AU2018217441A1

AU2018217441A1 - Immunogenic composition for modulating the immune system and methods to treat bacterial infections in a subject

Info

Publication number: AU2018217441A1
Application number: AU2018217441A
Authority: AU
Inventors: Alexandre Eduardo NOWILL
Original assignee: Individual
Current assignee: Individual
Priority date: 2017-02-13
Filing date: 2018-02-15
Publication date: 2019-10-03
Also published as: EP3579868A1; WO2018145180A1; CN110709099B; KR20190139209A; CN110709099A; BR112019016670A2; IL268626B1; IL268626A; MX2019009689A; IL268626B2; JP2020507629A; RU2019128674A; EP3579868A4; RU2019128674A3

Abstract

The present invention refers to pharmaceutical products comprising immunogenic compositions for modulating the immune system, which therapeutically effective amount of a Immmological Response Shifter (IRS) comprising two or more immunoactive antigenic agents presenting pathogen-associated molecular patterns (PAMPS) and/or danger associated molecular patterns (DAMPS) and/or Stress Response Signals (SRS) in association with an antibiotic and one or more physiologically acceptable carriers, excipients, diluents or solvents. In other embodiments, the present invention refers to methods to treat severe bacterial infections, sepsis and modulating the immune system.

Description

IMMUNOGENIC COMPOSITION EOS MODULATING THE IMMUNE SYSTEM AN» METHODS TO TREAT BACTERIAL INFECTIONS IN A SUBJECT

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of U. S, Patent Application Serial No. 14/006,077 filed October 23,2013, which is the National Phase of International Application No.

PC1VBR2012/000072, filed March 19, 2012, which designated die United Stales, which also Includes a claim of priority under 35 U.S.C. § 119(a) and §365(b) to Brazilian patent application No. PI 1100857-1 filed March 18,2011, the entirety of all applications is hereby incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to immunogenic compositions for modulating the immune system comprising a therapeutically effective amount of a. Immunological Response Shifter (IRS) comprising two or more immunoaetive antigenic agents presenting pathogen-associated

Stress Response Signals (SRS) (1) and one or more physiologically acceptable carriers, excipients, diluents or solvents.

The compositions of the present invention comprise immunoaetive antigenic agents presenting pathogen-associated molecular patterns (PAMPS) and/or danger associated molecular patterns (DAMPS) and/or stress response signals (SRS) (1) selected from the group consisting of: (A) antigenic agents with molecular patterns associated with bacteria: (B) antigenic agents -with molecular patterns associated with viruses; (C) antigenic agents with molecular patterns associated with fungi and yeasts; (D) antigenic agents with molecular patterns associated with protozoa; (E) antigenic agents with molecular patterns associated with multicellular parasites / or (F) antigenic agents with molecular patterns associated with prions.

BACKGROUND OF THE INVENTION

From the pioneering discovery of antibiotics in the end of first half of the 20th century', new antibiotics, semi-synthetic antibiotics and new’ chemotherapentics with antimicrobial, activity.

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PCT/BR2018/000004 have been developed on a large scale against most intracellular and extracellular bacteria. These developments have changed the history of medicine, allowing it to reach a wide spectrum of healing, for the vast majority of bacterial infections diseases, which racked humanity

The discovery of antibiotics and other drugs

Tirus, the discovery of antibiotics was a major milestone, a watershed, because Infection could be addressee and healed, is a specific way, with a clear relationship ofcause and effect, and measurable when established. This discovery greatly expanded the ability of healing in medicine, with enormous positive impact on human health and lifespans. The discovery' of antibiotics in the evolution and treatment of disease profoundly influenced the research and thinkmg of researchers from the success achieved by this experimental model (Reeves G, Todd I Lector© notes on immunology. 2nd ed: Blackwell Scientific Publications, 1991; Neto VA. Nicodemo AC, Lopes HV. Antibidticos naprtifica medica. 6th ed: Sander, 2007; Murray PR, Rosenthal KS, PfallerMA. Mierobioiogia Medica. Sth ed: Mosby, 2006; Trabulsi LR, Alterthum F. Mierobioiogia. Sth ed: Atheneu Editora, 2008).

Antibiotics were succeeded by the development and use of antifungal, antiparasitie and antiviral drugs. The “anti” drug model became a gold standard experimental model due to huge success against anti-etiologic agents, and was extended to diseases with unknown etiology against their physio pathologic process and to very similar autologous neoplastic cells, with less specificity, less selectivity and less eifectivity as:

« Anti-allergic;

• Anti-inflammatory;

• Anti-immune (immunosuppressive);

• Anri-neoplastic (cytotoxic); and • Anti-hormone.

thus, the new' “anti’' drugs brought an enormous capacity for medical intervention, with numerous benefits, with definitive and partial cures, with the prolongation of life In Incurable diseases, but also with huge morbidity due to side effects related to their lack of specificity to the pathophysiology of the diseases.

The innate immunity

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The innate immunity, in addition to preventing the entry of microorganisms and preventing their establishment, has another recently discovered vital function: discrimination between “self” and nos. self by the pattern recognition capability linked to the alarm and the command to start or inhibit an integrated immune response against an invading microorganism or to arrest, repair or inhibit a condition of destruction or self-aggression to the body, for example, in trauma autoimmune diseases and allergic diseases, among others.

This dual capability was previously erroneously attributed exclusively to adaptive immunity·· the innate immunity, through its own germinal receptors, recognizes invading pathogenic microorganisms, autologous or even allogeneic neoplastic cells, or allogeneic or heterologous transplants as “not seif ; sdenii Aing them as not belonging to the organism. From that moment, it triggers as alarm and a joint innate and adaptive immune response to eliminate them or suppress a response deleterious to the human or animal organism (Goldsbv RA, Kindt TJ, Osborne B. Imunologia de kuby. 6 ed; ARTMED; 2008, 704 p; Janeway C, Travers P, Walport M, Slhlomchik MJ. Immunobiology five. 5 ed: Garland Pub.; 2001. 732 p.; Voltarelli JC . imunologia clinica na pratieamedica: atheneu editora; 2009; Janewrty CA, Jr., Medzhitov R. Innate immune recognition. Annual review of immunology. 2002;20:197-216. Epub 2002/02/28; Matzinger P. The danger model: a renewed sense of self. Science. 2002:296 (5566) :301-5. Epub 2002/04/16; Steinman KM, Bancherean J. Taking dendritic cells into medicine. Nature. 2007; 449 (7161): 419-26. Epub 2007/09/28.; Beutier BA, TLRs and innate immunity.

©food. 2009; 113 (7 ): 1399-407. Epub 2008/09/02; Moresco EM, LaVine D, Beutier B. Toillike receptors. Current biology : CB . 2011; 21 (13 ): R488-93. Epub 2011/07/12) (1).

The recognition pattern of not self, of an invasive germ is performed by sentinel cells, represented by epithelial cells, mucosal cells, and the stromal cells, such as pericytes, dendritic cells, macrophages and fibroblasts, among others. These cells, strategically distributed throughout fire body, have PRRs (Pattern Recognition Receptors) and DRRs (Danger Recognition Receptors) and SRR (stress response receptors) winch are receptors respectively able to recognize a) standard identification molecules, characteristic of a wide range of microorganisms, b) certain patterns for chemical and physical of said Inert substances and changes to metabolic stress, such as release of free radicals and tissue chemical changes, caused by ionizing radiation or by chemical substances, among others and c) stress receptor signals that

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PCT/BR2018/000004 identify viruses, starvation, ER stress and oxidative stress (Pulendran, B Annual Review hnmuiiology 2015).

The PRE does not discriminate one specific individual microorganism, but the presence of microorganisms other than the human body . Each PER receiver may bind to several different pathogens, recognizing as PAMPs (Pathogen Associated Molecular Patterns) carbohydrates, lipids, peptides and nucleic acids from bacteria, viruses, firngi or parasites that are not found in the human or animal body.

The DRRs discriminate that there is tissue damage, a dangerous situation caused by not live or Inert agents. The DRRs identify DAMPs (Danger Associated Molecular Patterns) associated with tissue damage by toxic substances, radiation, or trauma, which cause metabolic stress, release of fine radicals and chemical changes in tissue, recognized by these receptors.

The SRRs (stress response receptors) identify the signal of the metabolic stress caused by environment aggressions as viral infections or viral effective vaccines, amino acid starvation, ER(endoplasmio reticulum) stress, oxidative stress, through evolutionary⁷ conserved stresssensing mechanism, that compose de integrated Stress Response ISR as recently discovered (Janeway C, Travers P, alport M, Slhlomchik MJ. Immunobiology five. 5th ed: Garland Pub,; 2001. 732 p.; Matzjnger P. The danger model: a renewed sense of self. Science. 2002 ; 296 ( 5566): 301-5. Epub 2002/04/16; BeutierBA. TLRs and innate immunity⁷. Blood. 2009;113 (7): 1399-407. Epub 2008/09/02; Moresco EM, LaVine D, Beutler B. Toll-like receptors. Current biology: CB. 2011;21 (13) :R488-93. Epub 2011/07/12) (I).

Thus, sentinel cells via their PRRs and their DRRs, and SRRs have a role in the breakdown of which belongs (’’self') and which, is does not belong (not self) and triggering inflammation and immune response, via recognition of PAMPs of invading pathogens and DAMPs caused by neoplastic cells, inert substances and toxic substances or modifications due to trauma, or stress response signals in infections in ISR leading to a situation of real danger to the human anti animal organism.

Immediately, these activated sentinel cells give alarm signals, triggering the innate immuneresponse through the NF-kB (Nuclear Factor-kB) signal translation system, leading to the

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PCT/BR2018/000004 secretion of pro-inflammatory cytokines and the IRF signal translation system, that produces Type I alpha and beta interferons. These cytokines, together, acting on cells and vessels, cause a local inflammatory’ process, initially to contain the invading agent, autologous (tumour cell), heterologous (microorganisms, prions, grafts and transplants) or allogeneic (grafts and transplants), or to repair danger situations. This contention happens through antibodies, preexisting, opsonizing acute phase proteins and through leukocytes and macrophages, which engulf and start to destroy the extracellular and intracellular microorganisms respectively , or eliminating other etiologic agents of any kind.

Interaction and integration of innate immunity with adaptive immunity'

Simultaneously at the site of invasion, aggression and inflammation. the innate immunity sentinel cells with the APC role (Antigen Presenting Cells), such as dendritic cells and macrophages, phagocytosis and pmocytosis microorganisms or tumour cells, or transplanted ceils, among other aggressors and process their antigens. These APC cells pulsed by the antigens migrate to regional lymph nodes and activate them. The APC cells in reactive lymph nodes, activated and mature present the antigens to lymphocytes, release cytokines and thereby induce, coordinate, polarize, amplify and maintain an adaptive immune response specific to the invading germs, or neoplastic ceils, or to transplanted cells, or other offending agent, allowing them to he fought and eliminated, where feasible and the consequent cure of tire infection or inflammation and repair and regeneration or wound healing (1) (3).

Tims, these immune mechanisms fight diseases through innate and adaptive primary' or secondary responses in an integrated and synergistic way, performed by sentinels cells, APC tonction sentinels, and innate immunity effectors, cellular mid molecular in conjunction with die cellular and molecular effectors of adaptive immunity’ that are respectively lymphocytes, cytokines and antibodies.

Tims, the interaction of the two immunities, innate and adaptive, is the context of an Infection or immune response against an aggressor of any kind helps to fight the disease In an integrated and synergistic way. The integration of the two initially occurs by the action of the innate immunity cells with APC function, such as dendritic cells and macrophages, hut mainly by the acti vity of dendritic cells, as they are the ones that are able to initiate an adaptive immune

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PCT/BR2018/000004 response against a primary infectious or parasitic agent, effectively protecting fee body(2, 3). in secondary¹ response memory', cells govern fee silent immunological process feat induce fall protection (1 „2,3,14,26,38,54,56,57,58,65)

Macrophages also function as APC cells, but are more specialized and involved as part of the effector loop in uhagocytosis and in the elimination of microorganisms. B lymphocytes, when mature, are also APC ceils and its most well-known action is the presentation of antigens to fee T lymphocytes, wi thin fee framework of cooperation of both lymphocytes to produce antibodies against T-dependent antigen, and fee secondary antibody^1, response in lymph nodes and bonne marrow. Macrophages, like other myeloid cells, are also involved in suppressing immune response in mostly in chronic infections or in acute infections. In these case of chronic infections or tumours. Its performance is unfavourable to fee defence of fee organism because if suppresses fee immune response and create a chronic infection or tumour facilitation.

When co-stimulatory molecules are not expressed on the APC cell surface, by fee absence of the alarm signal characterized by fee lack of activation of PRRs, DAMPs and SRR by¹ PAMPs, DAMPS and SRSs, only tire first signal occurs, given by fee TCR. After the TCR. binds wife the antigen, in fee absence of the second signal, fee T lymphocyte becomes tolerant to fee specific antigen shown and aborts fee immune response.

On. fee Other hand the CD 40L molecule of activated T lymphocytes, when it binds to fee CD40 molecule on the APC cells, significantly increases fee expression of CD80 and CD86 molecules, increasing the current response, which feus occurs only when fee adaptive T response is already engaged in defending fee body. The third signal given by cytokines such as IL- Lis given usually by fee APC cells after the binding of co-stimulatory molecules and fee emission of fee second signal. The IL-1 released by the APC cells acts on lymphocyte cells and leads to the complete expression of fee receptor for IL2 and to fee production or H-2 and others polarization cytokines by virgin or memory lymphocytes engaged in response initiating clonal selection and expausion(primary^z) or memory^1, clonal proliferation (secondary).

Therefore, fee activation of innate immunity by pathogens or by aggression is the key to unleashing fee second and third signals and the occurrence of a potentially effective immunity, through fee full activation of T lymphocytes engaged in fee response. Without the occurrence of

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PCT/BR2018/000004 the second and thi rd signal, the response is aborted and generates a tolerance specific to the antigen presented.

At the same time that the neutrophils, monocytes and macrophages initiate combat to bacteria and to other infectious agents by the linkage of PAMPs with PRRs SRSs on antigen presenting cells (ARC), they activate dendritic cells and macrophages, local and newly arrived or best activated by memory cells. These cells phagocytosis and pinocytosis bacteria and bacterial antigens, processing them and starting the maturation process. The activated and maturing dendritic cells now migrate to regional lymph nodes to present antigens and initiate immune response against the invading agent.

PAMPs alone can remodel lymph node feed arteriole and induce lymph node hypertrophy that is essential for an effective primary adaptive response occurs (4, 5). In secondary' responses activated and pulsed by DCs cells in inflammatory territory, effector memory CD4-CD40Iri-cell migrate in a CD62P-dependent fashion into the reactive lymph nodes via HE Vs and license dendritic cells for T cell priming against weak antigen, tolerate antigens and auto antigen starting an auto immune disease or improving an immune response in an ongoing infection or neoplastic disease(4). Also in inflammatory territories effector memory' CDS T cells secrete CCL3, drat in turn activate MFCs to produce TNF alfa that induce PMNNs and Others MFCs to produce ROIs and clear intracellular bacteria. Unrelated intracellular pathogen sensitive to ROIs can also he clear fey bystander activation in overlapping di seases or overlapping immune responses (6,7).

Tfae mature antigen-pulsed APC cells, especially dendritic cells, in lymph nodes, collaborate with the· T and B lymphocytes and initiate the adaptive primary or secondary response (I). Dendritic cells are the m ost potent cells for the presentation of antigens and the only APC cells able to activate a virgin CD4 T lymphocyte and to start a new immune response (2,3).

After a period of approximately' seven days in the lymph node, the collaboration between blank CD4 lymphocytes CD4-ThO), which become T CD4 Th2 or Tfh, with B lymphocytes and antigen presenting dendritic cells, initiates the differentiation of specific sensitized B lymphocytes. These B cells, now activated, recognize bacterial antigens by surface hmnunoglohulins, collaborate with T helper cells, cells after contact with these antigens.

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PCT/BR2018/000004 proliferate, mature, and differentiate into plasma cells that now release specific antibodies against this bacterium in a first moment outside of follicular node in the B cell area, in activated lymph nodes and after differentiation goes inside and induce germinal centre formation and secondary B cells responses with, collaboration with CD4Tfh and others CD4T helpers cells. In secondary⁷ B cells responses, long lived plasma cells secrete Ί cell dependent antibodies in bonne marrow, after initial production in lymph nodes (1,6) (8,9). Infections of ail types, bacterial, viral, fungal and parasitic may, in general, in the acute phase, evolve to a full cure with regeneration and healing, or for a cure with sequelae. They can also develop into an. incurable chronicity, with or without control of the disease, to chronicity with healing, with or without sequelae, or to death.

Polarisation of the immune response lire classic immune profiles known and induced by⁷ dendritic cells by direct and indirect contact with the different cytokines and generated by T CD4 cells are of four lypes(IG~ I2):

a.) cellular Till profile, which generates cellular immunity’ mediated by cells/13)

b) humoral Th2 profile, which generates humoral immunity mediated by antibodies! 13);

c) tissue or inflammatory Ibl7 profile, which generates inflammatory tissue immunity⁷, also mediated by⁷ cells and cytokines, which induce an important inflammation for the elimination of certain pathogens, and( 13,14)

d) Treg/Trl profile, which suppresses the immune response and controls, by inhibiting the other three profiles described above, ensuring tire return of the body⁷ equilibrium state.(13 ,15)

e) New profiles have been stablished, as the Tfh (follicular Helper) of the humoral response (16), the 1h9 profile for certain parasites like Helminths ( Γ7),Ί1ι22 that produce IL22 involved in Skin protection (17) or other profiles that may be discovered or no fully estabiished( 18).

Thus, the various profiles ensure the defence of the organism and the elimination of causative heterologous (infectious) agents invading and colonizing autologous (neoplasia). The last classic profile ensures the termination of the immune response, the balance, the regeneration, fiie safe return to normalcy and it prevents self-injury and allergy⁷ and Is therefore· vital to the

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PCT/BR2018/000004 health and preservation of fee human species and animal, as much as the other profiles.

The phenomenon of polarization of the immune response is defined as the predominance of a certain immunological profile such as Thl or Th2 at the expense of other profiles that become secondary or null, 'fins phenomenon happens according to the type of attack suffered by fee body. That is, according to fee type of infection, pathology, and infection stage or pathology' stage, the different type of immune response will be predominant, and it may be a cellular, humoral, tissue inflammatory, or immune-regulatory response, while other types of immune responses are inhibited, resulting in the phenomenon of polarization.(12)

By definition, there is a dominant profile in polarization, but other non-dominant profiles are also needed, and expressed m a complementary manner that will help eliminating the disease. For example, tuberculosis is the- appearance of Thi7 cells in the lung which allows Thl cells to settle arid may lead to cure this infection in the lung parenchyma (Stockinger, B. and Yeldhoen, M. EHf&tentiaiion and function of Tkl7 T cells. Current Opinion in Immunology, 19 (3), pp. 281-286. 2007). In viral infections, fee CTL cells of I'M profile destroy cells infected by Vituses, to eliminate the virus. However, antibodies are required to prevent the virus from infecting other healthy cells and thus preventing the spread of infection. The coordinated assembly of fee two profiles is essential for the healing of certain viral infections. Certain intestinal infections by extracellular Gram-negative bacilli require, for its cure, in the final stage, besides fee Tfh and Th2 profile, the generation of a supplementary Thl7 profile capable of generating a. strong inflammation, necessary to eliminate this type of bacteria.(12)

In conclusion, due to the fact feat fee dendritic cells are fee only professional APC cells capable to initiate a primary adaptive immune response and are the most potent in triggering a secondary specific immune response, in any profile, they are then commanding the interaction and integration of innate immunity wife adaptive immunity' to produce an effective immune response capable of curing a disease. Dendritic cells in collaboration with other APC and sentinel cells in contact wife different aggressors in different functional states, in the inflammation sites, in fee lymph nodes, in fee spleen, in the mucous membranes, are able to lead, coordinate, polarize, and amplify fee adaptive immune response governing them, primary and secondary, e.g., specific for the peptides of invading pathogens, which in this case is fee

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PCT/BR2018/000004 most appropriate forth© removal of the ongoing infection] 1,2,3).

Therefore, dendritic cells and other APC cells are key cells of the innate immune response, since they evaluate the nature of the autologous and heterologous causative agent, i.e., the type of pathogen or colonizing cells and aided by the sentinel ceils, they measure and evaluate the size of the heterologous or autologous aggression, its extension, its intensity and aggressiveness, besides commanding the adaptive response with the profile and the intensify required for the elimination of the pathogen. In other words, innate immunity con texteaiize the aggression in a primary response and recontextualize in a secondary effective one by the action of T B and some NK memory' cells (19) (20) (8, 9, 20-31)

After differentiation, a. re-differentiation can occur, induced by the microenvironment and/or the type of antigen or its presentation, in which a Thl or Th2 profile can be exchanged for an inflammatory profile or an immunosuppressant profile or vice versa. Hus extreme plasticity’' of the immune system to differentiate or re- differentiate in either direction indicates a strategic window for manipulation of the immune system, during infection, when the direction taken by the polarization is not the best one for curing the infection process or neoplasia (32).

As an illustrative example, we have what happens in a severe infection or septicaemia, that induce sepsis whh massive Inflammation caused by cytokine, induced by the large number of microorganisms which touch the sentinel cells throughout the body, induces also a Thl7 a profile, which hi turn increases the inflammation more and therefore becomes detrimental, leading to tissue destruction, rather than inducing healing and paradoxically inducing late immunosuppression by the Treg/Trlprofile and exhaustion state . In these cases the Thl7 profile, by tissue destruction and the amphfication of inflammation, is implicated m the generation of clinical complications such as severe ARDS (acute respiratory distress syndroms in adults), lung shock, renal failure, or shock, that compromises healing (4, 33, 34).

The re-differentiation of polarization for the Thl or Th2 profiles, with the inhibition of massive inflammation, is the logical and strategic path for a designed or prepared immunotherapy to try to resolve this dramatic and deadly type of situation, during a severe infection or sepsis, which has a significant mortality and morbidity' and for which antibiotics and ether antimicrobials, m current patterns such as single mode, have disappointing anti-infective results. The same

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PCT/BR2018/000004 example applies to serious intra cellular bacterial, fungal, viral and parasitic infectious, with extensive tissue destruction and massive infiannsation, usually of poor prognosis.

The use of adjuvants to stimulate immune response

The human and animal organisms do not usually produce antibodies against soluble proteins, necessitating the use of so-called nonspecific or unrelated adjuvants to obtain the desired immune response. These adjuvants used since the dawn of immunology, in immunizations and in vaccine applications, were and are made up of parts of microorganisms, mineral oils and other substances that activate tire innate immunity, which then gives the alarm and control necessajy for the devel opment of des ired immune response to the protein or to the vaccine in question (GOLDSBY RA, KINDT TI, OSBORNE BA. IMUNGLOGIA DE KUBY. 6 ed: ARTMED; 2008. 704 p); (Janeway C, Travers P, alport M, Slhlomchik MJ. Immunobiology five. 5 ed: Garland .Pub.; 2001. 732 p.): (VOLTARELU JC . IMUNGLOGIA CLINICA. NA PRATiCA MEDICA: ATHENEU EDITORA; 2009); (Janeway CA, Jr., Medzhitov R. Innate Immune recognition. Annual review of immunology. 2002)20:197-216. Epub 2002/02/28.); (Matzinger P. The danger model: a renewed sense of self. Science. 2002; 296 (5566): 301-5. Epub 2002/04/16.): (Steinman RM, Baachereau J. Taking dendritic cells into medicine. Nature. 2007 ; 449 ( 7161 ):. 19-26. Epub 2007/09/28.); (Beufier BA. TLRs and innate immunity'. Blood. 2009 ; 113 ( 7 ): 1399-407. Epub 2008/09/02.); (Moresco EM, LaVine D, Beutler B. Toll-like receptors. Current biology': CB, 2011 ; 21 ( 13 ): R.488-93. Epub 2011/07/12).

It should be noted that the use of adj uvants for immanization, despite being one of the oldest features, and still current, highly' used and essential for vaccinations and for studies of immunology, was considered only as a useful nonspecific effect. It was not envisioned, for more than a century', Its role in the innate immunity in the discrimination of what is Self' and not Self’ and its unique and fundamental capacity' to the survival of the human species and animals: to give the alarm signal and the command to start or not start, or inhibit an integrated, protective or healing, innate and adaptive, immune response (GOLDSBY RA, KINDT TJ, OSBORNE BA. IMUNGLOGIA DE KUBY. 6 ed: ARTMED; 2008. 704 p); (Janeway C, Travers P, Walport M, Slhlomchik MJ, Immunobiology five. 5 ed: Garland Pub.; 2001,732 p. ) ; (VOLTARELU JC. IMUNGLOGIA CLJN1CANA PRATICA MEDICA: ATHENEU

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EDITORA; 2009); (Janeway GA, Jr., Medzhhov R, innate immune recognition. Annual review of immunology. 2002;20:197-216. Epub 2002/02/28.); (Matzinger P. The danger model: a renewed sense of self Science. 2002;296 (5566); 301-5. Epub 2002/04 /16.).: (Stemman RM, Banchereau J. Taking dendritic ceils into medicine,Nature. 2007 ; 449 ( 7161 ):. 419-26. Epub 2007/09/28.); (Bender BA. TLRs and innate immunity. Blood. 2009 ; 113 ( 7 ); 1399-407. Epub 2008/09/02); (Moresco EM, LaVine D, BentlerB, Toll-like receptors. Current biology : CB. 2011; 21 (13 ): R488-93. Epub 2011/07/12).

Treatment of severe infections, sepsis, and septic shock

The current paradigm in infectious diseases is that antimicrobials are toxic selective drugs that destroy or block pathogens, like bacteria, fungus, virus and parasites, with little damage to the host and are responsible for the clearance of these agents . For this reason, they are traditionally employed in monotkerapeutic approaches. (Reeves G, Todd J. Lecture notes on immunology, 2nd ed: Blackwell Scientific Publications, 1991; Neto VA, Nicodemo AC, Lopes HE, Antibiotieos na pratioa medica, tith ed: Sander, 2007; Murray PR, Rosenthal KS, Pfaller MA. Microbiologia Medica. 5th ed: Mosby, 2006; Trabulsi LR, Alterthum F. Microbiologia. 5th ed: Atheneu Editors, 2008).

The treatment of severe infections, sepsis, and septic shock, combine more than, one antibiotic, avoiding microbial resistance in combination with support measures to prevent or limit SIRS, ARSD or MODS or helped by preventive vaccines. Therefore, the current research is mostly focused on new antimicrobial drugs, drugs that prevent microbial resistance, and new medicines or biological agents to inhibit or control pro-inflammatory and immunosuppressive microenvironments, and vaccines.(34~41)

Paradoxically, the detailed analysis of the experimental model, tnat gave rise to the current paradigm in infectious diseases reveals an unexpected and not foreseen different conclusion: In that model, there are 3 players in the Petri dish: the pathogen, the antimicrobial drug and an inert culture medium that don’t interfere in the interaction of tire first 2 components, m that case, if the drug is effective we can say that the antibiotic made the elimination or clearance of the pathogen in vitro.

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However, in the in vivo correlated situation, there are also 3 components: the antibiotic drug, the pathogen and the human or animal bodies, that are not an inert medium, and have .an immune system with the same task of the antibiotic, feat is, they also block and combat the pathogen. We .cannot translate the conclusion of a system in vitro with 3 components and 2 variables to a system in vivo wife 3 components and 3 variables. They are not scientifically comparable and fee conclusion in vitro cannot be translated to the in vivo system to explain emo.

For feat reason, in the case of the antibiotic feat can eliminate the isolated bacteria in vitro, it is not possible to say feat fee same antibiotic is responsible for the clearance of this pathogen or responsible for fee cure of fee infection in vivo when its occurs. The only conclusion feat can be made is that case is: fee success of fee antimicrobial treatment in the clearance of fee pathogen and in the cure of infection in vivo depends on the joint action of the antimicrobial drug and fee immune system.

Jn strong support of this view, fee immune system is deficient in fee extreme of ages, dysfunctional in elders and immature in fee first years of age. In this periods of life, infections are usually more severe and frequent, and there are also a higher rate of morbidity and mortality, even when antibiotics are used in correct indication, dosing and timing.

Also in the case of severe secondary immune deficiencies, like terminal AIDS, terminal oncologic patients, other terminal immune compromised patients and in terminal severe primary immune deficiencies of any kind, cure wife antimicrobial drugs are not possible. In the immune compromised host, fee antibiotics are used in higher doses compared to fee immune competent patient for fee very same .clinical or veterinary condition, la the undeveloped world, where most of human population lives, malnutrition compromises fee fitness and functionality of fee immune system

The lack of sewerage and drinkable water supply submits these populations to constant aggressions by innumerable pathogens, compromising fee efficiency of fee defence system and provoking disease. This constant aggression and frequent illness create an unhealthy positive feedback loop, compromising continuously the immune system and health. Finally, fee lack of protection from environment aggression also weakens the body and immune system. These three conditions combined in a synergic way also create an unhealthy positive feedback loop.

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PCT/BR2018/000004 that severely compromises, the immunological system, and decreases the efficiency of antimicrobial drugs, shortening the lifespan of these populations. There is no available data supporting of the isolated action of antimicrobial medicines in vivo without the collaboration of the immune system, since humans and animals cannot live without a functional immune system and once invaded the immune system react by innate and adaptive responses that only finish after the clearance of the pathogen and the end of tissue repair and the return to homeostasis (7,8).

In agreement with this interpretation, there is no clear evidence in the literature of clearance of pathogen m vivo by the sole action of antibiotics or antimicrobial drugs. In conclusion, without a functional immune system, it is impossible to cure severe infections with antimicrobial drugs in the monotherapeutic approach. In. contrast, the cure of some infections is possible without antimicrobial drags. Altogether, these evidences pointed to a definitive and. significant role exerted by the immune system in the cure reached by antimicrobial drugs in vivo in infections (Reeves G, Todd I. Lecture notes on immunology. 2nd ed: Blackwell Scientific Publications, 1991; Neto VA, Nicodemc AC, Lopes HV. Antibidticosnapraficamedica. 6th ed: Sarvier,

2007; Murray PR, Rosenthal KS, Pfaller MA. Microbiologia Medica. 5th ed: .Mosby, 2006: Trabulsi LR, Alterthum F. Microbiologia. 5th ed: Atheneu Editors, 2008).

A new explanation should be formulated in order to better understand the cure induced by the antimicrobial drugs in vivo, independently of the, well known mechanism of action in vitro against microbes. The inventors propose a new concept, in which the antimicrobial drugs can be considered as equilibrium shifters (ES) in a hos> x pathogen competition, tnat favours the host immune system in a multivariable context. The variables are: concomitant diseases, traumas, age, sex, race, psychological health, innate and adaptive immunity, metabolism, nutrition, physiological flora microbiota, environmental aggression by drugs, and exposure to radiation, gases, pathogens and medical, treatments.

What possibly occurs is that the antimicrobial drugs by their action against bacteria facilitate the work of the immune system in pathogen clearance, reverting the host x pathogen equilibrium comnetition. and promoting the cure. The antimicrobial drugs would function as equilibrium shifters of the host x pathogen competition by significantly: weakening the pathogens action and

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PCT/BR2018/000004 reducing their numbers in vivo and by that, way facilitating the role of the immune system in microbe clearance. Alternative outcomes are death or chronic infection, regardless of the use of antimicrobial drugs.

The application of this new concept in the context of the discovery of new treatments for severe or potential incurable infeetionsrinfiammatory syndromes, such as sepsis or septic shock deserves sonic considerations. As equilibrium shifters in the host versus pathogen balance, antimicrobial drugs have a compulsory' partner in vivo, the Immune system. By accepting the concept that antimicrobial drugs are not tire main players in achieving cure but act. as important and frequently necessary helper factors that contribute to shift the balance in favour of the host, in infection/infiammation disease, a primordial question emerges: how to change and improve an established initial exaggerated, ineffective, improper ore deleterious IR conducting the immune system to generate the best immunological response (IR) available, innate and adaptive capable to combat and make tire clearance of the pathogen and at the same time having an physiological benefic anti-inflammatory'· action during the course of the treated disease.

OBJECTIVES OF THE INVENTION

In general, one of the objectives of the invention is providing products comprising immunogenic compositions, in certain embodiments such compositions are combined with one or more antibiotics, as well as methods and uses thereof for treating and/or preventing infectious diseases and preparing medicaments therefor.

It is a specific object of the present invention to provide Immunogenic compositions for modulating the immune system comprising a. therapeutically effective amount of two or more Immunological Response Shifter (IRS) comprising an immune active antigenic agents that present pathogen-associated molecular patterns (PAMPS) and/or danger associated molecular patterns (DAMPS), and stress response signals{l) and one or more physiologically acceptable carriers, excipients, diluents or solvents.

In particular, it is an objective of the present invention providing immunogenic compositions for modulating the immune system which comprise Immunological Response Shifters (IRS) that have immune-active pathogen-associated molecular patterns (PAMPS) and/or danger associated

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PCT/BR2018/000004 molecular patterns (DAMPS) and/or stress response signals (SRS) selected from the group consisting of: A) antigenic agents with molecular patterns associated with. bacteria; (B) antigenic agents with molecular patterns associated with viruses; (C) antigenic agents with molecular patterns associated with fimgi and yeasts; (D) antigenic agents with molecular patterns associated with protozoa; (E) antigenic agents with molecular patterns associated With multicellular parasites / or (F) antigenic agents with molecular patterns associated with prions.

The present invention also aims to provide uses of the above-mentioned immunogenic compositions for preparing pharmaceutical products and methods for modulating the immune system, particularly tor real-time replacement, of an innefective immune response with an effective immune response.

Therefore, the present, invention aims to provide products and methods for treating infectious diseases, including severe infection, sepis and muliinesisiant bacteria, and modulating the immune system. The effectiveness of the invention is due to a real time replacement of an ineffective immune response with an effective immune response. Such replacement made by proactively creating anewimage of the aggressor pathogen to the host immune system, in order to reset, lead back, control and improve the same .

Real-time replacing the ineffective immune response for a. new effective one capable to change the host x pathogen equilibrium competition in favour to the host propitiating a chance of cure is the challenging task. This problem touches the Pasteur paradigm that says that it is possible to immunize the host to confer protection against the aggressor upon a second encounter, without significant clinical signs of the disease .

The basis of the se phenomenon is the established immunological memory phenotype In T and B lymphocytes and, also to a lesser extent in NK cells (7-21)), as recently demonstrated . Altogether, these cells may induce inflammatory innate and adaptive responses in the second contact with tire antigen. That is the basis of preventive vaccines, which are the most effective medicines ever created so far. Paradoxically, the state of the art lacks therapeutic vaccines for infections diseases.

Revisiting the paradigm of Pasteur, we can take as a model two of the most effective preventive

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PCT/BR2018/000004 virus vaccines ever developed against invariable pathogens; smallpox and yellow fever (YT17D). The first eradicated smallpox anti! now and the second led to the development of protective immunity that could last more than 35 years, after a single dose. A series of detailed moaem scientific studies with YF-17D Yellow Fever vaccine in system, biology and system vaccinology, demonstrated that virus, make contact with a wide range of sentinel and professions APC innate cells, activating the same. Activating also multiple DC subsets by the stimulation of multiple PRRs, DRRs, stress response receptors by multiple PAMPs and DAMPs, stress signals in each DC cell -type and subset and in multiple subsets and DC cells types and others APC cells and NK cells.

These multiple sentinel ceil activation that leads to an also complex and multiple synergic DCs activation in multiple iaftammatory and lymphoid territories lead to a systemic CD4 TH1, CD4 TH2, CTL CDS and B cell and antibodies polyclonal effective responses that abrogate the Uremia and make the inactivation and cl earance of the virus and infected cells letting fem without the capacity to recycle and to perpetuate themselves in environment (42).

Some malfunction of the immune system due to rare genetic defects can give rise to an also rare vaccine disease that is in general very severe or even fetal, proving further evidence that the elimination of the vaccine virus as a matter of competition between host immune system and virus in a beneficial induced disease and not as a single vaccine unmnnization{43). The activation context in a systemic subclinical disease is huge and complete different than a single repeated immunization with antigen vaccine these is one of the reason of tire high effectivity of these two vaccines/1) (44-50) in conclusion, an aggressive wildtype virus would affect the host-pathogen balance in a different way than a vaccine vims, leading to a severe disease in one case and a subclinical disease in the other(l) (44-50). It is well known that an overlapping acute infection over a chronic one, such as cancer or chronic infection, can induce the cure ofthe underlying disease (42, 5.1). A strong activation can prevail over an ineffective one, improving the last one an altering the host x pathogen equilibrium competition and the outcome (42,51). It Is also well known that the acti vation induced by the overlapping of an effecti ve unrelated specific immune response is the best way known to rescue a state of tolerance, immunosuppression or anergy to a

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PCT/BR2018/000004 slate of normal response (52).

In the same way, experiments with mutagenesis transforming low into high immunogenic tumours indues turnout rejection that cannot be generated with the wild tumour and, also induce CTLs against subdominant epitopes(53,54). PAMPs alone can remodel lymph node feed arteriole and induce lymph node hypertrophy that is essential for an effective primary' adaptive response. An unrelated activated or pulsed effector memory T specific CD4+ CD40L+ migrate in a CD62P~dependent. feshion into the reactive lymph nodes via HBVs and license dendritic cells for T cell priming against weak antigen, tolerate antigens and auto antigen starting an auto immune disease or improving an immune response in an ongoing infection or neoplastic disease (4, 52, 35). Effector Memory CD8 T cells release CCL3, that in turn activate MFCs to produce TNF alia that induce PMNNs and Others MPCs to produce ROis and clear bacteria. Unrelated pathogen sensitive to ROis can also be clear by bystander activation(6, 56-59), Recently, it was also recognized that the status of the microbiome of the intestinal flora intervenes and can determine the effectiveness of a given vaccination.

These situations, studied is parallel, of disease and vaccine disease, isolated disease and overlapping diseases, blocked specific immune response overlapped by effective specific immune response, natural no immunogenic tumours versus mutagenic immunogenic tumours, vaccine immunization and ongoing immune response to the flora, microbiome and T CD4 Effector Memory' cells and CDS T effector memory induced potent activation of innate cells, PAMPs effect on feeding lymph nodes arteriole and lymph nodes hypertrophy and the others studies described above, reveal very important points of the immune response In Pasteur paradigm that should be considered for the proposal of a new hypotheses of work destined to improve treatment of infections/inflammations, neoplastic, allergic and others diseases in tire context of th e design of sew therapeutic approach.

Such important points of observations are:

- The immune system Is reactive and not proactive and it has a unique huge response potential but only use the stimulated patch by which they see the aggressor in the context of the host x parasite competition balance. In consequence, the outcome of a given new immune response is always circumstantially a fortuitous reply determined by the host x parasite

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PCT/BR2018/000004 competition balance and even if is efficient they are sot the best possible response, hi conclusion, a primary immune response is always a fortuitous reply possible to be improved

2- The best possible response, or protection, occurs only in secondary' response due to effective memory formation after the cure of a severe disease ore effective vaccination. Thus, memory cells are key in generating protective immunity.

3- lire innate response is not specific by its own nature and can hold multiple specific adaptive responses at the same time and in the same territories with synergic or antagonist effects. Because human and animal organisms can hold multiple aggressions at the same time and even in the same territory, the sinks of the innate immunity receptors recognition system recognize an expandable and changeable universe of PA MPs, DAMPs, and Stress Signals in contrast to a defined recognition of the identity' of an aggressor pathogen by adaptive immunity.

4- Based on the characteristic cited above and on the study of the mechanism of protection induced by VT-17D vaccine the rational logistic to activate the innate immunity effectively , paradoxically should have to be based on the multiplicity and diversity of activation of different sinks PRRs, DRRs and Stress Signals in different cellular compartments and in multiple cells sentries and APCs cell types vrith multiple cytokines and chemokines secretion in multiples territories lymphoid and no lymphoid to reach the best available adaptive immune response independently of the antigenic receptors universe to be activated in the adaptive specific response.

5- The major role of the primary response is to circumscribe the pathogen in a proinflammatory environment until an effective adaptive response takes place. The primary adaptive response in acute infection is also pro-mflammatory. Both can be very harmful if the contact surface is big and usually induce a symptomatic illness and can also induce a deleterious lethal systemic inflammation

6- The secondary' innate and adaptive effective responses are provided by T, B memory cells and in some circumstances by NK memory cells that give a fester, correctly polarized, more accurate, quiet, low inflammatory and protective immune response, when available. These modified secondary adaptive immune responses for its anti-inflammatory nature had to the cells

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PCT/BR2018/000004 memory can effectively deal with systemic wide range of pathogen -surface .contact without being harmful for the human and animal organism.

7- In overlapping situations cited above the innate territory activated of both diseases ore immune responses corporate for the same cells sentries, APCs, with the release of common cytokines, common chemokines and will be in the same activated lymph nodes, and inflammatory territories all the scene ore battle context will be the same for the two responses. 'When secondary and primary adaptive response occur simultaneous the secondary adaptive immune response is the dominant immune response by the action of memory cells that reset the signal transmission in innate and adaptive cells and induce tire primary' responses to shift to a low inflammatory pattern in a target memory’ modified territory'.

8- Also, these effects caa be obtained by the inj ections of a mix of PAMPs and secondaty antigens to cognate memory cells that induce a secondary’ immune response and activate optimally PMvs and PMNNs to clearance bacteria sensitive to, ROIs and other mechanism and activate optimally lymph nodes and improve ongoing immune response or can induce a poor or tolerated or no immunogenic one, fo conclusion, the immune system is reactive and not proactive and the quality and effectiveness of the natural immune response depends mainly of two factors;

- hirst factor is the existence or not of an immunological effective specific memory’ that it determines a secondary or a primary immune response, fa the case of a secondary response tire best possible re sponse is available and the outcome is a quiet protection, in the case of a primary response the new immune response is always circumstantially a fortuitous reply and the outcome depends on the second factor and can be improved.

-The second factor Is the host x parasite competition balance (40,49,53, 54, 60-78).

Therefore, the immune system cannot improve by itself an. already’ ongoing primary immune' response and the answer for the question of how to change and improve an established initial primary improper immune response is apparently complex but strategically simple because there are only-^- two factors determining the outcome of an immune response . In a primary immunological reply, there are only one remainder factor that is the context of the host x

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PCT/BR2018/000004 pathogen competition, balance to be modified to possible improve the ongoing inefficient immune response. The antimicrobial drugs acts by weakening, the pathogens action and reducing their numbers in vivo, and would function as ES of fee host x pathogen competition like describe and proposal above. By this action the antimicrobial drug alter positively the host pathogen equilibrium balance and the outcome but don’t alter fee nature of the ongoing primary response. Following this rational analysis, it would be enough to changing fee nature of the ongoing primary improper natural immune response to a secondary' effective standard to be favourable to the organism. A task, that obviously, the immune system cannot accomplish without help, because it estimates an ordinated delay with a differentiation step. How to transform in real time, immediately a primary fortuitous reply in a secondary best possible response? The answer is by the best possible secondary activation.

in order to accomplish this task, the strict reactive characteristic of the immune system in a primary response that depend mainly on the pathogen hnmunogenicify and action and on the fitness of the immune system, open fee door for a proactive medical immune intervention that can. use all fee remainder vast immune potential of available reply to change the host x parasite competition balance in favour of the host with anew secondary? standard of this initial IR. This strategical and planned immunological action must be able to reset, lead back, control, modify and improve in real time the immune system action to induce a favourable secondary specific effective IR &r positi vely alter the context -of host x parasite competition and the outcome.

The only possible answer would be changing fee perception or how the immune sy stem sees and characterizes the aggressor agent by including a great amount and diversify of new secondary memory antigens determinants constructing anew perceived identity for the aggressor pathogen.

This new perceived identify may be built in all disease’s lymphoid sites or not, or even inflammatory territories, in controlled periods, feat naturally will change completely the activation by a secondary huge one. Now wife a new best secondary activation for the ongoing disease the immune system could reprogram, fee immune response based mostly in secondary well known antigenic determinants with a minority' of primary determinants deriving from the aggressive pathogen feat wili generate a complete new different effective specific and well

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PCT/BR2018/000004 polarized immune response. The best possible one will he generated with secondary' tracts in the secondary resetting, low inflammatory territories.

The sum ofthe total effective anti-inflammatory secondary response to the new created image ofthe aggressor pathogen could revert all the induced tolerance, anergy, scape mechanism and could also induce a immune response to all the weak antigens or subdominant epitopes to create the best possible effective response in a totally different poor inflammatory battle field, that «mate .a complete new host x parasite competition balance in favour ofthe host To reach this goal is accessary to create a new ES Equilibrium Shifter au IRS (Immunological Response Shifter) whose action and creation should be based on the important and significant observations made from the study of the Pasteur paradigm described in details above.

Illis new IRS for the proactive action ofthe proposed and planed immunotherapy must be constituted by a vast and very' diverse pathogen secondary' antigen universe for which the organism disposes an effective memory repertoire. These antigens must be with priority inert and be applied m ah the territory ofthe illness exceeding its limits.

Such antigens should be able to induce a multiple huge secondary anti- inflammatory activation to overlapping completely the primary pro inflammatory activation induced by the pathogen. These antigens should be applied each e to 5 day's, to inhibit the immune suppressive cells generation imitating a draw out illness. The propose of this- immunotherapy is to create at the biological level un new virtual but real exogenous ore endogenous pathogens foil identified bv foe innate and adaptive immunity in his most part as a secondary and well know aggressor bymemory effective ceils that will induce the best available immune response replacing the initial one. Changing the inner image ofthe pathogen picked-up by innate and adaptive memory' cells we proactively change the context ofthe host x pathogen competition now in fevour ofthe host. 'Ine reactive immune system activated excellently by the proactive immunotherapy' will real time reprogram, reset and leads back the best available secondary' anti-inflammatory' specific immune response against the etiologic agent reverting his initial advantage in an ongoing illness.

For the proor of concept that a new perceived image of the exogenous or endogenous pathogen by an innovative IRS may real time govern, reset and lead back an already' established

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PCT/BR2018/000004 pathological response we use some compassionated eases of reversed lethal irreversible sepsis mostly with multi-resistant microorganisms out of the scope of the best available antibiotics used in combined fashion.

The follo wing positive significant' results of this clinical cases shown in the Examples prove and sugS^st that it is possible real time governing, resetting, leading hack the immune system and create new secondary effective, anti-inflammatory immune responses during the treratment of a disease by replacing the initial exaggerated, ineffective, improper ore deleterious primary immune response one by proactively creating anew image of the aggressor pathogen.

This is the first demonstration that is possible to govern, reset and lead back an ongoing immune response r.n wvo in favour' of the host altering positively tire host x pathogen competition balance, as welt as the outcome, and also having a ssgnificant synergic effect with antimicrobial drugs.

Another object of the invention is the use of immunogenic compositions for preventing and/or treating infectious diseases. Particularly, providing methods of treating bacterial infections and sepsis and uses or the .above-mentioned immunogenic compositions for preparing medicaments and kits for treating bacterial infections.

in the context of tins patent application, abbreviations are used several times, and their definitions, according to their usage in this application, are summarized below:

• IRS: Immunological Response Shifter • BCG refers to attenuated Mycobacterium bovis, Bacille Calmette-Guerin;

• DAMPS refers to danger associated molecular patterns;

• DEva refers to the IRS composition la described in Example I of the present patent application;

• GM.-CSF refers to Granulocyte macrophage colony-stimulating factor;

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PCT/BR2018/000004 » FAMES refers to pathogen-associated molecular patterns.

* PFU: plaque forming units.

• PPD refers to purified protein derivative: of M. tuberculosis;

» PPD refers to the fraction of the purified protein extract culture of Koch’s bacillus (Purified Protein Derivative). The PPD is the major antigen of Mycobacterium tuberculosis;

* TDCI50 is a unit for quantification of viral particles and is the infectious dose in 50% of cells in a tissue culture;

• Koch’s Tuberculin refers to inactivated Mycobacterium bovis lysate;

* Units If or ' Limes flocculation units is the international unit for quantifying antigens in toxoid vaccines accepted by the World Health Organization;

® VITER: The IRS composition l b described in Example 1.

® ISR: Integrated Stress Response « SRS; Stress response signals • SRR; Stress response receptors ♦ ES: equilibrium shifter

In a first embodiment, the invention refers to a pharmaceutical product comprising one or more antibiotics with one or more immunogenic compositions tor modulating the immune system comprising a therapeutically effective amount of three or more (e.g., 3, 4, 5, 6,7, 8, 9,10,11, 12, 13,14, 15,16,17, 18,19, or 20 or mors) synthetic antigenic agents or natural antigenic agents, or fractions and combinations thereof, comprising pathogen-associated molecular two groups consisting of: (A) antigenic agents with molecular patterns associated with bacteria, (B) antigenic agents with molecular patterns associated with viruses, (C) antigenic agents with

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PCT/BR2018/000004 molecuEr patterns associated with fungs and yeasts, (D) antigenic agents with molecular patterns associated with protozoa, (E) antigenic agents with molecular patterns associated with helminfoes, and (F) antigenic agents with molecular patterns associated with prions; and one or more physiologically acceptable carriers, excipients, diluents or solvents.

Such pharmaceutical product may be a composition, a kit, a medical device or any other product wmch aims to deliver the antibiotics and the one or more immunogenic compositions as described above to a tissue.

The one or more antibiotics comprised mthe pharmaceutical product of the invention may be selected from the following classes; Amino Acid Derivatives, Aminoglycosides, Aureolic Acids, Aziridines, Ansamycins, Benzenoids, Carbapenems, Cephalosporins, Coumarin.glycosides. Diphenyl Ether Derivatives, Epipolythiodioxopiperazines, Fatty Acid Derivatives, Glucosamine, Giycopeptides, imidazoles, Indol Derivatives, Lipopeptides Macrolactams, Macrolides, Nucleosides. Penicillins and Cephalosporins (beta-Lacttuns), Peptides, Peptidyl Nucleosides, Phenicoles, Polyenes, Polyethers, Pyridines and Pyrimidines, Quinolones and fluoroquinolones, Statms, Steroids, Sulfonamides, Taxoides and Tetracyclines.

Preferably the immunogenic compositions of the present invention comprise immunoacrive antigenic agents presenting pathogen-associated molecular patterns (PAWS) and/or danger associated molecular patterns (DAMPS) selected from foe group consisting of: (A) antigenic agents with molecular patterns associated with bacteria; (B) antigenic agents with molecular patterns associated with viruses; (C) antigenic agents with molecular patterns associated with fungi and yeasts; (D) antigenic agents with molecular patterns associated with protozoa; (E) antigenic agents with molecular patterns associated with multicellular parasites / or (F) antigenic agents with molecular patterns associated with prions.

Still more preferably the immunogenic compositions of this invention include pathogenassociated molecular patterns (PAMPS) and/or danger associated molecular patterns (DAMPS) selected from among at least three categories (A), (B), (€), (D), (E) and (F) described above.

More preferably, the immunogenic compositions of this invention include pathogen-associated

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PCT/BR2018/000004 molecular patterns (PAMPS) and/or danger associated molecular patterns (DAMPS) selected from among at least four categories (A), (B), (Q, (D), (E) and (F) described above.

Antigenic agents of the present invention can be selected from epitopes, genetic materials, lipids, polysaccharides and/or immune active proteins of the present invention can be obtained by purification from isolated fragments of material existing in nature or fractions derived from plant, animal or microbiological extracts, or produced by genetic recombination, preferablyderived from viral, fengal, parasitic or bacterial prion strains.

Hsus, fee antigenic agents of the present invention with molecular patterns associated with bacteria of the present invention may be selected from, but not limited to antigenic agents with molecular pattern s associated wife bacteria of fe e genera Staphylococcus, Streptococcus, fanteroeoceus, voiyoebacterium, Bacillus, Listeria, Clostridium» Mycobacterium, Actinomyces, Nocardia, Escherichia, Proteus, Klebsiella, Senatia, Enterobacter, Salmonella, Shigella, Pseudomonas, Burkholderia, Stenotrophomonas, Acinetobacter, Vibrio, Campylobacter, Helicobacter, Bacteroides, Neisseria, Moraxella, Haemophilus, Bordetella, Brucella, rrancisella, Pasieurena, Yersinia, Legionella, Gardnerella, Treponema, Leptospira, Borrelia, Mycoplasma, Rickettsial and Chlamydia.

Antigenic agents with, molecular patterns associated wife. virus of the present invention may be selected from, but not limited to antigenic agents with molecular patterns associated with virus families Adenoviridae, Arenavrridas, Busyaviridas, CorOnaviridae, Filoviridae. Flaviviridae. Hepadnaviridae, Deltavirus, Caliciviridae, Herpesvirtdae, Orthomyxoviridae, Papovaviridae, P^ramyxoviridae, Parvoviridae, Picomaviridae, Poxyviridae, Reoviridae. Retroviridae, Rhabdoviridae and Togaviridae.

Antigenic agents with, molecular patterns associated with, fungi and yeasts of the present invention may be selected from, but not limited to antigenic agents with molecular patterns associated wife fungi and yeasts of the genus Sporothrix, Aspergillus, Blastomyces, Candida, Coccidroides, Cxyptococcas, Histoplasma and Pneumocystis.

An tige nic agents with molecular patterns associated wife protozoa of fee present invention maybe selected from, out not limited to antigenic agents with molecular patterns associated with

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PCT/BR2018/000004 protozoa of the genera Cryptosporidium, Ciclospora, Entamoeba, Nasglena, Giardia, tieishmsnia, Plasmodium, Toxoplasma, Trichomonas, Trypanosoma, microsporidia and Isospora.

Antigenic agents with molecular patterns associated with multicellular parasites of die present invention may be selected from, but not limited to antigenic agents with molecular patterns associated with multicellular parasites trematodes, cestodes and nematodes.

The antigenic agents of the present invention comprise protein, polysaccharide, lipid molecules and/or composite syntactic molecules that mimic protein, polysaccharide and/or lipid molecules

More specincahy, the agents of the invention comprise immune-active antigenic protein molecules which have enzyme activity, for example kinases, phosphatases, steeptoqninases. estreptodomases and Deoxyribonucleases (eg. domases).

thv immunogenic compositions for modulating the immune system of the present Invention comprise from 0.001 to 500 micrograms per mi of each immunogenic agent, tinch immunogenic agents can be encapsulated in capsules, micro particles, nanoparticles, coated tablets, liposomes.

Specifically, tire immunogenic compositions for modulating the immune system of the present in vend on comprise from 4 to 20 antigenic agents selected from the group consisting of antigens derived from agents: domase, levedurin, oidiomycin, PPD, prions, sireptoquinase,

Streptococcus toxoid, dipntheria toxoid, Tetanus toxoid, Koch’s tuberculin, inactivated lysate of Ascaris lumbricoides, Aspergillus spp;, Aspergillus flavus, Aspergillus fumigatus, Aspergillus terrens, Candida spp., Candida albicans, Candida glabrata, Candida parapsilosis, Chlamydia spp.,· Cnlamydia pneumoniae, Chlamydia psittaci, Chlamydia trachomatis, Cryptosporidium spp., Denuatopttytes, Entmnoeoa hystolitica, Enterobius vermicularis, Enterococcus faecaiis, Epidermopbyton floccosum, Escherichia coli, Giardia lamblia, Haemophilus influenzae. Microsponrm cannis, Mycobacterium spp., Mycobacterium bovis, Mycobacterium leprae. Mycobacterium tuberculosis. Neisseria gonorrhoeas, human papilloma virus, Polio virus,

Proteus spp., Proteus mirabilis, Proteus penerii, Proteus vulgaris, Salmonella spp., Salmonella bongori, Salmonella euterica, Serratia spp., Serratia liquefaciens, Serratia. marconcens. Shigella

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PCT/BR2018/000004 spp. Shigella flexneri, Shigella soanei, Staphylococcus spp., Staphylococcus aureus, Staphylococcus epidermidis, Strongyloides stercoralis, Streptococcus spp., Streptococcus bovis. Streptococcus viridans, Streptococcus equinus, Streptococcus pneumonias, Streptococcus pyogenes,· Toxoplasma gondii, Trichomonas vaginalis, trichophytin,. Trichophyton spp., Trichophyton rubrum, Trichophyton tonsurans. Trichophyton mentagrophytes, yellow fever virus, hepatitis is virus, rubella virus, varicella zoster virus, variola virus, mumps virus, measles vims, herpes virus and vaccinia vims or synthetic analogues that present pathogen-associated molecular patterns (PAMPS) and/or danger-associated molecular pattern s (DAMPS) associated with these antigenic agents.

In various embodiments, the immunogenic compositions for modulating the immune system of the present invention comprise 4,5, 6,7, 8, 9, 10, II, 12,13,14,15, 16, 17, 18, 19,or 2G antigenic agents selected from the group consisting of antigens derived from agents: domase, levedurin, oidiomycin, F.PD, prions, streptoqmnase, Streptococcus toxoid, diphtheriatoxoid, letanus toxoid, Koch s tuberculin, inactivated lysate of Asearis lumbricoides, Aspergillus spp-, Aspergillus flavus, Aspergillus iumigatus, Aspergillus terrens, Candida spp., Candida albicans, Candida glabrata, Candida psrapsilosss, Chlamydia spp., Chlamydia pneumoniae. Chlamydia psittaci, Chlamydia trachomatis, Cryptosporidium: spp., Dermatophytes, Entamoeba hystolitjca, Enterobius yenaicularis,. Enterococcus faecalis, Epidermophyton floccosum, Escherichia coli, Ciardia lambiia, Haemophilus influenzae, Mierosporum cannis, Mycobacterium spp., Mycobacterium bovis, Mycobacterium leprae, Mycobacterium tuberculosis, Neisseria .gonpnhoeae, human papiitonra virus. Polio virus, Proteus spp., Proteus mimbilis, Proteus penerii, Proteus vulgaris. Salmonella spp., Salmonella bongori, Salmonella enterica, Serratia spp., Serratia hquefaciens, Serratia marceneens, Shigella spp. Shigella flexneri. Shigella sonnet Staphylococcus spp., Staphylococcus aureus. Staphylococcus epidermidis, Strongyloides stercoralis, Streptococcus spp., Streptococcus bovis. Streptococcus viridans, Streptococcus equinus, Streptococcus pneumoniae, Streptococcus pyogenes. Toxoplasma gondii, Trichomonas vaginalis, trichophytin, Trichophyton, spp., Trichophyton rubrani, Trichophyton tonsurans, Trichophyton mentagrophytes, yellow fever virus, hepatitis B virus, rubella virus, varicella zoster virus, variola vims, mumps virus, measles virus, herpes virus and vaccinia virus or synthetic analogues that present pathogen-associated molecular patterns (PAMPS) and/or danger-associated molecular patterns (DAMPS) associated with these antigenic agents.

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PCT/BR2018/000004

A preferred immunogenic composition of fee invention comprises inactivated Mycobacterium bovis lysate, purified protein derivative of M. tuberculosis, inactivated Staphylococcus aureus lysate, inactivated Staphylococcus epideimidis lysate, inactivated Steptococcus pyogenes lysate, maetivated Streptococcus pneumonia lysate, inactivated Enterococcus faecalis lysate, Streptokinase/domase, inactivated Candida albicans lysate, inactivated Candida glabrata lysate, inactivated Epidermophyton floccosum lysate, inactivated Microsporam cannis lysate, inactivated Trichophyton mentagrophytes of fee interdigitate variety lysate. Inactivated enteropafeogeuic fcschenchia coli lysate, inactivated Salmonella bongori lysate, inactivated Salmonella enterica lysate and inactivated Salmonella subtenasea lysate.

A preferred immunogenic composition of fee invention comprising from 0.001 to 1 ng/ml of inactivated Mycobacterium, bovis lysate, 0.001 to 1 ng/ml of purified protein derivative of M. tuberculosis, 0.1 to 100 pg/ml of inactivated Staphylococcus aureus lysate, 0.1 ίο 100 pg/ml of inactivated Stapnyloeoccus epidermidis lysate; 0.1 to Γ00 gg/ml of inactivated Steptococcus pyogenes lysate; 0,1 to 100 pg/ml of inactivated Streptococcus pneumonia lysate; 0.1 to 100 ug/ml of inactivated nnterococcusfaecalis lysate, 0.01 to 10 ug/ml of streptokinase, 0.01 to 10 pgfeil of domase; 0.1 ίο 100 gg/ml of inactivated Candida albicans lysate; 0.1 to 100 gg/ml of inactivated Candida glabrata lysate, 0.1 to 100 pg/ml of inactivated Bpidermophyton floccosum lysate; 0.1 to 100 ug/ml of inactivated Microsporom cannis lysate, 0.1 to 100 ng/ml of inactivated Trichophyton mentagrophytes of the interdigitals variety lysate; 0.1 to 100 pg/ml of maetivated enteropatnogenic Escherichia coli lysate; 0.1 to 100 pg/ml inactivated Salmonella bongori lysate, 0.1 to 100 pg/ml inactivated Salmonella enterica lysate and 0.1 to '100 ug/ml of inactivated Salmonella subtenanea lysate.

The compositions of the present invention can further comprise excipients, such as bactericides, bacteriostats, antioxidants, preservatives, buffers, stabilizers, pH adjusters, osmolarity adjusters, antiroaming agents and surfactants, and residual antigen inactivating or fractionation agents, growth medium components and solvents commonly used in the production of vaccines and immunotherapies.

The compositions of the present invention may be a solid, liquid or gel. As used herein, fee use of the term ’’phatmaceutically acceptable carrier means a non-toxic solid, inert, semi-solid

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PCT/BR2018/000004 liquid excipient, diluent, auxiliary formulation of any type, or simply a sterile aqueous solution such as saline, Some examples of materials which can serve as pharmaceutically acceptable earners are sugars such as lactose, glucose and sucrose, starches such as com starch and potato starch, cellulose and its derivatives such as sodium carboxymethyl cellulose, a ethyl cellulose and cellulose acetate, cyclodextrin; oils such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, com oil and soya beau oil, glycols such as propylene glycol, polyols, such as glycerol, sorbitol, mannitol and polyethylene esters such as ethyl laurate, ethyl oleate, agar, buffering agents such as aluminum hydroxide and magnesium hydroxide, alginic acid, pyrogenfree water, isotonic saline , Ringer's solution, buffer solutions of ethyl alcohol and phosphate as weil as other non-toxic compatible substances used in pharmaceutical formulations.

A variety of administration routes in animals or humans for the immunotherapeutic compositions and vaccines described herein are available. The particular selected mode, will depend on the selected antigenic agents, the dosage required for therapeutic efficacy and patient to whom the composition is administered. The methods of the present invention can generally he practiced usmg aay mode of administration bioiogically acceptable, i.e., anv means that produces effective levels of immune response without causing clinically adverse reactions. Such modes of administration include intradermal, oral, rectal, sublingual, topical, nasal , traasdermal or parenteral administration, the term parenteral includes subcutaneous, intravenous, epmural, irrigation, intramuscular, release pumps or infusion. In particular, in this invention, oral, intradermal, parenteral, subcutaneous, intravenous, intramuscular, and, by the nasal mucosa and/or oral administration are preferred for administration of the compositions claimed herein.

For parenteral administration, the active ingredients may also be dissolved in a pharmaceutical earner and administered as a solution, emulsion, including micro-and nano-emulsions or suspension. Examples of suitable carriers are water, saline, dextrose solutions, fructose solutions or oils of animal, vegetable or synthetic origin. Other vehicles may also contain other mgredients, for example, preservatives, suspending agents, solubilizing agents, buffers rhe like.

In a second embodiment, the invention refers to a method to treat sepsis in a human or an

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PCT/BR2018/000004 animal who has a bacterial infection comprising administering to the human or animal an effective amount of one or more antibiotics and one or more immunogenic compositions for modulating the immune system comprising a therapeutically effective amount of three or more (©·§·> 4, 5, 6, i, 8, 9, 10, 11, J 2, 13, 14, 1.5,16,17,18, 19, or 20 or more) synthetic antigenii agents or natural antigenic agents, or fractions and combinations thereof, comprising pathogenassociated molecular patterns (PAMPS) and/or danger associated molecular patterns (DAMPS) selected from at. least .two groups consisting of: (A) antigenic agents with molecular patterns associated with bacteria, (B) antigenic agents with molecular patterns associated with viruses, G-7 antigenic agents with molecular patterns associated with fungi and yeasts, (D) antigenic agents with molecular patterns associated with protozoa, (E) antigenic agents with molecular patterns associated with helminthes, and (F) antigenic agents with molecular patterns associated with prions, and one or mors physiologically acceptable carriers, excipients, diluents or solvents.

Septicemia is defined as an extremely serious infection in winch one or more bacteria or microoiganisms, from their entry pornt, enter the bloodstream and start circulating in large uumbess, getting established at distant points, colonizing tissues, organs, and is the most severe cases, can successively reach most of the body surface and causing sepsis as a generalized inflammation that compromise the circulatory system. Generally, when the microorganism load is too large, a large number of bacteria, with their toxic and metabolic products, with countless PAMPS and DAMPS, stress signals touching with all the also countless PRRs and RDPs stress Signal receptors of most of the body surface, while generating, an extensive, intense and violent general inflammatory' process, with the massive release of cytokines (cytokine storm) from the translation of all these signs.

The unfavorable evolution of septicemia leads to sepsis, through the massive release of proinflammatory cytokines such as TNPs, ILl, ILl 8, IL6 and others, causing an inflammatory collapse with hemodynamic characteristic alterations, such as hypotension, rapid pulse, which may culminate in septic severe shock, usually irreversible. Septicemia, sepsis ate serious infretions/mflammations with high moibidiiy and mortality. In these severe miections/infiammation syndrome the immune system, in turn, with its compromised operability by weaknesses and blockages induced by bacteria, starts to act so as to eliminate the

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PCT/BR2018/000004 bacteria at any cost through the cytokine storm and through the inflammatory Thl7 tissue profile, mcreasmg inflammation disproportionately and therefore banning die organism (33).

hi this inflammatory tissue profile, die effector loops of innate immunity, controlled by the TCP4 lymphocytes, cause tissue damage and sometimes massive destruction, that compromise organs and tissues and that exacerbate infections, leading, for example, to respiratory failure, lung shock, and in A RD S (adult respiratory’ distress syndrome), also leading to renal failure and multiple organ failure.

Therefore, in septicemia, in sepsis and in septic shock there are two variables that should strategically be considered and should be the target of an immunotherapy, so it is successful. These two variables are the huge inflammation by the cytokine storm caused by the massive spread of countless bacteria in the whole body and its connection with the PRRs, DPPs, and stress signals in DCs and sentinels cells that induce polarization for the 1hl7 profile caused by the functional infeasibility of die Thl and Th2 profiles and described inflammation settings. These variables are the cornerstone of severity,, gravity, morbidity and mortality of these diseases.

Asking imo account, these two variables, for an immunotherapy to be effective in these infections, it should be applied to cover the entire body surface, including the greatest number or lymphatic territories to geographically overlap with the action of the pathogen or pathogens.

It should also be applied to the injured areas and to the perilesional region so that together they van cause widespread, recontextualization, that by its action can recover the integrity of the T loop and produce a wide, extensive and intensive, anti-inflammatory effect by effector/memory T cells- generated within the application sites. It should, is parallel, through the recontextualizarion and reprogramming above described with huge anti-inflammatory’ effect by inhibiting and decreasing cytokine storm, polarize the TCD4 response of the Thl7 inflammatory tissue profile for the humoral TH2 and cell TH1 profiles, further decreasing the generalized inflammation by the action of memory' cells the only cells in the body capable to abrogate physiologically huge inflammations.

rr used the loop amplification by IL2 should be very low, just enough to specifically amplify the repolarization of the immune response of the inflammatory profile to the immunity profile or

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PCT/BR2018/000004 to Treg/TRl regulatory profile.

Thus, the lecontesduaiizmg and the reprogramming achieved by immunotherapy using the compositions of the present invention to achieve a new perceived identity of the pathogen, by recovering immune cells through the anti-inflammatory action of κοπ-related specific memory T lymphocytes, by the inhibition of the cytokine storm and also by the ^polarization of the tissue inflammatory profile TH17 to elective and effective TH1 and TH2 immunity profiles, will together redirect the immune response. This immune response, renewed in real time during the infectious process, in conjunction with a biological balance shifter, in the case of the use of various antimicrobial agents, have a chance to reverse the biological equilibrium at the end of the curve in which is very favorable for the microorganism, to be favorable to fee host and now have a chance of solution.

Adequacy of the protocol to the status of the immune system in the pathology and in fee patient, being treated.

In the. case of septicemia and sepsis, by' fee own pathophysiological mechanisms, there is a breach of the integrity' and functionality? of fee T loop with an inadequate polarization for a suppressing TREG profile in cancer and for an cytokine storm and inflammatory tissue Thl7 profile in sepsis with a nearly' complete inoperability of the immune system overcome by disease. In these cases, as in the examples cited herein, the recontextualizisg induced by fee best available secondary⁷ achieved activation of the new perceived identity of the pafeosen must reach fee whole bony to reverse all immunosuppression, tolerance and immune Ignorance induced by fee pathology, as well as to restore all operational and functional capacity of the immune system to nave a reprogrammed and renewed effective immune response.

In a third em bodiment, the invention refers to a method to treat multi resistant bacteria infection in a human or an animal who has a bacterial infection comprising administering to fee human or animal an effective amount of one or more antibiotics and one or more immunogenic compositions for modulating the immune system comprising a therapeutically effective amount offeree or more (e.g., 3,4, 5, 6, 7, 8, 9,10,11,12,13,14,15, 16, 17,18, 19, or 20 or more) synthetic antigenic agents or natural antigenic agents, or fractions and combinations thereof, comprising pathogen-associated molecular patterns (PAMPS) and/or danger associated

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PCT/BR2018/000004 moteedar patterns (DAMPS) selected -ffom. at two groups consisting of (A) antigenic agents with molecular patterns associated with bacteri a, (B) antigenic agents with molecular patterns associated wxtli viruses, <C) antigenic agents with molecular patterns associated with fungi and yeasts, (D) antigenic agents with molecular patterns associated with protozoa, (E) antigenic agents with molecular patterns associated with helminthes, and (F) antigenic agents with molecular patterns associated with prions; and one or more physiologically acceptable earners, excipients, diluents or solvents.

In a fourth embodiment, tire invention refers to a method to modulate an immune system response in a human or an animal who has a bacterial infection comprising administering to the human or annual an effective amount of one or more immunogenic compositions for modulating the immune system, comprising a therapeutically effective amount of three or more (e.g, 3, 4, 5, 6, 7, 8, 9,.10, 11,12,13,14,15,16,17,18,19, or 20 or more) synthetic antigenic agents or natural antigenic agents, or fractions and combinations thereof, comprising pathogenassociated molecular patterns (PAMPS) and/or danger associated molecular patterns (DAMPS) selected from at least two groups consisting of: (A) antigenic agents with molecular patterns as&ociareo. with bacteria, .(B) antigenic agents with molecular patterns associated with viruses. (C) .antigenic agents with molecular patterns associated with fungi and yeasts, (D) antigenic agents with molecular patterns associated with protozoa, (E) antigenic agents with molecular patterns associated with faetaunth.es, ano (F) antigenic agents with molecular patterns associated with prions; and one or more physiologically acceptable carriers, excipients, diluents or solvents.

it is other aspects, the present invention refers to the use of immunogenic compositions in the manuraefure of medicaments and kits for preventing and/or treating of infectious diseases, immunogenic compositions of the invention are also may also be used in. the 'prevention and/or treatment of infections diseases in association with one or more antibiotics.

Properties of the immunogenic compositions of the present invention

The immunogenic compositions of the present invention have an unexpected effect on tbs immune response. As can be seen in the Examples below, tire immunogenic compositions of the present Invention show an unexpected technical effect of causing an immune response that.

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PCT/BR2018/000004 involves resetting, ^contextualizing, leading back, response in real time.

renewing and reprogramming the immune

More specifically, the immunotherapeutic compositions ofthe present invention by creating a new identity ofthe pathogen perceived by innate and adaptive immunological system are capable of provoking a reset, a moontextuatization a lead back ofthe operational action capacity of fee Immune system by changing the relationship of forces ag^ _&e ngg^^ m its favor, giving the immune system a competitive advantage, which does not occur spontaneously in the evolution of disease. This recontextaalization determines a consequent renewal and reprogramming of the established imm une response or incipientiy established, or erroneously established mistakenly attacking in a dysautonomical way the human or animal body, polarizing fee primary pro-mfiammafory response that Is always a fortuitous reply possible to be improved to a secondary, active anti-inflammatory, more effective and appropriate Immune response.

fhi's effect occurs via secondly stimulation, activation and joint action of certain components ofthe immune system, such as sentinel cells, antigen presenting sentinel cells, and memory lympnocytes. Specifically, the compositions of tins invention properly reset the activated sentinel cells, the activated dendritic cells and other activated AFC cells, by the action of memory cells, generating a new degree and intensity of CD4 T cell with a. secondary activation piofile feat turn to a secondary’ effective standard the degree and intensity of tire immune profile to properly treat the infection without causing immunological side-effects, such as inflammation.

Accordingly, the immunomodulatory antigenic compositions of the present invention, when in larger or significant amounts completely change the perceived image ofthe pathogen and trigger a specific secondary active adaptive immune response, desired to treat bacterial, viral or parasitic infections with a low inflammatory profile.

m addition, fee treatment with fee immunogenic compositions ofthe present invention is capable of stimulating the regenerative power of the immune system, a natural physiological property offers system providing a subsequent effect to fee elimination of infections disease and other diseases, to recover cells and tissues, by restoring organ function debilitated from trauma and damage which cause the loss of part ofthe organism. This property was demonstrated in the

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PCT/BR2018/000004 .cluneal cases of irreversible sepsis reported in the Examples. The patients had recoveiy and. regeneration of complex trauma wounds with important tissue loss, organ destruction in lungs, kidneys, liver, bones and extremities induced by CI W, and ischemic events by low blood flow and toxicity .

Thus, the immunogenic compositions ofthe present invention are able to mobilize the immune system and lead to an increased regenerative power of the body, through mobilization of stem cells or the activation of gene sets which allow the regeneration of cells and tissues and can even reconstruct organs and their functions, and can reconstitute organic systems such as the vascular system, the nervous system and the endocrine system, among others.

As can be seen m the Examples presented below, the immunogenic compositions ofthe present invention exhibit an unexpected technical effect of recontexlualizing, renewing, and reprogramming the immune response in real time and consequently significant cure rates when compared to drugs and methodologies m the art.

In. a first embodiment ofthe invention, immimo-moduiator agent(s) is/are used for preparing an mununofeerapy pharmaceutical composition capable of inducing anew innate secondary immune response, which triggers a cascade of immune events, including the main event of activation of memory lymphocytes from the agent(s) inoculated hv human intervention and the concomitant activation by antigens present in the patient's own body, resulting in a reeontexlualization, renewal lead back and reprogramming ofthe ongoing immune response to a particular established disease (or still in the establishment phase), generating an adaptive secondary response specific to this disease effectively, allowing combating the pathogen in an anti-mfiammaiory way. As such, the administration ofthe composition containing the agents of the present invention repolarizes or improves fee polarization of fee immune system In the presence of a disease when the established polarization is inadequate, by the action ofthe etiologic agent or colonizer. The activities of the .agents of the present invention affect the shape, time, accuracy and polarization of fee immune response, preferably leading to an secondary mnate and adaptive immune response that it is more effective to fight the disease, leading to a better reaction of organism itself.

The present invention provides methods to treat bacterial and other microbial infections with the

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PCT/BR2018/000004 use of the antigenic combinations described. The present invention also provides for the possibility of addi ng traditional therapies to the agents of this invention, aiding the process of elimination of the etiological heterologous invading agents and of the colonizing autologous cells, through the real therapeutic potential of antimicrobial drags, selective for the pathogens and other infectious agents. Tins is made possible by the principle of displacement of the biological equilibrium in favor oi the patient in combination with a correct polarization of the immune response as described herein.

When the immune stimulation follows a situation of immune response, after the termination of tne disease mechanism or aggression, the continued activation of the immune system by antigens or immunomodulatory' agents of the present invention leads, through tire activation of stem cells, to the regeneration of tissues, organs and systems, by mechanisms not vet folly understood, but related to healing or restitution ad integrum mechanisms observed in various medical situations.

The compositions of the present invention allow the recruiting of the maximum number memory ceils, new effective virgin cell s of the individual, producing more significant effe cts than an antibody increase as described in the prior art. The use of multiple antigenic agents with distinct enough FAMES, DAMPS and stress signals to simulate different types of attacks that the organism suffers and to which the organism has already immunologic memory of, be it by en vironmental exposure or vaccination programs, allows a wider recruitment of memory' cells and new effective virgins cells, enabling real-time recontextaalization, resetting and leading back of the immune response and thus potentially and radically altering the type of immune response and disease or illness progression that affects the individual in a positive, and in several cases, such amazing way as compared to the prior art. Furthermore, the present invention, unlike the prior art, applies a greater and diverse amount of bacterial components, ha ving representatives of both intracellular and extracellular bacteria in the composition, besides components of viruses, parasites, fungi and yeasts.

The present invention encompasses more areas of the body and tissues that have sentinel and APC cells, and preferably looks for exposure on locations close to the infection sites and other distal applications to the disease sites (as is the case in disorders or diseases that manifest

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PCT/BR2018/000004 themselves in specific locations of the body) io .secondary reset innate system m all the places of the disease. The compositions of the present invention, wh en applied according to the process of using the present invention in one or, usually, at various strategic of body regions drained by lymphoid territories or primary and/or secondary lymphoid organs, or even intralesional, are perceived by the PRjRs (pathogen-associated pattern recognition receptors) off all sentinel cells of the body.

Thus, the present invention employs Immunomodulatory agents in amounts, concentrations and specific locations to recontextualize, reset and lead back the immune system, activating and redirecting the mechanisms for tissue repair and regeneration, as occurs during healing and regeneration of tissue, organ or system, leading to a restitution ctd integrum? or reconstitution with scar. Thi s repair is usually triggered at the end of an immune response process, after healing the infection.

Use of the immunogenic compositions of the present in vention.

Considering the properties of the immunogenic compositions of the present invention, it constitutes another aspect of the present invention using the immunogenic compositions in tire manufacture of medicaments for the prevention .and/or treatment of infectious diseases.

These infectious diseases can he of viral, bacterial, fungal or parasitic origin.

Diseases of viral origin prevented and/or treated by the immunogenic compositions of the present invention can be caused by the following viruses but not limited to;

HIV, hepatitis virus, herpes virus, rhabdoviras, rubella vims, smallpox vims, poxvirus, and Morbillivirus paramyxovirus.

Diseases of bacterial origin prevented and/or treated by the immunogenic compositions of the present invention may be caused by the following bacteria, but not limited to, Pneumococcus, Staphylococcus, Bacillus, Streptococcus, Meningococcus, Gonococcus, Escherichia, Klebsiella, Proteus, Pseudomonas, Salmonella, Shigella, Haemophilus, Yersinia, Listeria,

Corynebacterfum, Vibrio, Clostridia, Chlamydia, Mycobacterium, Treponema, and

Helicobacter.

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Fungal diseases prevented and/or treated by fee immunogenic compositions of the present invention may be caused by fee following fungi but not limited to: Candida, Aspergillus, Cryptococcus neofctruans, and/or fengi that cause superficial and deep mycosis. Diseases caused by parasites are caused by the following parasites: Trypanosoma, Schistosoma, Leishmania, amoebas and tapeworm.

In one embodiment of fee invention, the compositions of the present invention are administered once, in one area of the body or in different sites in order to redirect the immune sy ste m with the highest possible efficiency.

Tire use of fee immunogenic compositions of fee present invention for modulation of the immune system, involving the exposure of part or all of the system for recognition of antigens in the immune system, such as dendritic cells, macrophages and lymph nodes from different parts of the body, inflammatoiy territories will depend on fee goal imposed by fee illness being fought, and occurs preferentially? through injections or use of guns, or delivery systems or controlled infusion or pulsed cells with in vitro antigens. The agent may? be applied to only one location in the body or in several tens of locations in several forms: subcutaneous, muscular, intravenous, oral, breathable aerosol, cutaneous (dermal patches) in organs, the viscera, or specific tissues, or in different body cavities, which can vary? in number from one to one hundred (100) applications in one to fifty? (50) sessions.

The antigenic compositions of this invention may also be combined with other drugs feat can weaken fee reproduction, growfe, or any other form of strengthening of fee disease’s causative agent, causing a shift of the equilibrium in favor of the biological Immune defenses of fee host, animal or human. Or still in concomitant treatment.

The antigenic compositions of this invention may? also be combined wife otherprocedures such as, but not limited to, antibiotics chemotherapy, therapy with antibodies and antisera, using hormones or other physiology modulating agents (cytokines,, chemokines , neurohormones, peptides), treatment w'ife antiviral agents, use of herbal medicines, vitamin supplementation, methods of therapeutic or prophylactic vaccination (with or without cells and not limited to the type of vaccine vehicles), gene therapy, surgery? or homeopathy , depending on fee disease or illness being fought related to an improper or inefficient immune activity.

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Recontextualfeing, response.

resetting, renewing, leading back and reprogramming the immune

Recontexfeahzing and resetting the immune system, as explained in the text offers patent application, is achieved oy means of stimulation of the immune system by antigens of different pathogens not related to fee pathology to be treated, for which the human or animal, preferably, already has an immunological memory for totally changing the inner perceived primary image or fee invader pathogen to a new secondary effective proactively induced one.

these varied and multiple antigens, in number greater than five, with multiple PAMPs DAMPs <md SRS induce in the sentinel cells and m the APC cells, especially in dendritic cells, an intense secondary' activation allowing the mobilization of these memory CD4 and also CDS memory? or eventually NK memory cells and lymphocytes specific for these antigens at fee site of application.

These stimuli must be capable or causing an intense, strong and effective secondary specific immune re sponse to these antigens of the new identity’' at fee site of application, in fee regional activated lymph nodes. In the lymph nodes at a distance and a systemic mobilization of fee immune system so that it can, in parallel, cause an effective secondary* response capable of eradicating fee specific pathology? in progress.

The innate and adaptive secondary· immune response caused intentionally by fee composition of the present invention should encompass fee full extent of the body area affected by the condition being treated and even exceed It if possible to be able to activate fee sentinel and APC cehs in fee number and intensity feat would be needed to properly address the aggression caused by fee pathogenic disease to be treated, and activating and triggering the best specific adaptive secondary? response, effectively and properly sequentially polarized, in order to cure the condition being treated.

Thus, the innate and adaptive response induced by the present invention will geographically overlap fee condition being treated and by its intense and extensive secondary activation will correct tne inexneient activation, purposely? limited by fee action of fee pathogen feat overcomes the body's defenses, by preventing competition, its proper mobilization and development of an

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PCT/BR2018/000004 effective adaptive response according to its greatest genetic and biological potential· This local activation should also reverse the immunosuppression, the tolerance and escape mechanisms established by pathogens because it is known and proven that an unrelated strong and intense immune response, that folly covers the response to be corrected, through the activated cells and cytokines of tire immune system, will correct these deficiency situations efficiently.

Effector cells and memories of specific antigens ofthe present invention, activated and generated at the site of application of the antigens, will, via tire bloodstream, enter the already activated lymph nodes by HEVs, which drain the region affected by the disease and will enable, in a strong and intense way induce the activation of all the existing dendritic cells there. Therefore, they will lead to an activation of the entire lymph node, causing it to grow with increased irrigation, increasing its size and making it a reactional lymph node capable of provoking an immune response against weak antigens, which by themselves are not capable of causing an immune response. PAMPs alone can remodel lymph node feed arteriole ano induce 1 vmoh node hypertrophy that is essential, for an effective primary? adaptive response and also for secondary immune responses

This adjuvant effect, well known and demonstrated experimentally and clinically, of the effeetorimemory T lymphocytes, will oppose the action ofthe target causative agent that is blocking the required activation of the lymph node for the development of an immune response that is necessary' to treat the disease in question. That, exclusively for the purpose and by the action of the present invention, through its potent antigenic composition, may occur that the sentinel cells and dendritic cells and macrophages ofthe immune response will be the same for unrelated antigens and to the pathological antigens, but from tins action, will be intensely tarn properly activated. Dendritic cells strongly activated by multiple antigens, have a slow? metabolism and ideally present all dominant and subdominant epitopes ofthe causative agent, bv the known ’’helper” effect, mobilizing all possible and available T lymphocytes able to soecifically recognize antigens of foe autologous or heterologous pathogen, ro be treated and to react against it.

The areas ofthe inflammatory process and lymphatic territories are exactly the same. The inflamed area, through the anti-inflammatory action of specific memory? cells, unrelated.

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PCT/BR2018/000004 mobilized by the present invention by their antigenic composition, will block the rnfiammasomes and exert an anti-inflammatory action that will correct the pathological inflammation responsible for the morbidity.' of the disease and. which was caused by its etiological agent, for the memory effect it’s important to note that tins known; action of the memory T ceils is fte major responsible for the fact that a second contact with any pathological agent, after an already established immunity, is asymptomatic, without causing a disease.

The lymphatic territories are exactly the same, only now intensely activated and with the necessary alarm signal, caused by the present invention, to cause any immune response, even for a weak antigen, similar to what occurs with dendritic cells common to tins invention and to the autologous or heterologous etiological agent to be fought. Lymphokines and innate cells that command an effective secondary response wall be the same and the T lymphocytes specific against the etiologic agent to be fought, will «hitch a ride” on tins ideal microenvironment for holding an effective immune response, lire dendritic cells activated by the present invention, can capture the antigens of the etiological agent to be fought at the site of the pathology and in the related lymphatic territories and be in contact with the pathogen specific TCD4 lymphocytes, in a correctly and ideally enabled lympaatic system. The role of the dendritic cells activated and matured with the TCD4 specific to the etiologic agent, occurs in a microenvironment conducive to conducting an immune response, with all die genetic and biological potential of the host organism’s immune system.

These dendritic cehs at the site of the pathology and at the lymph nodes wall properly gauge the severity, extent, intensity and type of aggression, activating, inducing, coordinating, polarizing, leading and maintaining anew effective adaptive immune response, whose effector loop, with toe collaboration of the cells and effector molecules of the intense and properly activated innate immunity may be able to eliminate the causative agent to be fought. So the answer is reprogrammed and lead back as noted above, reversing the biological balance in favor of th e host, which until then was under the y oke of the offending autologous or heterologous agent.

Such action may occur with or without the help of biological balance shifters such as antibiotics diugs, capable to clock, weaken or neutralize the effects and potential of the etiological agent, allowing the immune system to have a chance to heal the pathology' drat is the target of the

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PCT/BR2018/000004 treatment. Once triggered by any etiological agent, the immune system will only stop responding when the etiological agent is eliminated or the organism passes away, tins way the invention will help avoid the latter option, or it will improve the patient's condition if there is a chronic disease that cannot be cured.

Xhus, the actios oi the compositions of the present invention intentionally and strategically superimposed over the entire area under the action of the agent to be fought, will recontextuailze the immune system by activating the PAMPs and DAMPs in the sentinel cells and common APGs and by the unrelated specific secondary’ adaptive immune response. This intentionally induced immune response will efficiently activate the whole lymphatic territory’ and the organic territory' affected by the etiological agent in the recontextualized area and in the bulge, and within fee context of a greater immune response, stronger, more intense and more extensive secondary anti-inflammatory nature of the target immune response will be, as described, reprogrammed and efficiently renewed within tire scope of a greater chance for the host, now with a chance of reversing the biological balance in its favor.

Rationale of the therapeutic protocol

Hie therapeutic protocol of the present invention designed to be applied in cases of bacterial infection and septicemia must:

- be applied in most strategic lymphatic regions of the body or infection, fa the cases described herein, more than 10 lymphatic territories have been hit. ft must be applied within the infected and perilesional areas.

- the immunotherapy formulation must contain at least 5 antigens so it contains PAMPs and DAMPs so as to be able to recontextualize fee immune system.

~ the application area must overlap, cover, and overcome fee whole extension of regions dominated by the infection.

- tire antigenic stimuli must be repeated every 4 or 5 days in order to avoid the generation of suppressor cells capable of aborting fee new desired immune response or to suppress an achieved repolarization.

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- the treatment must be maintained in this manner until the end of the infection, or to the healing of the wound, organ or system.

- ra practice, 1 to 3 ml of this immunotherapy must be applied to 10 or mom lymphati c territories. Ibis invention should be jointly applied in intra and extra lesion areas h_y infection.

In summary, the immunotherapy is systenrically distributed in several (at least ten) lymphatic territories, peri- and intra-lesion with a volume able to disrupt and destabilize the lesion from the nomination of its micro and macro environment, or cover the area significantly affected by infection and inflammation, as well as to restore the microenvironment that is favorable to the immune response of the organism. It will be applied every 4 to 5 davs

In sepsis, severe sepsis and septic shock, the use of low doses of exogenous interieukin-2 should he avoided. The use of low doses of exogenous interleukin-2 in severe infections uninterruptedly should be carefully evaluated when a amplification of the immune loop is needed.

DESCRIPTION OF THE FIGURES

The following figures are part of this report and are included here to illustrate certain aspects of the invention. The object of the present Invention may be better understood by reference to one or more of these figures in combination with the detailed description of the preferred embodiment presented here.

figure 1 snows images of Examle 2. Al, A3 and A4 show wounds after surgical cleaning on January 29, 2011. It s possible to notice injury of polytrauma associated with sepsis caused by multi-resistant strain and majortissue loss that continued to perform poorly with a winy general appearance without any appearance of healthy granulation tissue. It is possible identifying, in XRay on January 29, 2011 (A2) the external fixation of the femur after surgical procedure. On February 2, 2011 (5 days after starting the treatment) the patient presented complete recovers⁷from sepsis and received ICU discharge (BI, B2 and B3). In BI to B3 it is possible to identify neaithy granulation tissue characteristic of the second intention healing process. In Cl (01 March, 2011) it’s clear the improvement of the leg injuries described in Al - A4, that’s foe

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PCT/BR2018/000004 reason why patient was discharged from hospital on 15 March, 2011.. In DI (medial.site) and D.2 (lateral site) is possible to verify the complete recovery from complex wound of polytrauma associated with; severe sepsis caused by multidrug-resistant Aciiietobacter baunnamii and osteomyelitis. These data strongly suggest a decisive role of fee DEC A immunotherapy, associated with debridement and antibiotics, to cure fee clinical scenario, in a relatively short timv, making possible not only the patient survives a natural disaster but also walk again without crutch or cane .

Figure z shows images of Example 3, A Chest CT scan. (Al and A2) of 01/11/2011 before inmmnoihempy and Ci scan (Bl and B2) of04/1.1/2011 after immune treatment performed in CMS patient, fa Al and A2 is possible to identify whitish areas (circled) characteristic of imection. Is Bl and B2 is clear the disappearance of whitish areas and recoveiy of fee lung parenchyma which the image became darker. These data show a recovery of aspiration pneumonia with fee combination of immunotherapy wife antimicrobial treatment

Figure 3 shows images of Example 4. An X-Ray (Al) of 24 April 2007 (3 day’s after immunotherapy starts) and CT scan (Bl to B6) of 27 April 2007 it’s easily to identify critical SARS condition under septic shock. X-Ray (Cl) of 06 May 2007 evidences complete recover after immune treatment performed in AMB patient. In Al is possible to identify whitish areas (circled) characteristic of infection. In Bl - B6 the clinical status is so critical that whitish areas barely allowto identify anatomical contours our parameters (circular). In Cl is clear the disappearance of whitish areas and complete recovery’ of fee lung parenchyma, without sequels, which she image became darker. These data show a recovery of sepsis associated with SARS,

Ci YD, neparie and renal, failure with the .combination of 6 sessions of immunotherapy wife antimicrobial treatment in 15 days.

In order to allow a better understanding of the invention and clearly demonstrate fee technical progress achieved, fee results of the various tests conducted wife respect to this invention are shown, below as examples.

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These Examples are presented for illustrative purposes only and should not be regarded in any way as limiting the scope and range of the invention.

Example 1: Immunogenic Compositions in order to achieve the reeontexfeiah'zing, renewal and reprogramming of the immune response m real time according to the innovative concepts described in the present invention, an expert skilled m the art can design different and distinct compositions, combinations or formulations of products, which tall within the scope of the invention.

As described, for such compositions to meet the technical requirements for the advantageous or unpublished results in treat a number of diseases and illnesses, they must have a high diversify of antigens from pathogens, so as to get the maximum synergistic effect in binding the PAMPs and vAMPs to their receptors and allowing the achievement of a high degree of activation of the innate immunity in the sentinel cells (with or without ATC function) thereby allowing the recontexiaahzing, renewal and reprogramming of the immune response in real time .

Such compositions should preferably use antigenic agents for which most people, because of pre vious contact, would have memory clones of in their immune system capable of inducing a broad anti-infiammatofy action in parallel to recontextuatization. Fortins, antigenic agents should preferably be selected that:

• correspond to tire most common infections contracted by the individual from childhood to maturity (when the animal or the human being acquires its repertoire of immunity).

• are nsec in immunization programs such, as childhood vaccination programs against endemic and/or epidemic diseases.

• those fiom organisms of potentially pathogenic imcroflora, especially of the gastrointe stinal tiact, where the memory lymphocytes play an active dynamic barrier ensuring the survival of the individual.

• Ideally each of tire antigenic agents should be present in a concentration of 0.001 to 500 micrograms permL.

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PCT/BR2018/000004 in accordance with these concepts, several taxations have been developed, using antigenic agents m their already available, safe, and approved forms for use in human vaccination programs or allergic response tests and immunity assessment tests.

Therefore. we present the following several examples of compositions which foil within the scope of the present invention, without however the intention to limit it, since the present mvention and its concepts allow for the design of immunogenic compositions comprising a very large number ot combinations of antigenic age composition la (DECA composition);

Component .......................	Concentration
Koch s furbereuiin (inactivated Mycobacterium bovis lysate).	0.004 ng/rnL
PPD .................................................	0.004 g/rnL
Inactivated Staphylococcus lysate (Staphylococcus aureus and Staphylococcus epidermidis in equal parts).	6.94 gg/mL
mactivatec Steptococcus lysate (Streptococcus pyogenes, 1 Streptococcus pneumoniae and Enterococcus faecaiis in equal parts).	6,94 ug/rnl
Streptokinase derived ft® inactivated beta-hemolytic Streptococcus 1 i lysate purification.	0.444 p.g/m.L ! j
Domase derived from inactivated beta-hemolytic Streptococcus lysate 1 purification, 1 {	0.111 pg/mL
1 inactivated Candida lysate (Candida albicans and Candida glabrata in equal parts).	6.94 pg/mL
\| Inacti vated dermatophytes lysate (Epidennophytonfioccosum, i Microsporum cannis, Trichophyton mentagrophytes of the interdigitate variety in equal parts).	6.94 pg/mL
Inactivated entsropathogenic Escherichia coli lysate (EFEC) i	6,94 ug/mL
Inactivated Salmonella lysate (Salmonella bongori, Salmonella enterica and Salmonella suhterranea in equal parts).	6.94 pg/mL
Sodium Chloride s	7,5 mg/mL

Sodium phosphate dibasic heptabydrate

0.48 mg/mL

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PCT/BR2018/000004 j rraassium pnosphate monobasic i Phenol ' Water •r··— j 0.06 mg/mL

2.5 mg/mL q,s.

Composition I b (VITER composition):

Component j c_oncesjj^jjQ_n
koch s 1 urberculin (inactivated Mycobacterium bovis lysate). ¹	0,0036 ng/mL
	0,0036 pg/mL
Inactivated Staphylococcus lysate (Staphylococcus aureus and Staphylococcus epidermidis in equal, parts).	6,31 gg/mL
inactivated Steptococc-us lysate (Streptococcus pvogenes, Streptococcus pneumoniae and Enterococcus faecalis in equal parts).	6.31 pg/ml
Mieptokmase derived from inactivated beta-hemolytic Streptococcus j 0.404 pg/rnL lysate purification.

ountieation.

Oidiomvcin (antigenic extract of Candida albicans

6.31 ng/mL

Trichophytin (antigenic extract ofTricophyion sf

6.31 gg/mL inactivated enteropathogenic Escherichia coli lysate (EPEC)

Inactivated SaimoneUa lysate (Salmonella bongori, Salmonella 6.31 pg/mL enterica. and Salmonella subterranea in equal parts).
Attenuated yellow fever virus strain 17 D204	20 pg/mL
Sodium Chloride	7.5 mg/'mL
Sodium phosphate dibasic heptahydrate	0.48 mg/mL
Potassium phosphate monobasic	0.06 mg/mL
Phenol	2.5 mg/mL
Water	q.s.

Composition 2:

Component

Concentration

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Koch s I urberculin (inactivated Mycobacterium bovis Ivsate).	0.004 ng/roL
PPD ............ ................................	0.004 g/mL
Inactivated Staphylococcus aureus Ivsate, inactivated Staphylococcus	6.94 gg/mL
epidennidis lysate in equal parts.
Streptokinase derived from inactivated beta-hemolytic Streptococcus lysate purification.	0.444 pg/raL
Domase derived from inactivated beta-hemolytic Streptococcus lysate purification.	0.111 pg/mL
inactivated Candida albincans lysate, inactivated Candida parapsilosis lysate, Inactivated Candida glabrata in equal parts.	6.94 pg/mL
tnactivared enteropathogenic (EPEC), shiga~like” toxin producer (STEC), enteroaggregative (EAEC), enterotoxigenic (BTEC), enteroinvasive (EI.EC) and extraintestinal (ExPEC) Escherichia coil lysate in equal parts.	6.94 pg/mL
Sodium Chloride	7.5 mg/mL
Sodium phosphate dibasic heptahydrate	0.48 mg/'mL
Potassium phosphate monobasic [	0.06 mg/mL
Phenol [	2.5 mg/mL
W ater „ , ........................... \| A^{ 5}·

Composition 3:

i vornponeni | Concentation

...................... —jSrniM”

-——------................ . ...,.. .......... ..... _ ___ ! Inactivated Streptococcus pyogenes lysate, inactivated Streptococcus j^94pgrinL pneumonic lysate, Enterococcus faccalis lysate in equal parts.

Inactivated Staphylococcus aureus lysate, inactivated Staphylococcus i 6,94 pg/mL i cpidermidis lysate in equal parts.

5__ .. .,, . ...... _ _ ____ _

Inactivated Candiaa albicans lysate, inactivated Candida pmspsilosis [6.94 pg/nrL· lysate, inactivated Candida glabrata lysate in equal parts. J [Sodium Chloride | 75 mg/mL~

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j Sodium phosphate dibasic heptahydrate	0.48 mg/mL
j Potassium phosphate monobasic	0.06 mg/mL
j Phenol
	2.5 mg/mL
j Water — --------------- - - - ______	q.s.

Composition 4:

i Component	Concentration
Inactivated BCG lysate	50 mg/mL
1 inactivated Staphylococcus aureus lysate, inactivated Staphylococcus epidennidis lysate in equal parts.	6.94 pg/mL
ma^uvated Streptococcus agalactiae lysate, inactivated Streptococcus mix (Streptococcus pyogenes, Streptococcus pneumonias and Enterococcus faecaiis) lysate in equal parts.	6,94 pg/'raL
Inactivated Candida albincans lysate. Inactivated Candida parapsilosis lysate, inactivated Candida giabmta in equal parts.	6.94 pgAnL
Sodium Chloride	7.5 mg/mL
Sodium phosphate dibasic hepiahydrate	0,48 mg/mL
Potassium phosphate monobasic	0.06 mg/mL
Phenol j	2.5 mg/mL
Water { -................................. .......................... S	q.s.

Composition 5:

Component	Concentration
PPD	0.004 g/mL
Inactivated Streptococcus pyogenes lysate, inactivated Streptococcus pneumoaie lysate, Enterococcus faecaiis lysate in equal parts.	6.94 gg/mL
Inactivated ApergiHus fumigates, Apsrgilius flaws, and ApergiHus tenons lysate in equal parts.	6.94 pg/mL
Inactivated dermatophytes lysate (Epidsnnophytonfloccosum, j Microsporum canals, Trichophyton mentagrophytes ofthe ... j	6.94 pg/mL

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	I imerdighale variety in equal parts). ....................j”~ --
oom a® vmonue	^: 7.5 mg/mL
	-’urn phosphide chbasrc heptahyorate	0,48 mg/mL
	Potassium phosphate monobasic	0.06 mg/mL
	J Phenol ........................................	2.5 mg/mL
	i Water ....................................... I— .............,.........................	q.s.
Cc	reposition 6;
	Component .................. j	Concentration
	Koca s / ur&ercuim (inactivated Mycobacterium bovis lysate). \|	0.004 ng/mL
	Inactivated Streptococcus pyogenes lysate, inactivated Streptococcus 1 pneumonic lysate, Enterococcus faecalis lysate in equal parts. i	6.94 pg/mL
	Inactivated Neissenanjeningitides lysate.	6.94 pg/mL
	inactivated Apergillus funtigatus, Apergillus Havas, and Apergillus j	6.94 gg/mL
	terrors lysate in equal parts.
	Sodium Chloride J	7.5 mg/mL
	Sodium phosphate dibasic heptahydtate	0,48 mg/mL
	Potassium phosphate monobasic i —-—-. —............................................ i	0.06 mg/mL
	Phenol i	2.5 mg/mL
	Water ..... \|	q.s.

©reposition 7:
Component	! Concentration
Koch s Turberculin (inactivated Mycobacterium bovis lysate).	0.004 ng/mL
Inactivated BCG lysate	j 50 mg/mL
Inactivated Staphylococcus aureus lysate, inactivated Staphylococcus	6.94 gg/mL
epidermidis lysate in equal parts.	I
Inactivated Streptococcus pyogenes lysate, inactivated Streptococcus pneumonic lysate, Enterococcus faecalis lysate in equal pails.	6.94 pg/mL
inactivated Candida albincans lysate, inactivated Candida parapsilosis	\| 6.94 gg/mL

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lysate, inactivated Candida glabrata in equal parts.	-
macavared Streptococcus equinus, Streptococcus bovis and Streptococcus viridans lysate in equal parts.	6.94 pg/'mL
inactivated emeropathogemc (EPEC), “shiga-like” toxin producer (STEC), enteroaggregative (EAEC), enterotoxigenic (ETEC), \| enteroinvasive (EIEC) and extraimestinal (ExPEC) Escherichia coli lysate in equal parts.	6.94 pg/mE
rinactivated Salmonella typhi, Salmonella paratyphi and Salmonella i enterica lysate in equal parte.	6.94 p.g/mE
Inactivated lysate of antigens of the measles virus (Schwarz strain).	10,000
	TOCKO/mL
Glycerol j	500 mg/mE
Phenol j	2.5 mg/rnL

Water

I

Composition 8:

Component	Concentration
Koch’s Turberculin (inactivated Mycobacterium bovis lysate).	0.004 ug/ml.
PPD ·	0.004 g/mL
Inactivated Staphylococcus aureus lysate, inactivated Staphylococcus epidermidis lysate in equal parte.	6.94 gg/mE
Inactivated enteropathogenic (EPEC), “shiga-like” toxin producer	J 6.94 pg/mL
(STEC), enteroaggregative (EAEC), enterotoxigenic (ETEC), enteroinvasive (EIEC) and extraintestinal (ExPEC) Escherichia coli lysate in equal parts.
Streptokinase derived from inactivated beta-hemolytic Streptococcus lysate purification.	0.444 ug/mL
Domase derived from inactivated, beta-hemolytic Streptococcus lysate purification.	0.111 pg/mL
Inactivated Streptococcus pvogcnes lysate, inactivated Streptococcus ......................;.......... ‘	6.94 pg/mE

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PCT/BR2018/000004 pneuraonie lysate, Enterococcus faecalis lysate in equal parts. f

Inactivated Helicobacter pylori lysate.	j 6.94 pg/mL
1 eianus toxojd ...........	50 units of
	\| Lf/mL
\| Inactivated Candida aibmeans lysate, inactivated Candida parapsilosis lysate, inactivated Candida glabrata in equal parts.	6,94 pg/mL
Sodium. Chloride ......	7.5 mg/mL
tiochum phosphate dibasic heptahydrate	0.48 mg/mL
eotassium phosphate monobasic	0.06 mg/mL
Phenol	2.5 mg/mL
Water	q.s.

Composition 9;

j Component	Concentration
Inactivated BCG lysate	50 mg/mL
Inactivated Mycobacterium tuberculosis lysate	0.004 ng/mL
inactivated Staphylococcus aureus lysate, inactivated Staphylococcus epideimidis lysate in equal parts.	6.94 pg/xaL
Inactivated entsropathogem'c (SPEC), ‘“shiga-like” toxin producer	6.94 pg/mL
(STEC), enteroaggregative (EAEC), enterotoxigenic (ETEC),
enteromvasive (E1EC) and extinintestinal (ExPEC) Escherichia coli
lysate in equal parts.
Inactivated Haemophilus influenza lysate. j	6.94 ug/ml.
inactivated Streptococcus agalactiae lysate, inactivated Streptococcus mix (Streptococcus pyogenes. Streptococcus pneumoniae and Enterococcus faecalis) lysate in equal parts.	6.94 pg/mL
Inactivated Salmonella typhi, Salmonella paratyphi and Salmonella j enierica lysate in equal parts.	6.94 pg/mL
Inactivated Proteus mimbihs, Proteus vulgaris, and Proteus penerii lysate in equal parts. j	6.94 pg/mL

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Inactivated lysate of antig ens of the measles vims (Schwarz strain)?

inactivatea Candida albincans lysate, inactivated Candida parapsilosi's inactivated Candida glabrata in equal parts.

Glycerol

Phenol

Water krniposition 10:

j Component

Inactivated Mycobacterium africanum lv;

sate.

Koch s Tnrbercnlin (inactivated Mycobacterium bovis lysate).

Activated eatero^^^c'^PEQT^ga-l^tito^i'preduc^” (STEC), enteroaggregative (EAEC), enterotoxigenic (ETEC), enteroinvasive ^EIuC) and extrarntestinal (ExPEC} Escherichia coll lysate in equal parts.

10,000

TDCl50/mL

6,94 gg/niL

500 mg/mi

2.5:

q.s.

i Concentration

0.004 ng/mL·

0.004 ng/mL

6.94 pg/mL

Inactivated Staphylococcus aureus lysate, inactivated Staphytoeoccus jC94 pg/mL epidermidis lysate in equal parts.

Inactivated Epidennophyton flocecsum, Microspomm cannis, | 6.94 ug/mL

Trichophyton mentagrophytes of the interdigitate variety lysate in equal parts).

Inactivated Streptococcus pyogenes lysate, inactivated Streptococcus | 6.94 ng/mL pneumonic lysate. Enterococcus faecalis lysate In equal parts, inactivated Acinetobacter banraannii lysate.

6.94 gg/mL inactivated Helicobacter pylori lysate.

Inactivated lysate of antigens of the mumps vims (Urabe AM9 strain) inactivated Polio virus lysate

6.94 pg/mL

10,000

TDCl50/inL

UD of type I antigens: 1.8 UD of type 2

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	antigens; 32 UD of type 3 antigens

Glycerol	500 mg/mL
Phenol ’ ............	2.5 mg/mL
j Water ~~.................
] q-s.
omposition 11;
Component	CoHcentxutiou
inactivated Mycobacterium leprae lysate j 0.004 ng/niL
Koch s Turbercuhn (inactivated Mycobacterium boms lysate), J 0.004 ng/mi.
Inactivated Staphylococcus aureus lysate, inactivated Staphylococcus epidermidis lysate in equal parts.	6.94 pg/mL
Inactivated Candida albincans lysate, inactivated Candida paiapsilosis lysate, inactivated Candida glabrata in equal parts.	6.94 pg/mL
inactivated Streptococcus agalactia© lysate, inactivated Streptococcus mix (Streptococcus pyogenes. Streptococcus pneumoniae and Enterococcus iaecaiis) lysate in equal parts. ;	6.94 pg/mL
Inactivated Streptococcus equinus. Streptococcus bovis, and i j : Streptococcus of the viridans group lysate in equal parts.	6.94 gg/mL
Inactivated Haemophilus influenza lysate. 6.94 pg/mL
inactivated Proteus mirabilis, Proteus vulgaris, and Proteus penerii lysate in equal pails.	6,94 pg/mL
Antigens of the rubella virus (Wister EA 27/3M strain)	10,000 TDCWmL
Inactivate antigen of the Varicella zoster vims lysate	149 231 PFU/mL
Glycerol J 500 mg/mL
~\| 2.5 mg/mL
Water j _{q s}

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Composition 12:

Component	J Concentration
inactivated Mycobacterium avium lysate	J 0.004 ng/mL
inactivated Mycobacterium kansasii lysate	[ 0.004 ng/mL
Inactivated Apergillus fumigates, Apergillus flavus, and Apergillus terreus ly sate in equal parts.	i 6.94 gg/mL

Inactivated Neisseria gonorrhoeae lysate. 6 94 gg/W,

inactivated Streptococcus equinus, Streptococcus bovis, and Streptococcus of the viridans group lysate in equal parrs.	6.94 gg/mL
Inactivated Epidermophyton floccosum, Mierosporum cannis, Trichophyton mentagrophytes of the interdigitale variety lysate in equal, parts).	6.94 gg/mL
Inactivated Chlamydia trachomatis, Chlamydia psittaci, and Chamydia pneumoniae lysate in equal parts.	6.94 gg/mL
Inactivated enteropathogenic (EPEC), “shiga-like” toxin producer _: (STEC), enteroaggregative (EAEC), enterotoxigenic (ETEC), enteroinvasive (EIEC) and extraintestinai (ExPEC) Escherichia coli lysate in equal parts. i	6.94 gg/mL
Antigens of the rubella vims (Wistar RA 27/3M strain) 10,000 TDCKO/mL ........ {

Inactivated antigen of the Vaccinia (smallpox) vims lysate I to 10 x E?

PFU/mL

\| Glycerol	500 mg/mL
phenol	2.5 mg/mL
1 Water	q.s.

Composition 13:

Component

Inactivated Mycobacterium tuberculosis lysate inactivated Mycobacterium, avium lysate

Concentration 0.004 ng/mL | 0.004 ng/mL

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inactivated Neisseria meningiiides lysate Diphtheria toxoid ...........................	I 6.94 ug/mL 67 units of Li/mL
inactivated Streptococcus agalactsae lysate, inactivated Streptococcus mix (Streptococcus pyogenes. Streptococcus pneumoniae and Enterococcus faecalis) lysate in equal parts.	6.94 pg/mL :
. uavuvated Landioa albmeans lysate, inactivated Candida parapsilosis lysate, inactivated Candida glabmta in equal parts.	6.94 pg/mL
inactivate» Helicobacterpylori lysate.	6.94 pg/mL
inactivated Serratia marcencens e Serratia liquefaciens lysate	6.94 pg/roL
Inactivated antigen ofHSV-I and HSV-II lysate 5 \| inactivated antigen of the measles virus (Schwarz strain) lysate i	.149 231 : PFU/mL
	10,000 TDCI50/mL
Glycerol	500 mg/mL
Phenol	2.5 mg/mL
Water	q.s.

Composition 14:

Component	j Concentration
Inactivated Mycobacterium africanism lysate	j 0.004 ng/mL
.Inactivated Mycobacterium tuberculosis lysate 0.004 ng/mL
Inactivated Neisseria gonorrhoeas lysate 6,94 mg/mL
inactivated Apergillus fumigates, Apergillus flavus, and Apergillus terreus lysate in equal parts.	1 6.94 pg/'rnL E
Inactivated Neisseria meningiiides lysate	J 6.94 pg/mL
Diphtheria toxoid	\| 67 units of
	i LfZmL
Inactivated Epidermophyton floccosum, Micresporum cannis. Trichophyton mentagrophytes of the interdigitate variety lysate in	J 6.94 ug/mL

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equal parts). ......	,
Inactivated Shigella flexneri and Shigella sonnei lysate in equal parts	6.94 pg/'mL
Inactivated surface antigen of the hepatitis B {HBs AG) virus, lysate	200 pg/mL
Inactivated antigen of the measles virus (Schwarz strain) lysate	10.000 TDCBOtinL
Glycerol	500 mg/mL
Phenol	2.5 mg/mL
Water .........................j	q.s.

Composition 15:

Component	J Concentration
j 0.004 ng/mL
Inactivated BCG lysate	i 50 mg/mL
Inactivated Streptococcus equinns, Streptococcus bovis, and Streptococcus of the viridans group lysate in equal parts.	\| 6,94 pg/mL 1
Inactivated Staphylococcus aureus lysate, inactivated Staphylococcus epidexmidis lysate in equal parts.	\| 6,94 pg/mL
Tetanus toxoid	1 50 units of i LfiraL
Diphtheria toxoid	67 units of : Lf/'mL
Inactivated Aciaetobacter baumannii lysate.	6,94 pg/mL
Inactivated enteropathogenic (EPEC), ”sh:ga-b.ke” toxin producer (STEC), enteroaggregative (EAEC), enterotoxigenic (ETEC), enteroinvasive (EIEC) and extraintestinal (ExPEC) Escherichia coli lysate in equal parts.	6.94 pg/'mL
Inactivated Apergillus fumigates, ApergiHus fiavns, and ApergiHus terreus lysate in equal parts.	6.94 pg/mL
Inactivated lysate of antigens of the mumps vims (Uiabe AM9 strain)	10,000 TDCISO/mL

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Glycerol			J 500 mg/mL
Phenol			j 2.5 mg/mL
Water			\| q.s.

Composition 16;

s Component	j Concentration
J Koch s lurperculm (inactivated Mycobacterium bovis lysate)..	I 0.004 ng/mL
J Inactivated Mycobacterium tuberculosis lysate	j 0.004 ng/mL
inactivated Salmonella typhi, Salmonella paratyphi and Salmonella	J 6.94 gg/mL
enterica lysate in equal pasts. .
inactivated Ktreptococeus pyogenes lysate, inactivated Streptococcus	16.94 gg/mL
pneumonic lysate, Enterococcus faecalis lysate in equal parts.
InactivaLed npidermophyton fioceosum, Microsporum cannis,	\| 6.94 gg/mL
Trichophyton mentagrophytes of the mterdigitaie variety Ivsate in 1 “ *' equal parts).
Bordetellapertussis toxoid	\| 75 gg/mL
Inactivated Haemophilus influenza lysate.	6.94 gg/mL
Tetanus toxoid	5 0 units of
	I Lf/mL
Inactivated Polio virus lysate	j 40 US of type I antigens; 1.8 US of type 2 antigens; 32 UD of ty pe 3 antigens
Inactivated antigen of the Vaccinia (smallpox) virus lysate	1 to 10 x 10⁹ i PFU/mL
Glycerol	J 500 mg/mL
Phenol	j 2.5 mg/mL
Water	\| q.s.

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Composition 17:

Component_____““.......................[Conception

Koch s Tarberculin (inactivated Mycobacterium bovis lysate). 0.004 ng/mL
Inactivated BCG lysate i50mg/mL
^FFD \| 0.004 ng/mL
Inactivated Staphylococcus aureus lysate, inactivated Staphylococcus epidennidis lysate in equal parts.	j 6.94 pg/mL i
Inactivated Streptococcus pyogenes lysate, inactivated Streptococcus pnemnonie lysate, Enterococcus faecalis lysate in equal parts.	6.94 ug/mL
Inactivated Klebsiella oxytoea and Klebsiella pneumonia lysate in equal parts	6.94 pg/mL
inactivated Epidermophyton Soccosum, Microsporum camris. Trichophyton mentagrophvtes of the mterdigitale variety' lysate in equal parts).	6,94 pg/mL
Inactivated Streptococcus equinus, Streptococcus bovis, and Streptococcus of the viridans group lysate in equal parts.	6.94 ,ug/tnL
Diphtheria toxoid	67 units of LfimL
Inactivated enteropathogenie (EPEC), “shiga-tike” toxin producer (STEC), eate roaggregative (EAEC), enterotoxigenic (ETEC), enteromvasive (EIEC) and extraintestinai (ExPEC) Escherichia coli lysate in equal parts.	6.94 gg/mL
Inactivated Salmonella typhi, Salmonella paratyphi and Salmonella enterica lysate in equal parts. ί	6,94 pg/snL
Bordetella pertussis toxoid ! 75 pg/mL
Inactivated Apergillus fumigates, Apergillus fiavus, and Apergillus 6.94 gg/mL terreus lysate in equal parts.
Inactivated lysate of antigens of the measles virus (Schwarz strain), 10,000 \| TDCI50/mL inactivated Candida albincans lysate, inactivated Candida parapsilosis j 6.94 gg/mL

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lysate, inactivated Candida glabrata in equal parts.
Glycerol	500 mg/mL
j Phenol	2.5 mg/mL
[Water	q.s.

Composition 18:

j Component	i Concentration
PPD ........................ .....	0.004 ng/mL
Inactivated Mycobacterium tuberculosis lysate	0.004 ng/mL
Koch s furberculin (inactivated Mycobacterium bovis lysate).	0.004 ng/mL
inactivated Staphylococcus aureus lysate, inactivated Staphylococcus epidermidis lysate in equal parts.	6.94 pg/mL
Inactivated Salmonella typhi, Salmonella paratyphi and Salmonella enterica lysate in equal parts.	6.94 pg/mL
Inactivated Streptococcus pyogenes lysate, inactivated Streptococcus pneumonic lysate. Enterococcus faecatis lysate in equal parts.	6.94 pg/mL
Streptokinase derived from inactivated beta-hemolytic Streptococcus lysate purification.	0.444 pg/mL
Domase derived fit® inactivated beta-hemolytic Streptococcus lysate purification.	0..Ill pg/mL
Inactivated Klebsiella oxytoca and Klebsiella pneumonia lysate in equalparts	6.94 pg/mL
Inactivated Streptococcus agalactiae lysate, inactivated Streptococcus mix (Streptococcus pyogenes, Streptococcus pneumoniae and Enterococcus faecalis) lysate in equal parts.	6.94 pg/mL
Inactivated Helicobacter pylori lysate.	6,94 pg/mL
Tetanus toxoid	5 0 uni ts of Lfi'mL
Inactivated enteropathogenic (EPEC), “shiga-like” toxin producer (STEC), enteroaggregative (EAEC), enterotoxigenic (ETEC),	6.94 pg/mL

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PCT/BR2018/000004 enteroinvasive (HEC) and extraintestinal (ExPEC) Escherichia cori~ lysate m equal parts.

Inactivated Candida albicans lysate, inactivated Candida parapsiiosis lysate, inactivated Candida glabrata lysate in equal parts;

Inactivated Apergilius fumigates, Apergdlus flaws’and ApergiUnT' tenens lysate in equal parts.

Inactivated YF-17D lysate ’ ~ ----

6.94 pg/mL

6,94 pg/mL

3,000,000

Glycerol

Phenol pWater

PFU/mL

500 mg/mL

2.5 mg/mL

q.s.

Composition 19:

Component	Concentration
inactivated BCG lysate	5G mg/mL
inactivated Mycobacterium tuberculosis lysate	0.004 ng/mL
Koen s iuroercnlm (inactivated Mycobacterium bows lysate).	0.004 ng/mL
inactivated Staphylococcus aureus lysate, inactivated Staphylococcus epidemndis lysate in equal parts.	6.94 ug/mL
Inactivated Streptococcus pyogenes lysate, inactivated Streptococcus pneumonic lysate, Enterococcus faeealis lysate in equal parts.	6.94 pg/m'L
inactivated Serratia marcencens e Serratia liquefaciens lysate	6.94 pg/mL
inactivated Haemophilus influenza lysate.	6.94 pg/mL
inactivated Streptococcus agalactiae lysate, inactivated Streptococcus mix (Streptococcus pyogenes, Streptococcus pneumoniae and Enterococcus faeealis) lysate in equal parts.	6.94 pg/mL
inactivated Klebsiella oxytoca and Klebsiella pneumonia lysate in equal parts	6 ,94 pg/mL
inactivated Epidermophyton floccosum, Microsporum cannis, j Trichophyton mentagrqphytes of the interdigitate variety lysate in j	6.94 gg/mL

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equal parts). ............. ....
inactivated Proteus mirabilis, Proteus vulgaris, and Proteus penerii lysate in equal parts.	J 6.94 pg/reL
Inactivated Salmonella iyplii, Salmonella paratyphi and Salmonella enterica lysate in equal parts.	j 6.94 pg/mL I 10,000
uniotivated lysate of antigens ot the measles virus (Schwarz strain¹’}
	TDClSO/niL
inactivated Candida albicans lysate, reactivated Candida parapsilosis lysate, much rated vandida glabrata lysate in equal parts.	16.94 gg/mL
Inactivated antigen of the Vaccinia (smallpox) vims lysate	1 to 10 χ 10⁹
	PFU/raL
Glycerol ................“	500 mg/mL
Phenol ’ ..........““j	2.5 mg/mL
water r.......................- ~ - i q.s.

Composition 20:

CepoM ' ' ~ I CoraiSta

inactivated Mycobacterium africanum lysate	\| 0.004 ng/mL
woch s luroercutin (inactivated Mycobacterium bovis lysate), 0.004 ng/mL
inactivated BCG lysate	j 50 mg/mL
inactivated Apeigiilus femigatus, Apergillus flaws, and Apergillus teneus lysate in equal parts.	\| 6.94 pg/mL
inactivated Staphylococcus aureus lysate, inactivated Staphylococcus epsdennidis lysate in equal parts.	6.94 gg/mL
inactivated Neisseria meniugitides lysate	6,94 pg/mL
inactivated Streptococcus pyogenes lysate, inactivated Streptococcus pneumonic lysate, Enterococcus faecalis lysate in equal parts.	6.94 ggz'mL
inactivated enteropaihogenic (EPEC), 'Vhiga-like” toxin producer (STEC), enteroaggregative (EAEC), enterotoxigenic (ETEC), enteromvasive (E1EC) and extiamtestinal (ExPEC) Escherichia coll	6.94 pc/mi..

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lysate in. equal parts.
inactivated Salmonella typhi, Salmonella paratyphi and Salmonella enterica lysate in equal parts.	6.94 pg/mL
inactivated Acinetobacter baumannii lysate.	6.94 pg/mL
inactivated Helicobacter pylori lysate.	6,94 pg/nrL
Inactivated Haemophilus influenza lysate.	6.94 pg/mL
Inactivated lysate ot antigens of the mumps vims (Urabe AM9 strain) Ί	50,000
inactivated Polio virus Ivsaie	TDCI50/mL ΛΛ ΤΤΓΥ -4? __

I antigens; 1.8 UD of type 2 j antigens; 32

	UD of type 3 1 antigens
Inactivated Candida albicans lysate, inactivated Candida parapsilosis lysate, inactivated Candida glabrata lysate in equal parts.	j 6.94 pg/mL
Glycerol	500mg/mL
Phenol	i 2.5 mg/mL
Water ..... .........	j q-s.

Composition 21:

j Component	Concentration
i Inactivated Mycobacterium leprae lysate ΐ_ ________ __________	0.004 ng/mL
i Koch s lurberculin (inactivated Mycobacterium bo vis lysate).	0.004 ng/mL
i Inactivated Mycobacterium tuberculosis lysate	0.004 ng/mL
1 Inacti vated Staphylococcus aureus lysate, inactivated Staphylococcus epidennidis lysate in equal parts.	6.94 pg/mL
Inactivated Epidermophyton floccosum, Microsporum cannis, Trichophyton mentagrophytes of the interdigitate variety lysate in equal parts).	6.94 pg/mL

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Diphtheria toxoid ...............	6 7 units of LfrmL
inactivated Streptococcus agalaetias lysate, inactivated Streptococcus mix (Streptococcus pyogenes, Streptococcus pneumoniae and Enterococcus faeealis) lysate in equal parts.	----------------- 6,94 pg/mL
tetanus toxoid	50 units of LfirnL
Inactivated Meissena memngitides lysate	6.94 pg/mL
inactivated Haemophilus influenza lysate . \| -------—........~.................................... i	6.94 pg/mL
Inactivated Proteus mitebilis, Proteus vulgaris, and Proteus penerii lysate in equal parts.	6.94 pg/mL
inactivated Serratia marcencens e Senatia Iique.facie.ns lysate {	6.94 pg/mL
Antigens oi the rubella virus (Wistar RA 27/3M. strain)	10,000
i :	TDCKO/mL
Inactivate antigen of the Van cells zoster virus lysate	149231
1	PFU/mL
Inactivated Apergillus fumigates, Apergdlus Raves., and Apergillus 1 1 terreus lysate is equal parts. 1	6,94 pg/mL
Glycerol	500 mg/mL
Phenol	2.5 mg/mL
Water \| -- - ___L	q.s.

Composition 22:

Component	Concentration
Inactivated Mycobacterium avium lysate	0.004 ng/tnL
-Inactivated Mycobacterium kansasii lysate	0.004 ng/mL
Koch’s Turberculin (Inactivated Mycobacterium bovis lysate).	0.004 ng/mL
Inactivated Apergillus fumigates, Apergillus Savus, and Apergdlus terreus lysate in equal parts.	6.94 pg/roL
Inactivated Neisseria gonorrhoeas lysate	6.94 mg/mL

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tetanus toxoid ..................	1 50 units of J LffmL
Inactivated Streptococcus equinus, Streptococcus bovis, and Streptococcus ofthe viriaans group lysate in equal parts.	j 6.94 gg/mL
inactivated Candida albicans lysate, inactivated Candidaparapsslosis lysate, inactivated Candida giabrata lysate in .equal parts.	j 6.94 gg/rnL
Inactivated Salmonella typhi. Salmonella paratyphi and Salmonella enterics lysate in equal, parts.	\| 6.94 gg/mL
inactivated Chlamydia trachomatis, Chlamydia psittaci, and Chamydia pneumoniae lysate in equal parts.	6.94 pg/mL
inactivated entempathogenic (EPEC), “shiga-like” toxin producer (STEC), enteroaggregative (EAEC), enterotoxigenic (ETEC), enteromvasive (EIEC) and extraintestmal (ExPEC) Escherichia cob lysate in equal parts.	6.94 gg/mL
Inactivated Klebsiella oxyioca and Klebsiella pneumonia lysate in equal parts	6.94 gg/mL
Antigens of the rubella virus {Wistar RA 27/3M strain)	10,000 TDCI50/mL
inactivated antigen of the Vaccinia, (smallpox) virus lysate	1 to 10 x 10⁹ PFU/mL
Inactivated YE-17D lysate	3,000,000 PFU/mL :
Glycerol	500 mg/mL
Phenol	2.5 mg/mL
Water —-—-------------—-----	q.s.

Composition 23:

i Component	i Concentration
j Inactivated Mycobacterium tuberculosis lysate	\| 0.004 ng/rnL
J Inactivated Mycobacterium avium lysate	j 0.004 ng^zmL 1 ...........

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Kovh s i tuberculin (inactivated Mycobacterium bovis lysate). Inactivated Neisseria meningitides lysate ........	j 0.004 ng/mL
6.94 pg/mL
'Diphtheria toxoid .................. r-—............—..............................	6 7 units of Lfi'mL ;
i 1 etanus toxoid ..................	50 units of Lf/'mL
Inactivated Streptococcus agalactiae lysate, inactivated Streptococcus mix (Streptococcus pyogenes. Streptococcus pneumoniae and	6.94 pg/mL
nnteroeoccus faecalis) lysate in equal parts.
inactivated Candida albicans lysate, inactivated Candida parapsilosis lysate, inactivatea Candida glahrata lysate in equal parts.	6.94 pg/mL
Inactivated hpidennophyton. fioecosum, Microspom® cannis, trichophyton mentagrophytes of the mterdigitale variety lysate in equal parts), j	6.94 pg/mL
inactivated .Helicobacter pylori lysate. \|	6.94 pg/mL
inactivated Serntia marcencens e Senatia iiquefaciens lysate	6.94 ug/raL
inactivatea SstinoBsha typhi, Salmonella paratyphi and Salmonella enterica lysate in equal parts.	6,94 pg/mL
inactivated antigen of HSV-Ϊ and HSY-JI lysate	149 231 PFU/mL
inactivated lysate of antigens of the measles virus (Schwarz strain). \| t	10,000 TDCI50/ttiL
i inactivated Apergidus timugatus, Apergilhis flaws, and Apergillas ”Ύ terreus lysate in equal parts. -- .................. .. ......... t	6.94 pg/mL
Glycerol Ϊ	500 mg/mL-
Phenol	2.5 mg/mL
Water Ί 5	q.s.

Composition 24: Component

Concentration

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tiwivated Mycobacterium atncannm lysate Inactivated Mycobacterium tuberculosis lysate	j 0.004 ng/mL i 0,004 ng/mL
rJrD —..................	j 0.004 ng/mL
inactivated Neisseria gonorrhoeae lysate	6.94 mg/mL
Inactivated Candida albicans lysate, inactivated Candida parapsilosis j lysate, inactivated Candida glabrata lysate in equal parts .	6.94 pg/mL
\| inacii valed Salmonella typln, Salmonella paratyphi and Salmonella enterica lysate in equal parts.	\| 6.94 pg/ml I
Inactivated Neisseria meningitides lysate	! 6.94 pg/mL
Diphtheriatoxoid ..........................	67 units of i LFmL
Inactivated Streptococcus equinus, Streptococcus bovis, and Streptococcus of die viridans group lysate in eq ual parts.	6,94 pg/mL

ϊ etarms toxoid	50 units of Lf'mL
inactivated Shigella flexneri and Shigella sonnei lysate in equal parts !	6.94 pg/mL
I inactivated Proteus mirabilis, Proteus vulgaris, and Proteus penerii lysate in equal parts.	6,94 pg/mL
Inactivated suriace antigen of the hepatitis B (HBs AG) virus lysate	200 pg/mL
inactivated ivsate of antigens of the measles virus (’’Schwarz strain).	10.000 TDCISO/mL
Inactivated YF-1/D lysate i	3,000,000 PFU/mL
Glycerol	500 mg/mL
Phenol !	2.5 mg/mL

Composition 25;

Component		j Concentration
PPD		0.004 ng/mL

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j BCG lysate	\| 50 mg/mL
Lodi 5 rurhe-cuim (inactivated Mycobacterium bovis lysate).	j 0.004 ng/mL
Inactivated Streptococcus pyogenes lysate, inactivated Streptococcus	ί 6.94 ug/inL
pneumonic lysate. Enterococcus faecatis lysate in equal parts.	I
maetivated Staphylococcus aureus lysate, inactivated Staphylococcus epidermidis lysate in equal parts.	6.94 pg/'mL i
Diphtheria toxoid '	I 67 unite of
	i Lf'raL
Tetanus toxoid ‘	j 50 unite of
	j LfimL
inactivated Salmonella typhi, Salmonella paratyphi and Salmonella enterica lysate in equal parts.	6.94 pg/mL
Inactivated Epidermophyton floccosum, Microsporura cannis, 1 richcphyton mentagrophytes of the interdigitate variety lysate in equal parts).	\| 6.94 pg/mE \| 6,94 pg/mL
Inactivated Acmetobacter bauraannii lysate.
Inactivated enteropathogenic (EPEC), “shiga-like'· toxin producer (STEC), enteroaggregative (EAEC), enterotoxigenic (ETEC), enteroinvasive (EIEC) and extraintestinal (ExPEC) Escherichia coli lysate in equal parts.	\| 6.94 pg/inL
Inactivated Candida albicans lysate, inactivated Candida parapsilosis lysate, inactivated Candida glabrata lysate in equal parts.	6.94 pg/mL
i Inactivated Apergilius fumigates, Apergjilus Saves, and Apergillus terreus lysate in equal parte.	6.94 pg/mE
Inactivated lysate of antigens of the mumps virus (Umhe AM9 strain) I i...................... „....................	50,000 TDCI50/mL
Inactivated antigen of the Vaccinia (smallpox) virus lysate	1 to 10 x 1C}⁹
	PEU/raL
Glycerol	500 mg/mL
Phenol	2.5 mg/mL

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?.s.

Composition 26:

roponent

Concentration

Koch’s Turbereulin (Inactivated Mycobacterium bovis lysate).' fooT^i/mT inactivated Mycobacterium tuberculosis lysate

Inactivated BCG lysate

0.004 ng/mL mg/mL

Inactivated Apergillus femigatns, Apergilbs flaws, aidA^ife Γθ4^ΛηΓ terreus lysate in equal parts. i mactivated Streptococcus pyogenes lysate, inactivated Streptococcus [ 6.94pg/mL pneumonic lysate, Enterococcus faecalis lysate in equal parts. f inactivated CUamydia trachomatis, Chlamydia psittaci, and Chamydia pneumoniae lysate in equal parts.

Bordetella pertussis toxoid

6.94 pg/mL

Inactivated Haemophilus influenza lysate.

Inactivated Neisseria gonorrhoeae lysate

5.94 pg/ml

6.94 mg/mL

tetanus toxoid ...............— —	S 50 units of J Lf/mL
Inactivated Candida afaicaus lysate, inactivated Candida parapsilcsis	i 6,94 pg/mL
lysate, inactivated Candida glabrata lysate in equal parts.	j
Inactivated enteropathogenic (EPEC), “shigadike” toxin producer	1~6.94 pg/mL
(SI EC), enteroaggregative (EAEC), enterotoxigenic (ETEC),	I
entemmvasive (EIEC) and extraintestinal (ExPEC) Escherichia coll	1
lysate in equal parts.	I
J Inactivated Polio virus lysate	I 40 UD of type
	I antigens; 1,8
	UD of type 2
	antigens; 32
	UD of iype 3
- .	antigens

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J Inactivated antigen of the Vaccinia (smallpox) viraslysate pTtolOxiO⁵ | | PFU/mL j Inactivated YF-l/D lysate 3,000,000

PFU/mL

Composition 27;

| Component

Inactivated YF-17D lysate

Concentration

3,000,000

PFU/mL

Koch’s Turberculin (inactivated Mycobacterium, bovis lysate).

4..

0.004 ng/mL

inactivated BCG lysate	50 mg/mL
LPU 0,004 ng/mL
Inactivated. Mycobacterium tuberculosis lysate	0.004 ng/mL
Inactivated Staphylococcus aureus lysate, inactivated Staphylococcus epidermidis lysate In equal parts.	6.94 pg/mL i 1 1
Inactivated Streptococcus pyogenes lysate, inactivated Streptococcus pneumonic lysate. Enterococcus faecalis lysate in equal parts.	6.94 pg/mL
Inactivated Klebsiella oxytoca and Klebsiella pneumonia lysate in equal parts	6.94 pg/mL
i Inactivated Neisseria meningitides Ivsate [ * :	6.94 pg/mL \|
i Inactivated Candida albicans lysate, inactivated Candida parapsilosis	6.94 pg/mL
lysate, inactivated Candida giabrata lysate in equal parts.
\| inactivated Streptococcus equirms, Streptococcus bovis. and j Streptococcus of the viridans group lysate in equal parts. <	6,94 pg/mL
\| Inactivated Epidennophyton fioceosum, Microsporum cannis. Trichophyton mentagrophytes of the interdigitate variety lysate in equal parts).	6.94 pg/mL J
Inactivated Shigella flexneri and Shigella sonnei lysate in equal parts	6.94 pg/mL J
inactivated enteropathogesic (EPEC), “shiga-Kfee” toxin producer (STEC), enteroaggregative (EAEC), enterotoxigenic (ETEC), j	6.94 pg/mL j

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enteroinvasive (EffiC) and extiaratestinal (ExPEC) Escherichia coli I lysate in equal parts.
teactivated Safamnella fyphi, Salmonella paratyphi and Salmonella enterics lysate io equal parts.	j 6.94 pg/mL \| 75 ag/mL J
Bordetella pertussis toxoid
inactivated antigen of the Vaccinia (smallpox) virus lysate	1 1 to 1.0 x 10⁹ PFU/mL
Inactivated Apergdlus fumigates, Apergillus flavus, and Apergillus 1 6.94 pg/mL terreus lysate in equal parts.
Inactivated lysate of antigens of the measles virus (Schwarz strain).	\| 10,000 TDCiSO/mL
Glycerol	j 500 mg/mL
Pnenol i 2.5 mg/tnL
Water	1^qs·

Composition 28:

j Component	Concentration
Inactivated Mycobacterium tuberculosis lysate	0.004 ng/mL 1
Koch’s Turberculin (inactivated Mycobacterium bovis lysate).	0.004 ug/ml.
inactivated Mycobacterium avium lysate	0.004 ng/mL
Inactivated Staphylococcus aureus lysate, inactivated Staphylococcus epidermidis lysate in equal parts.	6.94 pg/mL J
Inactivated Streptococcus pyogenes lysate, inactivated Streptococcus pneumonie lysate, Enterococcus iaecaiis lysate in equal parts.	6.94 pg/mL
Inactivated Epidermophyton floccosum, MIcrosporum cannis, Trichophyton mentagrophytes of the interdigitate variety lysate in equal parts).	6.94 gg/mL J ! J ! !
Inactivated Neisseria meningitides lysate	6.94 ug/mL
Streptokinase derived from inactivated beta-hemolytic Streptococcus	0.444 pghnL
lysate purifieation. s	. J

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Domase derived from inactivated beta-hemolytic Streptococcus lysate purification.	j 0.1 II pg/mL
inactivated Salmonella typhi, Salmonella paratyphi and Salmonella enterica lysate in equal parts.	6.94 pg/mL ! I
Inactivated Streptococcus agalactiae lysate, inactivated Streptococcus mix (Streptococcus pyogenes. Streptococcus pneumoniae and Enterococcus faecaiis) lysate in equal parts.	j 6.94 pg/mL ! i
inactivated Euterobaeter aerogenes, Enterobacter cloacae, and Enterobaeter agglomerans group lysate.	! 6,94 ug/mL 1 *
Inactivated Helicobacter py lori lysate .	6.94 pg/mL j
Tetanus toxoid	\| 50 units of J LfernL [
Inactivated enteropathogenic (EPEC), “shiga-like” toxin producer (STEC), enteroaggregative (EAEC), enterotoxigenic (ETEC), enteroinvasive (EIEC) and extraintestinal (ExPEC) Escherichia eoli lysate in equal parts.	6.94 pg/mL 1 1
Inactivated antigen of the Vaccinia (smallpox) virus lysate	I to 10 x 10^s PFU/mL
Inactivated Candida albicans lysate, inactivated Candida parapsilosis lysate, inactivated Candida glabrata lysate in equal parts.	6.94 gg/mL i
Inactivated Apergillus femigafus, Apergillus flavus, and Apergillus terrens lysate in equal parts.	1 6.94 pg/mL
inactivated YF-i 7D lysate	3,000,000 PFU/mL
Glycerol	500 mg/mL
Phenol	2.5 mg/mL
Water	q,s.

Composition 29:

Component

Concentration

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Inactivated lysate of antigens ofthe mumps vires (Urabe AM9 strain)	50,000 TDCI50/mL
Inactivated BCG lysate	50 mg/mL
Inactivated Mycobacterium tuberculosis lysate	0.004 ng/mL
Koch’s Turberculin (inactivated Mycobacterium bo vis lysate).	0.004 ng/mL
Inactivated Mycobacterium leprae lysate	0.004 ng'mL
Inactivated Staphylococcus aureus lysate, inactivated Staphylococcus epidermidis lysate in equal parts.	6.94 qg/mL ΐ
Inactivated Streptococcus equinus, Streptococcus bovis, and Streptococcus ofthe viridans group lysate in equal parts.	6.94 pg/mL
Inactivated Setratiaxnarcencens and Serratia liquefaciens lysate	6.94 ng/mL 1
Inactivated Epidermophyton floccosum, Microspomm caanis, Trichophyton mentagrophytes of the interdigitate variety lysate in equal pasts).	6.94 pg/mL 1
Inactivated Haemophilus influenza lysate.	6.94 pg/mL
Inactivated Streptococcus agalactiae lysate, inactivated Streptococcus mix (Streptococcus pyogenes, Streptococcus pneumoniae and Enterococcus faecalis) lysate in equal parts.	6.94 pg'mL j
inactivated enteropathogenic (EPEC), “shiga-like” toxin producer (STEC), enteroaggregative (EAEC), enterotoxigenic (ETEC), enteroinvasive (EIBC) and extraintestinal (ExPEC) Escherichia coli lysate in equal parts.	6.94 pg/mL j
Tetanus toxoid	50 units of Lf/mL
Inactivated Proteus mirabilis, Proteus vulgaris, and Proteus penerii lysate in equal parts.	6.94 pg/mL
Inactivated Salmonella typhi, Salmonella paratyphi and Salmonella enterics lysate in equal parts.	6.94 pg/mL
Inactivated Apergillus fomigatus, Apergillus flavus, and Apergillus terreus lysate in equal parts.	6.94 pg/mL . ^:

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Inactivated lysate of antigens of the measles virus (Schwarz strain”).	10,000 \| TDCI50/mL \| {
Inactivated Candida albicans lysate, inactivated Candida parapsilosis	6.94 pg/mL \|
lysate. Inactivated Candida glabrata lysate in equal parts.	j
Inactivated antigen of the Vaccinia (smallpox) virus lysate	1 to 10 x 10^ j PFU/mL \| 1
Glycerol	500 mg/mL \| ---------------·;
Phenol	2,5 mg/mL
Water	q-s- J

Composition 30:

Component | Concentration I

Inactivated Apergillus iumigatus, Apergillus flaws, and ApergiHus 6.94 pg/mL terreus lysate in equal parts.

Inactivated Mycobacterium afhcamim lysate 0.004 ng/mL j

Koch’s TnrbereuUn (inactivated Mycobacterium bovis lysate). 0’o04 ug/mL j

Inactivated BCGlysate | 50 mg/mL~__|

Inactivated Mycobacterium tuberculosis lysate J 0.004 ng/mL |

Inactivated Streptococcus equinns, Streptococcus bovis, and ] δ.94 ng/mL

Streptococcus of the viridans group lysate in equal parts.

Inactivated Staphylococcus aureus lysate, inactivated Staphylococcus epidennidis lysate in equal parts.

Inactivated Neisseria meningitides lysate

Diphtheria toxoid I units of

LCmL

Inactivatedenterop&thogenic ^PEC), “shiga-like”toxin producer j 6.94 pg/mL (STEC), enteroaggregative (EAEC), enterotoxigenic (ETEC), enteroinvaslve(EIEC) and extraintestinal (ExPEC) Escherichia coli

6.94 pg/miL·

6.94 pg/mL lysate is equal parts.

Inactivated Epidensrophyton floccosum, Microspomm cannis,

6.94 pg/srL

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Trichophyton mentagrophytes of the interdigitate variety lysate in. equal parts).	1
Inactivated Sahnonellatyphi, Salmonella paratyphi and Salmonella enterica lysate in equal parts.	6.94 pg/mL I J ! 1
inactivated Acinetobacter baumannii lysate.	6.94 pg/nrL j
Inactivated Helicobacter pylori lysate.	6.94 pg/mL
inactivated Haemophilus influenza lysate.	6.94 pg/mL
Inactivated YF-17B lysate	3,000,000 PFU/mL i
Inactivated lysate of antigens of the mumps virus (Urabe AM9 strain)	50,000 TDCI50/mL
Inactivated Polio virus lysate	40 UD of type I antigens; 1.8 UD of type 2 antigens; 32 UD of type 3 antigens
Inactivated Candida albicans lysate, inactivated Candida parapsilosis lysate, inactivated Candida glabraia lysate in equal parts.	6.94 pg/mL
Glycerol	500 ma/mL
Phenol	2.5 mg/mL
Water	q.s.

Composition 31:

Component	Concentration J
Inactivated Salmonella typhi. Salmonella paratyphi and Salmonella	6.94 ug/mL j
enterica lysate in equal parts.	5 ! 1 ——-—---
Inactivated Mycobacterium leprae lysate	0.004 ng/mL i
Koch’s Turberculin (inactivated Mycobacterium bovis lysate).	0.004 ng/mL
Inactivated Mycobacterium tuberculosis lysate	0.004 ng/mL

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PPD	0.004 ng/mL 1 i
Inactivated Staphylococcus aureus lysate, inactivated Staphylococcus epidermidis lysate in equal parts.	6.94 gg/mL ί
Inactivated Streptococcus pyogenes lysate, inactivated Streptococcus pneumonic lysate, Enterococcus faecalis lysate in equal parts.	6.94 gg/mL
Diphtheria toxoid	67 units of Lf/mL
Inactivated Neisseria gonorrhoeae lysate	6.94 mg/mL \|
Inactivated Streptococcus agalactiae lysate, inactivated Streptococcus mix (Streptococcus pyogenes, Streptococcus pneumoniae and Enterococcus faecalis) lysate in equal parts.	6,94 gg/mL
Inactivated Epidermophyton fioceosum, Micxosporum cannis, Trichophyton mentagrophytes ofthe interdigitate variety lysate in equal parts).	6.94 gg/mL \| ! i
Inactivated Neisseria meningitides lysate	6,94 gg/mL I.·.............................
Inactivated enteropachogenic (EPEC), “shiga-like” toxin producer (STEC), eniercaggregative (EAEC), enterotoxigenic (ETEC), enteroinvasive (EIEC) and extiaintestinal (ExPEC) Escherichia cols lysate in equal parts,	6.94 gg/mL
Inactivated Haemophilus influenza lysate.	6.94 gg/mL
Inactivated Proteus mirabilis, Proteus vulgaris, and Proteus penerii 6.94 gg/mt lysate in equal parts. j
Inactivated Serratia marceneens e Serratia liquefaciens lysate j 6.94 gg/mL
Inactivated Candida albicans lysate, inactivated Candida parapsilosis 6.94 gg/mL lysate, inactivated Candida glabrata lysate in equal parts.

Antigens of the rubella virus (Wistar RA 27/3M strain)

10,000 I TDCI50/mE

Inactivate antigen ofthe Varicella zoster virus lysate

149 231

I PFU/mL

Inactivated Apergillus fumigatus, Apergillus riavus,

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J terreus lysate in equal parts.
j Glycerol	500 mg/mL
\| Phenol	2.5 mg/mL
j Water	q.s.

Composition 32:

Component	! Concentration
Inactivated Candida albicans lysate, inactivated Candida parapsilosis lysate, inactivated Candida glabrata lysate in equal parts.	6.94 pg/mL 1 J---------
inactivated Mycobacterium avium lysate	0.004 ng/mL
Inactivated Mycobacterium kansasii lysate	! 0.004 ng/mL
Koch’s Turhercdin (inactivated Mycobacterium bovis lysate).	0.004 ng/mL
Inactivated BCG lysate	j 50 mg/mL
inactivated Apergillus fumigatus, Apergiilus flaws, and Apergillus terreus lysate in equal parts.	J 6.94 pg/mL
Inactivated Neisseria gonorrhoeae lysate	6.94 mg/mL

Tetanus toxoid units of

Lf'mt·

Inactivated Streptococcus pyogenes lysate, inactivated Streptococcus pneumonie lysate. Enterococcusfaecahs lysate in equal parts.	j 6.94 pg/mL I
Inactivated Streptococcus equinus, Streptococcus bovis, and	\| 6.94 pg/mL.·
Streptococcus of the viridans group lysate in equal parts.	I
Inactivated Epidermopbyton floccosum, Microsporum cannis, Trichophyton mentagrophytes of the interdigitate variety lysate in equal parts).	6.94 pg/mL
Inacti vated Salmonella typhi, Salmonella paratyphi and Salmonella enterics lysate In equal parts.	6.94 pg/mL ! . . .....>
Inactivated Helicobacter pylori, lysate.	\| 6.94 pg/mL
Inactivated Chlamydia trachomatis, Chlamydia psittaei, and Chamydia pneumoniae lysate in equal parts.	j 6.94 pg/mL

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Inactivated enteropathogenic (EPEC), '‘shiga-like” toxin producer (STEC), enteroaggregative (EAEC), enterotoxigenic (ETEC), enteroinvasive (EIEC) and extraintestinal (ExPEC) Escherichia coll lysate in equal parts.	6.94 pg/mL 1 !
Inactivated Klebsiella oxytoca and Klebsiella pneumonia lysate in	6.94 pg/mL \|
equal parts
Antigens of the rubella virus (Wistar RA 27/3M strain)	10,000 TDCi50/mL
Inactivated antigen of the Vaccinia (smallpox) virus ivsate	I to 10 x 10·’ PFU/mL 1
Inactivated YF-17D lysate	3,000,000 i PFU/mL \|
Glycerol	ί 500 mg/mL j
Phenol	2.5 mg/mL
Water	j q.s. 1

Composition 33:

Component	Concentration
Inactivated enteropathogenic (EPEC), ‘shiga-like” toxin, producer (STEC), enteroaggregative (EAEC), enterotoxigenic (ETEC), enteroinvasive (EIEC) and extraintestinal (ExPEC) Escherichia cob lysate in equal parts.	6.94 pg/mL
Inactivated Mycobacterium leprae lysate	0.004 ng/mL
Inactivated Mycobacterium avium lysate	0.004 ng/mL
'.....Koch’s Turberculin (inactivated Mycobacterium bovis lysate).	0.004 ng/mL
Inactivated Mycobacterium tuberculosis lysate	0,004 ng/mL
inactivated Neisseria mcningltides lysate	6.94 pg/mL
Diphtheria toxoid	67 units of Lf/mL
i Tetanus toxoid	i 50 units of

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	Lf/mL
Inactivated Streptococcus pyogenes lysate, inactivated Streptococcus pneumonic lysate, Enterococcus taecaiis lysate in equal parts.	6,94 pg/mL
Inactivated Apergillus fumigates, Apergillus flaws, and Apergillus terreus lysate in equal parts.	6.94 pg/mL
Inactivated Candida albicans ly sate, inactivated Candida parapsilosis lysate, inactivated Candida, glabrata lysate in equal parts.	6,94 pg/mL
Inactivated Shigella flexneri and Shigella sonnei lysate in equal parts	6.94 pg/mL
Inactivated Helicobacter pylori lysate.	6.94 pg/mL
Inactivated Serratia marcencens e Serratia liquefaeiens lysate	6.94 pg/mL
Inactivated Salmonella typhi, Salmonella paratyphi and Salmonella enterica lysate in equal parts.	6.94 pg/mL
Inactivated antigen of the Vaccinia, (smallpox) virus lysate	itolOxK? PFLVmL
Inactivated antigen of HSV-I and HSV-H lysate	149231 PFU/raL
Inactivated lysate of antigens of the measles virus (Schwarz strain).	10,000 TDCI50/mL
Glycerol	500 mg/mL
Phenol	2,5 mg/mL
Water	q.s.

Composition 34:

Comoonent *	Concentration
Inactivated Candida albicans lysate, inactivated Candida parapsilosis lysate, inactivated Candida glabrata lysate in equal parts.	6.94 pg/mL
Inactivated Mycobacterium aflicanum lysate	0.004 ng/mL
Inactivated Mycobacterium tuberculosis lysate	0.004 ng/mL
PPL	0.004 ng/mL
Inactivated BCG lysate	50 mg/mL

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Tetanus toxoid	\| 50 units of Lf/mL j
Inactivated Streptococcus pyogenes lysate, inactivated Streptococcus	\| 6,94 gg/mL i
pneumonic lysate, Enterococcus faecalis lysate in equal parts.	1 ϊ
Inactivated Salmonella typhi, Salmonella paratyphi and Salmonella	\| 6,94 ug/u:.L i
enterica lysate in equal parts .
Inactivated enteropathogenie (EPEC), “shiga-like” toxin producer	\| 6.94 gg/mL i
(STEC), enteroaggregative (EAEC), enterotoxigenic (ETEC),	i 1
enteromvasive (EffiC) and extraintestinai (ExPEC) Escherichia coli
lysate in equal parts.	1
Inactivated Neisseria meningitides lysate	j 6,94 gg/mL j
Diphtheria toxoid	\| 67 units of Lf/mL \| j. {
Inactivated Streptococcus equinus, Streptococcus bovis, and	6,94 gg/mL i
Streptococcus of the viridans group lysate in equal parts.	i
Inactivated Apergillus fumigates, Apergillus Eaves, and Apergillns	6.94 gg/mL j
terreus lysate in equal parts.	*
Inactivated Shigella flexneri and Shigella sonnei lysate in equal parts	6.94 gg/mL \| -J-I----—1
Inactivated Proteus mirabilis, Proteus vulgaris, and Proteus penerii	6.94 gg/mL i
lysate in equal parts.	1
inactivated surface antigen of the hepatitis B (HBs AG) virus lysate	200 gg/mL
1 Inactivated lysate of antigens of the measles virus ( Schwarz, strain ) .	1 110,000
[	I TDCI50/mL
Inactivated YF-I7B lysate	[ 3,000,000 i
1	I PFU/mL I
\| Glycerol 5 ' .....................	500 mg/mL j
j Phenol	2.5 mg/mL \|
[Water J 9-^s· j
imposition 35:
j Component	Concentration
j Inactivated Candida albicans lysate, inactivated Candida parapsilosis	6.94 gg/mL

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lysate, inactivated Candida glabrata lysate in equal parts.	1
PPD	0.004 ng/mL J
Inactivated BCG lysate	50 mg/mL j
Koch’s Turberculin (inactivated Mycobacterium bovis lysate).	0.004 ng/mL J
Inactivated Mycobacterium tuberculosis lysate	0,004 ng/mL I
Inactivated Streptococcus pyogenes lysate. Inactivated Streptococcus pneumonic lysate. Enterococcus fascahs lysate in equal parts.	6.94 pg/mL \|
Inactivated Staphylococcus aureus lysate, inactivated Staphylococcus epidennidis lysate in equal parts.	6.94 pg/mL
Inactivated Epidermophyton floccosum, Microsporum cannis, Trichophyton mentagrophytes of the interdigitate variety lysate in equal parts).	6.94 gg/mL
Inactivated Neisseria meningitides lysate	6.94 pg/mL j
Te tanus toxoid	SO units of LflmL J
Diphtheria toxoid	67 units of LflmL
Inactivated Streptococcus equinus. Streptococcus bovis, and Streptococcus of the viridans group lysate in equal parts.	6.94 pg/mL
Inactivated Serratiamarcencens e Serratia liquefeciens lysate	6.94 pg/mL J
Inactivated Acinetobacter baumannii lysate.	6.94 ug/m'L
Inactivated enteropathogenic (EPEC), “shiga-like” toxin producer (STEC), enteroaggregative (EAEC), enterotoxigenic (ETEC), enteroinvasive (EIEC) and extraintestinal (BxPEC) Escherichia coli lysate in equal parts.	6.94 pg/mL
Inactivated Salmonella typhi, Salmonella paratyphi and Salmonella enterica ly sate in equal parts.	6.94 pg/mL
Inactivated YF-17D lysate	3,000,000 PFU/mL
Inactivated Apergillus fumigaius, Apergiilus flaws, and Apergillus terreus lysate in equal parts.	6.94 pg/mL
Inactivated lysate of antigens of the mumps virus (Urabe AM9 strain)	50,000

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	1^TOC150/n>L i
Inactivated antigen of the Vaccinia (smallpox) vims lysate	1to 10 X IO⁹
	PFU/mL
Glycerol	i 500 mg/mL
Phenol	1 2.5 mg/mL \|
Water	\| q-s. {

Composition 36:

Component	J Concentration
Inactivated Apergillus femigatus, Apergillus Caves, and Apergillus	j 6.94 pg/mL
terreus lysate in equal parts.	I i
Koch’s Turberculin (inactivated Mycobacterium bovis lysate).	\|_: 0.004 ng/mL
Inactivated Mycobacterium tuberculosis lysate	Ϊ 0.004 ng/mL
Inactivated BCG lysate	J 50 mg/mL
PPD (purified protein derivative)	0.004 ng/mL
Inactivated Streptococcus pyogenes lysate, inactivated Streptococcus	6.94 ug/mL
pneumonie lysate, Enterococcus faeealis lysate in equal parts.	1..................
Inactivated Chlamydia trachomatis. Chlamydia psittaci, and Chamydia	! 6.94 pg/mL j
pneumoniae lysate in equal parts.	I
Inactivated Epidermophyton fioecosum. Microsporum cannis,	6.94 pg/mL j
Trichophyton mentagrophyies of the interdigitale variety lysate in
equal parts).	3 !
Bordetella. pertussis toxoid	j 75 pg/mL \|
Inactivated Haemophilus influenza lysate.	i 6.94 pg/mL
Streptokinase derived from inactivated beta-hemolytic Streptococcus	\| Q.444 pg/mL j
lysate purification.	j \|
Domase derived from inactivated beta-hemolytic Streptococcus lysate	i 0.111 pg/mL \|
purification.	i i
Inactivated Salmonella typ'd, Salmonella paratyphi and Salmonella	\| 6.94 pg/mL j
enterica lysate in equal parts.	1 ......1

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Tetanus toxoid

Inactivated surface antigen of the hepatitis AG) virus lysate inactivated enteropathogenie (EPEC), Cshiga-like” toxin producer (STEC), enteroaggregative (EAEC), enterotoxigenic (ETEC), enteromvasive (EIEC) and extraintestinal (ExPEC) Escherichia eoli lysate in equal parts.

Inactivated Candida albicans lysate, inactivated Candida parapsilosis lysate, inactivated Ganoids glabrata lysate in equal parts.

Inactivated Polio virus lysate units of EfrmL j 200 pg/mL

6.94 pg/mL

6.94 pg/rfL

UD of type I

I antigens; 1.8 CD of type 2 antigen s ; 32 UD of type 3

mactivated antigen of the Vaccinia (smallpox) virus lysate	j ..... 1 to 10 X 10^s
	1 PFU/mL
Inactivated YF-I7D lysate	ί 3,000,000
	PFU/mL
Glycerol	500 mg/mL j °
Phenol	j 2.5 mg/mL
Water \| _{q s}

When there are parasitic diseases, associated or to be fought, the formulations will preferentially contain antigenic agens of parasitic origin. In this case, according to the concept described in the present invention, the formulations snould comprise antigenic agents originating from the most prevalent parasites for which the individuals have more memory cells, according to the geographic distribution and the local and regional human development (developed or noaaeveloped countries). Such parameters are determinant for the occurrence of these parasites and the existence of corresponding memory⁷ cells in tire immune system of the population of a given region.

Composition 37: Association of Composition 2 with:

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Component	j Concentration j
inactivated Toxoplasma gondii lysate	J 400 gg/mL ί

Composition 3S: Association of Composition 3 with:
i Component	Concentration
	Inactivated Giardi lamblia lysate	400 gg/mL
Composition 39: Association of Composition 4 with:
	Component	Concentration
	Inactivated Entamoeba histolytica lysate	400 gg/mL . .
Composition 40: Association of Composition 5 with:
	Component	Concentration
	Inactivated Ascaris Inmbricoides lysate	400 gg/mL

Composition 41: Association of Composition 6 with:

j Component	i Concentration
	Inactivated Enterobins vennicuians lysate	\| 400 gg/mL
Composition 42: Association of Composition 7 with;
	Component	j Concentration
	Inactivated Entamoeba histolytica lysate	\| 400 gg/mL „ -!----------_;—
	Inactivated Ascaris Inmbricoides lysate	\| 400 gg/mL
Composition 43; Association of Composition 8 with;
	Component	j Concentration
	Inactivated Giardi lamblia lysate	4Q0 gg/mL
	Inactivated Enterobins vermieularis lysate	400 gg/mL ( ...... ............

Composition 44: Association of Composition 9 with:

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j Component	Concentration
( Inactivated Strongyloides stsrcoralis lysate	400 pg/mL
\| Inactivated Entamoeba histolytica lysate	400 pg/mL

Composition 45; Association of Composition 10 with:

Component	\| Concentration
Inactivated Giardia lamblia lysate	400 pg/mL
\| Inactivated ..Ascaris lumbricoldes lysate	\| 400 pg/mL

Composition 46; Association of Composition 11 with;

Component	Concentration
j Inactivated Toxoplasma gondii lysate	400 pg/mL
\| Inactivated Entamoeba histolytica lysate	400 pg/mL

Composition 47: Association of Composition 12 with

	Concentration
\| Inactivated Strongyloides stercoralis lysate !-*--, ........... ........................ . .. ....... .	400 pg/mL
j Inactivated Cryptosporidium: spp. lysate	400 pg/mL

Composition 48: Association of Composition 13 with:

Component	i Concentration
Inactivated Ascaris lumbricoldes lysate	400 pg/mL
Inactivated Toxoplasma gondii Ivsate	j 400 pg/mL

Composition 49: Association of Composition 14 with;

Component	Concentration
Inactivated Entamoeba histolytica lysate	400 pg/mL
Inactivated Giardia lamblia lysate i	400 pg/mL

Composition 50; Association of Composition 15 with:

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I Component		! Concentration
j Inactivated Strongyloides stercoralis lysate		J 400 pg/mL
Γ Inactivated Enterobins vermicularis lysate		i 400 pg/mL

Composition 51: Association of Composition 16 with:

Component	\| Concentration
Inactivated Trichomonas vaginalis lysate	400 pg/mL
Inactivated Ascaris lumbricoides lysate	i 400 pg/mL

Composition 52: Association of Composition 17 with:

Component	j Concentration
Inactivated Entamoeba histolytica lysate		1 400 pg/xnl.
Inactivated Ascaris Inmhricoides lysate		400 pg/mL
Inactivated Enterobias vermicularis lysate		400 pg/mL

omposition 53 : Association of Composition 18 with:
J Component	! Concentration i
i Inactivated Giardia lamblia lysate	j 400 pg/mL
i Inactivated Enterobius vermicularis lysate	400 pg/njL
\| inactivated Toxoplasma gondii lysate	400 pg/mL

Composition 54: Association of Composition '19 with;

Component	Concentration
Inactivated Strongyloides stercoralis lysate	400 pg/mt
Inactivated Entamoeba histolytica lysate	400 pg/mL,
Inactivated Chardin lamblia lysate	400 pg/mL

Composition 55: Association of Composition 20 with:

Component	Concentration
Inactivated Giardia lamblia lysate	400 pg/mL

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PCT/BR2018/000004 inactivated Ascaris lumbricoides lysate J 400 pg/mL

Inactivated Strongyloides stercoraiis lysate ~~ ~ ; dOO'Jm/mL

Composition 56: Association of Composition 21 with;

component	(Ccncemrarion 3
Inactivated Toxoplasma gondii lysate	400 pg/ntL
Inactivated Entamoeba, histolytica lysate	400 pg/mL
Inactivated Chardin laroblia lysate	400 pg/mL

Composition 57: Association of Composition 22 with:

Component	Concentration
Inactivated Strongyloides stercoraiis lysate	400 pg/mL
Inactivated Cryptosporidium spp. lysate	400 pg/mL
Inactivated Entamoeba histolytica lysate	400 pg/mL

Composition 58: Association of Composition 23 with;
j Component	j Concentration
\| Inactivated Ascaris lumbricoides lysate	400 pg/mL
I Inactivated Toxoplasma gondii lysate	j 400 pg/mL

Inactivated Enterohius vermicularis lysate ί 400 pg/mL

Composition 59: Association of Composition 24 with;

Component	\| Concentration
Inactivated Entamoeba histolytica lysate	400 pg/mL
Inactivated Giardia iamblia lysate	\| 400 pg/mL
Inactivated Ascaris lumbricoides lysate	\| 400 pg/mL

Composition 60: Association of Composition 25 with:
\| Component : ....	j Concentration
\| Inactivated Strongyloides stercoraiis lysate	i 400 pg/mL

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Inactivated Enterobius vermieularis lysate	400 ug/mL
Inactivated Entamoeba histolytica lysate	400 pg/mL

Composition 61; Association of Composition 26 with;

Component	: Concentration ! ..............,........................ ........ 1
Inactivated Trichomonas vaginalis lysate	[ 400 pg/inL
Inactivated Ascaris Inmbrieoides lysate	400 gg/mL i
Inactivated Giardia lamblia lysate-	400 pg/mL

Composition 62: Association of Composition 27 with:

I Component	Concentration
Inactivated Entamoeba histolytica lysate	400 pg/roL
1 Inactivated Ascaris Inmbrieoides lysate	400 ug/mL
! Inactivated Enterohlus vermieularis lysate	400 pg/rnL
j Inactivated Cryptosporidium spp. lysate ! '__________ ____	400 pg/mL

Composition 63: Association of Composition 28 with:

Component	j Concentration j
Inacti vated Giardia lamblia lysate	1 400 gg/mL
Inactivated Enterohlus vermieularis lysate	400 pg/mL
Inactivated Toxoplasma gondii lysate	400 pg/mL
Inactivated Ascaris Inmbrieoides lysate	400 ug/mL \|

Composition 64; Association of Composition 29 with ;

Component	Concentration i
inactivated Strongyioides stercoralis lysate	400 pg/mL i
Inactivated Entamoeba histolytica lysate	400 pg/mL j
Inactivated Giardia lamblia lysate	400 ug/mL \| 1
i Inactivated Entsrobius vermieularis lysate ; .	400 pg/rnL j

Composition 65 : Association of Composition 30 with:

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Component	I Concentration !
Inactivated Giardia lamblia lysate		I 400 μη/mL
Inactivated Asearis Inmbricoides lysate		\| 400 pg/mL
Inactivated Strongyloides stereoralis lysate		j 400 pg/mL
Inactivated Entamoeba histolytica lysate		400 pg/mL

Composition 66: Association of Composi tion 31 with:
i Component	\| Concentration
i Inactivated Toxoplasma gondii lysate	j 400 pg/inL
1 Inactivated Entamoeba histolytica lysate	400 pg/mL
i Inactivated Giardia lamblia lysate	400 pg/mL
[ Inactivated Enterobins vennicularis Ivsate I ^v	\| 400 pg/mL

Composition 67; Association of Composition 32 with:

Component	Concentration
inactivated Strongyloides stereoralis lysate	400 pg/mL
Inactivated Cryptosporidium spp. lysate	400 pg/mL
Inactivated Entamoeba histolytica lysate	400 pg/mL
Inactivated Asearis Inmbricoides lysate	400 pg/mL

Composition 68: Association of Composition 33 with:

Component	Concentration
Inactivated Asearis Inmbricoides lysate	400 pg/mL
Inactivated Toxoplasma gondii lysate	400 pg/mL -
Inactivated Esterobius vennicularis lysate	400 pg/mL
Inactivated Cn-ptosporidium spp. lysate	400 pg/mL . .............

Composition 69: Association of Composition 34 with:

• Component ~j Concentration ffoactivated Entamoeba histolytica lysate 400 pg/mL

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Inactivated Giardia lamblia lysate Inactivated Ascaris lumbricoides lysate Inactivated Trichomonas vaginalis lysate

	400 pg/mL
	400 pg/mL

Composition 70: Association of Composition 35 with:

Component	J Concentration
inactivated Stiongyloides stereorahs lysate	i 400 pg/mL
Inactivated Enterobius vemacularis lysate	400 pg/mL·
Inactivated Entamoeba histolytica lysate	J 400 ug/mL
Inactivated Cryptosporidium spp. lysate	j 400 pg/mL

Composition 71: Association of Composition 36 with:

Component	Concentration
Inactivated Trichomonas vaginalis lysate	400 pg/mL
Inactivated Ascaris lumbricoides lysate	400 ug/mL
Inactivated Giardia 1 am blia lysate	400 ug/mL

2: 1 rearing s

Patient data

Patient J-P, 58 years old, male.

Principal diagnosis

Septicemia,

Secondam' diagnoses

Polytrauma with:

• Complex infected wounds with major loss of tissue of approximately 40 cm.

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PCT/BR2018/000004 ^e extensive infected tissue necrosis with indication for amputation of the left lower limb, mfected grade IBB open fracture wife. osteomyelitis ofthe left femur with lateral exposure.

·· open wounds, infected cut-contusion without possibility of suture on the left arm, back ofthe left foot and on fee right lateral malleolus region.

Identification and summary of the clinical history

On January 12, 2011 fee patient was admitted to fee Intensive Care Unit ofthe Octavian Constantine Hospital das Chnicas of Teresopolis, victim of a landslide with a grade ΠΙ b open rracmre or fee left femur with the exposure ofthe lateral cut and medial cut-contusion wife an extension of 40 cm in depth feat communicated wife the exposure of fee side. Lacerations, contusion on the leit aim, back of the left, foot and right lateral malleolus region. Evolved to a sepsis scenario in 24 hours, wi fe microbiological, identification of Pseudomonas aeruginosa. Conventional proposed and realized treatment

External fixation ofthe femur in the emergency room, administration of clindamycin, vancomycin and cefepime, associated to a daily surgical debridement.

Results of the performed conventional treatment

Initially, it improved the septic scenario, followed by the evolution ofthe infection ofthe left tower limb wife extensive areas of muscle necrosis with a high risk of amputation. 15 davs after the admission the sepsis got worse, wife febrile episodes of 39° C, profound anemia (receiving transfusions) and exchange ofthe antimicrobial medication to Tazocim. The patient was transrerred with an aerial mobile J.CU to SSo Paulo under medical supervision.

The completion of conventional treatment showed a relapse in sepsis and increased necrosis of fee left leg with an indication for amputation.

Proposed IjIICA treatment associated with conventional surgical treatment

The patient was admitted to fee ICU of Hospital Alemao Oswaldo Cruz for debridement and application of treatment wife DECA which took fee following form:

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PCT/BR2018/000004 * Application of 1A cc of the DECA composition divided into 2 applications of 0.9 co per composition along the 10 main lymphatic territories.

* 3-4 cm distance margin between applications to facilitate the reading of the evolution of the treatment at an interval of 4±1 days. These applications were made together with the surgical debridement (on average 1 to 2 times per week).

• Administration of 36 extra perilesional compositions of 1,8 cc- of each DECA in two applications of 0.9 cc per set, skirting the following open injuries without possibility of suture: the left inguinal region, the lateral side of the left thigh, the anterior left thigh and medial aspect of the left thigh, instep region and left lateral malleolus of the right leg.

® Application of recombinant human inierleukro-2 at low doses, at a receptor saturation level with a concentration of 1 to 2 million units per m“ of the patient’s body surface located in the region of the extra DECA applications. 3 million daily units were subcutaneously injected in the left thigh or inguinal region for the pacient.

• in the exposed regions 15 compositions DECA were applied, 1.8 cc each, for infiltration, of exposed raw areas.

♦ This extensive immunotherapy was always applied in the operating days of cleansing and surgical debridement under general anesthesia.

Tirus, the first phase of immunotherapy began on 29 January, 2011 and ended on 19 March,

2011 totalling a total of nine DECA applications in periods ranging ftom one to two times per week, once the cleaning and debridement schedule was being followed, in the operating room (due to the se verity of the pain and risk of infection by the broad extensive exposure of internal tissues in the raw areas).

Results of the treatment with DECA associated with surgical debridement and antibiotic therapy

Initial assessment of the patient’s injuries in the operating room on 29 January', 2 011 showed all wounds bleeding with many clots, with extensive areas of necrosis and foul-smelling pus . After surgical cleaning, tissue continued to perform poorly with a winy general appearance without any appearance of healthy granulation tissue (Figure I - Al, A3 and A4). As described, the

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DECA immunotherapy was applied to these areas. It is interesting to note that on this occasion cultures of internal secretions and tissue fragments were performed.

After 24 hours the first, assessment of the surgical treatment associated with DECA immunotherapy was made and it demonstrated that: red lesions, w ith the appearance of healthy granulation tissue, with few' necrotic areas with sparse secretion without foul odor and no active bleeding. The lesions were cleaned and fee DECA immunotherapy was applied as noted above. On this occasion fee antibiotic therapy was changed to Tazpcim Meronem, Cubicin and Rifanrpicis pending culture results.

On 01 February 2011 the result of fee cultures from fee injury area, peripheral blood and central catheter showed:

• in the wound of fee left thigh isolation of multifeug-resistmit Pseudomonas aeruginosa, mnltiresistant Acinetobacter baunnamii sensitive only to polymyxin B and mnltiresistant Proteus mirabiles.

* in the peripheral blood and in fee central catheter fee isolation of multidrug-resistant Acinetobacter baunnamii sensitive only to polymyxin B.

Conclusion: These results demonstrated that the poor prognosis of injuries in the left leg led to a new sepsis episode with Acinetobacter baunnamii and because of its multidrug resistance and sensitivity only to polymyxin B, did not respond to treatment with intravenous Tazoeim. On the other hand, it strongly supports a beneficial effect of fee DECA composition in joint surgical treatment in fee local- and systemic protection against. this infection, since there was improvement in systemic infection and inj uries before fee application of polymyxin B could neutralize this etiologic agent.

That day, Meronem was exchanged for 20,000 Rl/feg twice daily of Polymyxin B without changing the other medication.

On 03 February, 2011, it was found that the combination antibiotic therapy, debridement and DECA immunotherapy caused fee remission of fee septic scenario, which allowed the transfer of fee patient from the ICU to fee ward thereafter (Figure I - Bl, B2 and B3).

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On 06 February, 2011, given the toxicity of Polymyxin B administration and other antimicrobials, the patient presented a picture of acute renal failure wife oliguria. As a consequence, on the period between 06 February, 2011 and 15 February, 2011 (12 days) administration or these antibiotics was suspended, with Limezolida (Zyvox) being introduced for protection against a hospital staphylococcal contamination. On 15 February , 2011 the complete remission of renal failure in the patient was confirmed, la this 12-dav period, with only the com bination therapy of debri dement, antibiotic prophylaxi s and DECA immunotherapy, the patient showed excellent overall progress of the infectious and injuries being, after this period, able to withdraw the external fixator, have a surgical cleanup, and introduction of an internal rod for fixing fee fracture on a surgery performed on 17 February, 2011, Thus, in this period, together with orthopedic surgery, there was a significant reduction in raw areas without skin with extensive tissue regeneration and no new’ infections.

The patient was discharged on 15 March, 2011, with complete cure of the Infection of all complex injuries and wounds, including osteomyelitis. The patient was discharged without antibiotic therapy.

Conclusion ofthe case

The existence of a severe and widespread infection and of a complex wound infected -wife with multldrug-resistant Acinetobacter baunnamii sensitive only to polymyxin B which was controlled without specific antibiotic therapy with broad progression to the healing of sepsis, of all exposed lesions, and of osteomyelitis, strongly suggest a decisive role of the DECA immunotherapy, associated with debridement and antibiotics, to cure the clinical scenario, in a relatively’ short time.

Table 1. Result ofthe association of DECA immunotherapy, antibiotics and surgical debridement for sepsis and severe infection of complex injuries.

Infected regions

Pre-immunotherapy’ cultures (29 January, 2011)

Result of fee association of immunotherapy, antibiotic therapy, and surgical debridement (15 March,

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		2011)
Injury in the left thigh	Multiresistant. Pseudomonas aeroginosa, muliiresisteut Acinetobacter baumannii only sensitive to Aztreouam and polymyxin B	No signs of infection
Peripheric blood	muitiresistent Acinetobacter baumannii only sensitive to Aztreonam and polymyxin 3	No signs of Infection
Central catheter i	muitiresistent Acinetobacter baumannii only sensitive to Aztreouam and polymyxin B	No signs of infection [

Example 3: Treating sepsis associated with urinary infections and concomitant

Patient information

Patient CMS - female, 38 years old.

Diagnosis 'Terminal'gastric carcinoma with comorbidity of aspnative pneumonia with chemical and infection pneumonia,: urinary tract and oropharyngeal .infections associated with sepsis on 03 October, 2011. The central catheter and tracheal fluid culture was positive for Pseudomonas aeruginosa (Serratia marecescens was isolated only in tracheal aspirates) while the urine culture had isolation of multiresistant Klebsiella pneumoniae sensitive only to ΙΜΪΡΕΝΕΜ and derivatives. At 1CU the sepsis was characterized by hemodynamic changes and crash initially requiring the use of vasoactive drugs and respiratory support to control the episode. The patient also presented platelet blockade with major bleeding associated with an acute anemic condition (hemoglobin 8.6 g/dL) also

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PCT/BR2018/000004 had hypokalaentic, h^onairemic and lymphopenic (lymphocyte count of3,000/mioroliter) condition.

Prior conventional treatment

Antibiotic therapy, vasoactive drugs, respiratory' support and parenteral nutrition.

Treatment with VITER

The immunotherapy treatment was performed during a single session on 04 October, 201 Iwiih the informed consent of the patient. VITER immunotherapy was- performed as follows:

• Application of 0.2 mL of each one of fee VITER formulation (Example 1). Attenuated yellow fever virus strain 17 D204 20 pgrinL near the main 10 lymphatic territories.

* Application ot a low dose of recombinant human interleukin 2, at a receptor saturation level with a concentration of 1 to 2 million units per meter of body surface.

Result of immunotherapy treatment with VITER

On 07/10/20Π, anemia and thrombocytopenia were reversed with a platelet count of 178,000/roieroliier and a platelet aggregation function compatible with normal parameters. We also noted the normalization of serum electrolytes.

The immunostimulation caused immunocompetence recovery and activation of the effector T loop as the lymphocyte count increased from 3,000/microliter on 03 October, 201 Ito 9,400/microliter on 07/10/2011, C-reactive protein concentration was reduced to 61 mg/1 indicating control the infection. It is necessary? to mention that the patient remained unther immunological treatment at Home care regimen. On 01/11/2011 was diagnosed an aspiration pneumonia confirmed by chest tomography with amazing recovery before the current state of the art in 03 days of immunotherapy associated with antimicrobial treatment according to CT scan of 04/11/2011 (Figure 2).

Case Conclusion

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Discharge from hospital to home care on 09/10/2011. Tie evaluated data and the clinical course of the patient indicate that the innovative immunotherapy was responsible for the amazing recovery' from the critical sepsis condition the patient was in. The continuity of immunostirnulatorj' treatment also contributes to the improvement of the patient’s life quality and an amazing improvement in life expectancy. According to the state of the art this widespread and terminal cancer condition leads to death in about 1 month,, while the immunostimuiation of the present Invention allowed for an unexpected survival of 1 year and. a half, enjoy tag tire company of relatives.

Example 4: Treating infection (mnlriresistant bacteria of SARS in septic shock) fatietti Irffitnietioto

Patient AMB - female, 39 years old.

Primary Diagnosis

Severe sepsis and Septic shock

Secondary Diagnosis

Presented as comoihity:

- Severe Acute Respiratory Syndrome (SARS);

-Shock;

- Acute Renal Failure;

- Disseminated Intravascular Coagulation;

- Hepatic failure signs;

identification and summary of the clinical history

On 19 April 2007 were hospitalized with dlgnosis ofcomunity pneumonia, non-produeed cough and high fever. After 10 hours of hospital admission, patient got worse requiring tranferece to Intense Care Unit (ICU) with respiratojy Infection and septic shock characterized by: hipotension, SARS; renal and hepatic failure; Disseminated Intravascular Coagulation; serum lactate increase, hemodynamic and eletroiytes colapse.

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PCT/BR2018/000004 .Prior conventional treatment

Os 20 April 2007 were treated with Ceftriaxone and Levofioxacin. However, after clinical complication and ICU admission when became essential: i) start respirator}' and hemodynamic support; ii) antimicrobial regimen replace by Meropenem with Vancomicin; iii) association of plasma transfusion 0SU and IV active protein C to reverse Disseminated intravascular Coagulation and make opsonization process possible. Inspite of all efforts patient did not experince any clinical and laboratory improvement

Proposed IRS with DECA treatment associated with conventional treatment

The immunotherapy treatment was performed nine sessions starting on 21/04/2011 after informed consent of the patient. DECA immunotherapy was performed as follows:

’ Application of 0.2 mL of each one of the 10 antigenic components (1. Koch’s Tuberculin ((lysate inactivated Mycobacterium bovis 0,0036 ng/mL); 2. PPD (0,0036 pg/mL); 3. Lysate inactivated Staphylococcus (Staphylococcus aureus and Staphylococcus epidermidis in equal parts 6,31 pg/mL); 4 Lysate inactivated Streptococcus (Streptococcuspyogenes, Streptococcus pneumonic and Enterococcus faecalis in. equal parts 6,31 pg/mL).; 5, Streptokinase derived from lysate inactivated and purified Streptococcus beta-hemolytic 0,404 pg/mL); 6. Dornase derived from lysate inactivated and purified Streptococcus beta-hemolytic 0,101 pg/mL); 7., Oidiomyein (antigenic extinct of Candida albicans 6,31 pg/mL); 8. Trichophytin (antigenic extract of Tricophyton spp 6,31 pg/mL); 9, Lysate inactivated. Escherichia coli (EPEC 6,31 pg/mL); 10. Lysate inactivated Salmonella (Salmonella bongori, Salmonella enterica and Salmonella subterranea in equal parts 6,31. ug/mL).

Result of immunotherapy with IRS -DEG.4 associated with conventional treatment

On 26 May 2007 serum eletrolytes and lactate reached normal levels and forcmbocytopenia were reversed with a platelet count of 167,000/mm'’ and a platelet aggregation function compatible with normal parameters.ON 27.04.2007 SAKS still very severe and start to improve. On 29 May 2007 arterial blood gas analysis saturation and pO?. were reversed evidencing hemodynamic recover. The rmmunostimulation caused immunocompetence recovery and

WO 2018/145180

PCT/BR2018/000004 activation of the effector T loop with normalized complement fractions on 28 April 2007, tire lymphocyte const decreased from 21,100/mm³ on 20 April 2007 (that got worse to 43.700/mm³on 22 April 2007) to 11.000/sss³ os 30 April 2007 when CDS, CD4 and CD8 fractions presented proper levels. Tire respiratory condition improve drastically after 29,04.2007 and respiratory support were removed. Patient was discharged from. ICU on 06 May 2007 with complete recover of severe sepsis. On 19 April 2007 was diagnosed an comunity pneumonia confirmed by chest X-Ray of 24/ zlpril 2007 (Figure 3 - A1) and worsened to SARS associated with sepsis as can see on CT scan of 27 April 2007 (Figure 3 - B1 to B6) with amazing recovery·' before the current state of the art in 15 days of immunotherapy (6 sessions) associated with antimicrobial treatment according to laboratories and X-Ray (Figure 3 - C1) exams of 06 May 2007.

Case Conclusion

Discharge from hospital on 06 May 2007. The evaluated data and the clinical course of the patient indicate that the innovative immunotherapy was responsible for the amazing recovery from the critical severe sepsis and septic shock conditions that the patient was in. The continuity of itmnunostimulatory treatment also contributes to the complete extinguish the severe infection and an amazing improvement in life expectancy. According to the state of the art this multiresistant bacteria of SARS in septic shock associated with renal and hepatic failure con ditions leads to death In hours, while the imamnostimulation of the present invention allowed for an unexpected survival with no sequel.

In short, the clinical cases presented hereinabove demonstrate that high complexify illnesses and diseases, with obscure to very poor prognosis, have been addressed more properly, with advantageous and more e fficient approaches through the use of the IRS compositions the present, invention,

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In order to better understand the above concept and definitions related to the present invention, the following references are incorporated into the present patent application:

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Claims

I. A pharmaceutical product comprising one or more antibiotics and one or more IRS immunogenic compositions for modulating the immune system comprising a therapeutically effective amount of three or more synthetic antigenic agents or natural antigenic agents, or fractions and combinations thereof, comprising pathogen-associated molecular patterns (PAWS) and/or danger associated molecular patterns (DAMPS) selected from at least two groups consisting of (A) antigenic agents with molecular patterns associated with bacteria, (B) antigenic agents with molecular patterns associated with viruses, (C) antigenic agents with molecular patterns associated with fongi and yeasts, (D) antigenic agents with molecular patterns associated with, protozoa, (B) antigenic agents with molecular patterns associated with helminths, and (F) antigenic agents with molecular patterns associated with pnons; and one or more physiologically acceptable carriers, excipients, diluents or solvents.
2. The pharmaceutical product of claim 1 wherein the antibiotics are selected from the following classes: Amino Acid Derivatives, Aminoglycosides, Aureolic Acids, Aziridmes, Ansamycius, Beszenoids, Benzimidazoles, Carbapenems, Cephalosporin, Coumarin-glycosides, Diphenyl Ether Derivatives, Epipolythiodioxopiperazines, Fatty Acad Derivatives,

Glucosamine, Glycopeptides, Imidazoles, fadol Derivatives, Lipopeptides Macrolactams, Macrohdes, Nucleosides. Penicillins and Cephalosporins (beta-Lactems), Peptides, Peptidyi Nucleosides, Phenicoles, Polyenes, Polyethers, Pyridines and Pyrimidines, Qumolones and Fluoroquinolones, Statins, Steroids, Sulfonamides, Taxoides and Tetracyclines.
3. The pharmaceutical product, of claim 2 wherein, the antibiotics are selected from the following classes: ansateycins, Penicillins, Cephalosporins, Carbapenems and Lipopeptides.
4. The pharmaceutical product of claim 1 wherein the antigenic agents are selected mom at least four groups (A), (B), (C), (D), (E) and (F).
5. The pharmaceutical product of claim 1 comprising from 4 to 20 antigenic agents selected from the group consisting of antigenic agents derived, from: domase, levedunn,

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PCT/BR2018/000004 oidiomycin, purified protein derivative of Koch’s bacillus (PPD), prions, streptokinases, Streptococcus toxoid,, diphtheria toxoid, tetanus toxoid, Koch’s original tuberculin, inactivated Ascaris lumhricoides lysates, Aspergillus spp., Aspergillus flaws, Aspergillus fumigaius, Aspergillus terreus, Candida albicans, Candida giabrata, Candida parapsilosis, Chlamydia spp., Chlamydia pneumoniae, Chlamydiapsitiaci, Chlamydia trachomatis, Cryptosporidium spp. . Dermatophytes, Entamoeba hystoUtica, Enterobius vermictilaris, Enterococcus faecalis, Epidermophyton fioceosum, Escherichia coli, Giardia lamblia, Haemophilus influenzae, Microsporum cards, Mycobacterium spp., Mycobacterium bovis, Mycobacterium leprae, Mycobacterium tuberculosis, Neisseria gonorrhoeas. Human papillomavirus, Potto virus, Proteus spp., Proteus mirabilis, Proteus penerii, Proteus vulgaris, Salmonella spp., Saimone'ua bongori, Salmonella enterica, Serratia spp. , Serratia liguefaciens, Serratia marcencens,

Shigella spp., Shigella flexneri, Shigella sonnei, Staphylococcus spp., Staphylococcus aureus, Staphylococcus epidermidis, Strongyloides stercoralis, Streptococcus spp., Streptococcus bovis, Streptococcus viridans. Streptococcus ecpiimis, Streptococcus pneumonias, Streptococcus pyogenes, Toxoplasma gondii, Trichomonas vaginalis, trichophytin, Trichophyton spp.. Trichoohyton rubrum, Trichophyton tonsurans, Trichophyton mentagrophytes, yellow fever virus, hepatitis B virus, rubella virus, varicella zoster vims, variola virus, mumps vims, measles virus, herpetic virus and vaccinia'virus or synthetic analogues present pathogen-associated molecular patterns (PAMPS) and / or danger-associated molecular patterns (uAMrb) associated with these antigenic agents.
6. A method to treat sepsis and multi resistant bacterial infection m a human or an animal comprising administering to the human or animal an effective amount of one or more antibiotics and one or more IRS immunogenic compositions comprising a therapeutically effective amount of three or more synthetic antigenic agents or natural antigenic agents, or fractions and combinations thereof, comprising pathogen-associated molecular patterns (PAMPS) and, or danger associated molecular patterns (DAMPS) selected horn at least two groups consisting o*. (A) antigenic agents with molecular patterns associated with bacteria, (B) antigenic agents wife molecular patterns associated wife viruses, (C) antigenic agents wife molecular patterns associated with fungi and yeasts, (D) antigenic agents with molecular patterns associated with protozoa. (E) antigenic agents wife molecular patterns associated wife hehninthes, and (F)

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PCT/BR2018/000004 antigenic agents with molecular patterns associated wife prions, and one dr more physiologically acceptable carriers, excipients, diluents or solvents.
7. A method to modulate an immune system response in a human or an animal who has a bacterial infection comprising administering to the human or animal as effective amount of one or more IRS immunogenic compositions comprising a therapeutically effective amount of three or more synthetic antigenic agents or natural antigenic agents, or fractions and combinations thereof, comprising pafeogen-associated molecular patterns (PAMPS) and/or danger associated molecular patterns (DAMPS) selected from at least two groups consisting of: (A) antigenic agents with molecular patterns associated with bacteria, (B) antigenic agents with molecular patterns associated with viruses, (C) antigenic agents wife molecular patterns associated wife fungi and yeasts, (D) antigenic agents wife molecular patterns associated with protozoa, (E) antigenic agents wife molecular patterns associated with helmmthes, and (F) antigenic agents wife molecular patterns associated with prions; and one or mote physiologically acceptable carriers, excipients, diluents or solvents.