one embodiment, the immune or vaccine composition is used to elicit an immune response against SARS-CoV-2, once it comprises at least one antigen against SARS-CoV-2, the microorganism (e.g., virus or bacterium) can produce at least one antigen against SARS-CoV-2, or it comprises genetic material necessary to express at least one antigen (typically mRNA) of SARS-CoV-2. In the first case, the antigen will be in contact with the mucosa immediately after administration, while in the second and third cases a period of latency, i.e. the time for antigen production after administration of the composition, is expected. Preferably, the microorganism is not pathogenic itself, and the only immune response it may elicit is that associated with the SARS-CoV-2 antigen.
According to a specific embodiment, the substance/antigen used to elicit an immune response against SARS-CoV-2 is selected from the group consisting of: (i) an inactivated SARS-CoV-2 virus, (ii) an attenuated SARS-CoV-2 virus (iii) a modified SARS-CoV-2 virus, preferably an inactivated or attenuated, that expresses or is capable of expressing one or more SARS-CoV-2 antigens (e.g., SARS-CoV-2 viral proteins), (iv) a genetically modified microorganism (e.g., bacteria or virus, preferably an inactivated or attenuated), that expresses or is capable of expressing one or more SARS-CoV-2 antigens (e.g., SARS-CoV-2 viral proteins), (v) a messenger ribonucleic acid (mRNA) that encodes one or more SARS-CoV-2 antigens (e.g., SARS-CoV-2 viral proteins), (vi) a deoxyribonucleic acid (DNA) that encodes one or more SARS-CoV-2 antigens (e.g., SARS-CoV-2 viral proteins), (vii) a SARS-CoV-2 viral protein or one or more fragments thereof, or (viii) a fusion protein or one or more fragments thereof comprising SARS-CoV-2 viral proteins. … … the substance/antigen used to elicit an immune response against SARS-CoV-2 may also be (ix) a SARS-CoV-2 virus, meaning a live virus that is not inactivated or attenuated, or even (x) a recombinant cell (e.g., a dendritic cell) that expresses or is capable of expressing one or more SARS-CoV-2 antigens, (xi) a DNA plasmid encoding one or more SARS-CoV-2 antigens (e.g., SARS-CoV-2 viral proteins), or (xii) a pseudoviral particle comprising one or more SARS-CoV-2 antigens. According to a specific embodiment, the substance/antigen used to elicit an immune response against SARS-CoV-2 is a genetically modified microorganism expressing or capable of expressing one or more SARS-CoV-2 antigens (e.g., SARS-CoV-2 viral proteins) or SARS-CoV-2 virus, preferably a genetically modified microorganism (particularly an adenovirus) expressing or capable of expressing one or more SARS-CoV-2 antigens (e.g., viral vectors). The viral protein fragment preferably comprises an immunodominant epitope or a biological analogue thereof. According to one embodiment, the viral protein fragment is an immunogenic fragment. The viral protein fragment may be recombinant.
According to a specific embodiment, the substance/antigen used to elicit an immune response against SARS-CoV-2 is selected from the group consisting of: (i) an inactivated SARS-CoV-2 virus, (ii) an inactivated SARS-CoV-2 virus (iii) a modified SARS-CoV-2 virus, preferably an inactivated or attenuated, that expresses or is capable of expressing one or more antigens (e.g., viral proteins of SARS-CoV-2 virus), (iv) a genetically modified microorganism (e.g., bacteria or virus, preferably inactivated or attenuated) that expresses or is capable of expressing one or more SARS-CoV-2 antigens (e.g., SARS-CoV-2 viral proteins), (v) a messenger ribonucleic acid (mRNA) that encodes one or more SARS-CoV-2 antigens (e.g., SARS-CoV-2 viral proteins), (vi) a deoxyribonucleic acid (DNA) that encodes one or more SARS-CoV-2 antigens (e.g., SARS-CoV-2 viral proteins), (vii) a SARS-CoV-2 virus.
The composition according to the invention may comprise one or more substances (antigens) for eliciting an immune response against SARS-CoV-2. According to one embodiment, the various substances (antigens) may be directed against different parts of the same virus (e.g. different epitopes on viral proteins), different strains of the same virus, variants of the same virus and even several different viruses (combination vaccines). The immunogenic or vaccine composition according to the invention may thus be monovalent or multivalent. Monovalent immunogenic or vaccine compositions provide protection against a single pathogen, while multivalent immunogenic or vaccine compositions provide protection against multiple pathogens.
According to one embodiment, the expression-SARS-CoV-2 viral protein "is understood more specifically to mean structural proteins and accessory proteins of the virus, preferably structural proteins. In this way, according to one embodiment, the viral protein is selected from: s, HE, M, N or E protein or ORF protein, more specifically ORF1a, ORF1b, ORF3, ORF6, ORF7a, ORF7b, ORF8a, ORF8b. Preferably, the viral protein is selected from S, HE, M, N or E proteins, more particularly S, HE, M or E, even more particularly S proteins. The immunogenic fragment of the S protein is more specifically the Receptor Binding Domain (RBD), the S1 subunit or the cleavage region between the S1 subunit and the S2 subunit. According to the present invention, a viral protein is understood to mean a natural protein of a virus (for example a viral protein found in nature), a protein that is mutated or mutated compared to a natural protein or a synthetic protein (modified, mutated or unmodified).
An immunogenic or vaccine composition according to the invention is administered to a subject. According to one embodiment, the immunogenic or vaccine composition is for use in the prevention and/or treatment of Covid-19 in humans. According to one embodiment, the immunogenic or vaccine composition is for use in the prevention and/or treatment of Covid-19 in children or adults, in particular Covid-19 in adults. According to the invention, an adult is understood to mean a person starting from the age of 16, preferably from the age of 18. Even more preferably, the adult is greater than or equal to 18 years old and up to 55 years old. According to one embodiment, the immunogenic or vaccine composition may be administered to a subject at least 12 years old. According to one embodiment, the immunogenic or vaccine composition may be administered to a subject at least 5 years old. According to one embodiment, the immunogenic or vaccine composition is also used for the prevention and/or treatment of Covid-19 in infants and humans over 55 years old.
According to another embodiment, veterinary use of the immunogenic or vaccine composition according to the invention is contemplated. In this case, the subject is an animal.
According to one embodiment, the immunogenic or vaccine composition is administered to the subject in an immunologically effective amount. Such amounts may be determined by the practitioner. The expression-immunologically effective amount "is understood to mean an amount sufficient for effective prophylaxis and/or treatment, in particular in a subject in need of such prophylaxis or such treatment. As an example, for an aslicon non-replicating viral vector vaccine, a spotnik V vaccine, a prednisone vaccine, a simovac inactivated covd-19 vaccine, or even a nuvaxoid vaccine of novovax, the dose of vaccine composition in each of one to several intraocular drops or subconjunctival injections, spaced at least one week apart, preferably 2 to 12 weeks, may be 0.005mL to 0.05mL.
According to one embodiment, the immunogenic or vaccine composition is administered to a subject that has not been contaminated or even infected with SARS-CoV-2 virus that has caused an infection, or to a subject that has been contaminated or even infected with SARS-CoV-2 virus that has caused an infection, who may have developed symptoms (mild or severe) or be asymptomatic.
According to one embodiment, the immunogenic or vaccine composition is administered once or several times, preferably once, twice or three times, on the ocular mucosa and/or genitourinary mucosa. According to a specific embodiment, the immunogenic or vaccine composition is administered at least twice (in other words, two doses of the immunogenic or vaccine composition are administered) on the ocular mucosa and/or genitourinary mucosa. According to a specific embodiment, when the immunogenic or vaccine composition is administered several times, it targets the same mucosa: for example, two or three times on the ocular mucosa, or two or three times on the genitourinary mucosa. Preferably, the first and second administrations are separated by at least one week, more particularly including a period of 4 to 12 weeks. By 1 to 12 weeks "is meant (days of 7 to 84 days) 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 weeks, or 7 to 84 days.
According to one embodiment, the immunogenic or vaccine composition is administered as drops, lyophilisates or other dry forms. According to one embodiment, the immunogenic or vaccine composition may also be administered as a dry, powder, gel, nanoparticle or hair oil composition (pomade composition). Typically, when administered in the form of drops, it means that the immunogenic or vaccine composition is a liquid formulation, and when administered in the form of a lyophilisate or a dry composition, the immunogenic or vaccine composition is in the form of a powder. The powder may be applied directly to the mucosa or on filter paper, polymers, gels, nanoparticles or hair oils or any other suitable substance support that will be in contact with the ocular mucosa and/or genitourinary mucosa. Thus, the immunogenic or vaccine composition will be transferred from the filter paper, polymer, gel or any other suitable substance or support to the ocular mucosa and/or genitourinary mucosa. The dried composition may be obtained after freezing the immunogenic or vaccine composition according to the invention, followed by drying with any suitable technique (except for freeze-drying, which is used to obtain a lyophilisate).
According to one embodiment, the immunogenic or vaccine composition is administered by using an applicator, for example, which makes instilling drops (eye-drop assist type) or powders or lyophilisates easier. The applicator may also be an ampoule, syringe, filter paper (with e.g. fluid or lyophilisate), dropper bottle, single dose applicator, vaginal spiral or sponge applicator, or even a fabric, a tampon comprising a modified outer surface (i.e. the surface comprises one or more substances for eliciting an immune response against SARS-CoV-2, such as proteins, viral vectors, etc.), or a condom comprising a modified outer surface, etc.
According to one embodiment, the immunogenic or vaccine composition comprises or consists of one or more substances (antigens) for eliciting an immune response against SARS-CoV-2. According to one embodiment, the immunogenic composition according to the invention may be considered to be comprised in a vaccine composition (vaccine). The term-vaccine "or-vaccine against Covid-19" may also be used instead of-vaccine compositions. For example, an immunogenic or vaccine composition according to the invention comprises (1) a Pfizer/BioNTech mRNA vaccine, commonly referred to as Bnt162b2 or (2) Moderna mRNA vaccine, commonly referred to as Moderna mRNA-1273 or Moderna COVID-19 vaccine; (3) Non-replicating viral vector vaccines of Alaslicon, commonly referred to as +.>ChAdOx1-S or Aoslercanic COVID-19 vaccine, or equivalent thereof(4) Janssen's non-replicating viral vector vaccine, commonly known as Ad26COV2.S, JMJ vaccine or J&J COVID-19; (5) Gamaleley a's non-replicating viral vector vaccine, commonly known as Sputnik V or Gam-COVID-Vac, even its light version is known as Sputnik light; (6) Sinovac R&D adjuvanted whole inactivated vaccine against covd-19, commonly known as CoronaVac; (7) An adjuvant (Matrix M) -containing recombinant nanoparticle subunit vaccine of Novavax, commonly referred to as Nuvaxovid, corovax or NVX-CoV2373; (8) A virus-like particle vaccine with SARS-CoV-2 spike protein, commonly referred to as +.>(9) Baylor College of Medicine/BioE Limited protein subunit vaccine, commonly referred to as +.>Or BioE COVID-19; (10) Cadila Healthcare DNA plasmid-based vaccines, commonly referred to as ZyCoV-D, a step of performing the process; or even (11) Bharat Biotech, commonly known as +.>
According to a preferred embodiment, the vaccine composition comprises an adjuvant and/or excipient.
According to one embodiment, the immunogenic or vaccine composition comprises a pharmaceutically acceptable vehicle.
Adjuvants and/or excipients and/or pharmaceutically acceptable vehicles are those conventionally used. For example, the pharmaceutically acceptable vehicle may be a solvent or solution for diluting the composition prior to administration by ocular route or administration on the genitourinary mucosa.
According to one embodiment, the immunogenic or vaccine composition according to the invention may further comprise one or more additional substances. Preferably, the additional substance is selected from:
the presence of a preservative agent(s),
a marker, such as a colorant,
-a surfactant, and
-an additive.
According to one embodiment, the immunogenic or vaccine composition according to the invention is characterized in that it is administered after administration of the first marker (e.g. a colorant) and before administration of the second marker (e.g. a colorant). Thus, the immunogenic or vaccine composition according to the invention is administered between two markers. The administration of these two markers, preferably different, is used to verify that the immunogenic or vaccine composition according to the invention is correctly administered to the mucosa, in particular the ocular mucosa.
For example, the preservative may be an antimicrobial preservative, the purpose of which is to prevent microbial contamination of the immunogenic or vaccine composition. According to the invention, the preservative is a mucosa-compatible preservative.
According to the present invention, a marker "is understood to mean any measurable or indicative substance that can be administered in an immunogenic or vaccine composition. Thus, it relates to pharmaceutically acceptable markers. The markers are also used to verify the amount and/or site of administration, which is done to ensure safe and effective use of the immunogenic or vaccine composition.
According to a specific embodiment, the marker is used for quantifying and/or visualizing the use of said immunogenic or vaccine composition on the ocular mucosa and/or the urogenital mucosa. More specifically, quantification is understood to mean measuring the amount of immunogenicity or vaccine composition administered. According to one embodiment, the marker is an indicator substance, such as a colorant. For example, fluorescein or indocyanine type colorants may be used. The markers are particularly useful for tracking the application of immunogenic or vaccine compositions to ocular and/or genitourinary mucosa. Staining may also be used to track dissolution of immunogenic or vaccine compositions on ocular and/or genitourinary mucosa. Visualization of markers (e.g., coloration) on the ocular and/or genitourinary mucosa is used to confirm that the immunogenic or vaccine composition is properly applied to the ocular and/or genitourinary mucosa, even in the amount of immunogenic or vaccine composition administered.
In order to obtain a higher antigenicity and thus a greater immune response, substances such as surfactants may be added to the immunogenic or vaccine composition to extend the exposure time on the ocular and/or genitourinary mucosa and possibly to enable calculation of the exposure time of the composition on the mucosa.
Other substances, such as additives, may be added to impart advantageous properties to the immunogenic or vaccine composition, such as substances that improve the immunogenicity or the permeability of the vaccine composition in the mucosa, or substances for extending the contact time between the mucosa and the composition (e.g. hyaluronic acid, one or more polymers for forming hydrogels (e.g. carbomers), cellulose derivatives, etc.).
The invention also relates to a method for preventing and/or treating covd-19 in a subject comprising administering an immunogenic or vaccine composition against SARS-CoV-2 on the ocular mucosa and/or genitourinary mucosa. More specifically, the present invention relates to a method for inducing a protective immune response against SARS-CoV-2 comprising administering an immunogenic or vaccine composition on the ocular mucosa and/or genitourinary mucosa.
The invention also relates to the use of an immunogenic or vaccine composition against SARS-CoV-2 in the manufacture of a medicament intended for the prevention and/or treatment of Covid-19, and wherein said medicament is intended for administration to the ocular mucosa and/or genitourinary mucosa.
Drawings
Fig. 1: results for group 1 hamsters are shown.
Fig. 2: results for group 2 hamsters are shown.
Fig. 3: the PENH whole body plethysmographic data of all groups prior to virus exposure (12 hours) are shown.
Fig. 4: the PENH whole body plethysmographic data of all groups after 3 days exposure to SARS-CoV-2 virus is shown.
Fig. 5: the PENH whole body plethysmographic data of all groups after 5 days exposure to SARS-CoV-2 virus is shown.
Fig. 6: the PENH whole body plethysmographic data of all groups 7 days after exposure to SARS-CoV-2 virus is shown.
Fig. 7: the PENH whole body plethysmographic data of all groups after 12 days exposure to SARS-CoV-2 virus is shown.
Fig. 8: the PENH whole body plethysmographic data of all groups after 14 days exposure to SARS-CoV-2 virus is shown.
Fig. 9: the maximum dilution (NT 50) that consistently inhibited SARS-CoV-2 infection in 50% of cases in serum from each group of hamsters is shown.
Fig. 10: average body weights of four groups of hamsters tested in example 5 are shown.
Detailed Description
Example 1: examples of liquid compositions
Table 1 below summarizes the compositions according to the present invention that may be used.
Table 1:liquid composition
Example 2:examples of lyophilized compositions
Table 2 below summarizes the compositions according to the present invention that may be used.
Table 2:freeze-dried composition
Example 3:immunization of hamsters against SARS-CoV-2 by ocular route
Hamsters have ACE2 receptors. Thus, they may be contaminated and diseased with SARS-CoV-2.
1. Comparison of two hamsters after two injections of virus
Two groups of hamsters were studied.
In group 1, 3X 10 6 The individual SARS-CoV-2 viruses (strain b.1.214) contaminated n=7 hamsters by nasal injection and contained 3×10 in group 2 6 Eye drops of the individual SARS-CoV-2 viruses (strain b.1.214) pollute n=7 hamsters.
During observation, hamsters of group 1 were ill, identifiable by significant weight loss, while hamsters of group 2 were not ill.
In fact, as can be seen in fig. 1, hamsters of group 1 begin to lighten from day 2, with the greatest lightening on day 5 and return to normal on day 12; this indicates that hamsters became ill after contamination/infection by nasal injection of SARS-CoV-2. In contrast, as can be seen in figure 2, group 2 hamsters did not lose weight after inoculation of SARS-CoV-2 by the ocular route. This indicates that these animals maintained good health.
After 14 days, both groups were again exposed to a solution containing 3×10 6 Nasal injection of individual doses of SARS-CoV-2 virus.
In both groups, hamster body weight was continuously increased (see figures 1 and 2). More specifically, on day 21, animals of group 1 did not become ill again after inhalation of the second dose of SARS-CoV-2 virus. This means that they have acquired immunity due to the disease that developed during the first 10 days of the experiment.
Furthermore, on day 21, hamsters of group 2 were not ill after inhalation of the second dose of SARS-CoV-2 virus. This means that hamsters were immunized as SARS-CoV-2 was first applied by ocular route.
Thus, hamsters of group 2 acquired immunity by periocular (epi-ocular) application, unlike group 1, which was obtained without developing severe systemic disease.
2. Study of hamsters after injection of viruses by ocular route
In addition, the eye route is accepted to contain 3×10 6 Studies of n=10 other hamsters for a single use of a composition of individual SARS-CoV-2 virus doses showed that they produced high yields of anti-viral neutralizing antibodies (at least 1:640 in serum). These results suggest that hamsters did not develop disease by periocular application of the virus and that immunity against SARS-CoV-2 was obtained that was detectable in serum.
3. Plethysmographic analysis
The pulmonary functions of groups 1 and 2 above (see point 1) were measured using four monophasic whole body plethysmographs (model PLT-UNR-RT-3) of EMKA Technologies. Each plethysmograph chamber is equipped with the same wired pneumotach and the same differential pressure sensor (EMKA Technologies, model usb_dp_t). The openings in each chamber allow for continuous extraction of dirty air at a constant rate (500 mL/min) and continuous replacement with fresh air from the room by a dedicated pump (model vent_4_plt). The measurement activity for each test animal lasted about 20 minutes. The flow rate signal developed in the plethysmographic chamber by calm and alert respiration was then recorded using the following procedure. The flow rates were systematically calibrated before and after the experiment. If a deviation exceeding 5% is detected, the collected data is rejected and the measurement activity is restarted.
The raw data curve is obtained by sampling the signal at 2 kHz. The regularity of the breathing pattern is first manually assessed by checking the constancy of the flow peak. According to this standard, most hamsters breathe normally in the 5 th to 20 th minutes spent indoors, except for a few cases of coughing and combing hair. Unlike experimental mice, hamsters are animals that can go from alert to deep sleep and resume within seconds. The breathing patterns between these two states are very different, and it is important to choose the onset of regular breathing in the observation state. Furthermore, these animals explore much more strongly than mice or rats, accompanied by a specific respiratory pattern consisting of strong sniffing. Therefore, it is not sufficient to select a single regular respiratory episode. For this reason, the selection of episodes to analyze must be done systematically manually by an experienced employee and then processed using IOX2 software (iiox_1pulmo_4a from EMKA Technologies) to generate a flow rate profile. The chest and abdomen flow rate curves are then analyzed to determine inspiration Time (TI) and expiration Time (TE), maximum inspiration flow rate (PIF), and maximum expiration flow rate (PEF) and current volume (TV). The latter is systematically measured twice per cycle, once during the inspiration portion (TI) and once during the expiration portion (TE) of the breathing cycle. Two other parameters were calculated: the time required for TV at 64% before exhalation, called Relaxation Time (RT), and bronchoconstriction index (Penh) by Hamelmann et al, using the formula Penh= [ (TE/RT) -1] (PEF/PIF) (Hamelmann E, schwarze J, takeda K, oshiba A, larsen GL, irvin CG, gelfand EW. Nonniva measurement of airway responsiveness in allergic mice using barometric pl ethylmask. Am J Respir Crit Care Med.1997Sep;156 (3 Pt 1): 766-75.Doi:10.1164/ajrccm.156.3.9606031.PMID: 9309991).
Finally, the breathing rate [ rr=60/(ti+te) ], minute ventilation (mv=rr×tv), average inhalation flow rate (mif=tv/TI), average exhalation flow rate (mef=tv/TE) and circulation ratio [%ti=ti/(ti+te) ] were also calculated from the parameters and Body Weight (BW) measured above. Based on the quantitative values obtained, median values were systematically determined and used to calculate representative average values for hamsters and the day of analysis.
Results:
penh is dimensionless and can be used to screen complex values for lung distress in experimental animals.
The results are shown in four groups as shown in table 3 below.
Table 3:description of hamsters analyzed
The results are shown in fig. 3 to 8.
Prior to infection, all animals had similar patterns of ventilation, regardless of the group (fig. 3). After infection with SARS-CoV-2 virus, two different patterns were observed.
First, the patterns of animals in groups G2, G3 and G4 were very similar to that observed before infection, with no significant differences, unlike group G1 (fig. 4 to 6).
Monday, 12 days (post infection) the hamsters of group G1 were observed to return to normal (FIGS. 7 and 8).
4. Evaluation of serum neutralizing antibodies
Whole blood samples of hamsters were collected in a freezer tube, coagulated at ambient temperature for 1 to 2 hours, and stored at 4 ℃ for 24 hours. The blood was then centrifuged and the serum placed in a freezer tube and complement removed at 56 ℃ for 45 minutes. The decompensated serum is then stored at-20 ℃ until they are used to determine neutralizing antibody titers.
Viral stocks were serially titrated in logarithmic dilutions on 96-well plates to obtain tissue culture infectious doses of 50% (TCID 50). Plates were observed daily with an inverted light microscope for five days to assess the presence of cytopathic Effects (ECP) and calculate final titers according to the Reed & Muench method.
Serum samples were stored for each hamster for quantification of neutralizing antibody titer. Virus neutralization assays were performed in 96-well plates containing pooled Vero E6 cells (ATCC CRL-1586) using the BetaCov/Belgium/Sarttilman/2020/1 strain of SARS-CoV-2.
Nine dilutions of each heat-inactivated serum (40 min at 56 ℃) were used (1:10-1:1280-corresponding to the final dilutions tested 1:20-1:2580). Dilutions were performed in three samples in DMEM/FBS on 96 well plates.
Serum (50. Mu.L/well) was mixed with the same volume (vol/vol) of solution containing 100TCID50 (tissue culture infectious dose 50) of SARS-CoV-2 virus.
The serum-virus mixture was then incubated in a humid environment with 5% CO2 for 1 hour at 37 ℃.
After incubation, 100 μl of Vero cell suspension was added to place 20,000 cells in each well. Plates were then incubated again for five days. This procedure was repeated twice for each serum. Five days later, ECP was evaluated under an optical microscope. Serum dilutions showing ECP were considered non-neutralizing (negative), while serum dilutions not showing any ECP were considered positive/neutralizing.
Serum virus neutralization titers were reported as the highest serum dilution that neutralized ECP and 50% wells (NT 50). The second procedure was performed by using higher dilutions (up to 1:20480) for all sera with NT50> 1:320.
A positive control (NT 50 = 1:160 from the belgium national human microbiology reference center) and a negative control (saline solution) were inserted into each plate.
The results are shown in FIG. 9.
Example 4:research of the spread of SARS-CoV-2 during nasal infection
The inventors analyzed the transmission of the virus in hamsters contaminated with SARS-CoV-2 by nasal injection, as described in example 3.
Thus, the inventors observed that during the first 48 hours after virus entry into the nose, the infection progressed slowly, with nasal infection only in the mucosa, forming an aerosol. These aerosols can then infect bronchi and alveoli, especially during inspiration, and contaminate others during expiration.
Example 5:vaccination by different immunogenic or vaccine compositions
Four new groups of hamsters were studied.
In group 1, at d=1, 20 μl of the vaccine containing the Janssen/Johnson & Johnson non-replicating viral vector (commonly referred to as ad26cov2. S) directly removed from the vial (without any modification) was administered to the left eye of n=8 hamsters. After 14 days (d=14), 20 μl of the same vaccine, which was directly removed from the vial (without any modification), was reapplied to the left eye of n=8 hamsters.
In group 2, at d=1, 50 μl of the vaccine containing the Janssen/Johnson non-replicating viral vector (commonly referred to as ad26cov2. S) directly removed from the vial (without any modification) was administered intramuscularly to the bilateral buttocks of n=8 hamsters. After 14 days (d=14), 50 μl of the same vaccine, taken directly from the vial (without any modification), was again administered intramuscularly to the bilateral buttocks of n=8 hamsters.
In group 3, 20 μlpbs (phosphate buffered saline) was administered in the left eye of n=8 hamsters on day d=1. After 14 days (d=14), 20 μl PBS (phosphate buffered saline) was again administered in the left eye of n=8 hamsters.
In group 4, 20 μl containing 3×10 was administered on day 14 of the experiment (d=14) in both eyes of n=8 hamsters 6 Solutions of individual SARS-CoV-2 viruses (the Whan-like variants of SARS-CoV-2 virus) (attenuated viruses, but not inactivated viruses).
After a further 14 days (d=28 since the start of the experiment), 200 μl of the composition containing 6×10 6 Intranasal contamination of animals of group 4 with a solution of TCID 50 (tissue culture infectious dose 50) of SARS-CoV-2 virus (a Wuhan-like variant of SARS-CoV-2 virus).
Weight loss (i.e., an indicator of hamster illness) was analyzed for animals in each of the four groups. The results are shown in fig. 10. The curves show the average weights of hamsters in the four groups.
The results show that unlike hamsters of group 3, hamsters of groups 1, 2 and 4 are protected and not diseased.
Example 6:human eye vaccination.
Vaccination by ocular route has been tested in humans.
Six months after intramuscular injection, two persons previously vaccinated with the covd-19 vaccine (two injections of the covd-19 vaccine in the deltoid muscle of the left arm) received a new dose of 20 μl of the covd-19 vaccine applied to the mucosa of the right eye.
IgG in serum and IgA in oral and pharyngeal mucosa were then determined by the day of administration of the new vaccine dose on the ocular mucosa, then blood was collected three weeks later and oral and pharyngeal washes were performed with 10ml of 0.9% sodium chloride for two minutes.
The results are shown in fig. 4 below.
Table 4: igG, igM and IgA levels in a subject
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Claims (13)
1. An immunogenic or vaccine composition against SARS-CoV-2 for use in the prevention and/or treatment of Covid-19, characterized in that said composition is applied to the ocular mucosa and/or to the urogenital mucosa.
2. The immunogenic or vaccine composition of claim 1, wherein the composition is administered to the ocular mucosa.
3. An immunogenic or vaccine composition according to any preceding claim, wherein the composition comprises one or more substances for eliciting an immune response against SARS-CoV-2.
4. An immunogenic or vaccine composition according to claim 3, characterized in that the substance for eliciting an immune response against SARS-CoV-2 is selected from the group consisting of SARS-CoV-2 virus, inactivated SARS-CoV-2 virus, attenuated SARS-CoV-2 virus, modified SARS-CoV-2 virus expressing or capable of expressing one or more SARS-CoV-2 antigens, genetically modified microorganism expressing or capable of expressing one or more SARS-CoV-2 antigens, messenger ribonucleic acid (mRNA) encoding one or more SARS-CoV-2 antigens, such as SARS-CoV-2 virus proteins, deoxyribonucleic acid (DNA) encoding one or more SARS-CoV-2 antigens, such as SARS-CoV-2 virus proteins, SARS-CoV-2 virus proteins or one or more fragments thereof, fusion proteins comprising SARS-CoV-2 virus proteins or one or more fragments thereof, recombinant cell-antigens encoding one or more SARS-CoV-2 antigens, SARS-2 plasmid-encoded DNA or pseudoparticle-encoded by one or more SARS-CoV-2 virus antigens.
5. The immunogenic or vaccine composition of claim 4, wherein the viral protein is selected from the group consisting of: s, HE, M, N or E protein or ORF protein, preferably selected from S, M, N or E protein.
6. The immunogenic or vaccine composition of any one of claims 4 to 5, wherein the viral protein is an S protein or fragment thereof, such as a Receptor Binding Domain (RBD), an S1 subunit, or a cleavage region between an S1 subunit and an S2 subunit.
7. An immunogenic or vaccine composition according to any preceding claim, wherein the composition is administered in the form of drops, lyophilisate, dry composition, powder, gel, nanoparticle or hair oil.
8. The immunogenic or vaccine composition according to any preceding claim, wherein the composition is administered by use of an applicator.
9. An immunogenic or vaccine composition according to any preceding claim for use in the prevention and/or treatment of Covid-19 in animals or humans, in particular for use in the prevention and/or treatment of Covid-19 in adults.
10. An immunogenic or vaccine composition according to any preceding claim, wherein the composition further comprises one or more additional substances.
11. The immunogenic or vaccine composition according to claim 10, wherein the additional substance is selected from the group consisting of:
the presence of a preservative agent(s),
markers, in particular indicator substances, such as colorants,
-a surfactant, and
-an additive.
12. The immunogenic or vaccine composition according to any one of claims 1 to 11, wherein the composition is administered after administration of the first marker and before administration of the second marker.
13. The immunogenic or vaccine composition according to any preceding claim, wherein the administration on the ocular mucosa and/or genitourinary mucosa is performed before or after at least one intramuscular administration of the immunogenic or vaccine composition.
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| PCT/EP2022/057548 WO2022200384A1 (en) | 2021-03-22 | 2022-03-22 | Novel use of an immunogenic or vaccinal composition against covid-19 |
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