AU2018217441B2 - Immunogenic composition for modulating the immune system and methods to treat bacterial infections in a subject - Google Patents

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 FOR MODULATING THE IMMUNE SYSTEM AND METHODS TO TREATBACTERIAL INFECTIONS IN A SUBJECT CROSS-REFERENCE TO RELATED APPLICATIONS

This application is acontinuation-in-part of US.Patent Application Serial No. 4/006,077 filed October 23, 2013, wich is the National Phase of International Application No. PCT/BR2012/000072, filed March 19,2012, which designated the United States, which also includes a claim ofpriority under35 US.C. §119(a) and §365(b) to Brazilian patentapplication No. Pi 1100857-1 fied March 18,2011, the entirety of all applications is hereby incorporated by reference,

FIELD OF THE INVENTION

The present invention relatesto immunogenic compositions for modulating the immune system comprising a therapeutically effective amount of aImmunological Response Shifter (IRS) comprising two or moreimmunoactive antigenic agents presenting pathogenassociated molecular patterns (PAMPS) and/or danger associated molecular pattems (DAMPS) and/or Stress Response Signals (SRS) (1) and one or more physiologically acceptable carriers, excipients, diluents or solvents.

The compositions of the present invention comprise immunoactive antigenic agents presenting pathogen-associated molecular patterns (PAMPS) and/or danger associated molecular patterns (DAMPS) and/or stress response signals (SRS) (1) selected fromthe 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 molecularpatterns associatedwith fungi and yeasts; (D) antigenic agents with molecular patterns associated with protozoa; (E)antigenic agents with molecular patterns associated with multicellular parasites I or (F) antigenic agents with molecular patterns associated with prions.

BACKGROUND OFTHE INVENTION

From thepioneering discovery of antibiotics in the end of first half ofthe 20th century, new antibiotics, semi-synthetic antibiotics andnew cheinotherapeutics with antimicrobial activity, have been developed on alarge scale againstmost 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 infectious diseases,which racked humanity.

The discovery of antibiotics and other drugs

Thus,the discovery of antibiotics was a majormilestone, a watershed, because infection could be addressed and healed, in a specific way, with a clear relationship of cause and effect, and measurable when established. This discovery greatly expanded the abiityofhealingin

medicine,with enormouspositive impact on human health and lifespans The discoveryof antibiotics in the evolution and treatment of disease profoundly influenced the research and thinking of researchers from the success achieved by this experimental model (Reeves G, Todd I. Lecture notes onimmunology, 2nded: Blackwvell Scientific Publications, 1991; Neto VA, Nicodemo AC, Lopes HV. Antibidticos na prAtica mdica. 6th ed; Sarvier, 2007; Murray PR, Rosenthal KS, Pfaller MA. Microbiologia Mddica. 5th ed: Mosby, 2006; TrabulsiLIR, Alterthum . Microbiologia. 5th ed: AtheneuEditora, 2008).

Antibiotics were succeeded by the development and use of antifungal, antiparasitic 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 ve similar autologous neoplastic cells, with less specificity, less selectivity and less effectivity as: Antiaflergic; Anti-inflanmnatory; Anti-immune(Immunosuppressive); Anti-neoplastic (cytotoxic); and * Anti-hormone. Thus, thenew "anti" drugs brought an enormous capacity for medical intervention, with numerous benefits, with definitive and partial cures, with the prolongation of life inincurable 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

The innate immunity, in addition to preventing the entry ofmicroorganisms andpreventing their establishment has another recently discovered vital function: discrimination between "self' and "not 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., autoinunune diseases and allergic diseases, among others.

This dual capability was previously erroneously attributed exclusively to adaptive immunity. The innate immunity, through its own genninal receptors, recognizes invading pathogenic microorganisms, autologous or even allogeneic neoplastic cells, or allogeneic or heterologous transplants as "not self identifyingg them as not belonging tothe organism. From that moment, it triggers an alarm and joint innate and adaptive immune response to eliminate them or suppress a response deleterious to the human or animal organism (Goldsby RA, Kindt TJ, Osborne B.inunologia de kuby. 6 ed: ARTMED; 2008, 704 p; Janeway C,Travers P. Walport M,SihlonichikNiJ.1-nuunobiology five, 5 ed: Garland Pub.; 2001. 732 p4Voltarelli JC Imunologia clinica na pratica medica: athenen editora; 2009; Janeway CA, Jr., Medzhitov R. Innate immune recognition- Annual review of imnmunology. 2002;20:197-216. Epub 2002/02/28;MatzingerP. The dangermodel: arenewedsense of self.Science.2002;296(5566) :301-5. Epub 2002/04/16; Steinman RM,L BanchereauJ.Taking dendritic cells into medicine. Nature 2007; 449 (7161): 419-26.Epub 2007/09/28; Beutler BA. TLRs and innate immunity. Blood. 2009; 113 (7): 1399-407 Epub 2008/09/02; Moresco EM, LaVine D, Beutler B, Toll like receptors. Currentbiology: 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 cellsand the stromal cells, such as pericytes, dendritic cells, macrophages and fibroblasts, among others These cells, strategically distributed throughout the body, have PRRs (Pattem Recognition Receptors) and DRRs (Danger Recognition Receptors) and SRR (stress response receptors) which 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 identify viruses, starvation, ER stress and oxidative stress (Pulendran B Annual Review Immunology 2015).

The PER does not discriminate one specific individual nicroorganism, but the presence of microorganisms other than the human body. Each PRR receiver may bind to several different pathogens, recognizingas PAMPs (Pathogen Associated.Molecular Patterns) carbohydrates, lipids, peptides and nucleic acids from bacteria, viruses, ftngi 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 DRRsidentify DAMPs (Danger Associated MolecularPattems) associated with tissue damage by toxic substances,radiation, or trauma, which cause metabolic stress, release of free radicals and chemical changes intissue, 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 vaccinesamino acid starvation, ER(endoplasric reticulum) stress, oxidative stress, through evolutionary conserved stress sensing mechanism, that compose de Integrated Stress Response ISR as recently discovered (Janeway C, Travers P, alport M, Shlomchik MIniinunobiologv five. 5th ed: Garland Pub.; 2001. 732 p.; Matzinger P. The danger model: a renewed sense of self Science. 2002 ; 296( 5566): 301-5. Epub 2002/04/16; BeutlerBA.TLRs and innate immunity. Blood. 2009;113 (7): 1399-407. Epub 2008/09/02;Moresco EM, LaVine D, Beutler B. Toil-like receptors. Current biology: CB. 201L;21 (13) R488-93 Epub 2011/07/12) (1)

Thus, sentinel cells via theirEPRRs and their DRRs, and SRRs have a role in the breakdown of which belongs ("self)and which isdoes 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 and animal organism.

Immediately, these activated sentinel cellsgive alarm signals, triggering the innate immune response through the NF-kB (Nuclear Factor-kB) signal translation system, leading to the secretion of pro-inflammatory cytokines and the IRF signal translation system, that produces Type I alpha and beta interferons. These cytokines, togetheractingoncellsandvessels,causea local inflammatory process, initially to contain the invading agent, autologous (tumourcell), reterologous(microorganisms, prions,grafts and transplants) or allogeneic (grafts and transplants),or to repair danger situations. This contention happens through antibodies, pre existing, opsonizing acute phase proteins and through leukocytes and macrophages, which engulf and start to destroy the extracellular and intracellularmicroorganisms respectively, or eliminating other etiologic agents of any kind.

Interaction and integration of innate immunity with adaptiveimmunity

Simultaneously at the site of invasion, aggression and inflammation, theinnate immunity sentinel cells with the APC role (Antigen Presenting Cells), such as dendritic cells and macrophages, phagocytosis and pinocytosis microorganisms or tumour cells, or transplanted cells, 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 lympb nodes, activated and mature presentthe antigens to lymphocytes, release cytokines and thereby induce, coordinate, polarize, amplify and maintain an adaptive immune response specific to the invading genus, or neoplastic cells, or to transplanted cells, or other offending agent, allowing thentohefoughtand eliminated,where feasible and the consequent cure ofthe infectionor inflammation and repair and regeneration or wound healing (1) (3).

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

Thus, the interaction of the two immunities, innate and adaptive, in 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, but mainly by the activity of dendritic cells, as they are the ones that are able to initiate an adaptive immune response against a primary infectious or parasitic agent effectively protecting the body(2, 3). In secondary response memory, cells govern the silent immunological process that induce full protection (1,,2,3,14,26,354,56,57,58,65)

Macrophages also fnction as APC cells, but are more specialized and involved as part of the effector loop in phagocytosis and in theelimination ofmicroorganisms. B lymphocytes, when mature, are also APC cells and its most well-known action is the presentation of antigens to the T lymphocytes, within the famework of cooperation of both lymphocytes to produce antibodies against T-dependentantigen, and the secondary antibody 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 the defence of the organism because it suppresses the immune response and create a chronic infection or tumour facilitation.

When co-stimulatory molecules are not expressed on the APC cell surface, by the absence of the alarm signal characterized by the lack of activation ofPRRs, DAMPs and SRR by PAMPs, DAMPs and SRSs, only the first signal occurs, given by the TCR. After the TCR binds with the antigen, in the absence of the second signal, the Tlymphocyte becomes tolerant to the specific antigen shown and abortst he immune response.

On the other hand, the CD 40L molecule of activated T lymphocytes, when it binds to the CD40 molecule on the APC cells, significantly increases theexpression of CD80 and CD86 molecules, increasing the current response, which thus occurs only when the adaptive T response is already engaged in defending the body. The third signal given by cytokines such as IL-1, is given usually by the APC cells after the binding of co-stimulatory molecules and the emission of the second signal. The IL-1 releasedby the APC cells acts on lymphocyte cells and leads to the complete expression of the receptor for UL2 and to the production of IL2 and others polarization cytokines by virgin or memory lymphocytes engaged in response initiating clonal selection and expansion(primary) or memory clonal proliferation (secondary).

Therefore, the activation of innate inmunity by pathogens or by aggression is the key to unleashing the second and third signals and the occurrence of a potentially effective immunity through the full activation of T lymphocytes engaged in theresponse. Without the occurrence of thesecond and third 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 PAM[Ps with PRRs SRSs on antigen presenting cells (APC) 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 ertor, neffectormemoryCD4-CD4 L+cell migrate in a CD62P-dependent fashion into the reactive lymph nodes via HEVs and license dendritic cells for T cell priming against weak antigen, tolerate antigens and auto antigen starting an auto immune disease or improving an imnuneresponse in an ongoing infection or neoplastic disease(4) Also ininflammratory territories effector memory CD8 T cells secrete CCL3, that in turn activate MPCs to produce TNF alfa that induce PMNNs and Others MPCs to produce RAsand clear intracellular bacteria. Unrelated intracellular pathogen sensitive to ROls can also be clear by bystander activation in overlapping diseases or overlapping immune responses (67)

Themature 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 (1). Dendritic cells are the most potent cels 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 (23).

After a period of approximately seven days in the lymph node, the collaboration between blank CD4 lymphocytes CD4-ThO), which become T CD4'1T2 or Tt, with B lymphocytes and antigen presenting dendritic cells, initiates the differentiation of specific sensitized B lymphocytes. These B cells, now activated, recognize bacterial antigens bysurae nmmnoglobulins, collaborate with T helper cells, cells after contact with these antigens, 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, inactivated lymph nodes and after differentiation goes inside and induce germinal centre formation and secondary B cells responses with collaboration with CD4Tfh and others CD4Thelpers cells In secondary B cells responseslong lived plasma cells secrete Tell dependent antibodies in bore marrow, after initial productionin lymph nodes (1,6) (8, 9). Infections of all types, bacteria, 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 sequelac.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.

Polarization of the immune response

The classic immune profiles known and induced by dendritic cells by direct and indirect contact with the different cytokines and generated by T CD4 cells are of four types(l0-12):

a) cellular Thl profile, which generates cellular immunity mediated by cells;(13)

b) humoral Th2 profile, which generates humoral inummity mediated by antibodies(13);

c') tissue or inflammatory Th17 profile, which generates inflammatory tissue immunity, also mediated by cells and cytokines, which induce an important inflanmation forte elimination of certain pathogens, and(I13, 14)

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

e) New profiles have been established, as the Tfh (follicular Helper) ofthe humoral response (16),the Th9 profile for eertain parasiteslikeHelminths (I7);Th22that produce IL22 involved in Skin protection (17) or other profiles that may be discovered or no fully established(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, the safe return to noralcy and it prevents self-injury and allergy and is therefore vital to the health and preservation of the human species and animal, as much as the other profiles.

The phenomenon of polarizationof the immune response is defined as the predominance of a certain immunological profile such as Th or Th2 at the expense ofother profiles that become secondary or null. This phenomenonhappens according to tie type of attack suffered by the body. That is, according tothe type ofinfection, pathology, and infection stage or pathology stage, the different type of immune response will be predominant, and it may be a ellular, humoral, tissue inflammatory, or immune-regulatory response, whie other types of immune responses are inhibited, resuming inthe phenomenon of polarization,(12)

By definition, there is a dominant profile in polarization, but othernon-dominant profiles are also needed, and expressedin a complementary manner-that will help eliminating the disease. For example, tuberculosis is the appearance of Th17 cells in the lung which allows Thl cells to settle and may lead to cure this infection in thelung parenchyma (Stockinger, B. and Veldhoen, M. Differentiation and function of ThIl7T cells. Current Opinion in Immunology, 19 (3), pp. 281-286. 2007). In viral infections, the CTL cells ofTh1profile destroy cells infected by viruses, 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 the two profiles is essential for the healing of certain viral infections. Certain intestinal infections by extracellular Gram-negative bacii require, for its cure, in the final stage, besides the Tfh and Th2 profile, the generation of asupplementaryTh7 profile capable of generating a strong inflammation, necessary to eliminate this type ofbacteria(12)

In conclusion, due to the fact that the denditic cells are the only professional APC cells capable to mitiate a primary adaptive immune response and are the most potent in triggering a secondary specific immune response, in any profile, they arethen conunanding the interaction and

integration of imate immunity with 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 with different aggressors in different functional states, in the inflammation sites, in the lymph nodes, in the spleen, in the mucous membranes, are able to lead coordinate, polarize, and amplify the adaptive immune response governing them, primary and secondary, e.g., specific for the peptides of invading pathogens, which in this case is the most appropriate for the removal ofthe ongoing infection(1,2,3).

Therefore, dendritic cells and other APC cells are key cells of the innate amune response, since they evaluate the nature of the autologous and heterologous causative agent,i1e, the type of pathogen or colonizing cells and aided by the sentinel cells, 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 intensity required for the elimination of the pathogenM In other words, innate immunity contextualize the aggression in a primary response and recontextualize in a secondary effective one by the action of T B and someN'K memory cells (19) (20) (8, 9, 20-31)

After differentiation, a re-differentiation can occur,induced by the nncroenvironment and/or the type of antigen or its presentation, inwhich a Thi or Th2 profile canbeexchangedforan inflammatory profile or an uimunosuppressant profile or vice versa. This 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 with massive inflammation caused by cytokine, induced by the large number of microorganisms which touch the sentinel cells throughout the body, induces also a Th17 a profile, which in turn increases the inflamation more and therefore becomes detrimental, leading to tissue destruction, rather than inducing healing and paradoxically inducing late immunosuppression by theTreg/TrIprofile and exhaustion state . In these cases the Th7 profile, by tissue destruction and the amplification of inflamnation-is implicated in the generation of clinical complications such as severe ARDS (acute respiratory distress syndrome in adults), lung shock, renal failure, or shock, that compromiseshealing (4, 33, 34

The re-differentiation of polarization for the TN or Th2 profilesxwith the inhibition of massive inflammation, is the logical and strategic path for a designed or prepared inunotherapy 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 other antimicrobials, in current pattems such as single mode, have disappointing anti-infective results. The same example applies to seriousintra cellar bacterial, fungal,viral and parasitic infections, with extensive tissue destruction and massive inflammnation,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 iuneue response. These adjuvants used since the daw-n of immunology, in immunizations and in vaccine applications, were and are made up of parts of microorganisms, mineral oils and other substances that activate the innate immunity, which then gives the alarm and control necessary for the development of desired immune response to the protein or to the vaccine in question (GOLDSBY RA, K1NDT TJ OSBORNE BA IMUINOLOGIA DE KUBY. 6 ed: ARTMED; 2008. 704 p); (Janeway C, Travers P, alport M SlbomchikMJn Immunobiology five. 5 ed: GarlandPub.; 2001. 732 p.); (VOLTARELLI JC .IM.NOLOGIA CLINICA NA PRATICA MEDICAL: ATHENEU EDITORA; 2009); (Janeway CA, Jr., Medzhitov R. Innate immune recognition. Annual review of immunology, 2002;20197-216. Epub 2002/02/28.); (MatzingerP. Thedangermodel: renewed sense of self Science.2002; 296 (5566):301-5 EpubA2002/04/16.): (Steinmian RM, Banchereau J. Taking dendritic cells into medicine. Nature. 2007; 449 ( 7161): 19-26. Epub 2007/09/28.); (Beutler BA. TLRs and innateimmunity. Blood. 2009; 113 (7 ): 1399-407.Epub 2008/09/021.); (Moresco EM, LaVine D, Beutler B Toll-like receptors. Current biology : CB 2011 ; 21 ( 13 ):R488-93 Epub 2011/07/12)

It should be noted that the use of adjuvants for fimnization, 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 century, its role in theinnate immunity in the discrimination of what is "Self 'and not "Self and its unique and fundamental capacity to the survival of thehuman species and animals: to give the alann signal and the command tostart or not start, or inhibit an integrated, protective or healing, innate and adaptive, immune response (GOLDSBY RA, KINDT TJI, OSBORNE BA. MUNOLOIADE KUBY.6 ed: ARTMED; 2008. 704 p); (Janeway C, Travers P, Walport M, Siblomchik MI.mmunobiology five.5 ed: Garland Pub. 2001 .732 p.) ;(VOLTARELLI JCIMUNOLOGIA 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): (Stinmian RM Banchereau J. Taking dendritic cells into medicine.Nature. 2007; 449 (7161 )419-26 Epub 2007/09/28.); (Beutler BA. TLRs and innate immunity. Blood. 2009; 113 (7 ):1399-407. Epub 2008/09/02); (Moresco EM.LaVineD, Beutler B. 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 monotherapeutic approaches. (Reeves G, Todd L Lecture notes on-immunology. 2nd ed: Blackwell Scientific Publications, 1991; Neto VA,Nicodeno AC, Lopes'HV. Antibioticos na pratica medica.6th ed: Sarvier, 2007; Murray PR, Rosenthal KS,Pfaller MA. Microbiologia Mdica. 5th ed: Mosby, 2006; Trabulsi LR, Alterthum F Microbiologia. 5th ed: Atheneu Editora, 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 focusedonnewantimicrobialdrugs, drugs that prevent microbial resistanceand new medicines or biological agents to inhibit or control pro-inflammatory and immunosuppressive 4 microenvronnients, andvaccines(34- 1)

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

However, in the in vivo correlatedsituation, there are also 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 antibioticthat 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 with components and 3 variables, They are not scientifically comparable and the conclusion invitro cannot be translated to the in vivo system toexplain cure.

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

In strong support of this view, the immune system is deficient in the extreme of ages, dysfunctional in elders and immature in the 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 inthe case of severe secondary inmune deficiencies, like terminal AIDS, terminal oncologic patients, other terminal immune compromised patients and in terminal severe primary immune deficiencies of any kind, cure with antimicrobial drugs are not possible. In the immune compromised host, the antibiotics are used in higher doses compared to the immune competent patient for the very same clinical or veterinary condition. In the undeveloped world, where most of human population lives, malnutrition compromises the fitness and functionality of the immune system

The lack of sewerage and drinkable water supply submits these populations to constant aggressions by innmerable pathogens, compromising the effiiency of the defece system and provoking disease. This constant aggression and frequent illness create an unhealthy positive feedback loop, compromising continuously the irmnunesystem and health. Finally the lack of protection from environment aggression also weakens the body and immune system,These three conditions combined in a synergy way also create an unhealthy positive feedback loop, 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 andadaptive responses that onlyfinish 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 in 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 possiblewithout antimicrobial drugs.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,Nicodemo ACLopes H. Antibidticos na pratica m6dica. 6th ed: Sarvier, 2007; Murray PR, Rosenthal KS, Pfaller MA, Microbiologia Medica. 5th ed: Mosby, 2006; Trabulsi LR, Aterthum F. Microbiologia,5th ed: Atheneu Editora, 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 host x pathogen competition, that favours the host immune system in amultivariable context. The variables are: concomitant diseases, traumas, age, sex, race, psychological health, innate and adaptive immunity,metabolism, nutrition, physiological flora microbiota, enviromnental aggression by drugs, and exposure toradiation, 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 competition 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 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 infections/inflammatory syndromes, such as sepsis or septic shock deserves some 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 the 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/inflammation 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 the clearance of the pathogen and at the same time having an physiological beneficial anti-inflammatory action during the course of the treated disease.

Any reference to or discussion of any document, act or item of knowledge in this specification is included solely for the purpose of providing a context for the present invention. It is not suggested or represented that any of these matters or any combination thereof formed at the priority date part of the common general knowledge, or was known to be relevant to an attempt to solve any problem with which this specification is concerned.

For the avoidance of doubt, in this specification, the terms 'comprises', 'comprising', 'includes', 'including', or similar terms are intended to mean a non-exclusive inclusion, such that a method, system or apparatus that comprises a list of elements does not include those elements solely, but may well include other elements not listed.

SUMMARY OF THE INVENTION

In a first aspect, the invention relates to a pharmaceutical composition comprising one or more antibiotics and: (a) i. 0,0036 ng/mL Koch's Turberculin (inactivated Mycobacterium bovis lysate); ii. 0,0036 pg/mL PPD; iii. 6.31 pg/mL Inactivated Staphylococcus lysate (Staphylococcus aureus and

Staphylococcus epidermidis in equal parts); iv. 6.31 pg/mL Inactivated Steptococcus lysate (Streptococcuspyogenes, Streptococcuspneumoniae and Enterococcusfaecalisin equal parts); v. 0.404 pg/mL Streptokinase derived from inactivated beta-hemolytic Streptococcus lysate purification; vi. 0.101 pg/mL Dornase derived from inactivated beta-hemolytic Streptococcus lysate purification; vii. 6.31 pg/mL Oidiomycin (antigenic extract of Candida albicans); viii. 6.31 pg/mL Trichophytin (antigenic extract of Tricophyton sp); ix. 6.31 pg/mL Inactivated enteropathogenic Escherichiacoli lysate (EPEC); x. 6.31 pg/mL Inactivated Salmonella lysate (Salmonella bongori, Salmonella enterica and Salmonella subterraneain equal parts); xi. 20 pg/mL Attenuated yellow fever virus strain 17 D204; xii. 7.5 mg/mL Sodium Chloride; xiii. 0.48 mg/mL Sodium phosphate dibasic heptahydrate; xiv. 0.06 mg/mL Potassium phosphate monobasic; xv. 2.5 mg/mL Phenol; and xvi. Water; Or (b) i. 0,004 ng/mL Koch's Turberculin (inactivated Mycobacterium bovis lysate); ii. 0,004 pg/mL PPD; iii. 6.94 pg/mL Inactivated Staphylococcus lysate (Staphylococcus aureus and Staphylococcus epidermidis in equal parts); iv. 6.94 pg/mL Inactivated Steptococcus lysate (Streptococcuspyogenes, Streptococcuspneumoniae and Enterococcusfaecalisin equal parts); v. 0.444 pg/mL Streptokinase derived from inactivated beta-hemolytic Streptococcus lysate purification; vi. 0.111 pg/mL Dornase derived from inactivated beta-hemolytic Streptococcus lysate purification; vii. 6.94 pg/mL Inactivated Candida lysate (Candida albicans and Candidaglabratain equal parts); viii. 6.94 pg/mL Inactivated dermatophytes lysate (Epidermophytonfloccosum,

15a

Microsporum cannis, Trichophyton mentagrophytes of the interdigitale variety in equal parts); ix. 6.94 pg/mL Inactivated enteropathogenic Escherichia coli lysate (EPEC); x. 6.94 pg/mL Inactivated Salmonella lysate (Salmonella bongori, Salmonella enterica and Salmonella subterranea in equal parts); xi. 7.5 mg/mL Sodium Chloride; xii. 0.48 mg/mL Sodium phosphate dibasic heptahydrate; xiii. 0.06 mg/mL Potassium phosphate monobasic; xiv. 2.5 mg/mL Phenol; and xv. Water.

In a second aspect, the invention relates to a method of treating sepsis and multi resistant bacterial infection in a human or an animal comprising administering to the human or animal an effective amount of the composition of the first aspect.

In a third aspect, the invention relates to use of the composition of the first aspect in the manufacture of a medicament for treating sepsis and multi resistant bacterial infection in a human or an animal.

In general, the invention relates to 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.

The present invention also relates to 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(1) and one or more physiologically acceptable carriers, excipients, diluents or solvents.

The present invention further relates to 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

15b molecular patterns (DAMPS) and/or stressresponse 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 agentsxwith molecular pattems associated with fingi 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 for real-time replacement of an innefective immuneresponse with an effective immune response.

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

Real-time replacing the ineffective immuneresponse 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 ofthe disease.

The basis of these phenomenonis the established immunological memory phenotype in'T and B lymphocytes and, also to a lesser extent in NK cells (7-21)), as recently demonstrated. Altogetherthese cells may induce inflammatory innate and adaptive responses in the second contact with the 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 infectious diseases.

Revisiting the paradigm of Pasteur, we can take as a model two of the mosteffective preventive virus vaccines ever developed against invariable pathogens: smallpox and yellow fever (Y 17D), The first eradicated smallpox until now and the second led to the development of protective immunity that could lastrore than 35 years, after a single dose. A series of detailed modem scientific studies with YF-I7D Yellow Fever vaccine in system biology and system vaccinology, demonstrated that virus, make contact with a wide range ofsentineland professional APC innate cellsactivating the same. Activating also multiple DC subsets by the stimulation of multiple PRRs, DRRs, stress response receptors by multiple PAMPs and DAMP, 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 cell activation that leads to an also complex and multiple synergic DCs activation in multiple inflammatory and lymphoid territories lead to asystemic CD4T-il, CD4 TH2, CTL CD8 and B cell and antibodies polyclonal effective responses that abrogate the viremia and make the inactivation and clearance of the virs and infected cells letting them without the capacity to recycle and to perpetuate themselves in environment (42).

Some malfunction of the immune system due to rare genetic defects can giverise to an also rare vaccine disease that is in general very severe or even fatal, proving father evidence that the elimination ofthe vaccine virus as amatter of competition between host immune systemand virus in a beneficial induced disease and not as asinglevaccineimmunization(43). The activation context in a systemic subclinical disease is huge and complete different than a single repeated immunization with antigen vaccine theseis one of the reason of the high effectivity of these two vaccines(l) (44-50)

In conclusionan aggressive wildtype virus would affect thehost-pathogen balance in a different way than a vaccine virus, leading to a severe disease in one ase 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 of the underlying disease (42, 51). 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 activation induced by the overlapping of an effective unrelated specific immune response is the best way known to rescue a state of tolerance, immunosuppression or anergyto a state of normal response (52).

In the same way, experiments with mutagenesis transfoing lowintohighimmunogenic

tumouts induce tumour 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 effectormemory T specific CD4+ CD40L+ migrate in a CD62Pdependent fshion into the reactive lymph nodes via HEVs and license dendritic cells for T cell priming against weak antigen, tolerate antigens andautoantigenstartinganauto immune disease or improving an immune response in an ongoing infection or neoplastic disease (4, 52. 55) Effector Memory CD8 T cells release CCIthat in tum activateMPCs to produce TNF alfa 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 theintestinal flora intervenes and can determine the effectiveness of agiven vaccination.

These situations, studied in 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 CD8 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 the context ofthe design of new therapeutic approach.

Such important points of observations are:

I- The immune system is reactive and not proactive and it has a unique huge response potential but oniy 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 competition balance and even if is efficient they arenot the best possible response In conclusion, a primary immune response is always a fortuitous reply possible to be improved

The best possibleresponse, or protection, occurs only in secondary response due to effective memory formation after the cure of a severe disease ore effective vaccmation. Thus, memory cells ar keyingenerating protective inmunity.

3- The innate response is not specific by its own nature and can hold multiple specific adaptive responses at the same time and inthe same territories with synergic or antagonist effects Because human and animal organisms canhold multiple aggressions at the same time and even in the same territory, the sinks of the innate immunity receptors recognition system recognizeanexpandable and changeable universe ofPAMPs, DAMPsand StressSignals 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 themechanism of protection induced by YF-I7D vaccine the rational logistic to activate the innate immunity effectivelyparadoxically 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 with multip 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 circuscribe the pathogen in a pro inflamnatory environment until an ecfitive adaptive response takes place. The primary adaptive response in acute infection is also pro-inflammatory. 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

The secondary innate and adaptive effective responses are provided by T B memory cells and in some circumstances byNK memory cells that give a faster, correctly polarized, more accurate, quiet, low inflanmatory and protective immune response, when available. These modified secondary adaptive immune responsesfor its anti-inflanunatorynature had to the cells memory can effectively deal withsystemic 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 corporatefor-the same cells sentries, APCs,with the release ofcommon cytokines, common chemokines and will be in the same activated lymph nodes, and inflanmatory territories all the scene are battle context will be the same for the to 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 the primary responses to shift to a low inflammatory pattern in a target memory modified territory,

8- Also .theseeffects can be obtained by the injections of amix of PAMPs andsecondary antigens to cognate memory cells that induce a secondary immune response and activate optimally PMCs and PMNNs to clearance bacteria sensitive to,ROs and other mechanism and activate optimally lymph nodes and improve ongoing immune response or can induce a poor or tolerated or no immunogenic one,

In conclusion, the immune system is reactive and not proactive and the quality and effectiveness ofthe natural immune response depends mainly of two factors:

- First factor is the existence or not of an immunological effective specific memory thatit determies a secondary or a primary imumunresponse, In the case of a secondary response die best possible response 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 inimune system cannot improve by itselfan already ongoing primary immune response and the answer for the question of how tochange 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 immuneresponse. In a primary immunological reply, there are only oneremainder factor that is the context of the host x 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 the host x pathogen competition like describe and proposal above. By this actionthe antimicrobial drug alter positively the host pathogen equilibrium balance and the outcome but don't alter the nature of the ongoing primary response. Following this rational analysis, it would be enough to changing the 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 sste in a primary response that depend mainly on the pathogen immunogenicity and action and on the fitness ofthe immune system, open the door for a proactive medical immune intervention that can use all the remainder vast immune potential of available reply to change the host x parasite competition balance in favour ofthehost with a new 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 effetive IR for positively alter the context of host x parasite competition and the outcome.

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

This new perceived identity may be built in all disease's lymphoid sites or not, or even inflammatory territories, in controlled periods,that naturally will change completely the activation by a secondary huge one. Now with a new best secondary activation for the ongoing disease the immune system could reprogram the immune response based mostly in secondary well known antigenic deteminants with a minority of primary determinants deriving from the aggressive pathogen that will generate a complete new different effective specific and well polarized immune response. The best possible one will be generated with secondary tracts in the secondary resetting low inflammatoryteitories.

The sum of the total effective anti-inflammatory secondary response to the new created image of the aggressor pathogen could revert all the induced tolerance, anergy, scape mechanismand could also inducea immune response to all the weak antigens or subdominartepitopestocreate the best possible efFective response in a totally different poor inflammatory battlefield,that

create a complete new host x parasite competition balance in favour of the host. To reach this goal is necessary to create a new ES Equilibrium Shifter an IRS (munological 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

This new IRS for the proactive action of the proposed and planed immunotherapy must be constituted by avast 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 in all the territory of the 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 3 to 5 days, 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 full identified by the innate and adaptive immunity in his most part as a secondary and well know aggressor by memory effective cells thatwill induce the best available immune response replacing the initial one. Changing the inner image of the pathogen picked-up by innate and adaptive memory cells we proactively change the context ofthe host x pathogen competitionnow in favour of the host. The reactive immune systemactivated excellently by the proactive immunotherapy will real time reprogram, reset and leads back the best available secondary anti-inflammatoy specific immune response against the etiologic agent reverting his initial advantage in an ongoing illness,

Forthe proof of concept thatanew perceived image of the exogenous orendogenous pathogen by an innovative IRS may real time govern, reset and lead back an already established pathological response we use some compassionated cases of reversed lethal irreversible sepsis mostly with multi-resistant rmcroorganismsout of the scope of the best available antibiotics used in combined fashion.

The following positive significant results of this clinical cases shown in theExamples prove and suggest that it is possible real time goveming, resetting, leading back the immune system and create new secondary effective, anti-inflanunatory immune responses during the treatment of a disease by replacing the initial exaggerated- ineffective, improper ore deleterious primary immune response one by proactively creating a new image of theaggressorpahogen.

This is the first demonstration that is possible to govern, resetand lead back an ongoing immune response in v/va in favour of the host altering positively the host x pathogencompetition balance, as well as the outcome, and also having a significant synergic effect withantimicrobial dmgs,

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

DEFINITIONS

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

oiRS- Immunological Response Shifter

* BCG refers to attenuated Mycobacterium bovis, Bacille Calmtte-Guerin

* DAMPS refers to danger associated molecular patterns;

* DECA refers to the IRS composition Ia describedin Example I of the present patent application;

oCM-CSF refers to"Granulocyte macrophagecolony-stimulating factor";

•PAMPS refers to pathogen-associated molecular patterns.

* PFU: plaqueformingunits

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

PPD refers to the fiction of the purified protein extract culture of Kochs bacillus ("Purified Protein Derivative"). 'The PPD is the majorantigen 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 inactivatedMycobacterium bovis lysate;

Units Lfor"Limes flocculation units" is theitemational unit for qantiing antigensin toxoid vaccines accepted by the World.Health Organization;

•VITER: The IRS composition l described in Example 1.

oISR: Integrated Stress Response

SRS: Stress response signals

• SRR: Stress response receptors

o ES: equilibrium shifter

DETAILED DESCRIPTION OF THE EMBODIMENTS

In a first embodiment, the invention refers to a pharmaceutical product comprising one or more antibiotics with one or more immunogenic compositions for modulating the immune system comprising a therapeutically effective amount ofthree or more (eg, 3 4, 5, 6, 7, 8, 9, 10, 1, 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 pattems (PAMPS) and/or danger associated molecular pattems (DAMPS) selected from at least two groups consisting of (A) antigenic agents with molecular patterns associated with bacteria. (B) antigenic agents with molecularpatterns 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 helminthes, and (F) antigenic agents with molecular patterns associated with prions; and one or more physiologically acceptable carriers, excipients,diluents or solvents.

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

The one or more antibiotics comprised in the pharmaceutical product ofthe invention may be selected from the following classes: Amino Acid Derivaties,Aminoglycosides, Aureolic Acids, Aziridines, Ansamycins, Benzenoids, Carbapenems, Cephalosporins, Coumarin glycosides, Diphenyl Ether Derivatives,Epipolythiodioxopiperazines, FattyAcid Derivatives, Glucosamine, Glycopeptides. Imidazoles, indol Derivatives, Lpopeptides Macrolactams, Macrolides, Nucleosides. Penicillins and Cephalosporins (beta-Lactams), Peptides, Peptidyl Nucleosides, Phenicoles, PolyenesPolyethers, Pyridines and Pyrimidines Quinolones and Fluoroquinolones, Stains, Steroids, Sulfonamides, Taxoides and Tetracyclines

Preferably the immunogenic compositions of the present invention comprise immunoactive antigenic agents presenting pathogen-associated molecular patterns (PAMPS) and/or danger associated molecular pattems (DAMPS) selected frorn the group consisting of (A) antigenic agents with molecularpatternsassociated with bacteria; (B) antigenicagents with molecular patterns associated with viruses; (C) antigenic agents 'withmolecular patterns associated with fungi and yeasts; (D) antigenic agentswith molecular patterns associatedwith protozoa; (E) antigenic agents with molecular patterns associated with multicellular paasites /or (F) antigenic agents with molecular patterns associated with prions.

Stillmorepreferablytheimmunogenic compositions of this invention include pathogen associated molecular pattens (PAMPS) and/or danger associated molecular patterns (DAMPS) selected from among at least three categories (A), (B), (C), (D ), (E) and (F) described above

More preferably, the immunogenic compositions of this invention include pathogen-associated molecular patterns (PAMPS) and/or danger associated molecular pattems (DAMPS) selected from among at least four categories (A)(), (), (D), (1E) and (F) described above

Antigenic agents of the present invention can be selected from epitopes, genetic materials, lipids, polysaccharides and/or immune activeproteins 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, preferably derived from viral, fungal, parasitic or bacterial prionstrains

Thus, the antigenic agents of the present invention with molecular pattems associated with bacteria of the present invention may be selected from, but not limited to antigenic agents with molecular patternsassociated with bacteria of the genera Staphylococcus, Streptococcus, Enterococcus, Corynebactenum, Bacillus, Listeria Clostridium, Mycobacterium, Actinomyces, Nocardia, Escericia,Proteus,Klebsiella, Serratia, Enterobacter, Salmonella, Shigella, Pseudomonas, Burkholderia, Stenotrophomonas, Acinetobacter, Virio, Campylobacter, HelicobacterBacteroides, Neisseria, Moraxella, Haemophilus, Bordetea, Brucella, Francisella, Pasteurella, Yersinia, Legionella, Gardnerella, Treponema, Leptospira Borrelia, Mycoplasma, Rickettsial and Chlanydia

Antigenic agents with molecular pattems associated with virus of the present invention may be selected from, but not limited to antigenic agents with molecular pattems associated with virus families Adenoviridae Arenaviridae Bunvaviridae, CoronaviridaeFiloviridac, IFlaviviridae, Hepadnaviridae, Deltavirus, Caliciviridae, Herpesviridae, Orthomyxoviridae, Papovaviridae, Paramyxoviridae, Parvoviridae, Picomaviridae, Poxyvirida, Reoviridae, Retrovirdae, Rhabdoviridae and Togaviridae.

Antigenic agentswithmolecular pattens associated with fungi and yeasts of the present inventionmay be selected from, but not limited toantigenic agents with molecular pattens associated with fungi and yeasts of the genus Sporothrix, Aspergillus, Blastormyces, Candida, Coccidioides, Cryptococcus, Histoplasma and Pneumocystis,

Antigenic agents with molecular pattems associated with protozoa of the present invention may be selected from, but not limited to antigenic agentswith molecularpatterns associated with protozoa of the genera Cryptosporidium, Ciciospora, Enamoeba, Naegleria, Giardia, Leishmania, Pasmodium, Toxoplasma, Trichomonas, Tiypanosoma, microsporidia and Isospora,

Antigenic agentswith molecular patterns associated with multicellular parasites of the present invention may be selected from, but notlimited to antigenic agents with molecular patterns

associated with multicellular parasites trematodes, cestodes and nematodes.

he antigenic agents of the presentinvention comprise protein, polysaccharide, lipid molecules and/or composite synthetic molecules that mmic protein polysaccharide and/or lipid molecules.

More specifically, the agents of the invention comprise immune-active antigenic protein moleculeswhichhaveenzyeactivity, for example kinases, phosphatases, streptoquinases. estreptodornases and Deoxyibonucleases (e g. dornases)

The immunogenic compositions for modulating theimmune system of the present invention comprise from 0,001 to 500 micrograms permlofeachimmunogeniagent.

Such inmmogenic agents can be encapsulated in capsules, micro particles, nanoparticles, coated tablets, liposomes,

Specifically, the imumogenic compositions for modulating the immune system of the present invention comprise from 4 to 20 antigenic agents selected from the group consisting of antigens derived from agents: domase, levedurin, oidiomycin, PPprios streptouinase, Streptococcus toxoid, diplitheria toxoid, Tetanus toxoid, Koch's tuberculin, inactivated lysate of Ascaris lumbricoides. Aspergillus spp., Aspergillus flavus, Aspergillus famigatus, Aspergillus terreus, Candida spp. Candida albicans, Candidaglabrata, Candida parapsilosis, Chlamydia spp., Chlamydia pneumoniae, Chamydia psittaci, Chlamydia trachomatis Cryptosporidium spp., Dermatophytes, Entamoeba hystolitica, Enterobius vermicularis, Enterococcus faccalis, Epidermophytonfloccosum, Escherichia col, Giardia lamblia, Haemophilus influenzae, Microsporun canis, Mycobacteriu spp., Mycobacterium bovis,Mycobacteiumleprac, Mycobacterium tuberculosis, Neisseria gonorrhoeae, human papilloma virus, Polio virus, Proteus spp.,Proteus mirabilis, Proteus peneril, Proteus vulgaris, Salmonella spp., Salmonella bongori, Salmonella enterica, Serratia spp., Serratia liquefaciens, Serratia marcencens, Shigella spp. Shigella flexneri, Shigella sonnei, Staphylococcus spp ,Staphylococcus aureus, Staphylococcus epidermidis, Strongyloides stercoralis, Streptococcus spp., Streptococcus bovis Streptococcusviridans, Streptococcus equinus, Streptococcus pneumoniae, Streptococcus p'ogenesToxoplasmagondii, Trichomonas vaginalis,tichophytin, Tchophtonspp,

Trichophyton rubrm, Trichophyton tonsurans, Trichophyton mentagrophytes, yellow fever virus hepatitis B virus, rubella virus, varicella zoster virus, variola virus, mumps virusmeasles virusherpes virus and vaccinia virus or synthetic analogues that present pathogen-associated molecular patterns (PAlIPS) and/or danger-associated molecular pattems (DAMPS) associated withese antigenic agents

In varioue embodiments, the immunogenic compositions for modulating the immune system of the present invention comprise 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 1 16, 17, 18, 19, or 20 antigenic agents selected from the group consisting of antigens derived from agents: dornase, levedurin, oidiomycin, PPD, prions, streptoquinase, Streptococcus toxoid, diphtheria toxoid, Tetanus toxoid, Koch's tuberculin, inactivated lysate of Ascaris lumbricoides, Aspergillus spp., Aspergillus flavus, Aspergillus fumigatus, Aspergillus terreus, Candida spp, Candida albicans, Candida glabrata, CandidapaapsilosisChiamydiaspp., Chiamydia pneumoniae Chlamydia psittaci. Chlamydia trachonatis, Cryptosporidium spp., Dermatophytes Entamoeba hystolitica, Enterobius vermicularis, Enterococcus faecalis, Epidermophvton floccosun, Escherichia coli, Giardia lamblia, Haemopailus influenzae.Microsporum cannis, Mycobacteriumn spp., Mycobacterium bovis, Mycobacterium leprae, Mycobacterium tuberculosis, Neisseria gonorrhoeae,himan papillo-ma virus, Polio vims, Proteus sppProteus mirabiis,Proteus penerii, Proteus vulgaris, Sahnonella spp. Salmonella bongori, Salmonella enterica, Serratia spp., Serratia liquefaciensSerratia marcencensShigella spp. $higella flexneri, Shigella sonnei, Staphylococcus spp, Staphylococcus aurus, Staphylococcus epidennidis, Strongyloides stercoralis, Streptococcus spp. Streptococcus bovis, Streptococcus viridans, Streptococcus equinus, Streptococcus pneumoniae, Streptococcus pyogenes, Toxoplasm gondui,Trichomonas vaginalis, trichophytin, Trichophyton spp. Trichophyton rubrumTrichophytontonsurans,

Trichophyton mentagrophytes, yellow fever virus, hepatitis B virus, rubella virus, varicela zoster virus, variola virus, mumps virs, measles virus, herpes virus and vaccinia virus or synthetic analogues that present pathogen-associated molecular patterns(PAMPS) and/or danger-associated molecular pattems (DAMPS) associated with these antigenic agents.

A preferredimnmunogenic composition of the inventioncomprises inactivated Myobacterium bovis lssate, purified protein derivative of M. tuberculosis, inactivatedStaphylococcusaureus

lysate, inactivated Staphylococcus epidermidis lysate, inactivated Steptococcus pyogenes lysate, inactivated Streptococcus pneumonia lysate, inactivated Enterococcus faecalis lysate Streptokinase/dornase, inactivated Candida albicans lysate, inactivated Candida glabrata lysate, inactivated Epidermophyton floccosumlysate, inactivatedMicrosponan cannis lysate, activated Trichophyton mentagrophytes of the interdigitale variety lysate, inactivated enteropathogenic Escherichia coli lysate, inactivated Salmonella bongori sate, inactivated Salmonella enterica lysate and inactivated Salmonella subterranea lysate.

A preferred imnaunogenic composition of the invention comprising from 0.001 to I ng/ml of inactivated Mycobacterium bois lysate, 0.001 to I ng/ml of purified protein derivative of M. tuberculosis 0,1 to 100pg/mil of inactivated Staphylococcus aureus lysate, 0.1 to 100 Pg/mI of inactivated Staphylococcus epidemidis lysate; 0-1 to 100 sg/ml of inactivated Steptococcus pyogenes lysate; 0. to 100 g/ml of inactivatedStreptococcus pneumonia lysate; 0.1 to 100 pg/ml of inactivated Enterococcus faecalis lysate, 0.01 to 10 pg/ml of streptokinase, 0.01 to 10 gg/l of dornase; 0.1 to 100 pg/m of inactivated Candida albicans lysate; 0. 1 to 100 pg/mIl of inactivated Candida glabrata lysate, 0. to 100 g/m ofinactivated Epiderrophyton fIoccosun lysate; 0 1 to 100 pg/ml of inactivated Microspoum ncannis lysate, 0.1 to 100 pg/ml of inactivated Trichophyton mentagrophytes of the interdigitale variety lysate; 0. 1 to 100 pg/nl of inactivated enteropathogenic Escherichia coli lysate; 0. to 100 g/ril inactivated Salmonella bongori lysate, 0 1 to 100pg/ml inactivated Salmonella enterica lysate and 0.1. to 100 pg/mil of inactivated Salmonella subternmea lysate.

The compositions of the present invention can further comprise excipients, such as bactericides, bacteriostats, antioxidants, preservatives, buffers,stabilizers, pH adjusters, osiolarity adjusters, antifoamning 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 inventionmay be a solid, liquid or gel.As used herein, the use ofthe termpharmaceutically acceptable carrier" means a non-toxic solid, inert'semi-solid liquid excipieat diluent auxiliary formulationofanytype,orsimplyasterileaqueous solution such as saline. Some examples of materials which can serve as phannaceuticaly acceptable carriers are sugars such as ]actose, glucose and sucrose, starches such as cor starch and potato starch, cellulose and its derivatives such as sodium carboxymethyl cellulose, a ethyl cellulose and cellulose acetate cyclodextrin; oils such as peanut oi, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soya bean oilglycols such as propylene glycol, polyols such as glycerol sorbitol mannitol and polyethylene esters such as ethyl larate, ethyl oleateagar, buffering agents such as aluminum hydroxide andmagnesium hydroxide, alginic acid, pyrogen free water, isotonic saline , Ringer's solution, buffer solutions of ethyl alcohol and phosphate as well as other non-toxic compatible substances used in pharmaceutical fornulations.

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 antigen ts, the dosage required for therapeutic efficacy and patient to whom the composition is administered. The methods of the present invention cangenerally be practiced using any mode ofadministration biologically acceptable, i.e., any means that produces effective levels of immune response without causing clinically adverse reactions. Such modes of administration include intradernal, oral, rectal, sublingual, topical, nasal. transdermal or parenteral administration. The term "parenteral" includes subcutaneous, intravenous, epidural, irrigation, intramuscular, release pumps or infusion. In particular, in this invention, oral, intradermal, parenteral, subcutaneous, intravenous, intranuscular, 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 carrier and administered as a solution, emulsion. including micro-and nano-emuisions or suspension. Examples of suitable carriers are water, salinedextrose solutions, fructose solutions or oils of animal, vegetable or synthetic origin. Other vehicles may also contain other ingredients, for example, preservatives, suspending agentssolubilizing agents, buffers and the like,

In a second embodiment the invention refers to a method to treat sepsis in a human or an animal who has a bacterial infection comprising administering to theumanoranimalan effective amount of one or more antibiotics and one or moreinmunogenic compositions for modulating the imnune system comprising a therapeutically effective amount of three ormore (e.g, 3 4 5,6, 7, 8, 9 10, 11,12 13, 14, 15,1617, 18,19, or 20 or more) syntheticantigenic agents or natural antigenic agents, or fractions and combinations thereof, comprising pathogen associated molecularpattems (PAMPS) and/ordanger associated molecularpatterns(DAMPS) selected from at least two groups consisting of: (A) antigenic agentsith molecular patterns associated with bacteria, (B) antigenic agentswith molecular pattems 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 helminthes, and (F) antigenic agents with molecular pattems associated with prions; and one or more physiologically acceptable carriers, excipients, diluents or solvents.

Septicemia is defined as an extremely serious infection inwhich one or more bacteria or microorganisms, from their entry point, enter the bloodstream and start circulating in large numbers, getting established at distant points, colonizing tissues, organs, and in 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 stomi) from the translation of all these signs.

The unavorable evolution of septicemia leads to sepsis, through the massive releaseof pro infianmatory cytokines such as TNFs,ILlIL18 IL6 and otherscausing an inflammatory collapse with hemodynamic characteristic alterations, such as hypotension, rapid pulse, which may culminate in septic severe shock, usually irreversible Septicemia, sepsis are serious infections/inflammations with high morbidity and mortality. In these severe infections/inflammation 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 bacteria at any cost through the ytokine storm and through the inflammatory ThL7 tissue profile creasig inflammation disproportionatelyand therefore harming the organism (33)

Inthisinflammatorytissueprofile,theeffectorloopsof innate iunuitv controlledbythe TCD4 lymphocytes, cause tissue damage and sometimes massive destruction, that compromise organs and tissues and that exacerbate infections, leading,forexame,torespiratoryfailure

lung shock, and in.ARDS (adult respiratory distress syndrome), also leading to renal failure and multiple organ failure.

Therefore insepticemiain sepsis and in septic shock there are two variables that should strategically be considered and should be the target ofan immunotherapy, so it issuccessful. 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 Th7 profile caused by the functional infeasibility ofthe Thl and Th2 profiles and described inflammation settings. The-se variables are the cornerstone ofseveritygravity, morbidity and mortality ofthese diseases.

Taking into account, these two variables, for an immunotherapy to be effectivein these infections, it should be applied to cover the entire body surface, including the greatest number of 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 peilesional region so that togetherthey can cause widespread recontextualization, that by its action can recover the integrity of the T loop and produce awide, extensive and intensive, anti-inflammatory effect by effector/memory T cells generated within the application sites. It should,in parallel through the recontextualization and reprogramming above described with huge anti-inflamrnmatory effect by inhibiting and decreasing cytokine storm, polarize the TCD4 response of the Thi7 inflammatory tissue profile for the humoral TH2 and cell Tl1 profiles, father decreasing the generalized inflammation by the action of memory cells the only cells in the body capable to abrogate physiologically huge inflanmations.

IF used the loop amplification by IL2 should be very lowdust enough to specifically amplify the repolarization of the inumune response ofthe inflammatory profile to the immunity profile or to Treg/TRI regulatory profile.

Thus, the reontextualizingand the reprogramning 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 ofnon-related specific memory T lymphocytes by the inhibition of the cvtokine storm and also by the repolarization of the tissue inflammatory profile TH17 to elective and effective THI and T2immunity profiles,wll 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 ofthe use of various antimicrobial agents, have a chance to reverse the biological equilibriumat the end of the curve in which is very favorable for the microorganism,to be favorable to the host and now have a chance of solution.

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

In the case of septicemia and sepsis, by the own pathophysiological mechanisms, there is a breach of the integrity and functionality of the T loop with an inadequate polarization for a suppressing TREG profile in cancer andfor ancytokine storm and inflammatory tissue Th7 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 recontextualizing induced by the best available secondary achieved activation of the new perceived identity ofthe pathogen must reach the whole body to reverse all immunosuppression, tolerance andimmune ignorance induced by the pathology, as well as to restore all operational and functional capacity ofthe immune system to have a reprogramnmed and renewed effective immune response.

In a third embodiment, the invention refers to a method to-treat multi resistant bacteria infection in a humanor an animal who has a bacterial infection comprising administering to the human or animal an effective amount of one or more antibiotics and one ormore 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, 15,1617, 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 molecular patterns (DAMPS) seletedf om at least two groups consisting of(A) antigenic agents with molecularpattens associatedwith bacteria, () antigenic agentswithmolecular pattens associated vith 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 pattems associated with prions; and one or more physiologically acceptable carrers, recipients, diluents or solvents,

In a fourth embodiment, the invention refers to a method to modulate an immune system response in a human or an animalwho has a bacterial infection comprising administering to the human or animal an effective amount of one or more immunogenic compositions for modulatingthe immune system.comprising atherapeutically 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 pathogen associated molecular patters (PAMPS) and/or danger associated molecular patterns (DAMPS) selected from at least two groups consisting of (A) antigenic agents with molecular pattems associated with bacteria, (B) antigenic agents with molecular patterns associated withviruses, (C) antigenic agents with molecular patterns associated with fungi and yeasts, (D) antigenic agents with molecular patterns associatedwith protooa,(E) antigenic agents with molecular patterns associated with hehninthes, and (F) antigenic agents with molecular patterns associated with prions; and one or more physiologically acceptable carriers, excipients diluents or solvents.

Itis other aspects, the present invention refers to the use of immunogenic compositions in the manufacture 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 tr-eatnent of infectious diseases in association with one ormore antibiotics

Properties ofthe immunogenic compositions of thepresentinvention

The immunogenic compositions of the presentinvention have an unexpected effect on the immune response. As can be seen in the Examples below, the immunogemc compositions of the present invention show an unexpected technical effect of causing an immune response that involves resetting. recontextualizing, leading back, renting and reprogramming the immune response in real time

More specifically, the immunotherapeutic compositions ofthepresentinvention bycreatinga new identity of the pathogen perceived by innate and adaptive immunological system are capable ofprovoking a reset, a recontextualization a lead back of the operational action capacity of the immune system by changing the relationship of forces against the aggressors in its favor giving the immune system a competitive advantage,which doesnot occur spontaneously in th evolution of disease.This recontextualization detemiines a consequent renewal and reprogramming of the established immune response orincipiently established, or erroneously established mistakenly attacking in a dysautonomical way the human or animal body, polarizing theprimary pro-infamnuatory response that is always a fortuitous reply possible to be improved to a secondary, active anti-inflammatory, more effbective and appropriate immune response

This effect occurs via secondary stimulation, activation and joint action of certain components of the immune system. such as sentinel cells, antigen presenting sentinel cells, and memory lymphocytes Specifically, the compositions of this invention properly reset the activated sentinel cells, the activated dendritic cells and other activated APC cells, by the action of memory cells,generating a new degree and intensity of CD4 T cell with a secondary activation profile that turn to a secondary effective standard the degree and intensity ofthe inunune 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 of the pathogen and trigger a specific secondary active adaptive inune response, desired to treat bacterialviral or parasitic infectionswith a low inflammatory profile

In addition, the treatment with the inununogenic compositions of the present invention is capable of stimulating the regenerative power of the immune system, a natural physiological property of this system providing a subsequent effect to the elimination of infectious 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 clinical cases of irreversible sepsis reported inthe Exampes. The patients had recovery and regenerationof complex trauma wounds with important tissue loss, organ destruction in lungs, kidneys, liver, bonesand extremities induced by C-D, and ischemic events by low blood flow and toxicity.

Thus,the immunogenic compositions of the present invention are able to mobilize the immune system and lead to an increased regenerative power of the body, through mobilization ofstem cells or the activation ofgene 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 in the Examples presented below, the immunogenic compositions of the present invention exhibit an unexpected technical effect of recontextualizing, renewing, and reprogramning the immune response in real time and consequently significant cure rates when compared to drugs and methodologies inthe an.

In a first embodiment of the invention, imnuno-modulator agent(s) is/are used for preparing an inununotnerapy pharmaceutical composition capable of inducing a new innate secondary imune response, which triggers a cascade of immune events, including the main event of activation of memory lymphocytes from the agent(s) inoculated by human intervention and the concomitant activation by antigens present in the patient's own body, resulting in a recontextualization, 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-inflammatory way. As such, theadministration of the composition containing the agents of the present invention repolarizes or improves the polarization of the immune system in the presence of a disease when the established polarization is inadequate, by the action of the etiologic agent or colonizer. The activities ofthe agents of the present invention affect the shape, time, accuracy and polarization ofthe immune response, preferably leading to an secondary innate and adaptive immune response that it is more effective to fight the disease. leadg to a better reaction of organism itself

The present invention provides methods to treat bacterial and other microbial infections with the use of the antigenic combinations described. The present inventioI also provides for the possibility of adding 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 drugs, selective for the pathogens and other infectious agents. This is made possible by the principle of displacement of the biological equilibrium in favor of the patient in combination with a correct polarization of the immune response as described herein.

When the immune stimulation follows a situation ofimmune response, after the termination of the disease mechanism or aggression, the continued activation of the immune system by antigens or immunoodulatoragents ofthe present invention leads through the activation of stem cells, to the regeneration of tissues, organs and systems; by mechanisms not yet filly 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 cells, new effective virgin cells of the individual, producing more significanteffects than an antibody increase as described in the priorart, The use of multiple antigenic agents with distinct enough PAMPS, DAMPS and stress signals to simulate different types of attacks that the organism suffers and to which the organism has already immunologimemory of, be it by environmental exposure or vaccination programs, allows awider recruitment of memory cells andnew effective virgins cells, enabling real-time recontextualization, resetting and leading back of the imnmne response and thus potentially and radicaly altering the type of immune response and disease or illness progression that arTects 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, having 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 thatmanifest themselves in specific locations ofthe body) to secondary reset innate system in all the places of the disease. Thecompositions of thepresent invention, when 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 PRRs (pathogen-associated pattern recognition receptors) off all sentinel cells ofthe body.

Thus, the present invention employs inmunomodulatory agents in amounts, concentrations and specific locations torecontextualize, reset and lead backthe immune system, activating and redirecting the mechanisms for tissue repair and regeneration, as occurs during healing and regenerationoftissue, organorsystem, leadingtoa"restitutionad integrum" orreconstitution with scar. This repair is usually triggered at the end of an immune response process, after healing the infection,

Use of the immunogenic compositions of the present invention.

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

These infectious diseases can be 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, hepatitisvirus, herpes virus, rhabdovius, ibella virus, smallpox virus, 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, Klebsiefla, Proteus, Pseudomonas, Salmonella, ShigeliaHaemophilus,Yersinia, Listeria, Corynebacterium, Vibrio, Clostridia, Chlamydia, Mycobacterium, Treponema, and Helicobacter.

Fungal diseases prevented and/or treated by theimmunogeniccompositionsofthe present invention may be caused by the followingfui but not limited to:Candida, Aspergillus, Cryptocoecus neofonnans, and/or fungi that cause superficial and deep mycosis. Diseases caused by parasites are caused by the following parasites: Typanosoma, Schistosoma, Leishmania, amoebas and tapeworm.

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

The use of the immunogenic compositions of the present invention for modulation of the immune system, involving the exposure of part orall 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, inflannatory territories will depend on the goal imposed by the illness being fought, and occurs preferentially through injections or use ofgns, or delivery systems or controlled infusion or pulsed cells with in vitro antigens.he agent may be applied to only one location in the body orin several tens of locations in several forms: subutaneous, muscular, intravenous, oral, breathable aerosol, cutaneous deniall patches) in organs, the viscera, or specific tissuesor in different body cavities, which can vary in munber from one to one hundred (100) applications in one to fifty (50) sessions

The antigenic compositions ofthis invention may also be combined with other drugs that can weaken the reproduction grovh,or any other form of strengthening of the disease's causative agent, causing a shift ofthe equilibrium in favor of the biological immune defenses of thehost animal or human. Or stillin concomitant treatment.

The antigenic compositions of this invention may also be combined with other procedures such as, but not limited to, antibiotics chemotherapy, therapywith antibodies and antisera, using hormones or other physiology modulating agents (eytokines, chemokines , neurohonones, peptides), treatment with antiviral agents, use ofherbal medicines, vitamin supplementation, methods of therapeutic or prophylactic vaccination (with or without cells and not united tothe type of vaccine vehicles),gene therapy, surgery or homeopathy, depending on the disease or illness being fought related to an improper or inefficient immune activity.

Recontextualzing resetting, renewing, leading back and reprogramming the immune response.

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

These varied and multiple antigens, in number greater than five, with multiple PAM'Ps DAMPs and SRS induce in the sentinel cells and in theAPC cells, especially in dendritic cells, an intense secondary activation allowing the mobilization of these memory CD4 and also CD8 memory or eventually NK memory cells and lymphocytes specific for these antigens at the site of application,

These stimuli must be capable of causing anintensestrong and effective secondary specific munune response to these antigens of the new identity at the site of application, in the regional activated lymph nodes, in the lymph nodes at a distance and a systemic mobilization ofthe immune system so that it can, in parallelcausean effective secondary response capableof eradicating the specific pathology in progress.

The innate and adaptive secondary immuneresponse caused intentionally by the composition of the present invention should encompass the fuH extent of the body area affected by the condition being treated and even exceed it if possible to be able to activate the sentinel and APC cells in the number and intensity that would be needed to properly address the aggression caused by the 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 geographical overlap the condition being treated and by its intense and extensive secondary activation will correct the inefficient activation, purposely limited by the action of the pathogen that overcomes the body's defenses, by preventing competition, its proper mobilization and development of an effective adaptive response according to its greatestgenetic and biological potential. This ideal activation should also reverse the iunnosuppression, the tolerance and escape mechanisms established by pathogens because it is known and proven that an unrelated strong and intense immune response, that fully covers theresponse to be corrected, through the activated cells and cytokines of the 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 ofthe antigens, will, via the bloodstream, enter the already activated iymph nodes by HEVs, which drain the region affected by the disease and will enable, in astrong and intense way induce the activation of all the existing dendritic cellsthere Therefore, they will lead to an activation ofthe entire lymph node, causing it togrowwith increased irrigation, increasing its size and making it a reactional lymph node capable of provoking an inmmne response against weak antigens, which by themselves are not capable of causing an immune response. PAMPs alone can remodel lymph node feed arteriole and induce lymph 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 effectormemory T lymphocytes, will oppose the action of the target causative agent that is blocking the required activation of the lymph node for the development ofan immune response that is necessary to treat the disease in question. That, exclusively for the purpose and by the action ofthe present invention, through its potent antigenic composition, may occur that the sentinel cells and dendritic cells and macrophages of the immune response will be the same for unrelated antigens and to the pathological antigens, but from this action,will be intensely and properlyactivated.Dendriticcellsstronglyactivatedby multipleantigens,haveaslow metabolism and ideally present alldominant andsubdominant epitopes ofthe causative agent, by the known. helper" effect, mobilizing all possible and available T lymphocytes able to specifically recognize antigens of the autologous or heterologous pathogen, to be treated and to react against it.

The areas of the inflammatory process and lymphatic territories are exactly the same. The inflamed area, through the anti-inflammatory action of specific memory cells, unrelated, mobilized by the present invention by their antigenic composition, will block the inflarnmasomes and exert an anti-nflammatory action that will correct the pathological inflammationresponsible for the morbidity of the disease and which was caused by its etiological agent For the memory effect it's important to note that this known action ofthe memory T cells is the 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 alarn signal, caused by the present invention, to cause any immune response, even for a weak antigen, similar to what occurswith dendritic cels common to this invention and to the autologous or heterologous etiological agent to be fought. Lymphokines and innate cells that command an effective secondary response wil be the same and the Tlymphocytes specific against the etiologic agent to be fought, will "hitch a ride"on this ideal microenvironment for holding an effectiveimmune response,

The dendritic ceds activated by the present invention, can capturethe antigens of the etiological agent to be fought at the site ofthe pathology and in the related lymphatic territories and be in contact'with the pathogen specificTCD4 lymphocytes, in a correctly and ideally enabled lymphatic system. The role of the dendritic cells activated and maturedwith theTCD4 specific to the etiologic agent, occurs in amicroenvironment conducive to conducting an immune response, with all the genetic and biological potential of the host organism's immune system.

These dendritic cols at the site of the pathology and at the lymph nodes wi properly gauge the severity extent, intensity and type of aggression, activating, inducing coordinating, polarizing, leading and maintaining anew elective adaptive immune response, whose effector loop, with the collaboration ofthe cells and effector molecules of the intenseand properly activated innate immunity may beable 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 ofthe host, which until then was under the yoke ofthe offending autologous or heterologous agent.

Such action may occur with or without the help of biological balance shifters such as antibiotics drugs, capable to block, weaken or neutralize theeffects and potential of the etiological agent, allowing the immune systemto have a chance to heal the pathology that is the target of the treaftrent. Once triggered by any etiological agent the immune system will only stop responding when the etiological agent is eliminated or the organism passes away, thisway 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.

Thus, the action ofthe compositions of the present inventionintentionally and strategically superimposed over the entire area under the action of the agent to be fought,will recontextuaze the immune system by activating the PAMPs and DAMPs in the sentinel cells and common APCs and by theunrelated specific secondary adaptive innmneresponse. 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 the context of agreater immune response, stronger, more intense and more extensive secondary anti-inflammatoy nature ofthe target immune response will be, as described, reprogrammed and efficiently renewed within the 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

The therapeutic protocol ofthe 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. In the cases described herein, more than 10 lymphatic territories have been hit. It must be applied within the infected and perilesional areas.

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

- the application area mustoverlap, cover, and overcome the whole extension of regions dominated by the infection.

-the antigenic stimuli must be repeated every 4 or5 days in order to avoid the generation of suppressor cells capable of aborting the new desired immune response or to suppress an achieved repolarization.

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

- in practice, I to 3ml of this imnmunotherapy must be applied to 10 or more lymphatic terriries This invention should be jointly applied in intra and extralesion areas damaged by infection.

In summarytheimmunotherapy is'systemically" distributed in several (at least ten) lymphatic territories, peri- and intra-lesionwith a volume able to disrupt and destabilize the lesion from the domination 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 ofthe organism. It will be applied every 4 to 5 days.

In sepsis, severe sepsis and septic shock, the use of low doses of exogenous interleukin-2 should be avoided- The nse of low doses of exogenousinterleukin-2 in severe infections uninterruptedly should be carefully evaluated when aamplification ofthe immune loop is needed.

DESCRIPTIONOF 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 ormre of these figures in combinationwith the detailed description of the preferred embodiment presentedhere.

Figure I shows images of Examle 2. A, 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 X Ray on January 29, 2011 (A2) the extemal fixation of the femur after surgical procedure. On February 2, 2011 (5 days after starting the treatment) the patient presented completerecovery fromsepsis and received ICU discharge (B1,B2 and B3)In B1I to B3 it is possible to identify healthy granulation tissue characteristic of the second intention healing process. In C1 (01 March, 2011) it's clear the improvement of the leg injuries described in Al- A4, that's the reason whypatient was discharged from hospital on 15 March, 2011. In DI (medial site) and D2 (lateral site) is possible to verify the complete recovery from complex wound of polytrauma associated with: severe sepsis caused by multidrug-resistant Acinetobacter bannami iand osteorayelitis These data strongly suggest adecisiveroleoftheDCAimmunotherapy associated with debridement and antibiotics,to cure the clinical scenario, in a relatively short time, making possible not only the patient survives a natural disaster but also walk again without crutch or cane.

Figure 2 shows images of Example 3. A Chest CT scan (AI and A2) of 01/11/2011 before imununotherapy and CT scan (B1and B2) of04/1112011 after immune treatment performed in CMS patient. In Al and A2 is possible to identify whitish areas (circled) characteristicof infection In BI and B2s clear the disappearance of whitish areas and recovery of the ung parenchyma which the image became darker- These data show a recovery of aspiration pneumonia with the combination ofiumnotheapy with antimicrobial treatment.

Figure 3 shows images ofExample 4. An X-Ray (Al) of24 April 2007 (3 days after immunotherapy starts) and CT scan (B1 to 36) of 27 April 2007 it'seasily to identify critical SARS condition under septic shock.X-Ray (C1) of 06May 2007 evidences complete recover after imune treatment performed in AMB patient. In A is possible to identify whitish areas (circled) characteristic of infection, InB1 - B6 the clinical status is so critical that whitish areas barely allowto identify anatomical contours ourparameters (circular). In Cl is clear-the disappearance of whitish areas and complete recovery of the lung parenchyma,without sequels; which the image became darker. These data show a recovery of sepsis associated with SARS, CVD, hepatic and renal failure with the combination of 6 sessions of imnmunotherapy with antimicrobial treatment in 15 days.

EXAMPLES

in order to allow a better understanding of the invention andclearly demonstrate the technical progress achievedthe results ofthe various tests conducted with respect to this invention are shown below as examples.

hesexampes are Presented for illustrative purposes only and should not be regarded in any va as limiting the scope and range of the invenon.

Example I immunogenic Compositions

In order to achieve the recontextuahzing, renewal and reprogrannning of the immune response in real time according to the innovative concepts described in the present invention, an expert skilledin the art can design different and distinct compositions, combinations or formulations of products, which fall 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 diversity of antigens from pathogens, so as to get the maximum synergistic effect in binding the PAMPs and DAMPs to their receptors and allowing the achievement of a high degree of activation of the innate immunity in the sentinel cells (with or withoutATfunction) thereby allowing the recontextualizingrenewaland reprogramming of the immune response in real time

Such compositions should preferably use antigenic agents for which most people, because of previous contact, would have memory clones of in their immune system capable of inducing a broad anti-infiammatoryaction in parallel to recontextualization. For this, antigenic agents should preferably be selected that:

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

- are used in immunization programs such as childhood vaccination programs against endemic and/or epidemic diseases.

o those from organisms of potentially pathogenic microflora, especially of the gastrointestinal tract, where the memory lymphocytes play an active dynamic barrier ensuring the survival of the individual.

ideally each ofthe antigenic agents should be present in a concentration of0,001 to 500 micrograms per mL.

In accordance with these concepts, several formulations have been developed, using antigenic agents in their already available. safe, and approved forms for use in huann vaccination programs or allergic response tests and immunity assessment tests.

Therefore, we present the following several examples of compositions which fall within the scopeofthe present invention, without however the intention to limit it, since the present invention and its concepts allow for the design of immunogenic compositions comprising a very large number of combinations of antigenic agents.

Composition la (DECA composition): Component Concentration Koch's Turberculin (inactivated Mycobacterumbovislysate) 0.004 ng/mL PPD C,004g/mL Inactivated Staphylococcus lysate (Staphylococcus aureus and 634 gimL Staphylococcus epidemtidis in equal parts Inactivated Steptococcus lysate (Streptococcus pyogenes, 9 6.94gg/ml Streptococcus pneumoniae and Enterococcus faecalis in equal parts). Streptokinase derived from inactivated beta-hemolytic Streptococcus 0.444gg/mL lysate purification. Dornase derived from inactivated beta-hemolytic Streptococcus lysate 0.11 pg/gmL purification. Inactivated Candida lysate (Candida albicans and Candida glabrata in 6,94 g/mL equal parts).

IMicrosporum Inactivated derratophytes lysate (Epidermophytonfloccosum, cannis, Tichophyton mentagrophytes ofthe interdigitale variety in equal parts), 634 ig/nL

activated enteropathogenic Escherichia coli Jysate(----E- -- - sate(4g/mL _ __

Inactivated Salmonella lysate (Salmonella bongori Salnonella 6-4 pghL enterica and Sahmonella subterranea in equal parts). Sodiun Chloride mL Sodium phosphate dibasic heptahydrate -. 8 mmgL

Potassium phosphate monobasic 0,6 mg/mL Phenol_ 2.5 mg/mL Water - _________________

Composition lb (VITER composition): Component Concentration Kochsurberculin (inactivated Mycobacterium bovis ysate). 104036ng/ui PPD 0,0036 pg/mL Inactivated Staphylococcus lysate (Staphylococcus aureus and 631 pg/mL Staphylococcus epidermidis in equal parts). Inactivated Steptococcus lysate (Strptococcuspyogene 6.31pg/r Streptococcus pneumoiae and Enterococcus faecalis in equal parts) Streptokinase derived from inactivated beta-hemolyticStreptococcus 0.404 pg/miL lysatepurification. Dornase derived from inactivated beta-hemolytic Streptococcus lysate 0. 101 pg/mL purification. Oidiomycin (antigeiic extract of Candida albicans 63 1pg/mL Trichophytin (antigenic extract of Tricophyton sp 631 pg/mL Inactivated enteropathogenic Escherichia collysate (EPEC) 6.31 ug/mL Inactivated Sahnonella lysate (Salmonella bongori, Sahnonella 631 gg/mL enterica and Salmonella subterranea in equal parts) Attenuated yellow fever vius strain 17 D204 20 .g/mL Sodium Chloride 75 mg/mL Sodium phosphate dibasic heptahydrate 0.48 mg/mL Potassium phosphate monobasic 0.06 mg/mL Phenol 25 mg/mL Water q.s.

Composition 2: Component Concentration

Koch'sTurberculinactivated Mycobacterium bovis lysate). 004ng/nL PPD f0.004 g/L Inactivated Staphylococcus aureuslysae. inactivated Staphylococcus 694 pg/mL epidermidis lysate in equal parts. Streptokinase derived from inactivated beta-hemolyticStreptococus 444 gg/mL lysate purification Dornase denved from inactivated beta-hemol-tic-Streptococcus lysate Djpg/mIL purification. fInactivated Candida albincans lysate, inactivated Candida parapsilosis 694 gg/mL ysate, inactivated Candida glabrata in equal parts Inactivated enteropathogenic (EPEC), "shiga-like"toxin producer 6.94 pg/niL (STEC),enteroaggregative (EAEC), enterotoxigenic (ETEC), enteroinvasive (EIEC) and extraintestinal (ExPEC) Escherichia coli lysate inequal parts. Sodium Chloride 75mg/niL, Sodiumphosphate dibasic heptahydrate 0.48 mg/mL Potassium phosphate monobasic 0.06 mg/nL Phenol 25 mg/nL 'Water

Composition 3; Component JConcenutration IPD 0.004 g/mL Inactivated Streptococcus pyogenes ysate, inactivated Streptococcus 6.94 ig/nL Wpneumonielysate, Enterococcus faccalis lysate in equal parts Inactivated Staphylococcus aureus lysate, inactivated Staphylococcus 6.94 pg/nL epidenidis isate in equal parts. Inactivated Candida albicans lysate, inactivated Candida parapsilosis 634 g/mT lysate, inactivated Candida glabratalysate in equal parts. Sodium Chloride f.mg/mt

Sodiun phosphate dibasic heptahydate O48mg/raL POtassium phosphate monbasic 0.46 ig/mL Phenol 2,5 mg/mL Water

Composition 4 Component Concentration Inactivated BCG lysate 50 mg/miL Inactivated Staphylococcus aureus lysate, inactivated Staphylococcus 6.94 gg/mL epidernidis lysate in equal parts. Inactivated Streptococcus agalactiae lysate, inactivatedStreptococcus 6.94 gg/mL mix (Streptococcus pyogenes, Streptococcus pneumoniae and Enterococcus faecalis) lysate in equal parts, Inactivated Candida albincans lysate, inactivated Candida paapsilosis 6,94 g/mL lysate, inactivated Candida glabrata in equal parts Sodium Chloride 7.5 mg/mLI Sodium phosphate dibasic heptahydrate 0,48 mg/mL Potassium phosphate monobasic _0_6 mg/mL Phenoi 25 m0g/mL Water In.s.

Composition 5: Componen t Concentration PPD 0.004 g/mL Inactivated Streptococcus pyogenes lysate, inactivated Streptococcus 6.94 pg/mL pneumonie lysate, Enterococcus faecalis lysate in equal parts. Inactivated Apergillus fumigatus.Apergillus flavus, and Apergillus 6.94 pg/mL terreus lysate in equal parts inactivated denratophytes lysate (Epidennohytonfloccosun 6.94 g/mIL Microsporui cannis, Trichophyton mentagrophytes of the interdigitale vadetyinequal parts) Sodium Choride 75a/a Sodium phosphate dibasic heptahydrate j048m Potassium phosphate monobasic 06rdmL FPhenol ____ 2 5mg/mL t2- _____ mgh-_ Water

Composition 6: Component Concentration Koch's Turberecunina tivatedMycoacterium bovi s'sate. j004g/mL Inactivated Streptococcus pyogenes lysate, inactivated Streptococcus [6.94g/mL pneumonielysate, Enterococcus faccalis ysate in equal parts. Inactivated Neisseriameningitides'lysate. 6.94 ig/aL Inactivated Apergillus funigatus, Apergillus flavus and Apergilus 694 gg/mL terreus lysate in equal parts. Sodium Chloride 7.5mg/mL Sodium phosphate dibasic heptahydrate 0.48 mg/mL Potassium phosphate monobasic 0.06 mg/mL Phenol 2-5 mag/mL Water qst

Composition 7 Component Concentraion Koch's Turberculin (inactivatedMycobacteriu bovis lysate) 0.004 ng/mL

tinactivated Intact vated BCG lysate Staphylococcus aureus lysate, inactivated Staphylococcus epidennidis lysate in equal parts. 50 rng/mL 6.94 pg/mL

Inactivated Streptococcus pyogenes lysate, inactivated Streptococcus 6.94 pg/mL pneumonic lysate, Enterococcas facalis lysate in equal parts. Inactivated Candida aibincans lysate,inactivated Candida parapsilosis 6.94 gg/mL lysateInactivated Candida glabrata in equal parts. Inactivated Streptococcus equinus, Streptococcusbovis and 6.94 g/mL Streptococcus viridans lysate in equal parts. Inactivatedenteropathogenic (EPEC),shiga-ike"toxin producer 6.94 pg/mL (STEC), enteroagregatve (EAEC), enterotoxigenic (ETEC) enteroinvasive (EEC) andextraintestinal (ExPEC) Escheichia coi lysate In equal parts

Inactivated Salonellatyphi Samnonella paratyphi and Sa-one a 64 pg/nL enterica lysate mi equal parts.

Inactivated lysate of antigens of themaslesvirus ("SchwarzStrain). 10,000 ________TDC150/mL

Glycerol 500 mg/mL Phenol25m nL Water

Composition 8: Component Concentration Koch's Turberculin (inactivatedlMycobacteriu bois lysate) 0.004 ng/mL PPD 0.004 gniL inactivated Staphylococcus aureus lysate, inactivated Staphylococcus 6.94 g/r epidennidis lysate in equal parts. inactivated enteropathogenic (EPEC) "shiga-like" toxin producer 6.94 pg/nL (STEC) enteroaggregative (EAEC), enterotoxigenic (ETEC), enteroinvasive (EIEC) and extraintestinal (ExPEC) Escherichia col iysate in equal parts. Streptokinase derived from inactivated betahenolytic Streptococcus 0.444 gg/mL lysate purification. Donase derived from inactivatedobeta-hemolytic Streptococcus lysate 0.l 1 pg/mL purification. Inactivated Streptococcus pyogenes lysate, inactivated Streptococcus 6.94 pg/ni pneunloielysate, Enterococcus faccalis lysate in equal parts Iniactivated Helicobacter pylori ysat. 694 pg/raL Tetanus toxoid 50 units of

Inactivated Candida abinan e 6 94 g/rL ysate, inactivated Candida glabrata in equa pans,

fSodium Sodium Chloride phosphate dibasic heptahydrate Potassium phosphate monobasic lnQ 0.48 mg/nL 0.06 mg/mL Pheo 2.5 mg/nL

[Water - .________ q~s

Composition 9: 'Component Concentration Inactivated BCG isate 50 mg/mI Inactivated Mycobacterium tuberculosis lysate 0.004 ngnI inactivated Staphylococcus aureus lysateinactivated Staphyococcus 6.94 .g/mL epidermidis ysate in equal parts. Inactivated enteropathogenic (EPEC)shiga-like" toxin producer 6.94 pg/mL (STEC) enteroaggregative (EAEC), enterotoxigenic(ETEC) enteroinvasive (EIEC) and extraintestinal (ExPEC) Escherichia coli lysate in equal pas, Inactivated Hlaemophilus influenza lysate. 6.94i pg/m-zL Inactivated Streptococcus agalaatiae lysate, inactivatedStreptococcus 6.94 gg/mL mix (Streptococcus pyogenes, Streptococcus pneumoniae and Enterococcas faecalis)lysate in equal pats. Inactivated Salmonella typhi, Sahnonella paratyphi and Salmonella 6.94 pg/mL enterica lysate in equal parts Inactivated Proteus mirabilis Proteus lgaris, and Proteus penerii 6.94 pg/mL lysate in equal parts.

Inactvated lysate of antigens of the measles vims ("Schwarz strain"),0,000 TDC150/mLT Inactivated Candida albincans lysate,inactivated Candidaparapsilosis 6,94gg/m ysate, inactivated Candidaglabrata in equal parts, *Glycerol -___ ____

500 mg/mL PhenolK 2mg/mL } Water

Composition 10:

Component Concentration Inactivated Mycobacterium africanun lysate- 0,004 ag/mL Koch s Turberculin (inactivated Mycobaterium bovis lysatej 0,004ng/mL Inactivated enteropathogenic (EPEC),½"shiga-fike toxin producer 6.94 pg/mL (STEC), enteroaggregative (EAEC), enterotoxigenic (ETEC), enteroinvasive (EEC) and extrintestinal (ExPEC)Escherichia coli lysate in equal parts. InactivatedStaphylococcus aureus lysate, inactivated Staphylococcus 6.94 g/mL epidermidis lysate in equal parts. Inactivated Epiderophyton floccosum, Microsporm-m cannis, 694 ug/mL Trichophyton mentagrophytes of the interdigitale variety lysate in equal parts). Inactivated Streptococcus pyogenes lysate, inactivated Streptococcus 694 pg/mL pneumonia lysate, Enterococcus faecalis lysate in equal parts Inactivated Acinetobacter baumannii lysate 6.94gg/mL Inactivated Helicobacterpylori lysate 6.94 g mL IInactivated lysate of andgens of themumps virus (Uabe AM9 strain) 10,000

fInactivated Poiovirus lysate. TDCI50/mL 4 U2D4oftp Iantigens; 1 8 UD of type 2 antigens; 32 UD of type 3 I antigens Glycerol 50n1ig/nuL1 Water ==q

Composition 11: Component Concentration Inactivated Mycobacterium leprae lvsate 0.004ng/nL Koch's Turberculin (inactivated Mycobactenum bovis lysate) 0.004ng/mL Inactivated Staphylococcus aureus. lysate, inactivated Staphylococcus 6,94 pg/mL epidennidis lysate in equal parts. Inactivated Candida albincans lysateinactivated Candida paapsilosis 6,94 pg/nL lysate, inactivaTed Candida glabrata in equal parts Inactivated Streptococcus agalactiae lysate inactivated Streptococcus 6.94 pg/nL "mix (Streptococcus pyogenes, Streptococcus pneumoniae and Enterococcus faccalis) lysate in equal parts Inactivated Streptococcus equinusStreptococcus bovis, and 6.94 pg/mL Streptococcus of the viridans group lysate in equal parts. Inactivated Haemophilus influenza lysate. 6.94pg/mL Inactivated Proteus mirablis, Proteus vulgaris, and Proteus penerii 6 94 g/nZ lysate in equal pats. Antigens of therubella virus (Wistar RA 27/3M strain) 10,000 3TDC150/mnL Inactivate antigen of the Varicella zoster virus lysate 149231 PFU/mL Glycerol 500 mg/mL Phenol 2.5 mg/mL Water q~s.

Composition 12 Component Concentration Inactivated Mycobacterium avium lysate 0.004ng/mL t: Inactivated Mycobacterium kansasii lysate 0.004ng/mL InactivatedApergillus fi3migatus, Apergillus flavus, and Apergillus 6.94 g'mi terreus lysate in equal parts InactivatedNeisseria gonorrhoeae lysate. 6.94 gg/ml Inactivated Streptococcus equinus, Streptococus bovis, and 6.94 g/nL Streptococcus of the viridans group lysate in equal pars. inactivated Epidermophyton floccosum, Microsporum cannis, 6.94 tg/mL Trichophyton mentagrophytes of the interdigitale variety lysate in equal parts). Inactivated Chlamydia trachornatis, Chamydia psittaci, and Chamydia 6.94 pg/mL pneumoniae lysate in equal parts, Inactivated enteropathogenic (EPEC), "shigalike"toxin producer 6.94 gg/mL (STEC), enteroaggregative (EAEC), enterotoxige-nic (ETEC) enteroinvasive (EIEC) and extraintestinal (ExPEC) Escherichia coli lysate in equal parts Antigensof the rubella virus (WistarRA 27/3M strain) -0,000

TDCI50/mnL inactivated antgen of the Vaccinia (smallpox) virus lysate I to 10x PFU/mL Gyvceroi 500 mg/mL fheno 2,5mg/n Water q.s

Composition 13: Component Concentration Inactivated Mycobacterium tuberculosis lysate 0.004 ng/mL inactivated Mycobacterium. avium lysate 0.04 ng/mL

Inactivated Neisseria neingitide,, ilsat - .94 Diphtheria toxoid 167units of Lf/mL Streptococcusagalactialysate, inactivated Streptococcus 694 pg/mL nix (Streptococcus pyogenes, Streptococcus pneumoniae and Enterococcus faecalis) lysate in equal parts. Inactivated Candida albincans lysate inactivated Candidaa sos 6.94 aghmL lysate, inactivated Candidaglabrata in equal pants, Inactivated Hlicobacter pylori lysate 6943 g/mL Inactivated Serratia marcencens e Serratia liquefaciens lysate 6.94 jg/mL Inactivated antigen of HSV-I and HISVI lysate 149231 PFU/nL Inactivated antigen of the measles virus ("Schwarz strain" vsate 10;000 TDCI50/mL Glycerol 500 mg/nL Phenol 2.5 mg/mL Water q.s Composition 14: Component Concentration inactivated Mycobacterium africanum lysate 0.004n glnL activated Mvcobacteriun tuberculosis lysate 0004 rgimL Inactivated Neisseria gonorrhoeae lysate 6.94 mg/mL Inactivated Apergillus fumigatus Apergillus favus, and Aper us 6.94 pgimL terreus lysate in equal parts. nactivatedNeisseriaineningitideslysate 6-94 pg/mL Diphtheria toxoid 67 units of ILmL InactivatedEpidermophyton floccosum, Microsporum canis 6.94 pg/mL Trichophyton mentagrophytes often interdigitale variety lysate in equal parts). Inactivated Shigella flexneri and Shigea so.nnyi sate in equalparts 694 pg/mL Inactvated surface antigen of the hepatitis B (I-sAG) virus ysate 200 pg/mL Inactivated antigen of the measles virus ("Schwarzstrain") ysate 10,000 TDC150/nL Gc ----- 500 mg/nL Phenol ---- 2 5--- I mg/mL IWater .-. q~s ______

Composition 15: Component concentration PPD '0.00.nglmt Inactivated BCG lysate 50 mg/mL InactivatedStreptococcus equias Streptococcus bovis, and 6,94 gg/mL Streptococcus ofthe viridans group lysate in equal parts. Inactivated Staphylococcus aureus lysate, inactivated Staphylococcus 6.94 pghnL epidernidis lysate in equal parts Tetanus toxoid 50 units of Lf/mL Diphtheria toxoid 67 units of LfiniL Inactivated Acinctobacter baumannii lysate 6,94 g/mL Inactivatedenteropathogenic (EPEC), "shigaike"toxia prducer 6.94 pg/mL (STEC), enteroaggregative (EAEC), enterotoxigenic(ETEC), enteroinvasive (FIEC) and extraintestinal (ExPEC) Escherichia coli lysate in equal parts. Inactivated Apergillus fumigatus, Apergillus flavus,and Apergillus 6.94 gmL terreus lysate in equal parts. -- ------ ____________ _--------------

Inactivated lysate of antigens ofthe mumps virus (Urabe AM9 strain) 10,000 TDCI5O/mL

Glycerol 500 mg/mjL. Phenol 2.5 mg/mL Water q.s'

Composition 16 Component Concentraion1 s Turberculin (inactivated Mycobacterium bovislysate).. 0.004 ng/mL ctivatedMycobacterium tuberculosis lysate 0.004 nghmL Inactivated Salnonella typhi Sahnonela paratypi and Salmonella 634p/ enterica lysate in equal parts InactivatedStreptococcus pyogenes lysate, inactivatedStreptococcus 6.94!ig/mL pneumonia lysate, Enterococcus faecalis lysate in equal pans, Inactivated Epidenmophyton floccosum, Microsporum cannis, 624 mL Trichophyton mentagrophytes of the interdigitde variety lysate n equal parts), Bordetella pertassis toxoid 5 pg/mL Inactivated Haernophilus influenza sate. 6.94 pg/rn Tetanus toxoid - 50 units of LFmL inactivated Polio virus lysate 40 UD oftype antigens; 1-8 UD of type antigens; 32 UD of type 3 antigens Inactivated antigen ofthe Vaccinia (smalpox) virs lysate I to 10x PFU/mL IGlycerol 500 mg/mL henol 2.5mg/mL % ater q.s.

Composition 17: Component IConcentration Koch's Turberculin (inactivated Mycobacteriuni bovis lysate). 0.004 ng/rmL Inactivated BCG lysate 50 mg/nL PPD [ 04nghnt Inactivated Staphylococcus aureus lysate, inactivatedStaphylococcus 6.94 gg/mL epidennidis lysate in equal parts Inactivated Streptococcus pyogenes lysate, inactivated Streptococcus 6,94 pg/mL pneumonie lysate, Enterococcusfaccalis lysate in equal parts. inactivated Klebsiella oxytoca and Kiebsiella pneumonia lysate in 6.94pg/mL equal parts Inactivated Epidermophyton floccosumMicrosporum cannis, 694 pg/mL 1 Trichophyton maentagrophytes of the interdigitale variety lysate in equal parts). Inactivated Streptococcus equinus, Streptococcus bovis, and 6.94 g/mL Streptococcus of the viridans group lysate in equal parts. Diphtheria toxoid 67 units of LfImL Inactivated enteropathogenic (EPEC),"shigalike toxiroducer 6 .94 gg/mL (STEC), enteroaggregative (EAEC), enterotoxigenic (ETEC), enteroinvasive (EiEC) and extraintestinal(ExPEC) Escheiichia coli lysate in equal parts. Inactivated Salmonella typhi, Salmonella paratyphi and Salmonella 6.94 pg/nL enterica lysate in equal parts Bordetella pertussis toxoid 75 gg/mL Inactivated Apergillusfiumigarus, Apergliusflavusand.Apergillus 6.94 g mL terreus lysate in equal parts. Inactivatedlysateof antigens of the measles virus ("Schwarz strain") 10,000 TDCI50/mL Inactivated Candida aibincans lysate, inactivated Candida parapsiosis 6.94 g/mL lysate inactivated Candida glabraa in equal parts. Glycero 500mg/ml Phenol25 mg Water _____ __ _ ___I q.s.

Composition 18: Component Concentraton

PPD M0.004 nghL InactivatedMycobacterium tuberculosis lysate 0.004 na/mL Koch's Turberculin (inactivatedMycobacterium bovis lysate) 0.004 ng/mL Inactivated Staphylococcus aureus lysatenactivated Staphylococcus 6.94 gg/nL epidermidis lysate in equal parts, Inactivated Salmonella typhi, Salmonella paratyphi and Salmonella 6.94 pg/ni enterica lysate in equal parts. I- ------ ---. . . . . . . .. . . . ._______________ ------ - -------------------- _

Inactivated Streptococcus pyogenes lysate, inactivated Streptococcus 6.94 g/nL pneumonia lysate Enterococcus faccalis lysate in equal parts Streptokinasederived from inactivated beta-hemolyic Streptococcus 0 444 pg/mL yvsate purification. Domase derived from inactivated beta-hemolytic Streptococcus lysate 0.1II pg/mL purification

Inactivated Kebsiella oxytoca and KIebsiella pneumonia lysate in 6.94jpg/mb equal parts

Inactivated Streptococcus agalactiae lysate, inactivated Streptococcus 6.94jyg/mL mix (Streptococcus pyogenes, Steptococcus pneurnoniae and Enterococcus faecalis) lysate in equal parts Inactivated Helicobacter pylori lysate. 694 gg/ml Tetanus toxoid 50units of LfnmL Inactivated enteropathogenic (EPEC), "shiga-ike"toxin producer 6.94 pg/mb (STEC), enteroaggregative (EAEC), enterotoxigenic (ETEC) enteroinvasive ( C)andextraintestinal (ExPEC) Escherichiacoi lysate in equal pans. Inactivated Candida albicansysate, inactivated Candidaparapsilosis 6.94pg/mL lysate, inactivated Candida glabrata lysate in equal parts Inactivated Apergillus fumigatu, Apergllus flav, and Apergillus 6,94 g/mL terreslysate in equal parts, Inactivated YFI7D lysate 3,000,000

Glycerol 500 mgnL heno,21 mg/mL Waters.rg L q~s

Composition 19:

Component -. Concentrtion Inactivated BCG lysate 50 mg/mL Inactivated MycobacteriumtberculosisIlsate 0.004nag/nL Koch's Turberculin (inctivated Mycobacterium bovis lysate). LInactivated Staphylococcus aureus lysate, inactivated Staphylococcus j0.004 nghnL 6.94 ug/mL epidemidis lysate in equal parts. Inactivated Streptococcus pyogenes lysate, inactivated Streptococcus 6.94pg/mL pneumonic lysate, Enterococcusfaecalis lysate in equal parts. inactivated Senatiamarencens e Serratia liquefaciens lysate 694 gghL activated Hacmophilusinfluenza lysate. 694 pg/mL inactivatedStreptococcusagalactiaelysate, inactivated Streptococcus 6.94 pg/mL mix(Streptococcus pyogenes, Streptococcus pneumoniae and Enterococcus faecalis)lysate in equal parts, inactivatedKilebsiella oxytoca and Klebsiella pneumonialysate in j694pg/mL equal parts Inactivated Epidermophyton floccosum, Microsporum cannis, 694pg/mt Trichophyton mentagrophytes of the interdigitale variety lysate in equal parts) Inactivated Proteus mirabilis, Proteus vulgaris and Proteuspeer 6,94 gg/mL lysate in equal parts. nctaty Sahonellaparatyphi and Salmonella 6.94 gg enterica lysate in equal pats. Inactivated lysate of antigens of theeasesvirus"Sch astra i o00 TDCIS0/mL InactivatedCandidaalbicanslysate, inactivatedCandidaparapsilosis 6 94 pg/ml lysate, inactivated Candida glabrata lysate in equal patsI Inactivated antigen ofthe Vaccinia (smallpox -vrus sa --- .to 10 x

FU/m L Glycerol 500rig/m! Phenol Water Iq g/m

Composition 20: Coionent Concentration Inactivated Mycobacterium africanum lysate 0.004 ng/mL Koch's Turberculin (inactivated Mycobacterium bovis lysate). 0.004 ngmL Inactivated BCG lysate 50 mg/mL fInactivated1Apergillus nngatus Aergillus flawus, and Apergilus 6.94 pg/inL terrus ysate in equal parts

Inactivated Staphylococcus amreus I'sate, inactivated Staphylococcus 694 gg/mL epidridislysate in equal parts, Inactivated Neisseria meningitides lysate 6.94 pg/mL Inactivated Streptococcus pyogenes lysateinactivated Streptococcus 6.94 gg/mL pneunonie lysate, Enterococcus faecalis lysate in equal parts. Inactivated enteropathogenic (EPEC), "shiga-iike"toxin producer 6.94 ig/mL (STEC), enteroaggregative (EAEC), enterotoxigenic (ETEC), enteroinvasive (EIEC) and extraintestinal (ExPEC) Escherichia coli ysiate in-equalparts inactvated Salmonella typhi. Salmonella partyphi and Salmonella 6.94 pg/mL enterica lysate in equal parts. InactivatedAcinetobacter baumanniivsate 6.94 pg/raL Inactivated Helicobacter pylori lysate- 6.94 yu Inactivated H-emophilus influenza lysate. 64 pm Inactivated lysate of antigens of the mmpsvirus(Urabe AM9 strain) 50,000 TDCi50/mL Inactivated Polio viruslysate 40 UD of type I antigens; 18 UD of tpe 2 antigens; 32 UD of type 3 antigens Inactivated Candida albicans lysate, inactivatedCandida parapsilosis 6.94 pg/mL lysate, inactivated Candida glabrata lysate in equal parts, Glycerol 500 mg/mL Phenol 215 mg/mL Water qs

Composition 21: Component Concentration Inactivated Mycobacteriumeprae lysate 0.004 ng/mL Koch's urberculin (inactivated Mycobacterium bovis lysate). O04ngmL Inactivated Mycobacterium tuberculosis IVsate 0.004 ng/rL Inactivated Staphylococcus aureus lysate, inactivated Staphylococcus 6.94 pgmL epidennidis lysate in equal parts. Inactivated Epidermophyton floccosum, Microspoma cannis, 6.94pg/mL Tichophyton mentagrophytes ofthe interdigitale variety lysate in equal parts),

Diphtheria toxoid 67 unitsof LffmL Inactivated Streptococcus agalactiae lysate inactivated Streptococcus 6.94 g/mL mix (Streptococcus pyogenes, Streptococcus pneumoniae and Enterococcus faecalis)lysate in equal parts. Tetanus toxoid 50 units of L£'mL Inactivated Neisseria meningitides lysate 6.94 pg/mL inactivated Haemophilus influenza lysate. 6.94 g/imL Inactivated Proteus mirabilis, Proteusvulgaris, and Proteuspeneri 694 pg/mL lysate in equal parts. Inactivated Serratiamarcencens e Serratia liquefamcens lysate 694 pg/hmL Antigens of the rubella virus (Wistar RA27/3M strain) 10,000 TDC150/mnL Inactivate antigen ofthe Varicea zoster virus lysate 149 231 PFUmL Inactivated Apergilius fumigates, Apergillusflavus, and Apergilus 6.94 p.ig/mL terreuslysate in equal parts. Glycerol 500 mgnimL Phenol 25 mg/mL Water q's.

Composition 22: Unponent Concentration Inactivated Mycobacteriumi avi um lysate 0004 ng/ml, Inactivated Mycobacterium kansasii lysate 0.004ughnL Koch 'sTurberculin (inactivatedMycobacteriurn bovis lysate) 0.004 ng/mL Inactivated Apergillus fumigatus Apergillus flavus, and Apergifus 6.94 ig/mL terreus lysate in equal parts. Inactivated Neisseria gonorrhoeae lysate 6.94mg/nL

Tetanus toxoid 50 unitsof Lf/mL Inactivated Streptococcus equinusStreptococcus bovis, and 6.94 pg/mL Streptococcus ofthe viridans group lysate in equal parts. Inactivated Candida albicans lysate inactivated Candida parapsilosis 6.94yg/mL lysate, inactivated Candida glabrata lysate in equal parts, InactivatedSalonellatyphL Salmonella paratypbi and Salmonella 634 g/mt enterica lysate in equal parts. Inactivated Chlamydia trachoimatisGhlanydia pstaci, and Chaxnydia 6.94 g/mL pneumoniae lysate in equal. pans Inactivated enteropathogenic (EPEC)"shiga-like"toxin producer 6.94 pg/nl (STEC), enteroaggregative (EAEC) enterotoxigenic (ETEC), enteroinvasive (EIEC) and extraintestinal (ExPEC) Escherichia coli lysate in equal parts. inactivated Iebsiella oxytoca and Klebsiellapneumonialysate in 6.94 uglmL equal parts Antigens of the rubella virus (WistarPRA 27/3Mstrain) 0,000 TDCI50/mL Inactivated antigen of the Vaccinia (smallpox) virus lysate Jto10x PFU/niL Inactivated YF-17Dlysate 000,00o PFUJ/mL Glycerol 500 mg/mL t2.5n2mg/tmL Water

Composition 23: Component Concentration inactivated Mycobacterium tuberculosis lysate 0,004 ng/mL Inactivated Mycobacteriun avium lysate 0.004 ng/mL

Koch's Turberculin (inactivated Mycobacterium bovis 1ysate) L04 ng/mL Inactivated Neisseria meningitidesU-sate 6 .94 gg/mL -Diplhtheria toxoid 67 units of ____ ___ ___ ____ ___ ___ ____ ___ ___ ___ LfrnL Tetanus toxoid 50 units of Lf/mL *InactivatedStreptococcusagalactiae lysate inactivated Streptococcus 634 g/ml mix (Streptococcus pyogenes Streptococcus pneumoniae and Enterococcus faecalis) lysate in equal parts. tativated Candidaalbicans lysateinactivated Cididaparapsilosis 6594 pg/mL lysate, inactivated Candida glabrata lysate im equal pats Inactivated Epidernophyton floccosum, Microsporum cans, 694 gg/mL Thchophyton mentagrophytes of the interdigitale variety lysate in equa parts) inatvated Helicobacter pylori lysate. 6.94 pg/mL Knactivated Serratia marcencens e Serratiaiquefaciens lysate 6.94 ggnL Inactivated aionellatyphi,SalmonellaparatyphiandSalmonella 6,94 pg/mL enterica lysate in equal parts. Activated antigen ofIHSV- and HSV-I lysate 149231

Inactivated lysate ofantigens of the measles virus ("chwarzstrain") 10,000 TDCI50/mL niactivated Apergillusfunigatus, Apergilus flavs, and Apergillus 6.94 pg/mL. terreus lysate in equal parts Glycerol 500 mg/mL Phenol 2- mg/mL Water q&

Composition 24:

Component Concentration

Inactivated Mycobacteriumnafricanumvlsate 40.004 ng/mL Inactivated M cobacteriumtuberculosislysate 0.004ng/mL PPD-ti~e 0. 004ag/ni ERPD Inactivated Neisseriagonorrhoeae lvsate ,

10004 ngh-nL r4g/mL Inactivated Candida albicans lysate inactivated Candida arapsiosis 694 pg/nL lysateinactivated Candida glabratalysate in equal parts. inaetivated Salmonella typhi, Salmonella paratyphi arnd Salmonella 6,94 pghnL eritericalvsatein equal parts inactivated Neiseia menigidessatepgL -_ _- Diphtheria toxoid _ _ ----- j67units---... ._ L7 ni of

Lf/mL Inactivated Streptococcus equinus, Streptococcus'bovind6

Streptococcus of the viridans group lysate in equal parts. Tetanus toxoid 50 units of

inactivatedSigela flexnen and Shigella sonneilysateinequalparts 6.94 pg/mL Inactivated Proteus mirabilis, Proteus vulgaris and Proteus opener 694pg/nL lysate in equal parts Inactivated surface antigen of the hepatitis B (HBs AG) vius lysate 200pg/nL inactivated lysate of antigens of the measles virus ("Schwarz strin"). 10,000 TDCI50/mL inactivatedYF-17Dlysate 3,000,000 PFU/mL Glycerol 500 mg/mL Phenol 2.5 Water

Composition 25: Component Concentration PPD 0.004 ng/mL

Inactivated BCG lvsate 50 mg/mL Koch's Turberculin (inactivated Mycobacterium bovis lysate)I 0004 g/niL InactivatedStreptococcus pyogenes lysate, inactivated Streptococcis 6.94ugnL pneumonie 'Pueniomyatelysate,,Enterkyococcuincitetahlocs Enterococcus faecalis lysate in equalparts. 6.4gnU InactivatedStaphylococcus aureus lysate inactivated Staphylococcus 6 4 pg/m epidermidis lysate in equal parts. Diphtheria toxoid 67units of LEI mL Ketanus toxoid 50 units of IfsmL Inactivated Salmonela typhi, Salmonella paratyphi and Salmonella 6.94 gg/nL enteica lysate in equal parts, Inactivated Epidennophyton floccosumn Microspoum cannis, 6.94 pg/mL Trichophyton mentagrophytes ofthe interdigitale variety lysate in equal parts) Inactivated Acinetobacter baumannii lysate. 6.94 gg/mL Inactivated enteropathogenic (EPEC) "shiga-like"toxin producer 6,94 gmL (STEC), enteroaggregative (EAEC), enterotoxigenic (ETEC), enteroinvasive (EIEC)and extraintestinal (ExPEC) Escherichia coli lysate in equal parts. Inactivated Candida albicans lysate, inactivated Candida parapsilosis 6.94gg/mL lysate, inactivated Candida glabrata lysate in equal pats. Inactivated Apergillus fUmigatus, Apergilus flavus, and Apergillus 6.94 pg/mL terreus lysate in equal parts. Inactivated lysate of antigens of the mumps virus (Urabe AM9 strain) 50.000 DCI50/mL Activated antigen of the Vaccinia (smallpox) virus ysate I to10 x 109 PFU/mL Glycero 00 mg/ Phenol 2 .5smg/mL

Water

Composition 26 Component Concentration Koch'sTurberculin(inactivated Mycobacterium hovis yst 0,004 nghL Inactivated Mycobacterium tuberculosislysate 0004ngmL Inactivated BCG lysate Inactivated Apergillusfumigatus, Aprllsflavus and Apergillus 6.94 pg/IL *terreus lysate in equal parts. dStrepnoccusjyogenelysate, inactivatedStreptococcus 6.94p /mL pneumonie lysate, Enterococcus faecalis lysate in equal parts. Inactivated Chlamydiatrachonatis, Chlamdiapsittaci, and Chamyda 46.9pg/miL pneumoniae lysate in equal parts Bordetella pertussis toxoid 75gg/mL Inactivated Haemophiius influenzalysate 6.94g/m Inactivated Neisseria gonorrhoeae lysate 6,94 mig/mL Tetanus toxoid 50 units of Lf/mL Inactivated Candida lbicans iysate,inactivatedCandidaparapsi osis 6.94 g/ML lysate, inactivated Candida glabrata lysate in equal parts. Inactivated enteropathogenic (EPEC), "shiga-ike"toxin producer 6.94.pg/mL I(STEC), enteroaggregative (EAEC), enterotoxigenic (ETEC), enteroinvasive (EIEC) and extraintestinal (ExPEC) Escherichia col lysate in equal parts. inactivated Polio virus sate 40 UD of type I antigens; 1.8 UD of type 2 antigens; 32 UD of type 3

Inactivated antigen of the Vaccinia (smallpox) vims lysate I to10x161 PFU/mL nactivated YF-17D lysate 3:000,000 PFU/mL

Composition 27: Component Concentration Inactivated YF-7D lysate PFU/mL ---- --------------- 4-- Koch's Turberculin (inactivated Mycobacterum bovis ysate. 0.004 ng/mL Inactivated BCG lysate 0 mg/nL PPD 0.004 ngImL Inactivated Mycobacterium tuberculosis lysate 0.004 ng/mL Inactivated Staphylococcus aureus lysate, inactivated Saphyococcus 694 g/mIL epidennidis lysate in equal parts Inactivated Streptococcus pyogenes lysate, inactivated Streptococcus 6 94 pg/mL pneumonia lysate Enterococcus faecalis lysate in equal parts, Inactivated Klebsiella oxytoca and Klebsiella pneumonia lysatein 6,94 g/rL equal parts Inactivated Neisseriarmeniingitides lysate 6,94 ig/mL Inactivated Candida albicans lysate, inactivated Candida parapsilosis 6-94 pg/mL lysate, inactivated Candida glabrata lysate in equal parts. inactivated Streptococcus equinus. Streptococcus bovisand 6.94 pg/nL Streptococcus of the viridans group lysate in equal parts Inactivated Epidennophyton floccosuriMicrosporwacannis., 694 pg/mL Trichophyton mentagrophytes of the interdigitale variety lysate in equal parts). Inactivated Shigella flexnei and Shigella sonnei lysate in equal parts 6.4 pg/nL Inactivated enteropathogenic(EPEC),"shiga-like" toxin producer 6.94pg/mt (STEC), enteroaggregative (EAEC), enterotoxigenic (ETEC), enteroinvasive (IEC) and extraintestinal (ExPEC) Escherichia coli lysate in equal parts Inactivated Salmonella typhiSalmonella paratyphi and Salmonella 6.94 pg/mL enterica lysate in equal parts Bordetela pertussis toxoid 75 gg/mL Inactivated antigen of the Vaccinia smallpoxo) vijrus lysatie 1Ito 10ox 10) PFU/mL Inactivated Apergiius fuimigatus, Apergillus flavus andApergilhus 6.94 pg/mL terreuslysate in equal parts Inactivated lysate of antigens of themeasles virus (Schwarz strain"). 10,000 TDCI50/mL Glycerol 500 mg/mL Phenol 2.5 mg/mL Water

Composition 28: Component Concentration nactivatedMycobacterium tuberculosis sate O04 ng/mL Koch's Turberculin (inactivated Mycobacterium bovis ysate). 0.004 ug/mL Inactivated.Mycobacterium avium lysate .0004 ng/nL Inactivated Staphylococcus aureus lysate, inactivated Staphylococcus 6.94 pg/raL epidenmidis lysate in equal parts inactivated Streptococcus pyogenes lysate, inactivated Streptococcus 6.94 pg/mL pneumonia lysate, Enterococcus faecalis lysate in equal parts --------------- Inactivated Epidermnophyton floccosum,Microsporum cannis, 6.94 ig/nL Trichophyton mentagrophytes of the interdigitale variety lysate in equal parts). Inactivated Neisseria meningitides lysate 6.94 g/mL Streptokinase derived from inactivated beta4iemolytic Streptococcus 0.444 pgmnL lysate purification

Dornase derived from inactivated betaaemolyvtic Streptococcus lysate 0.111 pg/rnL purification Inactivated Salmonella typhi Salmonella paratyphi and Salmonella 6.94 pg/mL etenca lysate in equal parts. Inactivated Streptococcus agalactiae lysate- inactivated Streptococcus 694 pg/mL mix(Streptococcus pyogenes Streptococcus pneumoniae and Enterococcus faecalis)lysate in equal parts. inactivated Enterobacter aerogenes, Enterobacter cloacae and 6.94 g/mL Enterobacter agglomerans group ysate. Inactivated Helicobacter pylorilysate. 6.94 g/mL Tetanus toxoid 50 units of Lf/mL Inactivated enteropathogenic (EPEC) "shiga4ike"toxin producer 6,94 pg/mL (STEC), enteroaggregative (EAEC), enterotoxigenic (ETEC) enteroinvasive (EIEC) and extraintestinal (ExPEC) Escherichia co lysate in equal parts. Inactivated antigen of the Vaccinia (smallpox) virus lysate Ito10x 10

Inactivated Candida albicans ysate, inactivated Candida parapsilosis 6.94 pg/mL lysate, inactivated Candida glabrata lysate in equal parts. Inactivated Apergillus fanigatus, Apergillus flavus, and Apergillus 6.94 pg/mL terrenssate in equal parts Inactivated YF-17D lysate 3,000,000 PFU/mL Glycerol 500 mg/mL Phenol 2.5 mgmL Water q.s.

Comuposition 29: Component Concentration

Inactivated lysate of antigens ofthe mumps virus (Urabe AM9 strain) .50,000 TDCI50/rnL Inactivated BCG lysate 50 mg/nL activated Mtycobacteium tuberculosis lysate 0.004 ngrnL Koch's Turberculin activatedd Mycbactrium bovis lysate). 0.004 ng/mL InactivatedMycobacteriumilepraelysate U0d4tg'mL uacivatedStaphylococcus aureus lysate, inactivated Staphylococcus 6.94 pg/L epidermidislysate in equal parts. InactivatedStreptococcus equinus, Streptococcus bovis, and 694 pg/mL Streptococcus of the viridans group lysate in equal parts. Inactivated Serratiamarcencens and Serratia liquefaciens lysate 6.94 pg/mL Inactivated Epidermophyton floccosum, Microsporum cannis, 6.94 pg/mL Trichophyton mentagrophytes of the interdigitale variety lysate in equal pasts). Inactvated Haemnophius influenza lysate- 6.94 pg/nL Inactivated Streptococcus agalactiae lysate, inactivated Streptococcus 6.94 gg/mL mix (Streptococcus pyogenes, Streptococcus pneumoniae and Enterococcus faecalis) lysate in equal parts. Inactivated enteropathogenic (EPEC), "shigadike" toxin producer 6,94 pg/mL

(STEC), enteroaggregative (EAEC), enterotoxigenic (ETEC), enteroinvasive (EIEC) and extraintestinal (ExPEC) Escherichia col ysate in equal parts. Tetanus toxoid 50 units of LfiL

Inactivated Proteus mirabilis, Proteus vulgaris, and Proteus penerii 6.94 pg/nL lysate.in equal parts. Inactivated Sahnonella typhi, Salmonella paratyphi and Salmonella 6.94pug/mL enterica lysate in equal parts. Inactvated Apergillus fumigatus, Apergillus flavus, and Apergialus 6.94gg/mL terreus lysate in equal partsJ

I Inactivated lysate of antigens ofthe measles virus ("Schwarz train-"). 10,000 TDCI50/nl Inactivated Candida albicans lysae, inactivated Candida parapslosis 6.94 pg/mL lysate, inactivated Candida glabrata lysate in equal parts. Inactivated antigen of the Vaccinia (smallpox) virus lysate I to 10x1 PFU/nL Glycerol 500 mg/nL Phenol 2. mg/nL Water q.s.

Composition 30: Component Concentration

Inactivated Apergilius fumigatus, Apergillus flavus, and Apergilhus 6.94 pg/mL terreus lysate in equal pas. Inactivated Mycobacteriun africanumlysate 0,004ng/mL

IKoch's Turberculin (inactivated Mycobacteriuan bovis lysate) 0.004 ngnIL Inactivated BCG lysate 50 mg/mL Inactivated Mycobacterium tuberculosis lysate 0 004 ng L Inactivated Streptococcus equinus, Streptococcus bovis, and 6.94 g/mL Streptococcus of the viridans group lysate in equal parts Inactivated Staphylococcus aureus lysate, inactivated Staphylococcus 6.94pg/mL epidennidis lysate in equal parts. inactivatedNeisseriameningitides lysate ghnl '64

IDiphtheria toxoid 67 units of

inactivated enteropathogenic (EPEC),"sigaike" toxinproducer 6.94 pg/mL

(STEC), enteroaggregative (EAEC) enterotoxigenic (ETEC), enteroinvasive (EIEC) and extraintestinal (ExPEC) Escherichia coli lysate in equal parts. Inactivated Epidermophyton foccosuni Microsporm cannis, 94p/mL

Trichophytonmentagrophytes ofthe interdigitale variety lysate in equal parts). Inactivated Sahonelatyphi,Sahnonella paratyphi and Salmonela 6,94 pg/mL enterica lysate in equal parts. Inactivated Acinetobacter baumanniisa 6.94 sg/mL Inactivated Helicobacter pylori lysate 6,94 pg/mL InactivatedHaemophilusinfluenza lysate. 6.94 pg/mL Inactivated YF-47D lysate 3 000;000 PFU/mL Inactivated lysateofatigensof the mumps virus (Urabe AM9 strain) 50,000 TDC150/mL Inactivated Polio virus lysate 40 UD of type I antigens; 1.8 IUD oftype 2 antigens; 32 UD of type 3 antigens

Inacuvated Candida albicanslysate, inactivated Candida parapsilosis 6.94 ig/mL lysate, inactivated Candida glabrata lysate in equal parts. GIVOCTO-1500 mg/mL Grivcerol 0 gm Phenol .mS nL Water

Composition 31: Component Concentration

Inactivated Salmonella typhi, Salmonella paratyphi and Salmonella 6-94 pg/mL :ntepricalysateinequalparts. inactivaed Mycobacteriumleprae lysate 0.04 ng/mL Koch's Turberculin (inactivated Mycobacterium ovis lysate) 0.004 ng/nmL 1...~~---- Inactivated Mycobacteriurntuberculosis lysate ____4_____ -..-.--..................--- 0.004 ng/mxL ___ J

PPD 0004ngrL Inactivated Staphylococcus aureis ivsate, inactivated Staphylococcus 6.94 jg/niL epidennidis lysate in equal parts. Inactivated Streptococcus pyogenes lysate inactivated Streptococcus 6-94 pg/mL pneumonia lysate, Enterococcus faecalis lysate in equal parts. Diphiheria toxoid 67 units of L/mL InactivatedNeisseria gonorrhoeae lysae 6 94mg/mL Inactivated Streptococcus agalactiac lysate, inactivated Streptococcus 694 pg/mL mix (Streptococcus pyogenes, Streptococcus pneumoniae and Enterococcus faecalis) lysate in equal parts Inactivated Epidermophyton floccosum, Microsporurn cannis, 6,94pg/mU Trichophyton mentagrophytes of the interdigitale variety lysate in equal parts), Inactivated Neisseria meningitides lysate 6,94 pg/mL Inactivated enteropathogenic (EPEC), "shiga-ike" toxin producer 6.94 pg/mt (STEC) enteroaggregative (EAEC), enterotoxigenic (ETEC), enteroinvasive (EIEC) and extraintestinal(ExPEC) Escherichia coli lysate in equal parts. Inactivated Haerophilus influenza lysate. 6.94 pg/mL Inactivated Proteus uirabilis, Proteus vulgaris and Proteus pener 6.94 pgh lysate in equal parts. Inactivated Serratiamarencens e Serratia liquefaciens lysate 6-94 pg/mL Inactivated Candida albicanslysate. inactivated Candida paraps losis 6.94 pg/mL Mysate, inactivated Candida glabrata lysate in equal parts, Antigens of the rubella virus (Wistar RA 27/3M stram) 10,000 TDC 50/mL Inactivate antigen ofthe Varicella zoster virus lysate 149 231 PFU/mLt

Inactivated Apergillus fumigatus, Apergillus flavus, and Apergillus 6.94_pg/mt terreus lysate equal parts Glycerol 500 mg/mL Phenol 2.5 ma/mL IWater q.s

Composition 32: Component Concentation Inactivated Candida albicans lysate, inactivated Candida parapsilosis 6.94 pg/ML lysate inactivated Candida glabrata lysate in equal parts. Inactivated Mycobacterium avium .ysate 0,004 ng/mL Inactivated Mvcobacterium kansasiilysate 0,004 ng/mL Koch s Turberculin (inactivatedMycobacterium bovis lysate). 0.004 ng/mL Inactivated BCG lysate 50 mg/mL Inactivated Apergillus fumigatus, Apergillusfl avus and Apergilus 6.94 pg/mL terreus lysate in equal parts. Inactivated Neisseriagonorrhoeaelysate 6.94 mg/mL Tetanus toxoid 50 units of

Inactivated Streptococcus pyogenes lysate, inactivated Streptococcus 6.94 pg/mLJ pneumonia lysate, Enterococcusfaecalis lysate in equal parts. Inactivated'Streptococcus equinus, Streptococcus bovis, and 6.94 ig/mL Streptococcus of the viridans group lysate in equal parts Inactivated Epidermopbyton floccosun, Microsporum cannis, 694 pg/mL Trichophyton mentagrophytes of the interdigitale variety lysate in equal parts). Inactivated Sahnonella typhi, Salmonella paratyphi and Salmonella 6.94 g/inL enterica lysate in equal parts. Inactivated Helicobacter pylori lysate , 6.94 gmAnL inactivated Chlamydia trachomatis, Chlamydia psittaci, and Chamydia 6.94 ig/mL pneumoniae lysate in equal parts.

Inactivated enteropathogenic (EPEC), "shigadike" toxin producer 694 ug/mL (STEC), enteroaggregative (EAEC), enterotoxigenic (ETEC), enteroinvasive (EIEC) and extraintestinal (ExPEC) Escherichia coli lysate inequal pars. Inactivated Klebsiella oxytoca and Klebsiella pneumonialysate in 6,94ag/ equal parts Antigens of the rbella virus (istar RA 27/3M strain) 0,000 TDCI50/niL

Inactivated antigen of the Vaccinia (smallpox) virus lysate 1 tol 0x1 PFU/mL

Inactivated YF-I7D lysate 3,000,000 PFU/mL

Glycerol 500 mg/miL ______-------_ - ________ --- ------ --------------

Phenol 25 mgn/mL Water j

Composition 33: Component Concentration

inactivatedenteropathogenic(EPEC),"shiga-ike'toxinproduce 6.94 pg/mL (STEC), enteroaggregative (EAEC), enterotoxigenic (ETEC), enteroinvasive (EIEC) and extraintestinal (ExPEC) Escherichia cohl lysate in equal parts. hiactivated Mycobacterium leprac lysate 04 ng/m Inactivated Mycobacterium avium lysate 0004 ng/mL Koch's Turberculin (inactivated Mycobacterium bovis lysate). 0.004na/niL Inactivated Mycobacterium tuberculosis lysate 0.004 ng/mL

inactivatedNeisseria meningitides lysate 6.94 pg/mL Diphtheria toxoid 67 units of !-X/mL

Tetanustoxoid 50 units of

Lfim L Inactivated Streptococcus pyogenes lysate, inactivated Streptococcus 6.94 ghnL pneumonic lysate, Enterococcus faecalis lysate in equal parts. Inactivated Apergillus fumigatus, Apergillus flavus, and Apergillus 6,94pg/mL terreus lysate in equal parts. Inactivated Candida albicans lysate, inactivated Candidaparapsilosis 6.94 ighnL sate- inactivated Candida glabrata lysate in equal parts. Inactivated Shigella flexneri and Shigella sonnei lysate in equal parts 6.94 pg/mL Inactivated Helicobacterpylori lysate. 6,94 g/nL Inactivated Serratia marcencense Serratia liquefaciens lysate 6,94 pg/imL

Inactivated Salmonella typhi Salmonella paratyphi and Salmonella 6.94 pg/mL enterica lysate in equal parts Inactivated antigen ofthe Vaccinia(smallpox) virus lysate I.to 10 X 10 PFUJ/mL Inactivated antigen of HSV-l and HSV-H lysate 149 231 PFU/mL Inactivated lysate of antigens of the measles virus(Schwarz strain"). 10,000 TDC150/mL Gcerol 500 mg/mL

Phenol 2.5 mg/nL Water q-s

Composition 34: Component Concentration

Inactivated Candida albicans lysate, inactivated Candida parapsloss 6.94 pg/mL lysate, inactivated Candidaglabrata lysate in equal parts. InactivatedMycobactenium aficanumlysate 0.004 ng/mL Inactiated Mycobactenum tuberculosis lysate 0.004 nghnL PPD 0 004 ng/mL Inactivated BCG lvsate 50 mg/mL

Tetanustoxoid 50 unitsof LnL Inactivated Streptococcus pyogenes lysate, inactivated Streptococcus 6.94 pg/mL pneumonic lysate,Enterococcus faecalis lysate in equal parts. Inactivated Salmonella typhi, Salmonella paratyphi and Salmonella 6 94 g/mnL ertericalysate in equal parts. Inactivated enteropathogenic (EPEC), "shigaike"toxinproducer 6.94 gg/mL (STEC), enteroaggregative (EAEC), enterotoxigenic (ETEC), enteroinvasive (EEC) and extrintestinal (ExPEC) Escherichia col lysate in equal parts. InactvatedNeissena menigitides lysate 6,94 gg/rL Diphtheria toxoid 67 units oLf /mL InIcivated Streptococcus equinus, Streptococcus bovis, and 6.94 g/nL Streptococcus of the viridans group lysate in equal parts. Inactivated Apergillus fumigatus, Apergillus flavus, and Apergiflus 6.94 gg/mL terreus lysate in equal parts. Inactivated Shigella flexni and Shigella sonnei lysate in equal parts 6.94 pg/mL Inactivated Proteus mirabilis, Proteus vulgaris, and Proteus peneru 6.94 g/mL lysate in equal parts. Inactivated surface antigen of the hepatitisB (HBs AG) virus lysate 200 pg/nmL Inactivated lysate of antigens of the measles vius ("Schwarz strain"). 10,000 TDCI50/mL

Inactivated YF-7D lysate 3,000,000 PFU/mL

Glycerol 500 mg/mL Phenol 25 mg/mL Water i Composition 35: Component Concentration

Inactivated Candida albicans lysate inactivated Candida parapsilosis 6 94 pg/mL lysate, inactivated Candidagabrata lysate in equal parts. PIPD 0.004ng/ml Inactivated BCG lysate 50 mg/mL Koch's Turberculin (inactivated Mycobacterium bovis lysate). 0004 ng/mL Inactivated Mycobacterium tuberculosis lysate 0,004 ng/mL Inactivated Streptococcus pyogenes lysate inactivated Streptococcus 6.94 yg/mL pneumonie lysate, Enterococcus faccalis lysate in equal parts. Inactivated Staphylococcus aureus lysate, inactivated Staphylococcus 6.94 pg/mL epidennidis lysate in equal parts. Inactivated Epidermophyton floccosum, Microsporm cannis, 6.94 pg/mL Trichophytonmentagrophytes ofthe interdigitale variety lysate in equal parts). Inactivated Neisseriameningitides lysate 6.94 pg/mL Tetanus toxoid 50 units ofLfimL Diphtheria toxoid 67 units of Lf/mL Inactivated Streptococcus equinus Streptococcus bovis, and 6.94 pg/mL Streptococcus of the viridans group lysate in equal parts. inactivated Serratiamarcencens e Serratia liquefaciens lysate 6.94 g/nil Inactivated Acinetobacter baumannii lysate. 6.94pg/mL Inactivated enteropathogenic (EPEC)tshiga-like"toxin producer 6.94pg/mL (STEC), enteroaggregative (EAEC), enterotoxigenic (ETEC), enteroinvasive (EIEC) and extraintestinal (ExPEC) Escherichia coli lysate in equal parts. Inactivated Salmonella typhlSanonella paratyphi and Salmonella 6.94 pgJmL enterica lysate in equal parts, Inactivated YF-17D lysate 3,000,000 PFU/mL Inactivated Apergillus fumigatus, ApergillIus flavus, and Apergillus 6.94 pg/nL terreus lysate in equal parts. Inactivated lysate of antigens ofthe mumpsvirus (Urabe AM9 strain) 50,000

TDCI50/mnL activated antigen of the Vaccinia (smallpox) virus lysate I to 10x 109 PFU/mL Glycero 500 mg/m L Phenol 2.5 mg/mL Water q.s.

Composition 36: Component Concenttion Inactivated Apergillus famigatus, Apergillus flavus, and Apergillus 694 pg/mL terreus lysate in equal parts. Koch's Turberculin (inactivated Mycobacterium bovis lysate). 0,004 ng/mL Inactivated Mycobacterium tuberculosis lysate 0.004 ng/mL Inactivated BCG lysate 50mg/mL PPD )urified protein derivative) 0004 ng/mL Inactivated Streptococcus pyogenes lysate, inactivated Streptococcus 6-94 glmL pneumonia lysate, Enterococcus faecalis lysate in equal parts. InactivatedChlamydiatrachomatis,Chlamydia psittaci.andChamydia 6.94 glmL pneumoniae lysate in equal parts. Inactivated Epiderophyton floccosum, Microsporum cannis 6.94 pg/mnL Trichophyton mentagrophytes of the interdigitale variety lysate in equal parts). Bordetella pertussis toxoid 5g/nL Inactivated Haermophilus influenza lysate. 6,94 pg/mL Streptokinase derived from inactivated beta-henolytic Streptococcus 0444 pg/aL lysate purification. Domase derived from inactivated betahemolytic Streptococcus lysate 0 111 gg/mL purification, Inactivated Sahnonela typhi, Salmonella paratyphi and Salmonella 6.94 pgnL entenca lysate in equal parts

Tetanus toxoid 50units of fnL Inactivated surface antigenofthe hepatitis B (HBs AG) virus lysate 200 pg/mL Inactivated enteropathogenic (EPEC), "shiga-ike" toxin producer 6.94 pg/mL (STEC), enteroaggregative (EAEC), enterotoxigenic (ETEC), enteroinvasive (ETEC) and extraintestinal (ExPEC) Escherichia col lysate in equalparts. Inactivated Candida albicans lysate, inactivated Candida parapsilosis 6.94 pg/mL lysate, inactivated Candida glabrata lysate in equal parts. Inactivated Polio virus lysate 40 UD of type I antigens; 1.8 UD of type 2antigens; 32 UD of type 3 antigens Inactivated antigen of the Vaccinia (smallpox) virus lysate I to lox 1 PF/L Inactivated YF 7D ate 3,000,000 PFU/mIL flycero 500 mghL Phenol 25 mg/L Water

Whenthere are parasitic diseases, associated or to be fought the formulationswill preferentially contain antigenic agens of parasitic origin. In this case, according to the concept described in the present invention,the formulations should comprise antigenic agents originaing from the most prevalent parasites forwhich the individuals have more memory cells,accordingto the geographic distribution and the local and regional human development (developed or non developed countries). Such parameters are determinant for the occurrence of these parasites and the existence of corresponding memory cellsin the immunesystem of the population of a given region.

Composition 37: Association of Composition 2 with:

Concentration Component Inactivated Toxoplasmagondii lysate 400 pg/mL

Composition 38: Association of Composition 3 with: Component Concentration Inactivated Giari lamblia lysate 0pghnL

Composition 39: Association of Composition 4 with: Component Concentration

Inactivated Entamoeba histolticalysate 400gg/mL

Composition 40: Association of Composition 5with: Component ________-Concentration

Inactivated Ascaris lumbricoides lysate 400 p.g/mL

Composition 41: Association of Composition 6 with: Component Concentration Inactivated Enterobius vermicularis lysate 400 gg/mL

Composition 42: Association of Composition with: Component Concentrtion Inactivated Entamoeba histolyticalysate 400 g/mL ----- __ __ - - - ------- -___-_-------_-V

inactivated Ascarislirbicoides lysate --- - 400 pg/mL 3 Composition 43 :Association of Composition with: Component ConcentationU

Inactivated Giardi lamblia lysate 400tg/ImL activated Enterobius vermicularis lysate 400 gg/nL

Composition 44: Association of Composition 9,with:

Component Concentration Inactivated Strongyloides stercoralis lysate 400 ig/mL Inactivated Entamoebaihistolytica sate g400pg/mL

Composition 45: Association of Composition 10 with Component Concenration Inactivated Giardia lamblialysate 400 pg/mL Inactivated.Ascaris umbricoides lysate 400 pg/mL

Composition 46 Association of Composition 11 with: Component Concentration Inactivated Toxoplasma gondii lysate 400 pg/mL Inactivated Entamoeba histolyticalysate 400 g/nL

Composition 47: Association of Composition 12 with Component Concentration Inactivated Strongyloides stercoraislysate 400 pgimL Inactivated Cryptosporidium spp. lysate 400 gg/mL

IComponent Composition 48: Association of Composition 13 wth:

Inactivated Ascaris lumbricoides lysate Concentration 400 ig/mL lactivated Toxoplasma gondii lysate 400 gg/mL

Composition 49: Association of Composition 14with: Component Concentration Inactivated Entamoeba histolytica lysate 400 gg/mL inactivatedGiardialaiblia lysate 400 gg/mL

Composition 50 Association of Composition 15with:

Component oncentration iInactivated Strongyloides stercora is1'sate 400 g Inactivated Enterobius vemaicularis lysate 400 pghnL

Composition 51: Association of Composition 16 with: Component Concentation Inactivated Trehomonas vaginalis lysate 400 pg/mL Inactivated Ascaris lumbricoides lysate 400 pg/mL

Composition 52: Association of Composition 17 with: Component {Concentration Inactivated Entamoeba histolytica lysate 400 pg/mL Inactivated Ascaris lumbricoideslysate 400pg/mL Inactivated Enterobius vermicularis lysate 400 pg/mL

Composition 53: Association of Composition 18 with: Component IConcentration activated Giardia ambiiaysate 400 pg/mL Inactivated Enterobius vennicularis lysate 400gg/mb inactivatedTooplasma gondii lysate 400 pg/mL

Composition 54: Association ofComposition 19 with, Comment Concentration Inactivated Strongyloides stercoralis lysate 400pg/mb Inactivated Entamoeba histolytica lysate 400 pg/mL Inactivated Giardialamblialysate 400 pg/mL

Composition 55:Association of Composition 20 with: Component Concentration Inactivated Giardia lamblia lysate 400 g/mL

Inactivated Ascaris lumbricoides VSate 400 pg/mL Inactivated Strongyloides stercoralis lysate 400 gln/mL

Composition 56: Association of Composition 21 with. Component IConcentration Inactivated Toxoplasma gondii lysate ____________iv__ ________ ____ O u/rr4 L Inactivated Entamoeba istolytica lysate 400 gg&n Inactivated Giardia lanblia lysae 400 pg/mL

Composition 57: Association of Composition 22 with: Component oncntration Inactivated Strongyloides stercoralis lysate 400 g/mL. Inactivated Cryptosporidium spp lysate 400 g/mL Inactivated Entamoeba histolyticalysate 400 pg/mL

Composition 58: Association of Composition 23with: Component Concentraton Inactivated Ascaris lumbricoides lysate 400 4g/mL nactivated Toxoplasma gondii lysate 400 g/mL ] inactivated Enterobius vennicularislysate 400 g/mL

Composition 59: Association of Composition 24 with: Component Concentration Inactivated Entamoeba istolytica lysate 400 gg/mL Inactivated Giardialamblia lysate 400 gg/mL Inactivated Ascaris lumbricoides lysate 400 pg/mL

Composition 60: Association of Composition 25 with: Component Concentration InactivatedStrongyloides stercoralis lsate 400 pg/mL

Inactivated Enterobius vermicularis lysate 400 pg/mL Inactivated Entamoeba histolytica lysate 400 pg/mL

Composition 61: Association of Composition 26 with: Component Concentration

Inactivated Trichomonas vaginas lysate 400 pg/mL Inactivated Ascaris lumbricoides lysate 400 pg/mL Inactivated Giardia lamblia lysate 400 pg/mL

Composition 62: Association of Compositioa 27 with: Component Concentration

Inactivated Entamoeba histolytica lysate 400 g/mL

Inactivated Ascaris lumbricoides lysate 400 pg/mL

inactivated Enterobius vermiculais lvsate 400 pg/mL

Inactivated Cryptosporidium spp. lysate 400 pg/mL

Composition 63: Association of Composition 28 with Component Concentration

nactinvated Giardia lamblia lysate 400 /igmL

Inactivated Enterobius vermicularis lysate 400 pg/mL

Inactivated Toxoplasma gondii lysate 400 pg/mL

Inactivated Ascaris lumbricoides lysate 400 ig/mL

Composition 64: Association of Composition 29 with: Component Concentration

inactivated Strongyloides stercoralis lysate 400 ptg/mL

inactivated Entamoeba histolytica lysate 400 pg/mL Inactivated Giardiaambiia lysate 400 pg/mL Inactivated Enterobius vennicularis lysate 400 g/mL

Composition 65: Association of Composition 30with

IComponent Concentration Inactivated.Giardia lamblia lysate 400 pg/mL Inactivated Ascaris lumbricoides lysate 400 pg/mL Inactivated Strongyloides stercoralis lysate 400 pg/mL Inactivated Entarnoeba histolyticalysate 400 pg/mL

Composition 66: Association of Composition 31 with Component Concentration Inactivated Toxoplasmagondii lysate 400 pg/mL

inactivatedEntamoebahistolyticalysate 400 pg/mL

Inactivated Giardialamblia lysate 400 pg/mL Inactivated Enterobius vermicularis ysate 400 pg/mL

Composition 67: Association of Composition 32 with Component Concentration

Inactivated Strongyloides stercorals lysate 400 pg/mL inactivated Cryptosporidium spp lysate 400 pg/mL T 400pg/mL nactivated Entamoeba histolytica lysate Inactivated Ascaris lumbricoides lysate 400 pg/mL

Composition 68: Association of Composition 33 with Component Concentration Ilnactivated Ascaris lambricoides lysate 400 pg/ml

inactivated Toxoplasma gondui lysate 400 g/mL Inactivated Enterobius vermicularislysate 400 pg/mL Inactivated Cyptosporidium spp lysate 400 pg/mL

Composition 69: Association of Composition 34 with:

Component Concentration

InactivatedEntamoeba histolytica lysate 400 pg/mL

Inaziivated Giardia lamblia lysate 400 ggmL Inactivated Ascaris lumbricoideslysate 400 g/n InactivatedTrichomonasgvainalisdysate 400 g/hnL

Composition 70: Association of Composition 35 with Component Concentration Inactivated Strongyloides stercoralis lysate 400 g/mnL Inactivated Enterobius vermicularis lysate 400 g/mL Inactivated Entamoeba histolytica lysate 400 g/mL InactivatedCryptosporidium spp lysate 400pg/nL

Composition 71: Association of Composition 36 wth: Component Concentration Inactivated Trichomonas vaginalis lysate 400 pg/mL Inactivated.Ascaris humbricoides lysate 1400 pg/mL fnactivated Giardia lamblia lysate 400 g/mL

Example 2- Treating septicemia

Patient data

Patienti- JP, 58 years old, male.

Principal diagnosis

Septicemia.

Secondary diagnoses

Polytrauma with:

Complex infected wounds with major loss of tissue of approximately 40 cn.

extensiveinfectedtissuenecrosiswithindication for amputation of the left lower limb.

infected grade 1B open fracture with osteomayelitisofthe left femur with lateral exposure.

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

Identificationand summary ofthe clinicalhistory

On January 12, 2011 the patient was admitted to theintensive Care Unit ofthe Octavian Constantine Hospital das Clinicas of Teresopolis victim of a landslide with a grade II b open fracture of the left femur with the exposure of the lateral cut and medial cut-contusion with an extension of 40 cm in depth that communicated with the exposure ofthe side. Lacerations, contusion on the left arm, back of the left foot and right lateral malleolus region, Evolved to a sepsis scenario in 24 hours, with microbiological identification ofPseudomonas aeruginosa

Conven'tionalproposedandrealizedtreatment

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

Resuts of the performed conventional treatment

Initially,it improved the septic scenario, followed by the evolution of the infection of the left lower limb withextensive areas of muscle necrosis with a high risk of amputation. 15days after the admission the sepsis got worse, with febrile episodes of 39' C, profound anemia (receiving transfusions) and exchange of the antimicrobial medication to Tazocin The patient was transferred with an aerial mobile ICU to Sao Paulo under medical supervision.

The completion of conventional treatment showed a relapse in sepsis and increased necrosis of the leftleg with an indication for amputation.

ProposedDEC0A treatment associatedwith conventional surgicaltreatment

The patient was admitted to the ICU of Hospital Alemio Oswaldo Cruz for debridement and application of treatment with DECA which took the following form:

Application of 1.8 cc ofthe DECA composition divided into 2 applications of0.9cc per composition along the 10 main lymphatic territories.

34 cm distance margin between applications to facilitate the reading ofthe evolution of the treatment at an interval of 4+1 days These applications were made together ith the surgical debridement (on average I to 2 times per week),

oAdministration of 36 extperilesional compositions of 18 cc of each DECA in two applications of 0.9 cc per set, skirting thefollowing open injuries without possibility of suture: the left inguinal region, the lateral side of the left thigh, the anterior leftthigh and medialaspect of the left thigh, instep region and left lateral malleolus of the right leg.

- Application of recombinant huan interleukin-2 at low doses, at a receptor saturation level with a concentration of 1 to 2 million units perm2 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 ofcleansing and surgical debridement under general anesthesia

Thus, the first phase of immunotherapy began on 29 January,2011 and ended onl9 March. 2011 totalling a total of nine DECA applications in.periods ranging fromone to two times per week, once the cleaning and debridement schedule was beingfollowed,intheoperatingroom

(due to the severity of the pain and risk of infection by the broad extensive exposure of internal tissues in the raw areas).

ResuIs of the treatmentwithDECA associatedwith surgical debidement and antibiotic therapy

Initial assessment ofthe patients injuries in the operating room on 29 January,2011 showed all wounds bleeding with many clots, with extensive areas of necrosis and foul-ssmelling pus. After surgical cleaning,tissue continued to peiorm poorly with a winy general appearance without any appearance of healthy granulation tissue (Figure1- AA3 and A4), As described.the

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 ofthe surgical treatment associated with DECA immunotherapy was made and it demonstrated that: red lesions, with 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 the DECA imnunotherapy was applied as noted above. On this occasion the antibiotic therapy was changed to Tazocim Meronen Cubicin and Rifampicin pending culture results.

On 01 February 2011 the result of thecultures from the injury area, peripheral blood and central cathetershowed:

in the wound of the left thigh isolation ofmultidrug-resistant Pseudomonas aeruginosa multiresistant Acinetobacter baunnamii sensitive only to polymyxin B andmuliresistant Proteus mirabiles.

-in the peripheral blood and in the central catheter the isolationofmutidrug-resistant Acinetobacter bannamii sensitive only to polymyxin B.

Concluion: These results demonstrated that the poor prognosis of injuries in the left leg led to a new sepsis episode with Acinetobacter baunnanii and because ofits iultidrug resistance and sensitivity only to polymyxin B, did not respond to treatment with intravenous Tazocim. On the other hand, it strongly supports a beneficial effect of the DECA composition injoint surgical treatment in the local andsystemic protection against this infection, since there was improvementinsystemicinfectionandinjuriesbefore the application of polymyxin B could neutralize this etiologic agent,

That day, Meronem was exchangedfor 20,000 IU 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 the remission ofthe septic scenario, which allowed the transfer of the patient from the ICU to theward thereafter (Figure I Bl B2 and B3)

On 06 February, 2011, given the toxicity of Polynyxin B administration and other antimierobialsthe patient presented a picture of acute renal failure with oliguria. As a consequence, on the period between 06 Febraary,2011 and 15 February, 2011 (12 days) administration of these antibiotics was suspended- with Linezolida (Zyvox) being introduced for protection against ahospital staphylococcal contamination. On 15 February,2011the complete remissionof renal failure in the patient was confined. in this 124day period, with only the combination therapy of debridement antibiotic prophylaxis and DECA immunotherapy the patient showed excellentoverall progress of the infectious and injuries being, after this period, able towithdraw the external fixator, have a surgical cleanup, and introduction of an internal rod for fixing the fracture on a surgery performed on 17 February, 2011. Thus, in this period, together with orthopedic surgery, there was a significantreduction in raw areas without skia with extensive tissue regeneration and no new infections.

The patient was discharged on15 March, 2011, with complete cure of the infectionofall complex injuries and wounds, including osteomyelitis. The patient was discharged without antibiotic therapy.

Concisionofthe case

The existence of a severe and widespread infection and ofa complex wound infected with with multidrug-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 ofDECA immunotherapy, antibiotics and surgical debridement for sepsis and severe infection of complex injuries.

Infected regions Premnimunotherapy cultures Result ofthe association of

(29 January, 2011) iumnunotherapy, antibiotic therapy, and surgical debridement (15 March,

12011)

Injury inthe left thigh Multiresistant Pseudornonas No signs of infection aeroginxosa,mutltiresistent

Acinetobacter baumannii only sensitiveto Aztreonam and polymyxin B

Peripheric blood mulfiresistent Acinetobacter No signs of infection baumannii only sensitive to Aztreonam and polhnyxin B

Central catheter multiresistent Acinetobacter No signs of infection baumannii only sensitive to Aztreonam and polymyxin B

Example 3: Treatingsepsis associated with urinary infections and concomitant oropharynx with terminal gastric carcinoma

PatienrnJrmaiIon Patient CMS - female, 38 years old&

Diagrosis Terminal gastric carcinoma with comorbidity of aspirative pneumonia withchemical and infection pneumonia, urinary tract and oropharyngeal infections associatedwith sepsis on 03 October 20 1. The central catheter and tracheal fluid cuWre was positive for.Pseudomonas aeruginosa(Serratia marecescens was isolatedonly in tracheal aspirates) while teurine culture had isolation of nrultiresistantKlebsielapneumoniae sensitive only to IMIPENEM and derivatives. At ICU 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 bleedingassociated with an acute anemic condition (hemoglobin 8.6 g/dL) also had hypokalaemic, hyponatremic and lymphopenic (ymphocyte count of 3000/microliter) condition.

Priorconventionaltreatment Antibiotic therapy .vasoactive drugs, respiratory support andparenteral nutrition.

Treatment withVITER

The immunotherapy treatment was performed during a single session on 04 October2011with the informed consent of the patient. VITER innnunotherapy was performed as follows:

•Application of 0.2 mL of each one of the VITER formulation (Example 1). Attenuated yellow fever virs strain 17 D204 20 g/iLnear the main 10 lymphatic teritoies.

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

Result ofimmunoherapyteatmentwith JTER On 07/10/2011, anemia and thrombocytopenia were reversed with a platelet coumt of 1 7 8,000/microliter and a platelet aggregation functioncompatible with normal parameters-We also noted the normalization of serum electrolytes. The immunostimulation caused inmunocompetence recovery and activation ofthe effector T loop as the lymphocyte count increasedfrom 3000/microliter on 03 October, 201Ito 9,400/microliter on 07/10/2011. C-reactive protein concentration was reduced to 61 mg/ indicating control the infection, it isnecessary 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 ofimmunotherapy associated with antimicrobial treatment according to CT scan of 04/11/2011 (Figure 2).

Case Conclusion

Discharge from hospital to home care on 09/10/2011. The 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 imunnostirnulatory treatment also contributes to the improvement of the patient's life quality and an amazing improvement in life expectancy. According to the state ofthe art this widespread and terminal cancer condition leads to death in about I month, while the inmunostimulation of the present invention allowed for an unexpected survival of 1 year and a half, enjoying the company of relatives

Example 4.: Treating infection (multiresistant bacteria of SAR$ in septic shock) Patientinformaion Patient AMB- female, 39 years old.

PrImery Diagnosis Severe sepsis and Septic shock

Secondary Diagnosis Presented as comorbity:

- Severe Acute Respiratory Syndrome (SARS); -Shock: - Acute Renal Failure; - Disseminated Intravascular Coagulation; - Flepatic failure signs;

Identificationandsummaryofthe clinicalhistory

On 19 April 2007 were hospitalized with dignosis of community pneunonianon-producedcugh and high fever. After 10hours of hospital admission, patient got worse requiring tranferece to Intense Care Unit (ICU) with respiratory infection and septic shock characterized by: hipotension, SARS; renal and hepatic fiure;Disseminated Intravascular Coagulation; serum lactate increase, hemodynamnic and eletrolytes colapse,

Priorcoiventionaltreatment On 20 April 2007 were treated with Ceftriaxone and Levofloxacin. Howeverafter clinical complication and ICU admission when became essential: i) start respiratory and hemodynanuc support; ii) antimicrobial regimen replace byMeropenem with Vancomicin-iii) association of plasmatransfusion 08U and IV active protein C to reverse Disseminatedintravascular Coagulation and make opsonization process possible,. Inspire of all efforts patient didnot experince any clinical and laboratory improvement.

Proposed RSwith DEC treatmentassociatedwith conventionaltreatment

The imnunotherapy treatment was performed nine sessions starting on 21/04/2011 after infoinned consent of the patient. DECA immunotherapy was performed as follows: -Application of0.2 mL of each one of the10antigenic components (1 Koch's Tuberculin ((lysate inactivated Mycobacteriumbovis0,0036ng/mL); 2.FEPD(0,0036 pg/mL);3. Lysate inactivated Staphylococcus (Staphylococcusaureus and Staphylococcus epidermidis in equal parts 6,31 pg/mL); 4Lysate inactivated Streptococcus (Streptococcuspyogenes Streptococcus pneumonie andEnterococcusfaecalisin equal parts 6,31 g/mL);5. Streptokinase derived from lysate inactivated and purified Streptococcus beta-hemolytic 0,404 pgImL);6. Donase derived from lysate inactivated and purifiedStreptococcus beta-hemolytic 0,101 pg/m); 7. Oidiomycin (antigenic extract of Candidaalbicans 6,31 ig/mL); 8. Trichophytin antigenicc extract of Tricophyton spp 6,31 tg/mLQ; 9. Lysate inactivatedEscherichiacol (EPEC 6,31 pg/nL); 10. Lysate inactivatedSalmonella(Salmonellabongori, Salmonella entericaand Salmonella suberraneain equal parts 6,31 tg/nL).

Result of immunotherapywith IRS -DECA associatedwith conventional treatment On 26 May 2007 serum eletrolytes and lactate reached normal levels and thrombocytopenia were reversed with a platelet count of 167000/mm' and a platelet aggregation function compatible with normal pammeters.ON 27.042007 SARSstill very severe and start to improve. On 29 May 2007 arterial blood gas analysis saturation and pO werereversed evidencing hemodynamic recover. The iununostimulation caused iimunocompetence recovery and activation of the effector T loop with nornalized complement fractions on 28 April 2007, the lymphocyte count decreased from 21 100/mm on 20 April 2007 (that got worse to 43.700/nm 3 on 22 April 2007) to 11 .000/nrin on 30April 2007 when CD3, CD4 and CD8 fractions presented proper levels. The 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 community pneumoma confirmed by chest X-Ray of 24/ April 2007 (Figure 3 - AI) andworsened 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 artin 15 days ofimmunotherapy (6 sessions) associated with antimicrobial treatment according to laboratories and X-Ray (Figure3- Cl) exams of06 May 2007.

Case Conclusion Discharge from hospital on 06 May 2007. The evaluated data and the clinical course ofthe 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 immunostimulatory treatment also contributes to the complete extinguish thesevere infection and an amazing improvement in life expectancy, According to the state of the art tlis inultiresistant bacteria of SARS in septic shock associated with renal and hepatic failure conditions leads to death in hours, while thein nostimulationof the present invention allowed for an unexpected survival with no sequel. In short, the clinical cases presented hereinabove demonstrate that high complexity illnesses and diseases, withobscure to very poor prognosishave been addressed more properly, with advantageous and more efficient approaches through the use of theIRS compositions the present invention.

REFERENCES 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: 1. Pulendran B. The varieties of immunological experience: of pathogens, stress, and dendritic cells Annual review of immunology. 2015;33:563-606.

2. Steinman RM Decisions about dendritic cells: past,present, and future. Annual review of immunology. 2012;30:1-22 3 Steinnan RM, Banchereau I Taking dendritic cells into medicine. Nature. 2007;449(7161):419-26, 4. Martin-Fontecha A,Baimjohan D, Guarda G, Reboldi A, Hons M, Lanzavecchia A, et al. CD4OL+ CD4+ memory T cells migrate in a CD62P-dependent fashion into reactive lymph nodes and license dendritic cells for T cell priming.The Journal of experimental medicine, 2008;205(11):2561-74. 5. Soderberg KA, Payne GW, Sato A, Medzhitov R, Segal SS, iwasaki A. Innate control of adaptive immunity via remodeling of lynph node feed arteriole, Proceedings of the National Academy of Sciences ofthe UnitedStates ofAmerica, 2005102(45):16315-20. 6. Narni-Mancinelli E Canipisi L, Bassand D, Cazareth J, Gounon P, Glaichenhaus N, et al Memory CD8+ Tcellsmediate antibacterial immunity via CCL3 activation of TNFROI+ phagocytes, The Journal of experimental medicine. 2007;204(9):2075-87 7. Jeffrey K. Rechallenging immunological memory. Nature medicine.2007;13(10):1142, 8. Weisel FJ, Zuccarino-CataniaGV, Chikina M, Shlomchik MJ.A Temporal Switch in the Germinal Center Determines Differential Output of Memory B and Plasma Cells. Immunity. 2016;44(1):116-30. 9. De SilvaNS, Klein U. Dynamics of B calls in germinal centres.Nat Rev 1nmuno 2015;15(3):137-48. 10. Sallusto F, Monticelli S. The many faces ofCD4 T cels: roles in immunity and disease. Seminars in immunology.2013;25(4):249-5 1 I1 Sallusto F, Lanzavecchia A. Heterogeneity of CD4+ memory T cells: functional modules for tailored immunity. Europeanjournal ofimmunoogy2009;39(8):2076-82. 12. Becattini S,Latorre D, MeF, Foglierini M, DeGregorlo C, CassottaA, etal.Tcell immunity. Functional heterogeneity of huan memory CD4(+) T cell clones primed by pathogens or vaccines. Science. 2015;347(6220):400-6. 13. Zhu J, Paul WE. CD4 T cells: fates, functions, and faults. Blood 2008;112(5):1557-69. 14. Sallusto F, Zielinski CE, Lazavecchia A. Human Th17subsets. European journal of immunology. 2012;42(9):2215-20.

15i Duhen1T, Duhen RLanzavecchia ASallusto FCampbell Dl.Functionally distinct subsets of human FOXP3+ Treg cells that phenotpically mirror effector T cells. Blood. 2012;119(19):4430-40. 16. Crotty S. FoUicular helper CD4 T cells (TFH). Annual review of immunology. 201l;29:621-63. 17.Zielinski CE Corti D, Mele F, Pinto D, Lazavecchia A, Sailusto F. Dissecting the human immunologic memory for pathogens. Immunological reviews 2011;240(1):40-51. 18. Townsend EC, Murakani MA Christodoulou A, Christie AL, Koster ,DeSouzaT A, et al. The Public Repository of Xenografts Enables Discovery and Randomized Phase I-like Trials in Mice. Cancer Ce., 2016;29(4):574-86, 19. In this issue. Nature Reviews Immunology 2016-16(2):69-. 20. Cerwenka A, Lanier LL. Natural killer cell memory in infection, inflammation and cancer. Nat Rev immunol. 2016;16(2):112-23. 2L Leavy 0. Immune memory: T-box tuning forTRM cell fate. Nat Rev-Imrnu ol 2016;16(2):7L 22, Mackay LK, Wynne-Jones E, Freestone D, Pellicci DGMielke LA, Newman DM, et al. T-box Transcription Factors Combine with the CytokinesTOEbetaandIL-I5to.Immunit. 2015;43(6):1101-11 LID 10.016j.immuni.2015i11i008 [doij LID - S1074-7613(15)00460-4 {pii}. 23, Bird L. nmune memory: ILC2s drive allergen recall. Nat Rev Immunol 2016;16(2)72 3 24. Halin TY Hwang YY, Scanlon ST, Zaghouani R Garbi N, Falon PG, et al, Group 2 innate lymphoid cells license dendritic cells to potentiate memory T12 cell responses. Nat Imnmunol, 2016;17(1):57-64. 25. Leavy 0 Immune memory: Sequential evolution of B cell memory. Nat Rev Inmunol. 2016;16(2):72-3. 26. Kugelberg .Immune memory: Lingering human T cells. Nat Revimmuno. 2016;l6(2):73. 27. Oliveira0, Ruggiero E, Stanghellini MT, ieri N, D'Agostino M, Fronza R, et al. Tracking genetically engineered lymphocytes long-ten reveals the dynamics of T. Sci Transl Med. 2 0 15;7(317):317ra198LID- 10-1126/scitranshmed.aac8265 [doij.

28. Mueller SN, Mackay LK. Tissue-resident memory T cells: local specialistsin imunune defence. Nat Rev Immunol. 2016;6(2)79-89. 29, Rosenblum MD.Way SS, Abbas AK Regulatory T cell memory. Nat Rev nuno. 2016;16(2):90-10L 30. Farber DL. Netea MG, Radbruch A, Rajewsky K, Zinkernagel R Immunological memory: lessons from the past and a look to the future Nat Rev Imunol. 2016;16(2):124-8. 31. Laidlaw BJ, Craft JE, Kaech SM. The multifaceted role of CD4(+) T cells in CD8(+) T cell memory. Nat Rev inmunL 2016;16(2):1,02-11 LID - 10. 1038/nri.2015.10 [doij. 32. Tubo NJ, Fife BT, Pagan A Kotov DlGoldbergM, Jenkins MK Most microbe specific naive CD4(+) T cells produce memory cells during infection. Science. 2016;351(6272):511-4 33. Flierl MA, Rittirsch D,Gao H, Hoesel LM,Nadeau BA,Day DE, et al. Adverse functions of IL-17A in experimental sepsis. FASEB journal : official publication of the Federation of American Societies for ExperimentalBiology2008;22(7):2198-205 34 Xiao H, Siddiqui 3 Remick D Mechanismsof mortalityin early and late sepsis Infection and iimunity. 2006;74(9t5227-35 35. Buras JA, Holzmann B, Sitkovsk M. Animal models of sepsis: setting the stage. Nature reviews Drug discovery 2005;4(10):854-65 36. DiPaolo RJ, Shevach EM. CD4+ T-cell development in amouse expressing a transgenic TCR derived from a Treg Eur JInununol, 2009;39():234-40. 3. Weber SU.Schewe JC, Lehmann LE, Muller S, Book M. Klaschik S et al Induction of Bim and Bid gene expression during accelerated apoptosis in severe sepsis. Crit Care. 2008;12(5):R128. 38. SchwulstSJ, MuenzerJT,Peck-PalmerOMChangKC, Davis CGMcDonoughJS,et al Bim siRNA decreases lymphocyte apoptosis and improves survival in sepsis. Shock. 2008;30(2):127-34. 39. Martignoni A, Tschop J, Goetzman HS, Choi LG, Reid MD, Johannigman JA, et al. CD4-expressing cells are early mediators of the innate innune system during sepsis. Shock. 2008-29(5):591-T 40. Schmoeckel K, Traffehn S, Eger C, Potschke C, Broker BM. Full activation of CD4+ T cells early during sepsis requires specific antigen. Shock. 2015;43(2):192-200.

4L LatifiSQORiordan MA.LevineAD.interleukin-10 controls the onset of irreversible septic shock. Infection and immunity. 2002;70(8):4441-6. 42. Querec T, BennounaS Fau~ Alkan S, Aikan S Fau - LaouarY, Laouar Y Faa~ Gorden K. Gorden K Fan ~ Flavell R, Flavell R Fau ~ Akira S, et at Yellow fever vaccine YF-17D activates multiple dendritic cellsubsets viaTLR2 J Exp Med. 2006;203(2)413-24. 43. PulendranB, Miller J, Querec TD, Akondy , Moseley N, Laur 0, eta .Case of yellow fever vaccine-associated viscerotropic disease with prolonged viremia, robust adaptive immune responses, and polymorphisms in CCR5 and RANTES genes.The Joumal of infectious diseases. 2008-198(4):500-7 44. NakayaHIPuendranBVaccinology in the era of high-throughput biology, Philosophical transactions of the Royal Society of London Series B, Biological sciences. 2015;370(1671). 45. Hagan T,Nakaya Hi, Subramaniam S, Pulendran B. Systems vaccinology: Enabling rational vaccine design with systems biological approaches. Vaccine.2015. 46. Li S, Nakaa nKinDA, O hJPulendran. Systems biological approaches to measure and understand vaccine inunnityin humans Seminars in immunology. 2013;25(3):209-18. 47. Pulendran BAhmed . nmaunological mechanisms of vaccination. Nature imunology. 2011:12(6):509-i7 48. Buonaguro L, Pulendran B. hmunogenonics and systems biology of vaccines. immunological reviews. 2011239(1:197-208. 49. Pulendran B, Li S., Nakaya H. Systems vaccinology. Immunity 2010;33(4)516-29. 50. Ahmed R, Pulendran B. Learning vaccinology from viral infections. TheJournal of experimental medicine. 2011;208(i2):2347-9 51. Edward F. McCarthy ID. THETOXINSOF WILLIAM B. COLEY ANDiTH TREATMENT OF BONE AND SOFTTISSUE SARCOMAS. The Iowa Orthopaedic Journal 2006;26 52. Waldner H. Activation of antigen-presenting cells by microbial products breaks self tolerance and induces autoinunune disease. Journal of Clinical Investigation 2004;113(7):990 7

53. Maryanski JL, Boon T. Immunogenic variants obtained by mutagenesis of mouse Mastocytoma P815 IV. Analysis ofvariant-specific antigensby selection of antigen-loss variantswith cytolytic T cell clones. Europeanjoumal of immunology. 1982;12(5):406-12. 54. Boon T, Maryanski J. Tumour cell variants with increased imunnogenicity obtained by mutagen treatment. Cancer Surv, 1985;4():135-48. 55. Koguchi Y, Thauland TI, Slifka MK Parker DC. Preformed CD40 ligand exists in secretary lysosomes in effector and memory CD4+ T cells and is quickly expressed on the cell surface in an antigen-specfic manner.Blood. 2007;110(7):2520~7. 56. Narni-Mancineli E, Soudja SM, Crozat K,Dalod M, Gounon P Geissmann F, et a]. Inflammatorymonocytes and neutrophils are licensed to kill during memory responses in vivo. PLoS pathogens. 2011;7(12):e1002457. 57. Narni-Mancineli E, Vivier E. Delivering three punches to knockout intracellular bacteria. Cell. 2014;157(6):1251-2. 58. Bajenoff M, Nami-Mancinelli EBrau F, Lauvau G. Visualizing early splenic memory CD8 T cells reactivation against intracellular bacteria in the mouse.Plos one.

10;5(7):el1524. 59. Soudja SM Ruiz AL, Marie JC, Lauvau G, Inflammatory monocytes activate memory CD8(+) T and innate NK lymphocytes independent of cognate antigen during microbial pathogen invasion. Immunity 2012;37(3):549-62. 60. Kohlhapp Fl, Kaufman HL. Molecular Pathways: Mechanism ofAction forTalimogene Laherpareupvec, a New Oncoltic Virus Immunotherapy. Clinical cancer research: an official journal of the American Association for Cancer Research. 2016;22(5):1048-54. 61. Topalian SL, Woichok JD, Chan TA, Mellman 1 Palucka K, Banchereau , eta. imnmunoitherapy: The path to win the war on cancer? Cell, 2015;161(2):185-6. 62. Kaufman HL Vaccines for melanoma and renal cell carcinoma. Seminars in oncology. 2012;39(3):263-5 63. Gimcher LH, Lindvall 0, Aguirre V,Topalian SL, Musunum K FauciAS.Translating research into therapies. Cell. 2012;148(6):1077-8, 64. NakayaHl Wrammert J, Lee EK, Racioppi L, Marie-Kunze S, Haining WN et a. Systems biology of vaccination for seasonal influenza in humans. Nature immunology. 201112(8):786-9 5

65. SallustoF,LanzavecchiaA,Araki K,AhmedK From vaccinestomemory andback Jmmunity. 2010;33(4):451-63, 66- Querec TD, Akondy RS Lee EK, Cao W Nakaya HI, Teuwen D, et al. Systems biology approach predicts immunogenicity of the yellow fever vaccine inhumans. Nature immunology. 2009;0(l):116-25, 67. Amanna i, Carlson"NE, Slifka MK Duration of humoral immunity to common viral and vaccine antigens. The New Englandjourmal ofmedicine.2007;357(19):1903-15. 68. Querec T, Bennouna S, Akan S, Laouar Y, Gorden K, Flavell R et al. Yellow fever vaccine YF-17D activates multiple dendritic cell subsets via TLR2, 7 , 8,and 9 tostmulate polyvalent iimunity The Joumal ofexperimental medicine. 2006;203(2):413-24, 69. Pulendramn B, Ahmed R. Translating innate immunity into immunological memory: implications for vaccine development. Cell. 2006;124(4):849-63. 70. Amanna I, Slifka MK, Crotty S,immunity and immunological memory following smallpox vaccination. Immunological reviews. 2006;211:320-3. 71 Alen PM, Kaufman HL, DiPaola RS. Pox viral vaccine approaches. Seminars in oncology. 2005;32(6)549-55 72. Hamnmarlund E, Lewis MW, Hansen SG, Strelow LI, Nelson JA, Sexton GJ, et al. Duration of antiviral inunnity after smallpox vaccination. Nature medicine. 2003;9(9):I131-7. 73. Crotty S, Feigner P, Davies H, Glidewell J, Villarreal L, Ahmed R. Cutting edge: long term B cell memory in humans after smallpox vaccination. Journal of immaunology. 2003;171(l0):4969-73. 74. Cono J, Casey C, Bell DM Centers for Disease C, Prevention. Smallpox vaccination and adverse reactions. Guidance for clinicians.iMMWR Recomm Rep. 2003;52(RR-4):1-28, 75. Frey SE, CouchRB, Tacket CO, Treanor JJ, WolffM, Newman FK, et al Clinical responses to undiluted and diluted smallpox vaccine.The New Englandjournal ofmedicine. 2002;346(17):A265-74. 76. Almed R, Gray D. Immunological memory and protective imnunity:understanding their relation. Science. i996;272(5258):54-60. 77 Koplan JP, Maton KJ Smallpox vaccination revisited. Some observations on the biology of vaccinia. The Americanjournal oftropical medicine andhygiene. 197524(4):656 63.

78. Theiler M, Smith HR. The Use ofYellow Fever Vis Modified by in Vitro Cultivation for Human lnmunization. The Joumal of expemental medicine, 1937;65(6):787-800.

Claims (5)

THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:

1. A pharmaceutical composition comprising one or more antibiotics and: (a) i. 0,0036 ng/mL Koch's Turberculin (inactivated Mycobacterium bovis lysate); ii. 0,0036 pg/mL PPD; iii. 6.31 pg/mL Inactivated Staphylococcus lysate (Staphylococcus aureus and Staphylococcus epidermidis in equal parts); iv. 6.31 pg/mL Inactivated Steptococcus lysate (Streptococcuspyogenes, Streptococcuspneumoniae and Enterococcusfaecalisin equal parts); v. 0.404 pg/mL Streptokinase derived from inactivated beta-hemolytic Streptococcus lysate purification; vi. 0.101 pg/mL Dornase derived from inactivated beta-hemolytic Streptococcus lysate purification; vii. 6.31 pg/mL Oidiomycin (antigenic extract of Candida albicans); viii. 6.31 pg/mL Trichophytin (antigenic extract of Tricophyton sp); ix. 6.31 pg/mL Inactivated enteropathogenic Escherichiacoli lysate (EPEC); x. 6.31 pg/mL Inactivated Salmonella lysate (Salmonella bongori, Salmonella enterica and Salmonella subterraneain equal parts); xi. 20 pg/mL Attenuated yellow fever virus strain 17 D204; xii. 7.5 mg/mL Sodium Chloride; xiii. 0.48 mg/mL Sodium phosphate dibasic heptahydrate; xiv. 0.06 mg/mL Potassium phosphate monobasic; xv. 2.5 mg/mL Phenol; and xvi. Water; Or (b) i. 0,004 ng/mL Koch's Turberculin (inactivated Mycobacterium bovis lysate); ii. 0,004 pg/mL PPD; iii. 6.94 pg/mL Inactivated Staphylococcus lysate (Staphylococcus aureus and Staphylococcus epidermidis in equal parts); iv. 6.94 pg/mL Inactivated Steptococcus lysate (Streptococcuspyogenes, Streptococcuspneumoniae and Enterococcusfaecalisin equal parts); v. 0.444 pg/mL Streptokinase derived from inactivated beta-hemolytic Streptococcus lysate purification; vi. 0.111 pg/mL Dornase derived from inactivated beta-hemolytic Streptococcus lysate purification; vii. 6.94 pg/mL Inactivated Candida lysate (Candida albicans and Candidaglabratain equal parts); viii. 6.94 pg/mL Inactivated dermatophytes lysate (Epidermophytonfloccosum, Microsporum cannis, Trichophyton mentagrophytes of the interdigitale variety in equal parts); ix. 6.94 pg/mL Inactivated enteropathogenic Escherichia coli lysate (EPEC); x. 6.94 pg/mL Inactivated Salmonella lysate (Salmonella bongori, Salmonella enterica and Salmonella subterraneain equal parts); xi. 7.5 mg/mL Sodium Chloride; xii. 0.48 mg/mL Sodium phosphate dibasic heptahydrate; xiii. 0.06 mg/mL Potassium phosphate monobasic; xiv. 2.5 mg/mL Phenol; and xv. Water.

2. The pharmaceutical composition of claim 1 wherein the antibiotics are selected from the following classes: Amino Acid Derivatives, Aminoglycosides, Aureolic Acids, Aziridines, Ansamycins, Benzenoids, Benzimidazoles, Carbapenems, Cephalosporin, Coumarin-glycosides, Diphenyl Ether Derivatives, Epipolythiodioxopiperazines, Fatty Acid Derivatives, Glucosamine, Glycopeptides, Imidazoles, Indol Derivatives, Lipopeptides Macrolactams, Macrolides, Nucleosides. Penicillins and Cephalosporins (beta-Lactams), Peptides, Peptidyl Nucleosides, Phenicoles, Polyenes, Polyethers, Pyridines and Pyrimidines, Quinolones and Fluoroquinolones, Statins, Steroids, Sulfonamides, Taxoides and Tetracyclines.

3. The pharmaceutical composition of claim 2 wherein the antibiotics are selected from the following classes: ansamycins, Penicillins, Cephalosporins, Carbapenems and Lipopeptides.

4. A method of treating sepsis and multi resistant bacterial infection in a human or an animal comprising administering to the human or animal an effective amount of the composition according to any one of claims 1-3.

5. Use of the composition of any one of claims 1-3 in the manufacture of a medicament for treating sepsis and multi resistant bacterial infection in a human or an animal.

Figure 1

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SUBSTITUTE SHEET (RULE 26)

Figure 2

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SUBSTITUTE SHEET (RULE 26)

Figure 3

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SUBSTITUTE SHEET (RULE 26)