WO2018145180A1 - Immunogenic composition for modulating the immune system and methods to treat bacterial infections in a subject - Google Patents
Immunogenic composition for modulating the immune system and methods to treat bacterial infections in a subject Download PDFInfo
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- WO2018145180A1 WO2018145180A1 PCT/BR2018/000004 BR2018000004W WO2018145180A1 WO 2018145180 A1 WO2018145180 A1 WO 2018145180A1 BR 2018000004 W BR2018000004 W BR 2018000004W WO 2018145180 A1 WO2018145180 A1 WO 2018145180A1
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Definitions
- the present invention relates to immunogenic compositions for modulating the immune system comprising a therapeutically effective amount of a immunological Response Shifter (IRS) comprising two or more immunoactive antigenic agents presenting pathogen-associated molecular patterns (P AMPS) and/or danger associated molecular patterns (DAMPS) and/or Stress Response Signals (SRS) (I) and one or more physiological !y acceptable carriers, exeipients. diluents or solvents.
- IRS immunological Response Shifter
- P AMPS pathogen-associated molecular patterns
- DAMPS danger associated molecular patterns
- SRS Stress Response Signals
- 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 from the group consisting of: (A) antigenic agents with molecular patterns associated with bacteria; (B) antigenic agents with molecular patterns associated with viruses; ( €) antigenic agents with molecular patterns associated with fungi and yeasts; (D) antigenic agents with molecular patterns associated with protozoa; (E) antigenic agents with molecular patterns associated with multicellular parasites / or (f ) antigenic agents with molecular patterns associated with prions.
- PAMPS pathogen-associated molecular patterns
- DAMPS danger associated molecular patterns
- SRS stress response signals
- the new "anti” chugs brought an enormous capacity for medical intervention, with numerous benefits, with definitive and partial cures, with the prolongation of life in incurable diseases, but also with huge morbidity due to side effects related to their lack of specificity to the pathophysiology of the diseases.
- the irssaie immunity in addition to preventing the entry of microorganisms and preventing 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, autoimmune diseases and allergic diseases, among others.
- the recognition pattern of "not self, of an invasive germ is performed by sentinel cells, represented by epithelial cells, mucosal ceils, and the stromal cells, such as pericytes, dendritic cells, macrophages and fibroblasts, among others. These cells, strategically distributed throughout the body, have PRRs (Pattens Recognition Receptors) and DRRs (Danger
- SRR stress response receptors
- SRR stress response receptors
- 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 mat identify viruses, starvation, ER stress and oxidative stress (Pulendran, B Annual Review Immunology 2015).
- the PR.R does not discriminate one specific individual microorganism, but the presence of microorganisms other than the human bom-'.
- Each PRR receiver may bind to several different pathogens, recognizing as PAMPs (Pathogen Associated Molecular Patterns) carbohydrates, lipids, peptides and nucleic acids from bacteria, viruses, fungi or parasites that are not found in the human or animal body.
- PAMPs Pulthogen Associated Molecular Patterns
- the DRRs discriminate that, there is tissue damage, a dangerous situation caused by not live or inert agents.
- the DRRs identify- DAMPs (Danger Associated Molecular Patterns) associated with tissue damage by toxic substances, radiation, or trauma, which cause metabolic stress, release of tree radicals and chemical changes in tissue, recognized by these receptors.
- the SRRs stress response receptors identify' the signal of the metabolic stress caused by environment aggressions as viral infections or viral effective vaccines, amino acid starvation, ER(endoplasmic reticulum) stress, oxidative stress, through evolutionary conserved stress- sensing mechanism, that compose de integrated Stress Response ISR as recently discovered (Janeway C, Travers P. a!pon: M, SlMomchik Ml imtmmobioiogy five. 5th ed: Garland Pub.: 2001. 732 p.: Matzinger P. The danger model: a renewed sense of self. Science. 2002 ; 296 ( 5566) : 30.1 -5. Epub 2002/04/16; Beuiler BA. TLRs and innate immunity. Blood.
- sentinel cells via their PRRs and their DRRs, and SRRs have a role in the breakdown of which belongs ("self) and which, is does not belong (not “self) and triggering inflammation and immune response, via recognition of PAMPs of invading pathogens and DAMPs caused by neoplastic ceils, 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 .
- NF-kB Nuclear Facior-kB
- the innate immunity sentinel ceils with the APC role (Antigen Presenting Ceils), such as dendritic cells and macrophages, phagocytosis and pinocytosis microorganisms or tumour cells, or transplanted ceils, among other aggressors and process their antigens.
- APC cells pulsed by the antigens migrate to regional lymph nodes and activate them.
- the APC cells in reactive lymph nodes, activated and mature present the antigens to lymphocytes, release cytokines and thereby induce, coordinate, -polarize, amplify and maintain an adaptive immune response specific to the invading germs, or neoplastic ceils, or to transplanted cells, or other offending agent, allowing them to be fought and eliminated, where feasible and the consequent cure of the infection or inflammation and repair and regeneration or wound healing (1 ) (3).
- APC function sentinels, and innate immunity effectors, cellular and molecular in conjunction with die cellular and molecular effectors of adaptive immunity that are respectively lymphocytes, cytokines and antibodies.
- the interaction of the two immunities, innate and adapti ve, 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 adapti ve immune response against a primary infectious or parasitic agent effectively protecting the body(2, 3).
- APC function such as dendritic cells and macrophages
- Macrophages also function as APC cells, but are more specialized and involved as part of the effector loop in phagocytosis and in the elimination of microorganisms.
- B lymphocytes when mature, are also APC ceils and its most well-known action is the presentation of antigens to the T lymphocytes, within the framework of cooperation of bom lymphocytes to produce antibodies against T-dependent antigen, 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.
- the CD 40L molecule of activated T lymphocytes when it binds to the CD40 molecule on the APC ceils, significantly increases the expression ofCDSO 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-j is given usually by the APC cells after the binding of co-stimulatory molecules and the emission of the second signal.
- the JL-1 released by the APC ceils acts on lymphocyte ceils and leads to the complete expression of the receptor for 1L2 and to the production of 1.L2 and others polarization cytokines by virgin or memory 7 lymphocytes engaged in response initiating clonal selection and expansion(primary) or memory clonal proliferation (secondary).
- the activation of innate immunity 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 the response. Without the occurrence of the second and third, signal, the response is aborted and generates a tolerance specific to the antigen presented.
- neutrophils, monocytes and macrophages initiate combat to bacteria and to other infectious agents by the linkage ofPAMPs with PRRs SRSs on antigen presenting ceils (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.
- effector memory CD4-CD40- L+cell migrate in a €D62P-dependent fashion into the reactive lymph nodes via H ' EVs and license dendritic cells for T cell priming against weak antigen, tolerate antigens and auto antigen starting an auto immune disease or improving an immune response in an ongoing infection or neoplastic disease(4).
- effector memory CD8 T cells secrete CCL3, that in turn activate MFCs to produce TNF alfa that induce PMNNs and Others MFCs to produce ROIs and clear intracellular bacteria. Unrelated intracellular pathogen sensitive to ROIs can. also be clear by bystander activation in overlapping diseases or overlapping immune responses (6, 7).
- isnmxmoglobulins 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, in activated lymph nodes and after differentiation goes inside and induce germinal centre fonnation and secondary B cells responses with collaboration with €D4Tfh and others CD4T helpers cells.
- secondary B ceils responses long lived plasma cells secrete Tcell dependent antibodies in bonne marrow, after initial production in lymph nodes (1,6) (8, 9).
- Infections of ail types, bacterial, viral, fungal and parasitic may, in general, in the acute phase, evolve to a full cure with regeneration and healing, or for a cure with sequelae. They can also develop into an incurable ciifonicity, with or without control of the disease, to chronicity with healing, with or without sequelae, or to death.
- Treg/Td profile which suppresses the immune response aad controls, by inhibiting the other three profiles described above, ensuring the return of the body equilibrium state.
- New profiles have been stablished, as the Tfh ⁇ follicular Helper) of the humoral response (16), the Th9 profile for certain parasites like Helminths ( 17),Th22 that produce IL22 involved in Skin protection ( 17) or other profiles that may be discovered or no fully estab!ished( 18).
- 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, die balance, the regeneration, the safe return to normalcy 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 polarization of the immune response is defined as the predominance of a certain, immunological profile such as Thl or Th2 at the expense of other profiles thai become secondary or null.
- This phenomenon happens according to the type of attack suffered by the body. That is, according to die type of infection, pathology, and. infection stage or pathology stage, the different type of immune response will be predominant, and it may be a cellular, humoral, tissue inflammatory, or immune-regulatory response, while other types of immune responses are inhibited, resulting in the phenomenon of polarizat-on. ⁇ !2)
- tuberculosis is the appearance of Thi7 ceils in the lung which allows Thl ceils to settle and may lead to cute this infection in the lung parenchyma (Siockmger, B. and Veidhoen, M. Differentiation and function of Thl 7 T cells. Current Opinion in Immunology, 19 (3), pp. 281-286. 2007).
- the CTL cells ofThi profile destroy cells infected by viruses, to eliminate the vims.
- antibodies are required to prevent the virus from infecting other healthy cells and thus preventing the spread of infection.
- Dendritic ceils in collaboration with other APC and sentinel ceils is contact wi th 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 of the ongoing rafeetkm( 1 ,2,3)
- dendritic cells and other APC cells are key cells of the innate immune response, since they evaluate the nature of the autologous and heterologous causative agent, i.e., the type of pathogen or colonizing cells and aided by the sentinel cells, tfeey 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 pathogen.
- innate immunity comexiuaiize the aggression in a primary response and recontextualize in a secondary effective one by the action of T B and some NK memory cells (19) (20) (8, 9, 20-31)
- a re-differentiation can occur, induced by the microenvixonment and/or the type of antigen or its presentation, in which a Thl or Th2 profile can be exchanged for an inflammatory profile or an immunosuppressant profile or vice versa.
- 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).
- Thl? a profile, which in turn increases the inflammation more and therefore becomes detrimental, leading to tissue destruction, rather than inducing healing and paradoxically inducing late immunosuppression by the Treg/Trl profile and exhaustion state .
- Thl7 profile by tissue destruction and the amplification of inflammation, 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 compromises healing (4, 33, 34).
- 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 in the 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 mere are also a higher rate of morbidity and mortality, even when antibiotics are used in correct indication, dosing and timing.
- the inventors propose a new concept, in which the antimicrobial drags can be considered as equilibrium shifters (ES) in a host x pathogen competition, that favours the host immune system in a multivariable context.
- the variables are: concomitant diseases, traumas, age, sex, race, psychological health, innate and adaptive immunity, metabolism, nutrition, physiological flora microbiota, environmental aggression by drugs, and exposure to radiation, gases, pathogens and medical treatments.
- 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 drags would function as equilibrium shifters of the host x pathogen competition by significantly: weakening the pathogens action and reducing their numbers is 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 drags.
- one of the objectives of the invention is providing products comprising immunogenic compositions, in certain embodiments such compositions are combined wife one or more antibiotics, as well as methods and uses thereof for treating and/or preventing infectious diseases and preparing medicaments therefor.
- It is a specific object of the present invention to provide immunogenic compositions for modulating the immune system comprising a therapeutically effective amount of two or more Immunological Response Shifter (IRS) comprising an immune active antigenic agents that present pathogen-associated molecular patterns (PAMPS) and/or danger associated molecular patterns (DAMPS), and stress response signais(l) and one or more physiologically acceptable carriers, excipienis, diluents or solvents.
- IRS Immunological Response Shifter
- PAMPS pathogen-associated molecular patterns
- DAMPS danger associated molecular patterns
- stress response signais(l) one or more physiologically acceptable carriers, excipienis, diluents or solvents.
- 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 molecular patterns (DAMPS) and/or stress response signals (SRS) selected from the group consisting of: A) antigenic agents with molecular patterns associated with, bacteria; (B) antigenic agents with molecular patterns associated with viruses; (C) antigenic agents wife molecular patterns associated with fungi and yeasts; (D) antigenic agents with molecular patterns associated with protozoa; ⁇ £ ⁇ antigenic agents with molecular patterns associated with multicellular parasites / or (F) antigenic agents with molecular patterns associated with prions.
- IRS immunological Response Shifters
- PAMPS immune-active pathogen-associated molecular patterns
- DAMPS danger associated molecular patterns
- SRS stress response signals
- 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 innefeciive immune response with an effective immune response.
- the present invention aims to provide products and methods for treating infectious diseases, including severe infection, sepis and mufti rresistant bacteria, and modulating the immune system.
- the effectiveness of the invention is due to a real time replacement of an ineffective immune response with an effective immune response. Such replacement made by proactively creating a new image of the aggressor pathogen to the host immune system, in order to reset lead back, control and improve the same.
- an aggressive wiidtype virus would affect the host-pathogen balance in a different way than a vaccine virus, leading to a severe disease in one case and a subclinical disease in the other(l) (44-50).
- 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).
- 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 anergy to a state of normal response (52)
- Effector Memory CD8 T cells release CCL3, that in turn activate MFCs to produce TNF alfa that induce PMNNs and Others MFCs to produce ROIs and clear bacteria. Unrelated pathogen sensitive to ROIs can also be clear by bystander activation ⁇ 56-59). Recently, it was also recognized that the status of the rrucrobiome of the intestinal flora intervenes and can determine the effectiveness of a given vaccination.
- the innate response is not specific by its own nature and can hold multiple specific adaptive responses at the same time and in the same territories with synergic or antagonist effects. Because human and animal organisms can bold multiple aggressions at the same time and even in the same territory, the sinks of the innate immunity receptors recognition system recognize an expandable and changeable universe of PAMPs, DAMPs, and Stress Signals in contrast to a defined recognition of the identity of an aggressor pathogen by adaptive immunity.
- 5- lite major role of the primary response is to circumscribe the pathogen in a proinflammatory environment until an effective adaptive response takes place.
- the primary adaptive response in acute infection is also proinflammatory. 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 by NK memory cells that give a faster, correctly polarized, more accurate, quiet, low inflammatory and protective immune response, when available.
- These modified secondary adaptive immune responses for its anti-infiammatory nature had to the ceils memory can effectively deal with systemic wide range of pathogen surface contact without being harmful for the human, and animal organism.
- these effects can be obtained by the injections of a mix of FAMFs and secondary antigens to cognate memory cells that induce a secondary immune response and activate optimally PMCs and PMNNs to clearance bacteria, sensitive to, ROIs and other mechanism and activate optimally lymph nodes and improve ongoing immune response or can induce a poor or tolerated or no immunogenic one.
- the immune system is reactive and not proactive and the quality and effectiveness of the natural immune response depends mainly of two factors;
- First factor is the existence or not of an immunological effective specific memory that it determines a secondary or a primary immune response.
- a secondary response the best possible response is available and the outcome is a quiet protection.
- 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) .
- the immune system cannot improve by itself an already ongoing primary immune response and the answer for the question of how to change and improve an established initial primary improper immune response is apparently complex but strategically simple because there are only two factors determining the outcome of an immune response, in a primary immunological reply, there are only one remainder factor that is the context of the host x pathogen competition balance to be modified to possible improve the ongoing inefficient immune response.
- the antimicrobial di'ags 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 action the antimicrobial drug alter positively the host pathogen equilibrium balance and the outcome but don't alter the nature of the ongoing primary response.
- the strict reactive characteristic of the immune system in a primary response that depend mainly on the pathogen immnnogenieity and action, and on the fitness of the 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 of the host with anew secondary standard of this initial IR.
- This strategical and planned immunological action must be able to reset, lead back, control, modify and improve in real time the immune system action to induce a favourable secondary specific effective IR for positively alter the context of host x parasite competition and the outcome.
- 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.
- the immune system could reprogram the immune response based mostly in secondary well known antigenic determinants with a minority of primary determinants deriving from the aggressive pathogen that will generate a complete new different effective specific and well polarized iimiume response. The best possible one will, be generated with secondary tracts in the secondary resetting, low inflanunatory territories.
- This new IRS for the proactive action of the proposed and planed immunotherapy must be constituted by a. vast and very diverse pathogen secondary antigen universe for which the organism disposes an effective memory repertoire. These antigens must be with priority inert and be applied 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 im 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 ceils that will 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 of the host x pathogen competition now in favour of the host.
- the reactive immune system activated excellently by the proactive immunotherapy will real rime reprogram. reset and leads back the best available secondary anti-inSammators' specific immune response against the etioiogic agent reverting his initial advantage in an ongoing illness.
- Another object of the invention is the use of immunogenic compositions for preventing and/or treating infectious diseases. Particularly, providing methods of treating bacterial infections arid sepsis and uses of the above-mentioned immunogenic compositions for preparing medicaments and kits for treating bacterial infections.
- ⁇ 8CG refers to attenuated Mycobacterium bo vis. Bacille Calmette-Guerin;
- D AMPS refers to danger associated molecular patterns
- ⁇ DECA refers to the IRS composition la described in Example 1 of the present patent application.
- ⁇ GM.-CSF refers to "Granulocyte macrophage colony-stimulating factor"; * PAMFS refers to pathogen-associated molecular patterns. • PFXJ: plaque forming units.
- PPD refers to purified protein derivative of M. tuberculosis
- ⁇ PPD refers to the fraction of the purified protein extract culture of Koch's bacillus ("Purified Protein Derivative").
- the PPD is the major antigen of Mycobacterium tuberculosis;
- ⁇ TDCI50 is a unit for quantification of viral particles and is the infectious dose in 50% of ceils in a tissue culture:
- Koch's Tuberculin refers to inactivated Mycobacterium bovis iysate
- Lf or "Limes flocculation units” is the international unit for quantifying antigens in toxoid, vaccines accepted by the World Health Organization;
- 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 of three or more (e.g., 3, 4. 5. 6, 7, 8, 9, 10, 1 1 , 1.2, 13. 14, 15, 16, 17, 18, 19, or 20 or more) synthetic antigenic agents or natural antigenic agents, or fractions and combinations thereof, comprising pathogen-associated molecular patterns (PAMPS) and/or danger associated molecular patterns (DAMPS) selected from at least two groups consisting of: (A) antigenic agents with molecular patterns associated with bacteria. (B) antigenic agents with molecular patterns associated with viruses, (C) antigenic agents with molecular patterns associated with fungi and yeasts.
- PAMPS pathogen-associated molecular patterns
- DAMPS danger associated molecular patterns
- Such pharmaceutical 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 of the invention may be selected from the following classes: Amino Acid Derivatives, Aminoglycosides, Aureolic Acids, Aziridioes, Ansamycias, Benzenoids, Carbapenems, Cephalosporins, Coumarin- glyeosides, Diphenyl Ether Derivatives, Epipolvlhiodioxopiperazines, Fatty Acid Derivatives, Glucosamine, Glycopeptides, imidazoles, indol Derivatives, Lipopeptides Macrolactams, MacToHdes, Nucleosides.
- Penicillins and Cephalosporins (beta-Lactams), Peptides, Peptidyl Nucleosides, Phenico!es, Polyenes, Polyethers, Pyridines and Pyrimidines, Quinolones and Fluoroquinolones, Statins, Steroids, Sulfonamides, Taxoides and Tetracyclines.
- the immunogenic compositions of the present invention comprise immunoactive antigenic agents presenting pathogen-associated molecular patterns (PAMPS) and/or danger associated molecular patterns (DAMPS) selected from the group consisting of: (A) antigenic agents with molecular patterns associated with bacteria; (B) antigenic agents with molecular patterns associated with viruses; (C) antigenic agents with molecular patterns associated with fungi and yeasts; (D) antigenic agents with molecular patterns associated with protozoa; (E) antigenic agents with molecular patterns associated with multicellular parasites / or (F) antigenic agents with molecular patterns associated with prions.
- PAMPS pathogen-associated molecular patterns
- DAMPS danger associated molecular patterns
- the immunogenic compositions of this invention include pathogen- associated molecular patterns (PAMPS) and/or danger associated molecular patterns (DAMPS) selected from among at least three categories (A), (B), (C), (D ), (E) and (F) described above.
- PAMPS pathogen- associated molecular patterns
- DAMPS danger associated molecular patterns
- the immunogenic compositions of this invention include pathogen-associated molecular patterns (PAMPS) and/or danger associated molecular patterns (DAMPS) selected from among at least four categories (A), (B), (C), (D), (E) and (F) described above.
- PAMPS pathogen-associated molecular patterns
- DAMPS danger associated molecular patterns
- Antigenic agents of the present invention can be selected from epitopes, genetic materials, lipids, polysaccharides and/or immune active proteins of the present invention can be obtained by purification .from isolated fragments of material existing in nature or fractions denved from plant, animal or microbiological extracts, or produced by genetic recombination, preferably- derived from viral, fungal, parasitic or bacterial prion strains.
- the antigenic agents of the present invention with molecular patterns associated with bacteria of the present invention may be selected from, but not limited to antigenic agents with molecular patterns associated with bacteria of the genera Staphylococcus, Streptococcus, Enterococcus, Coiynebacterium, Bacillus, Listeria, Clostridium, Mycobacterium, Actinomyces, Nocardia, Eschericliia, Proteus, Klebsiella, Serratia, Enterobacter, Salmonella, Shigella, Pseudomonas, Burkholderia, Stenotrophomonas, Aemetobacter. Vibrio, Campylobacter, Helicobacter, Bacteroides, Neisseria, Moraxella, Haemophilus, Bordetei!a, Brucella,
- Antigenic agents with molecular patterns associated with, virus of the present invention may be selected from, but not limited to antigenic agents with molecular patterns associated with virus families Adenoviridae, Aienaviridae, Bunyaviridae, Coronaviridae, Fiioviridae, Flaviviridae, Hepadrtaviridae, Deitavims., Caiiciviridae, Herpesviridae, Orthom>3 ⁇ 4oviridae, Papovaviridae, Paramyxoviridae, Parvoviridae, Pjcomaviridae, Poxyvindae, Reoviridae, Retroviridae, Rnabdoviridae and Togaviridae.
- Antigenic agents with molecular patterns associated with fungi and yeasts of the present invention may be selected from, but not limited to antigenic agents with molecular patterns associated with fungi and yeasts of the genus Sporothrix, Aspergillus, Blastomyces, Candida, Coocidioides, Cryptococcus. Histoplasma and Pneumocystis.
- An tigenic agents with molecular patterns associated with protozoa of the present invention may ⁇ be selected from, but not limited to antigenic agents with molecular patterns associated with protozoa of the genera Cryptosporidium, Cfcioapora, Entamoeba, Naegieria, Giardia,
- Antigenic agents with molecular patterns associated with multicellular parasites of the present invention may be selected from, but not limited to antigenic agents with molecular patterns associated with multicellular parasites trematodes. cestodes and nematodes.
- the antigenic agents of the present invention comprise protein, polysaccharide, lipid molecules and/or composite syniJietic molecules that mimic protein, polysaccharide and/or lipid molecules.
- the agents of the invention comprise immune-active antigenic protein molecules which have enzyme activity, for example kinases, phosphatases, streptoquinases, estreptodornases and Deoxyribonucl eases (e.g. domases).
- enzyme activity for example kinases, phosphatases, streptoquinases, estreptodornases and Deoxyribonucl eases (e.g. domases).
- the immunogenic compositions for modulating the immune sy stem of the present invention comprise from 0.001 to 500 micrograms per ml of each immunogenic agent.
- Such immunogenic agents can be encapsulated in capsules, micro particles, narroparticles, coated tablets, liposomes.
- the immunogenic compositions for modulating the immune system of the present invention comprise frorn 4 to 20 antigenic agents selected from the group consisting of antigens derived from agents: doraase, !evedunn, oidiomycin. PP.D, prions, strepioquinase,
- Streptococcus toxoid diphtheria toxoid. Tetanus toxoid, Koch's tuberculin, inactivated lysate of Ascaris lumbricoides, Aspergillus spp., Aspergillus fiavus, Aspergillus fumigatus, Aspergillus ierreus, Caadida spp., Candida albicans, Candida glabrata, Candida parapsilosis. Chlamydia spp.. Chlamydia pneumoniae, Chlamydia psiitaci.
- Chlamydia trachomatis Chlamydia trachomatis, Cryptosporidium spp., Dermatophytes, Entamoeba hystolitica, Enterobius vermicularis, Enterococcus faecalis, Epidermophyton floccosum, Escherichia eolL Giardia lamblia, Haemophilus iafhienzae, Microsporum cannis, Mycobacterium spp.. . Mycobacterium bovis, Mycobacterium leprae.
- Mycobacterium tuberculosis Neisseria gonorrhoeae, human papilloma virus. Polio virus, Proteus spp., Proteus mirabilis, Proteus penerii, Proteus vulgaris. Salmonella, spp. , Salmonella bongori. Salmonella enterica, Serratia spp. , Serraiia !iquefaciens, Serratia maxcencens. Shigella spp. Shigella flexneri. Shigella sonnei, Staphylococcus spp. , Staphylococcus aureus.
- Staphylococcus epidermidis Sirongyloides stercorals.
- Streptococcus spp. Streptococcus bovis.
- Streptococcus viridans Streptococcus equinus, Streptococcus pneumoniae, Streptococcus pyogenes.
- Toxoplasma gondii Trichomonas vaginalis, trichophyton, Trichophyton spp. , Trichophyton rubram. Trichophyton tonsurans.
- Trichophyton mentagrophytes yellow fever virus, hepatitis B vims, rubella virus, varicella zoster vims, variola vims, mumps virus, measles vims, herpes vims and vaccinia virus or synthetic analogues that present pathogen-associated molecular patterns (PAMPS) and/or danger-associated molecular patterns (DAMPS) associated with these antigenic agents.
- PAMPS pathogen-associated molecular patterns
- DAMPS danger-associated molecular patterns
- the immunogenic compositions for modulating the immune system of the present invention comprise 4, 5, 6, 7, 8, 9, 10, 1 L 32, 13, 14, 15, 16, 17, 18, 19, or 20 antigenic agents selected from the group consisting of antigens derived from agents: domase, ievedurin, oidioxnycin, ?PD, prions, streptoqsiinase.
- Streptococcus toxoid diphtheria toxoid, Tetanus toxoid, Koch's tuberculin, inactivated lysate of Ascaris !umbricoides, Aspergillus spp., Aspergillus f!avus, Aspergillus fumigatus, Aspergillus terreus, Candida spp., Candida albicans, Candida glabrata, Candida parapsilosis, Chlamydia spp.. Chlamydia pneumoniae.
- Chlamydia psittaei Chlamydia trachomatis, Cryptosporidium spp., Dermatophytes, Entamoeba hystolitica, Enterobius verraicularis, Enterococcus faecalis, Epidermophyton fiocccsum, Escherichia coli, Giardia lambiia, Haemophilus influenzae, Mierosporum cannis, Mycobacterium spp.,
- Mycobacterium bovis Mycobacterium leprae, Mycobacterium tuberculosis., Neisseria gonorrhoeae, human papilloma virus. Polio vims. Proteus spp., Proteus mitahiiis, Proteus penerii, Proteus vulgaris. Salmonella spp. , Salmonella bongori, Salmonella enterica, Serratia spp. , Seixatia liqwefaciens, Serratia marceacens, Shigella, spp. Shigella flexneri. Shigella sonnei. Staphylococcus spp. , Staphylococcus aureus.
- Staphylococcus epidermidis Sirongyloides stercoralis, Streptococcus spp., Streptococcus bovis, Streptococcus viridans, Streptococcus equinus., Streptococcus pneumoniae. Streptococcus pyogenes. Toxoplasma gondii, Trichomonas vaginalis, trichophyton. Trichophyton, spp.
- a preferred immunogenic composition of the invention comprises inactivated Mycobacterium bovis Iysate, purified protein derivative of M.
- tuberculosis inactivated Staphylococcus aureus iysate, inactivated Staphylococcus epidermidis Iysate, inactivated Steptococcus pyogenes Iysate, inactivated Streptococcus pneumonia iysate, inactivated Enterococcus faecaiis iysate.
- a preferred immunogenic composition of the invention comprising from. 0.001 to 1 ng/ml of inactivated Mycobacterium bovis Iysate, 0.00! to 1 ng/ml of purified protein derivative of M. tuberculosis, 0.1 to 300 ug/ml of inactivated Staphylococcus aureus Iysate, O. i to 100 ug/ml of inactivated Staphylococcus epidermidis Iysate; O. i to 100 ug/ral of inactivated Steptococcus pyogenes Iysate; 0.1 to 100 pg/ml of inactivated Streptococcus pneumonia Iysate; 0.1 to 100 ug/m!
- inactivated Enterococcus faecaiis Iysate 0.01 to 10 ug/ml of streptokinase, 0.01 to .10 ⁇ / ⁇ 1 of doroase; 0.1 to 100 ⁇ / ⁇ of inactivated Candida albicans iysate; 0.1 to 100 ug/ml of inactivated Candida glabrata Iysate.
- compositions of the present invention can further comprise excipients, such as bactericides, bacteriostats. antioxidants, preservatives, buffers, .stabilizers, pH adjusters, osmolality adjusters, antifoaming agents and surfactants, and residual antigen inactivating or fractionation agents, growth medium components and solvents commonly used in the production of vaccines and im monotherapies .
- excipients such as bactericides, bacteriostats. antioxidants, preservatives, buffers, .stabilizers, pH adjusters, osmolality adjusters, antifoaming agents and surfactants, and residual antigen inactivating or fractionation agents, growth medium components and solvents commonly used in the production of vaccines and im monotherapies .
- compositions of the present invention may be a solid, liquid or gel.
- pharmaceutically acceptable carrier means a non-toxic solid, inert, semi-solid liquid excipieut diluent auxiliary- formulation of any type, or simply a sterile aqueous solution such as saline.
- Some examples of materials which can serve as pharmaceutically acceptable earners are sugars such as lactose, glucose and sucrose, starches such, as com starch and potato starch , cellulose and its derivatives such as sodium caiboxy-methyl cellulose, a ethyl cellulose and cellulose acetate, cyclodextrin; oils such as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, com oil and soya bean oil, glycols such, as propylene glycol, polyols, such as glycerol, sorbitol, mannitol and polyethylene esters such as ethyl laurate, ethyl oleaie, agar, buffering agents such as aluminum hydroxide and magnesium 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.
- compositions and vaccines described herein are available.
- the particular selected mode will depend on the selected antigenic agents, the dosage required for therapeutic efficacy and patient to whom the composition is administered.
- the methods of the present invention can generally be practiced using any mode of administration biologically acceptable, i.e.. any means that produces effective levels of immune response without causing clinically adverse reactions.
- modes of administration include intradermal, oral, rectal, sublingual, topical, nasal, transdermal or parenteral administration.
- parenteral includes subcutaneous, intravenous, epidural, irrigation, intramuscular, release pumps or infusion.
- oral, intradermal, parenteral, subcutaneous, intravenous, intramuscular, and, by the nasal mucosa and/or oral administration are preferred for administration of the composi tions claimed herein.
- the active Ingredients may also be dissolved in a pharmaceutical carrier and administered as a solution, emulsion, including micro-and naao-emulsions or suspension .
- suitable carriers are water, saline, dextrose solutions, fructose solutions or Oils of animal, vegetable or synthetic origin.
- Other vehicles may also contain other ingredients, for example, preservatives, suspending agents, solubilizing agents, buffers and the like.
- the invention refers to a method to treat sepsis in a human or an animal who has a bacterial infection comprising administering to the human or animal an effective amount of one or more antibiotics and one or more immunogenic compositions for modulating the immune system comprising a therapeutically effective amount of three or more (e.g., 3, 4, 5, 6, 7, 8, 9, 10, I I, 12, 13, 14, 15, .16, 17, 18, 19, or 20 or more) synthetic antigenic agents or natural antigenic agents, or fractions and combinations thereof, comprising pathogen- associated molecular patterns (PAMPS) and/or danger associated molecular patterns (DAMPS) selected from at least two groups consisting of: (A) antigenic agents with molecular patterns associated with bacteria, (B) antigenic agents with molecular patterns associated with viruses, ( €) 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
- PAMPS
- Septicemia is defined as an extremely serious infection in which 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 circulators' system.
- septicemia leads to sepsis, through the massive release of proinflammatory cytokines such as TNFs, ILL IL18, 1L6 and others, causing an inflammatory collapse with hemodynamic characteristic alterations, such as hypotension, rapid pulse, which may culminate in septic severe shock, usually irreversible.
- Septicemia, sepsis are serious infections/inflammations with high morbidity and mortality. In these severe
- 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 cytokine storm and through the inflammatory Thl7 tissue profile, increasing inflammation disproportionately and therefore harming the organism (33).
- the effector loops of innate immunity controlled by the TCD4 lymphocytes, cause tissue damage and sometimes massive destruction, that compromise organs and tissues and that exacerbate infections, leading, for example, to respiratory failure, lung shock, and in ARDS (adult respiratory distress syndrome), also leading to renal failure and multiple organ failure.
- IF used the loop amplification by IL2 should be very low, just enough to specifically amplify the repolarization of the immune response of the inflammatory profile to the immunity profile or to Treg/TRI regulatory profile.
- the recontextoalizing and the rsprogramming achieved by immunotherapy using the compositions of fee present invention to achieve a new perceived identity of the pathogen, by recovering immune cells through the anti1 ⁇ 2flammatory action of non-related specific memory T lymphocytes, by the inhibition of the cytokine stoma and also by the repolarization of the tissue inflammatory profile TH17 to elective and effective TH! and ⁇ 2 immunity profiles, will together redirect the immune response.
- fee invention refers to a method to treat multi resistant bacteria infection in a human or an animal who has a bacterial infection comprising adnfensfering to the human or animal an effective amount of one or more antibiotics and one or more immunogenic compositions for modulating the immune system comprising a therapeutically effective amount of three or more (e.g., 3. 4, 5, 6, 7, 8.
- PAMPS pathogen-associated molecular patterns
- DAMPS danger associated molecular patterns
- the invention refers to a method to modulate an immune system response in a human or an animal who has a bacterial infection comprising administering to the human or animal an effective amount of one or more immunogenic compositions for modulating the immune system comprising a therapeutically effective amount of three or more (e.g., 3 ; 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14.
- PAMPS pathogen- associated, molecular patterns
- DAMPS danger associated molecular patterns
- the present invention refers to the use of immunogenic compositions in the manufacture of medicaments and kits for preventing and/or treating of infections diseases.
- Immunogenic compositions of the invention are also may also be used in. the pre vention and/or treatment of infectious diseases in association with one or more antibiotics.
- the immunogenic compositions of the present invention have an unexpected effect on the immune response.
- the immunogenic compositions of the present invention show an unexpected technical effect of causing an immune response that. involves resecting , recontextualizing, leading back, renewing and reprograraming the immune response in real tuns.
- the iniinurioiherapeuiic compositions of the present invention by creating a new identity of the pathogen perceived by innate and adaptive immunological system are capable of provoking a reset, a recontextualization a lead back of the operational action capacity of the immune system by changing the relationship offerees against the aggressors in its favor, giving the immune system a competitive advantage, which does not occur spontaneously in the evolution of disease.
- This recontextuaiization determines a consequent, renewal and reprogramming of the established immune response or incipiently established, or erroneously established mistakenly attacking in a dysautonomical way the human or animal body, polarizing the primary pro-inflammatory response that is always a fortuitous reply possible to be improved to a secondary, active anti-inflammatory, more effective and appropriate immune response.
- compositions of this invention properly reset the activated sentinel ceils, 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 of the immune profile to properly treat the infection without causing immunological side-effects, such as inflammation.
- 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 immune response, desired to treat bacterial, viral or parasitic infections with a low inflammatory profile.
- the treatment with the immunogenic compositions of the present invention is capable of stunuJatmg 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 of the organism.
- This property was demonstrated in the clinical cases of irreversible sepsis reported is the Examples. The patients had recover ⁇ ' and regeneration of complex trauma wounds with important tissue loss, organ destruction in lungs, kidneys, liver, bones and extremities induced by CIVD, and ischemic events by low blood flow and toxicity.
- the immunogenic compositions of the present invention are able to mobilize the immune system and lead to an increased regenerative power of fee body, through mobilization of stem cells or the activation of gene sets which allow the regeneration of ceils 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.
- the im munogenic compositions of the present invention exhibit an unexpected technical effect of recontextxaalizing, renewing, and reprogramming the immune response in real time and consequently significant cure rates when compared to drugs and methodologies in the art.
- immuno-moduiator agent(s) is/are used for preparing an immunotherapy pharmaceutical composition capable of inducing a new innate secondary immune response, which triggers a cascade of immune events, including the main event of activation of memory lymphocytes from the ageni(s) inoculated by human intervention and the concomitant activation by antigens present in the patient's own body, resulting in a.
- the administTation 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 of the agents of the present invention affect the shape, time, accuracy and polarization of the immune response., preferably leading to an secondary innate and adaptive immune response that it is snore effective to fight the disease, leading to a better reaction of organism itself.
- the present invention provides methods to -treat bacterial and other microbial infections with the use of the antigenic combinations described.
- Hie present invention 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.
- the continued activation of the immune system by antigens or immunomodulatory 1 agents of the present invention leads, through the activation of stem cells, to the regeneration of tissues, organs and systems, by mechanisms not yet fully understood, but related to healing or restitution ad integrum mechanisms observed in various medical situations.
- compositions of the present invention allow the recruiting of the maximum number memory cells, new effective virgin cells of the individual, producing more significant effects than an antibody increase as described in the prior art.
- 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 aid APC cells, and preferably looks for exposure on locations close to the infection sites and other distal applications to the disease sites (as is the case in disorders or diseases that manifest themselves in specific locations of the body) to secondary reset innate system in all the places of the disease.
- the compositions of the present 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 intralesiona!, are perceived by the PRRs (pathogen-associated pattern recognition receptors) off all sentinel cells of the body.
- the present invention employs immunomodulatory agents in amounts, concentrations and specific locations to recontextuaiize, reset and lead back the immune system, activating and redirecting the mechanisms for tissue repair and regeneration, as occurs during healing and regeneration of tissue, organ or system, leading to a "restitution ad integrum" or reconstitution with scar.
- This repair is usually triggered at the end of an immune response process, after healing die infection.
- the immunogenic compositions of the present invention constitutes another aspect of the present invention using the immunogenic compositions in the manufacture of medicaments for the prevention and/or treatment of infectious diseases.
- infectious diseases can be of viral, bacterial, fungal or parasitic origin.
- HIV hepatitis virus
- herpes virus rhabdovirus
- rubella vims smallpox virus
- poxvirus poxvirus
- Diseases of bacterial origin prevented and/or treated by the immunogenic compositions of the present invention may be caused by the following bacteria- hut not limited to, Pneumococcus, Staphylococcus., Bacillus, Streptococcus, Meningococcus, Gonococcus, Escherichia, Klebsiella. Proteus, Pseudomonas, Salmonella, Shigella. Haemophilus, Yersinia, Listeria,
- Fungal diseases prevented and/or treated by the immunogenic compositions of th e present invention may be caused by the following fungi but not limited to: Candida, Aspergillus, Cryptococcus neofortnans, and/or fungi that cause superficial and deep mycosis.
- Diseases caused by parasites are caused by the following parasites: Trypanosoma, Schistosoma-.
- compositions of the present invention are administered once, sis one area of the body or in difierent sites in order to redirect the immune system with the highest possible efficiency.
- immunogenic compositions of the present invention for modulation of the immune system, involving the exposure of part or all of the system for recognition of antigens in the immune system, such as dendritic cells, macrophages and lymph nodes from different parts of the body, inflammatory territories will depend on the goal imposed by fee illness being fought, and occurs preferentially through injections or use of guns, or delivery systems or controlled, mfusion or pulsed cells with in vitro antigens.
- the agent may be applied to only one location in the body or in several tens of locations in several forms: subcutaneous, muscular, intravenous, oral, breathable aerosol, cutaneous (dermal, patches) in organs, the viscera, or specific tissues, or in different body cavities, which can vary in number from one to one hundred (100) applications in one to fifty (50) sessions.
- the antigenic compositions of this invention may also be combined with other drugs feat can weaken the reproduction, growth, or any other form of strengthening of the disease's causative agent, causing a shift of "the equilibrium in favor of the biological immune defenses of the host, animal or human. Or still in concomitant treatment.
- the antigenic compositions of this invention may also be combined wife other procedures such as. but not limited to, antibiotics chemotherapy, therapy with antibodies and antisera, using hormones or other physiology modulating agents (cytokines, chemokines , neurohormones, peptides), treatment with antiviral agents, use of herbal medicines, vitamin supplementation, methods of therapeutic or prophylactic vaccination (with or without cells and not limited to the type of vaccine vehicles), gene therapy, surgery or homeopathy, depending on the disease or illness being fought related to an improper or inefficient immune activity. Recenlextualszing, resetting, renewing, leading back and reprograssming the immum response.
- hormones or other physiology modulating agents cytokines, chemokines , neurohormones, peptides
- treatment with antiviral agents use of herbal medicines, vitamin supplementation, methods of therapeutic or prophylactic vaccination (with or without cells and not limited to the type of vaccine vehicles), gene therapy, surgery or homeopathy, depending on the disease or illness being fought related to an improper
- Recontextua3iz3Bg and resetting the immune system is achieved by means of stimulation of the immune system by antigens of different pathogens not related to fee pathology to be treated, for which the human or animal, preferably, already has an immunological memory for totally changing the inner perceived primary image of the invader pathogen to a new secondary effective proactively induced one.
- These stimuli m ast be capable of causing an intense, strong and effective secondary specific immune 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 of the immune system so that it can, in parallel cause an effective secondary response capable of eradicating the specific pathology in progress.
- the innate and adaptive secondary nnmune response caused intentionally by the composition of the present invention should encompass the full 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 intercity 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 property sequentially polarized, in order to cure the condition being treated.
- the innate and adaptive response induced by the present invention will geographically overlap the condition being treated and by its intense and extensive secondary activation will correct the inefficient activation, picposely 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 greatest genetic and biological potential.
- This ideal activation should also reverse the immunosuppression, the tolerance and escape mechanisms established by pathogens because it is known and proven ' that an unrelated strong and intense immune response, that fully covers the response 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 of the present invention activated and generated at the site of application of fee antigens, will, via the bloodstream, enter the already activated lymph nodes by HEVs, which drain the region affected by the disease and will enable, in a strong and intense way induce fee activation of ail the existing dendritic cells there.
- lymph node capable of provoking an immune response against, weak antigens, which by themselves are not capable of causing an immune response.
- PAMPs alone can remodel lymph node feed arteriole and induce lymph node hypertrophy that is essential for an effective primary adaptive response and also for secondary- immune responses
- the areas of the inflammatory process and lymphatic territories are exactly the same.
- the inflamed area through the anti-inflammatory action of specific memory ceils, unrelated. mobilized by the present invention by their antigenic composition, will block the
- inflammasGmes and exert an anti-inflammatory action that will correct the pathological inflammation responsible for the morbidity of the disease and which was caused by its etiological agent.
- this known action of the 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.
- lymphatic territories are exactly the same, only sow intensely activated and with the necessary alarm signal caused by the present invention, to cause any immune response, even for a weak antigen, similar to what occurs with dendritic cells common to this invention and to the autologous or heterologous etiological agent to be fought. Lymphokmes and innate cells that command an effective secondary response will be the same and the T lymphocytes specific against the etiologic agent, to be fought, will "hitch a ride" on this ideal microenvironmeni for holding an effective immune response.
- the dendritic ceils activated by the present invention can capture the antigens of the etiological agent to be fought at the site of the pathology and in the related lymphatic territories and be in contact with the pathogen specific TCD4 lymphocytes, in a correctly and ideally enabled lymphatic system.
- the role of the dendritic cells activated and matured with fee TCD4 specific to the etiologic agent occurs in a microenvironment conducive to conducting an immune response, with all the genetic and biological potential of the host organism's immune system.
- dendritic cells at the site of the pathology and at the lymph nodes will properly gauge the severity, extent, intensity and type of aggression, activating, inducing, coordinating, polarizing, leading and maintaining a new effective adaptive immune response., whose effector loop, with tiie collaboration of the cells and effector molecules of the intense and properly activated innate immunity may be able to eliminate the causative agent to be fought. So the answer is reprogrammed and lead back as noted above, reversing the biological balance in favor of the host, which until then was under the yoke of the 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 the effects and potential of the etiological agent, allowing the immune system to have a chance to heal the pathology that is the target of the treatment.
- biological balance shifters such as antibiotics drugs, capable to block, weaken or neutralize the effects and potential of the etiological agent, allowing the immune system to have a chance to heal the pathology that is the target of the treatment.
- compositions of the present invention intentionally and strategically superimposed over the entire area under the action of the agent to be fought, will recontextualize the immune system by activating the PAMPs and DAMFs in the sentinel cells and common APCs and by the unrelated specific secondary adaptive immune response.
- This intentionally induced immune response will efficiently activate the whole lymphatic territory and the organic territory affected by the etiological agent, in the recontextualized area and in the bulge, and within the context of a greater immune response, stronger, more intense and more extensive secondary anti-inflammatory nature of the target immune response will be, as described, reprogrammed and efficiently renewed within the scope of a greater chance for the host, now with a chance of reversing the biological balance in its favor,
- Be therapeutic protocol of the present, invention designed to be applied in cases of bacterial infection and septicemia must:
- the immunotherapy formulation must contain at least 5 antigens so it contains PAMPs and DAMPs so as to be able to recontextuaiize the immune system.
- the application area mast overlap, cover, and overcome the whole extension of regions dominated by the infection.
- the antigenic stimuli must be repeated every 4 or 5 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 Ms manner until the end of the infection, or to the healing of fee wound, organ or system.
- the immunotherapy is "systemica!!y” distributed in several (at least ten) lymphatic territories, peri- and mtra-lesion with 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 of the organism. It will be applied every 4 to 5 days.
- Figure 1 shows images ofExamie 2.
- a I , .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 mu!ti -resistant strain and major tissue 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) fee external fixation of the femur after surgical procedure. On February .2, 201 1 (5 days after starting the treatment) the patient presented complete recovery from sepsis and received ICU discharge (BL B2 and B3).
- Figure 2 shows images of Example 3.
- a Chest CT scan Al aad A2 of 01/1 1/201 i before muriunotherapy and CT scan (81 and B 2) of 04/1 1/201 1 after immune treatment performed in CMS patient, in Al and A2 is possible to identify whitish areas (circled) characteristic of infection.
- BI and B2 is clear the disappearance of whitish areas and recovery of the !ung parenchyma which the image became darker.
- Figure 3 shows images of Example 4.
- An X ⁇ Ray (Al) of 24 April 2007 (3 days after immiuioiherapy starts ⁇ and CT scan (B I to B6) of 27 April 2007 it's easily to identify critical SARS condition under septic shock.
- X-Ray (CI) of 06 May 2007 evidences complete recover after immune treatment performed in AMB patient.
- a I is possible to identify whitish areas (circled) characteristic of infection.
- B i - B6 the clinical status is so critical that whitish areas barely allow to identify anatomical contours our parameters (circular).
- C I is clear die disappearance of whitish areas and complete recover ⁇ ' of the lung parenchyma, without sequels, which the image became darker.
- 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 ceils (with or without ATC function) thereby allowing the reeontextualizing, renewal and reprogrammiog of the immune response in real time.
- 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-irtflamraatory action in parallel to rscontexiuaikarion .
- 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 die human being acquires its "repertoire of immuniiy").
- ⁇ are used in immunization programs such, as childhood vaccination programs against, endemic and ' Or epidemic diseases.
- each of the antigeni c agents should be present in a concentration of 0.001 to 500 micrograms per mL.
- antigenic agents m their already available, safe, and approved forms for use in human vaccination programs or allergic response tests and immunity assessment tests.
- composition la (DECA composition):
- Composition 12 is a composition of Composition 12:
- Composition 17 is a composition of Composition 17:
- the formulations When there are parasitic diseases, associated or to be fought, the formulations will preferentially contain antigenic agens of parasitic origin.
- the formulations should comprise antigenic agents originating from the most prevalent parasites for which the indi viduals have more- memory cells, according to 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 ceils in the immune system of the population of a given region.
- Composition 37 Association of Composition 2 with:
- Composition 44 Association of Composition 9 with:
- Composition 50 Association of Composition 15 with: Inactivated Ascaris Iumbricoides iysate 400 .ug/mL j Inactivated Strongyloides stercoraiis Iysate j 400 pg/rnL
- Composition 56 Association of Composition 21 with:
- Composition 57 Association of Composition 22 with:
- Composition 58 Association of Composition 23 with:
- Composition 59 Association of Composition 24 with;
- Composition 60 Association of Composition 25 with
- Composition 65 Association of Composition 30 with:
- compositions DECA were applied, 1.8 cc each, for infiltration of exposed raw areas.
- the first phase of immunotherapy began on 29 January, 2011 and ended on 19 March. 2011 totalling a total of nine DECA applications in. periods ranging from one to two times per week, once the cleaning and debridement schedule was being followed, in the operating room (due to the severity of the pain and risk of infection by the broad extensive exposure of internal tissues in the raw areas).
- Acinetobacter baunnamii sensitive only to polymyxin B.
- the patient was discharged on .15 March, 201 1, with complete cure of the infection of all complex injuries and wounds, including osteomyelitis.
- the patient was discharged without antibiotic therapy.
- Example 3 Treating sepsis associated with urinary infections and concomitant oropharynx with terminal gastric carcinoma
- hypoglobin 8.6 g/dL also had hypokalemic, hyponatremic and lyraphopenic (lymphocyte count of 3,000/microliter) condition.
- the immunotherapy treatment was performed during a single session on 04 October. 201 ] with the informed consent of the patient.
- VITER immunotherapy was performed as follows:
- the immunostimu!ation caused immiasocompetence recovery and acti vation of the effector T loop as the lymphocyte count increased from 3,000/microliter on 03 October., 20.1 ito
- the innnimostimulaiiori of the present invention allowed for as unexpected survival of I year and. a half, enjoying the company of relatives.
- Example 4 Treating infection (mu!tireststant bacteria of SARS in septic shock)
- SARS Severe Acute Respiratory Syndrome
- ICU Intense Care Unit
- Coagulation arid make opsonization, process possible, inspite of all efforts patient did not expcrince any clinical and laboratory improvement.
- the immunotherapy treatment was performed nine sessions starting on 21/04/201 1 after informed consent of the patient.
- DECA immunotherapy was performed as follows:
- Streptokinase derived from lysate inactivated and purified Streptococcus beta-hemolytic 0,404 ug/mL); 6. Domase derived from lysate inactivated and purified Streptococcus beta-hemolytic 0, 10! pg/mL); 7. Gidiomycm (antigenic extract of Candida albicans 6,31 ⁇ g/mL); 8. Trichophytin (antigenic extract of Tricophyton spp 6,31 ⁇ / ⁇ ,); 9. Lysate inactivated Escherichia co!i (EP.EC 6,31 p.g/m.L); 10. Lysate inactivated Salmonella (Salmonella hongori, Salmonella enterica and Salmonella subierranea in equal parts 6,31 ,ug/mL).
- 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 ceils: past, present, and fliture. Annual review of immunology. 2012;30: 1-22.
- Soderberg KA Payne GW, Sato A, Medzhrtov R, Segal SS, Iwasaki A. Innate control of adaptive immunity via remodeling of lymph node feed arteriole. Proceedings of the National Academy of Sciences of the United States of America. 2005;102 ⁇ 45): 16315-20.
- Bim siRNA decreases lymphocyte apoptosis and improves survival in sepsis. Shock.
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Application Number | Priority Date | Filing Date | Title |
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KR1020197026857A KR20190139209A (en) | 2017-02-13 | 2018-02-15 | Immunogenic Compositions for Modulating the Immune System and Methods of Treating Bacterial Infections in Individuals |
JP2019564565A JP2020507629A (en) | 2017-02-13 | 2018-02-15 | Immunogenic compositions for modulating the immune system and methods for treating a bacterial infection in a subject |
RU2019128674A RU2019128674A (en) | 2017-02-13 | 2018-02-15 | IMMUNOGENIC COMPOSITION FOR IMMUNE SYSTEM MODULATION AND METHODS FOR TREATMENT OF BACTERIAL INFECTIONS IN SUBJECT |
CN201880023729.7A CN110709099B (en) | 2017-02-13 | 2018-02-15 | Immunogenic compositions for modulating the immune system and methods of treating bacterial infections in subjects |
EP18751350.2A EP3579868A4 (en) | 2017-02-13 | 2018-02-15 | Immunogenic composition for modulating the immune system and methods to treat bacterial infections in a subject |
MX2019009689A MX2019009689A (en) | 2017-02-13 | 2018-02-15 | Immunogenic composition for modulating the immune system and methods to treat bacterial infections in a subject. |
IL268626A IL268626B2 (en) | 2017-02-13 | 2018-02-15 | Immunogenic composition for modulating the immune system and methods to treat bacterial infections in a subject |
BR112019016670A BR112019016670A2 (en) | 2017-02-13 | 2018-02-15 | immunogenic composition to modulate the immune system and methods to treat bacterial infections in an individual |
AU2018217441A AU2018217441A1 (en) | 2017-02-13 | 2018-02-15 | Immunogenic composition for modulating the immune system and methods to treat bacterial infections in a subject |
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US15/431,329 US10213504B2 (en) | 2011-03-18 | 2017-02-13 | Immunogenic composition for modulating the immune system and methods to treat bacterial infections in a subject |
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EP (1) | EP3579868A4 (en) |
JP (1) | JP2020507629A (en) |
KR (1) | KR20190139209A (en) |
CN (1) | CN110709099B (en) |
AU (1) | AU2018217441A1 (en) |
BR (1) | BR112019016670A2 (en) |
IL (1) | IL268626B2 (en) |
MX (1) | MX2019009689A (en) |
RU (1) | RU2019128674A (en) |
WO (1) | WO2018145180A1 (en) |
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-
2018
- 2018-02-15 AU AU2018217441A patent/AU2018217441A1/en active Pending
- 2018-02-15 KR KR1020197026857A patent/KR20190139209A/en not_active Application Discontinuation
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- 2018-02-15 JP JP2019564565A patent/JP2020507629A/en active Pending
- 2018-02-15 IL IL268626A patent/IL268626B2/en unknown
- 2018-02-15 EP EP18751350.2A patent/EP3579868A4/en active Pending
- 2018-02-15 MX MX2019009689A patent/MX2019009689A/en unknown
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Also Published As
Publication number | Publication date |
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MX2019009689A (en) | 2019-12-18 |
JP2020507629A (en) | 2020-03-12 |
CN110709099B (en) | 2024-03-29 |
IL268626B2 (en) | 2024-04-01 |
EP3579868A4 (en) | 2021-01-06 |
BR112019016670A2 (en) | 2020-04-14 |
AU2018217441A1 (en) | 2019-10-03 |
CN110709099A (en) | 2020-01-17 |
KR20190139209A (en) | 2019-12-17 |
IL268626A (en) | 2019-10-31 |
EP3579868A1 (en) | 2019-12-18 |
RU2019128674A3 (en) | 2021-06-18 |
RU2019128674A (en) | 2021-03-16 |
IL268626B1 (en) | 2023-12-01 |
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