EP4301406A1 - Vaccins pour le traitement et la prévention d'infections zoonotiques - Google Patents

Vaccins pour le traitement et la prévention d'infections zoonotiques

Info

Publication number
EP4301406A1
EP4301406A1 EP22763831.9A EP22763831A EP4301406A1 EP 4301406 A1 EP4301406 A1 EP 4301406A1 EP 22763831 A EP22763831 A EP 22763831A EP 4301406 A1 EP4301406 A1 EP 4301406A1
Authority
EP
European Patent Office
Prior art keywords
seq
composition
epitope
composite
pathogen
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP22763831.9A
Other languages
German (de)
English (en)
Other versions
EP4301406A4 (fr
Inventor
Luke T. Daum
Gerald W. Fischer
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Longhorn Vaccines and Diagnostics LLC
Original Assignee
Longhorn Vaccines and Diagnostics LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Longhorn Vaccines and Diagnostics LLC filed Critical Longhorn Vaccines and Diagnostics LLC
Publication of EP4301406A1 publication Critical patent/EP4301406A1/fr
Publication of EP4301406A4 publication Critical patent/EP4301406A4/fr
Pending legal-status Critical Current

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    • A61K39/12—Viral antigens
    • A61K39/145—Orthomyxoviridae, e.g. influenza virus
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
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    • A61K39/02—Bacterial antigens
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    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
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    • C07K—PEPTIDES
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    • C07K—PEPTIDES
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    • C07K—PEPTIDES
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    • C07K—PEPTIDES
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    • C07K14/24—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from bacteria from Enterobacteriaceae (F), e.g. Citrobacter, Serratia, Proteus, Providencia, Morganella, Yersinia
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    • C07K14/43504—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from invertebrates
    • C—CHEMISTRY; METALLURGY
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Definitions

  • the present invention is directed to composite antigens and vaccines composed of a plurality of epitopes of one or more pathogens, and to tools and methods for generating an immune response.
  • the invention is directed to compositions comprising viral specific peptides and/or nucleic acid sequences as vaccines for the treatment and prevention of viral diseases.
  • a zoonotic agent is an infectious agent, such as for example, a bacterium, a virus, or a parasite, that has been transmitted from an infected animal to a human.
  • Ebola virus and Human Immunodeficiency Virus (HIV) are believed to have originated in animals and been transmitted to humans. Once transmitted, the now human pathogen may have mutated or become mutated to be a purely human disease and is transmitted to others.
  • Many strain of influenza that originally infect birds and swine can be transmitted to humans. Pigs are considered as important intermediate hosts for interspecies transmission of the avian influenza virus, because of their susceptibility to infection with both avian and mammalian influenza viruses.
  • the resulting mixing of viruses is believed to produce novel recombinant strains that are more adaptable to humans or other mammals.
  • the human infection typically shows up in workers that are in close proximity to the infected animals or the intermediate host animal.
  • the virus may have mutated to infect a human, and that worker transmits the virus to others in the community or mutates when passed through an intermediate host. Thereafter the infection often spreads worldwide.
  • Zoonotic diseases have many different modes of transmission. In direct zoonosis the disease is directly transmitted from infected animals or intermediate animals to humans through the air, through direct contact, or through indirect contact with water sources and feedstuffs.
  • Influenza is believed to spread to humans via breathing infected air, whereas varicella virus is transmitted through direct contact.
  • the genetics of the host intermediate or human often determine susceptibility to infection or the severity of the disease.
  • Many pathogens require few mutations to establish an infection.
  • Three genera of influenza viruses currently comprise the Orthomyxoviridae Family: Influenza virus A, Influenza virus B, and Influenza virus C. Each of these genera contains a single species of influenza virus.
  • the genus Influenza virus A consists of a single species, influenza A virus, which includes all of the influenza virus strains currently circulating among humans, including, for example, but not limited to, H1N1, H1N2, H2N2, H3N1, H3N2, H3N8, H5N1, H5N2, H5N3, H5N8, H5N9, H7N1, H7N2, H7N3, H7N4, H7N7, H9N2, and H10N7 serotypes.
  • influenza viruses are RNA viruses.
  • the genus Influenza virus B consists of a single species, influenza B virus, of which there is currently only one known serotype.
  • Influenza B virus is almost exclusively a human pathogen but is significantly less common and less genetically diverse than influenza A strains. Because of this limited genetic diversity, most humans acquire a certain degree of immunity to influenza B virus at an early age; however, the mutation frequency of the virus is sufficiently high enough to prevent lasting immunity by most humans, but not high enough to permit pandemic infection by influenza B virus across human populations.
  • the genus Influenza virus C also consists of a single species, denoted influenza C virus, of which there is also currently only one known serotype. This serotype is known to infect both primates and porcine, and while infections of influenza C virus are rare, the resulting illness can be severe. Epidemics of influenza C virus are not uncommon in exposed populations, however, due to its rapid transmissibility in humans having close contact.
  • Hemagglutinin (HA) and neuraminidase (NA) are the two large glycoproteins on the outside of the viral particles.
  • HA is a lectin that mediates binding of the virus to target cells and entry of the viral genome into the target cell, while NA is involved in the release of progeny virus from infected cells, by cleaving sugars that bind the mature viral particles.
  • NA is involved in the release of progeny virus from infected cells, by cleaving sugars that bind the mature viral particles.
  • these proteins are targets for antiviral drugs.
  • they are antigens to which antibodies can be raised.
  • Influenza A viruses are classified into subtypes based on antibody responses to HA and NA.
  • HA and NA form the basis of the H and N distinctions in, for example, H5N1.
  • H5N1 There are 18 HA and 11 NA subtypes known, but only HA 1, 2 and 3, and NA 1 and 2 are commonly found in humans.
  • Influenza A virus in particular, has many different serotypes, upwards of 144 possible “HN” serotypes based on variations within these two proteins alone. Only a small number of these combinations are believed to be circulating within susceptible populations at any given time.
  • Influenza viruses are etiologic agents for a contagious respiratory illness (commonly referred to as the flu) that primarily affects humans and other vertebrates. Influenza is highly infectious and an acute respiratory disease that has plagued the human race since ancient times.
  • Influenza virus infection can cause mild to severe illness and can even lead to death. Every year in the United States, 5 to 20 percent of the population, on average, contracts the flu with more than 200,000 hospitalizations from complications and over 36,000 deaths. Because of the high disease-related morbidity and mortality, direct and indirect social economic impacts of influenza are enormous. Four pandemics occurred in the last century, together causing tens of millions of deaths worldwide. Influenza virus spreads from avian to human hosts through close contact.
  • avian influenza virus (AIV) consists of eight segments of single-stranded, negative-sense RNA that codes for 11 proteins (PB2, PB1, PB1-F2, PA, HA, NP, NA, M1, M2, NS1, and NS2/NEP).
  • Poultry workers are typically the first human hosts of a new strain of influenza. Therefore, it would be beneficial to treat the poultry before transmission to humans can occur.
  • Annual influenza outbreaks occur as a result of “antigenic drift.” Antigenic drift is caused by mutations within antigenic (i.e., immunity stimulating) portions of viral proteins within viral subtypes circulating in host populations that alter the host's ability to recognize and defend effectively against the infecting virus, even when the virus has been circulating in the community for several years.
  • Immunodominant antigens are those antigens belonging to a pathogen that are the most-easily and most-quickly recognized by the host immune system and, consequently, account for the vast majority of immune response to the invading pathogen.
  • immunodominant antigens exist within regions of the pathogen that are most exposed to the environment, i.e., are on the external surfaces or on protruding elements of the pathogen, and so are most readily accessible to the host immune system.
  • Non-immunodominant antigens are those that are capable of raising a host immune response but account for only a small amount of the total immune response.
  • non-immunodominant antigens are at least partially shielded from the host immune system, as in the case of an antigen that is located in a cleft or fold of the microbial surface or is surrounded by protruding elements of the microbe.
  • non- immunodominant antigens occurring near the capsid surface are shielded from the host immune system by the immunodominant HA and NA spikes protruding from the surface.
  • Non- immunodominant antigens tend to show less mutation in response to host immune pressure than do immunodominant antigens.
  • the CDC and the leading authorities on disease prevention in the world recommend the single best way of preventing a viral respiratory infection in humans is through regular vaccinations.
  • Conventional vaccines typically target the immunodominant proteins, HA and NA antigens for influenza. These vaccines have not been universally protective or 100 percent effective at preventing the disease. Antigenic shift prevents flu vaccines from being universally protective or from maintaining effectiveness over many years. The ineffectiveness of conventional vaccines may also be due, in part, to antigenic drift and the resulting variation within antigenic portions of the HA and NA proteins most commonly recognized by the immune system (i.e., immunodominant antigens). As a result, many humans may find themselves susceptible to the flu virus without an effective method of treatment available since influenza is constantly improving its resistant to current treatments.
  • H5N1 virus which is highly virulent but for which there is currently no widely available commercial vaccine to immunize susceptible human populations.
  • flu vaccines are reformulated each year due to the yearly emergence of new strains, and generally induce limited immunity.
  • some vaccines are administered with high doses of antigen. This is particularly true for H5N1 vaccines.
  • influenza vaccines including H5N1 vaccines, typically present epitopes in the same order as the epitopes are found in nature, generally presenting as whole- viral proteins; consequently, relatively large amounts of protein are required to make an effective vaccine.
  • T cells are important tools of the immune system and a major source of the cascade of cytokines that occurs following an immune response.
  • Two of the principle forms of T cells are identified by the presence of the cell surface molecules CD4 and CD8.
  • T cells that express CD4 are generally referred to as helper T cells.
  • T helper cells include the subsets Th1 and Th2, and the cytokines they produce are known as Th1-type cytokines and Th2-type cytokines, both sets of which are of critical importance in developing an immune response.
  • the Th1-type cytokines produce a pro-inflammatory response stimulating the opsonization of intracellular parasites, basically the humoral immune response.
  • Interferon gamma is one of the principle Th1 cytokines.
  • the Th2-type cytokines include interleukins 4, 5, 10 and 13, which are closely associated with the promotion of a cellular immune response.
  • Th1 and Th2 response is most desired.
  • Newcastle disease virus (NDV) is responsible for devastating disease in poultry and has a large economic impact in the industry. Newcastle disease belongs to the genus Rubulavirus within the family Paramyxoviridae. However, NDV is believed to be distantly related to other members of the genus Rubulavirus.
  • NDV is a contagious viral agent of avian disease affecting both domestic and wild bird species.
  • the negative-strand RNA virus genome of NDV contains six genes encoding six major structural proteins (3′-NP-P-M-F-HN-L-5′). The virus is transmissible to humans, although in most cases the human disease is non-symptomatic.
  • the genome of NDV contains six open reading frames which encode the nucleoprotein (NP), the phosphoprotein (P), the matrix protein (M), the fusion protein (F), the haemagglutinin- neuraminidase (HN) and the large protein (L).
  • At least one additional, non-structural protein (V) and possibly a second one (W) are generated by RNA editing during P gene transcription.
  • the viral particle of Newcastle has been modified to be non-pathogenic and used as a vector for vaccinations.
  • attenuated strains of NDV and virulence tends to correlate with cleavage of the F protein, although not exclusively.
  • a single U-to-C modification within the U stretch of the P gene attenuated the virus for administration to chicken embryos without substantially reducing replication.
  • Another advantage of live attenuated NDV vaccines is the ability to apply via drinking water or spray, making the cost for administration inexpensive.
  • Live attenuated ND vaccines are known to stimulate both mucosal and systemic immune responses similar to those of the natural infection. These attenuated NDV strains can be modified with recombinant technology to contain foreign genes.
  • Insertion of the foreign genes can be at different positions in the NDV genome without severely affecting replication efficiency or virus yield. Attenuated strains containing foreign components may be useful for generating a suitable immune response against the foreign component, while maintaining the advantages of NDV.
  • Vaccines containing inactivated influenza virus or simply influenza antigen are currently in use worldwide. Typically, vaccinations are administered to animals individually, which is impractical and expensive.
  • a vaccine that could be administered to large groups of susceptible animals collectively, and also, wherein the vaccine provides protection across a broad range of different strains and/or variations of the target pathogen and/or against multiple pathogens.
  • Such vaccines would be useful both to the industry and to prevent transmission to humans, in other words, short circuiting a pandemic.
  • Such vaccines could be administered against existing as well as new and emerging pathogens.
  • Summary of the Invention The present invention provides new and useful compositions, as well as tools and methods directed to vaccines against one or more pathogens administered to humans, mammals, birds, or other animals to prevent zoonotic infections such as influenza and, in particular, for administration to humans and animals.
  • One embodiment of the invention is directed to peptides containing one or more viral antigens, epitopes and/or composite antigens or epitopes.
  • the virus is influenza virus and the antigen and/or epitope is obtained or derived from an HA protein, an NA protein, an M1 protein, an M2 protein, an M2e protein of the influenza virus.
  • the virus is an avian influenza virus.
  • Peptides of the invention may comprise multiple influenza virus epitopes.
  • Peptide may be part of an immunogenic composition which may optionally contain an adjuvant such as, for example, Freund’s, a liposome, saponin, lipid A, squalene, and derivatives and combinations thereof.
  • Preferred adjuvants include, for example, AS01 (Adjuvant System 01) which is a liposome-based adjuvant which comprises QS-21 (a saponin fraction extracted from Quillaja saponaria Molina), and 3-O-desacyl-4’-monophosphoryl lipid A (MPL; a non-toxic derivative of the lipopolysaccharide from Salmonella minnesota) and on occasion a ligand such as a toll-like receptor (e.g., TLR4), AS01b which is a component of the adjuvant Shingrix, ALF (Army Liposome Formulation) which comprises liposomes containing saturated phospholipids, cholesterol, and/or monophosphoryl lipid A (MPLA) as an immunostimulant.
  • AS01 Adjuvant System 01
  • QS-21 a saponin fraction extracted from Quillaja saponaria Molina
  • MPL 3-O-desacyl-4’-monophosphoryl lipid A
  • AS01b which is a component
  • ALF has a safety and a strong potency. AS01 is included in the malaria vaccine RTS,S (Mosquirix).
  • ALF modifications and derivatives include, for example, ALF adsorbed to aluminum hydroxide (ALFA), ALF containing QS21 saponin (ALFQ), and ALFQ adsorbed to aluminum hydroxide (ALFQA).
  • a preferred adjuvant formulation comprises Freund’s adjuvant, a liposome, saponin, lipid A, squalene, unilamellar liposomes having a liposome bilayer that comprises at least one phosphatidylcholine (PC) and/or phosphatidylglycerol (PG), as phospholipids, which may be dimyristoyl phosphatidylcholine (DMPC), dipalmitoyl phosphatidylcholine (DPPC), distearyl phosphatidylcholine (DSPC), dimyristoyl phosphatidylglycerol (DMPG), dipalmitoyl phosphatidylglycerol (DPPG), and/or distearyl phosphatidylglycerol (DSPG), a cholesterol, a monophosphoryl lipid A (MPLA), and a saponin.
  • PC phosphatidylcholine
  • PG phosphatidylglycerol
  • the immunogenic composition is a vaccine that treats or prevents influenza virus infection in humans, mammals and other animals including but not limited to porcine and avian species.
  • Another embodiment of the invention comprises a peptide containing one or more avian influenza virus antigens or epitopes and/or composite antigens or epitopes, and one or more T cell stimulating epitopes.
  • the T cell stimulating epitope is obtained or derived from tetanus toxin, tetanus toxin heavy chain proteins, diphtheria toxoid, CRM, recombinant CRM, tetanus toxoid, Pseudomonas exoprotein A, Pseudomonas aeruginosa toxoid, Bordetella pertusis toxoid, Clostridium perfringens toxoid, Escherichia coli heat-labile toxin B subunit, Neisseria meningitidis outer membrane complex, Hemophilus influenzae protein D, Flagellin Fli C, Horseshoe crab Haemocyanin, and/or a fragment, derivative, or modification thereof.
  • the T cell stimulating epitope is at the N-terminus or the C-terminus of the peptide.
  • Peptides of the invention may comprise multiple influenza virus epitopes and/or multiple T cell stimulating epitope.
  • Peptide may be part of an immunogenic composition which may optionally contain an adjuvant such as, for example, Freund’s, ALFQ, ALFQA, ALFA, AS01, AS01b, a liposome, saponin, lipid A, squalene, and derivatives and combinations thereof.
  • the immunogenic composition is a vaccine that treats or prevents influenza virus infection in animals.
  • viral vectors containing sequences, such as mRNA sequences, that encode one or more antigens or composite antigens disclosed herein and, optionally the T cell stimulating epitope.
  • sequences such as mRNA sequences
  • the mRNA sequence upon administration to a host, expresses an epitope that generates an immune response in the host.
  • the viral vector is an attenuated strain of NDV which encode influenza virus antigens and/or composite antigens of the invention.
  • nucleic acids encoding the peptide and/or composite peptides as disclosed herein are inserted into the genome of NDV and developed into an attenuated strain of live virus.
  • VLP virus-like-particle
  • the VLP vector contains antigens and/or composite antigens of the invention.
  • Another embodiment of the invention is directed to methods to treat and/or prevent an infection by administering an immunogenic composition via a viral vector containing nucleic acids sequences corresponding to peptides and/or composite peptides of the invention, or to VLP vectors containing one or more peptides and/or composite peptides of the invention.
  • Administration comprises dispersing the viral vector or VLP to a collection of animals, such as birds (e.g., chickens, turkeys) or swine.
  • the viral vector is an attenuated NDV.
  • the immunogenic composition produces a protection against infection in the animal.
  • Another embodiment of the invention is directed to methods for generating an immune response in a mammal or an animal comprising administering to a collection of animals the antigens and/or composite antigens as disclosed herein or attenuated NDV strain containing nucleic acid sequence, antigens and/or composite antigens as disclosed herein, to a mammal or an animal.
  • the immune response generated in the mammal or the animal is protective against a number of different strains, serotypes or species of the one or more pathogens.
  • Vaccinations and vaccines are often the best mechanism for avoiding an infection and preventing the spread of debilitating and dangerous pathogens.
  • vaccinations are often the only effective option as treatment options are few and those that are available provide only limited effectiveness.
  • Conventional vaccinations require a priori understanding or general identification of the existing antigenic regions of the pathogen.
  • the pathogen itself is propagated and a suitable vaccine developed from heat-killed or otherwise attenuated microorganisms.
  • an antigen or collection of antigens is identified that will generate a protective immune response upon administration.
  • the need for a vaccine is especially urgent with respect to preventing infection by certain bacteria and viruses. Many bacteria and especially certain viruses mutate constantly or mutate when passing through an intermediate host, often rendering the vaccine developed to the prior or originating bacteria or virus useless against the new strains that emerge. As a consequence, vaccines against infections are reformulated yearly and often administered at fairly high doses. The development and manufacturing costs are high and administering vaccines pose a great many complications and associated risks to patients. Many viral and also bacterial infections originate in animals including domesticated animals (e.g., bovine, porcine, caprine, avian) and can be transmitted to humans.
  • domesticated animals e.g., bovine, porcine, caprine, avian
  • the human infection typically shows up in workers that are in close proximity to the infected animals or is passed through an intermediate host such as a farm animal.
  • the infectious agent may have mutated to infect a human, and that worker transmits the virus to others in the community or mutates when passed through an intermediate host. Thereafter the infection often spreads worldwide.
  • Approximately two thirds of pathogenic infections in humans today are believed to have originated in animals. It has been surprisingly discovered that an effective protection against a zoonotic infection can be provided by vaccinating the original animal host.
  • Vaccines can be produced from an antigen or composite antigen as described herein and that vaccine can be administered to animals to prevent later transmission to humans and other hosts.
  • the vaccine comprises an immunogenic composition or, upon administration (e.g., an mRNA vaccine) expresses one or more immunogenic antigens or epitopes that generates an immune response in the animal and protest the animal from a subsequent exposure.
  • Antigens and epitopes as disclosed herein contains or are derived from a plurality of antigenic regions (e.g. epitopes) of a pathogen or of different pathogens.
  • Composite antigens of the invention may contain an antigenic region that represents a combination of all or parts of two or more epitopes (e.g., a composite peptide), or a plurality of immunologically responsive regions derived from one or multiple antigenic sources (e.g., epitopes of virus particles, parasites, bacteria, fungi, cells). These immunological regions are amino acid sequences or epitopes that are representative of sequences found at those antigenic regions of a pathogen or other antigen associated with an infection or a disease or, importantly, associated with stimulation of the immune system to provide protection against the pathogen. Administration may be to individuals such as via injection (e.g., intradermal, intravenous, oral, nasal, intraperitoneal).
  • injection e.g., intradermal, intravenous, oral, nasal, intraperitoneal.
  • immunogenic compositions are administered collectively to animals such as in a water or food supply, or as an aerosol dispensed in a closed or partially closed environment, thereby avoiding the need and expense of providing the vaccine individually.
  • a pathogen such as viral and/or bacterial antigens.
  • Antigens may be selected regions of the virus or bacterium that are known or believed to generate an effective immune response after administration.
  • the peptide sequence of the antigen may contain a plurality of immunologically responsive regions or epitopes of one or more pathogens, which are artificially arranged, preferably along a single amino acid sequence or peptide.
  • the plurality may contain multiples of the same epitope, although generally not in a naturally occurring order, or multiples of a variety of different epitopes from one or more pathogens.
  • Epitopes may be identical to known immunological regions of a pathogen, or entirely new constructs that have not previously existed and therefore artificially constructed.
  • the antigen of the invention induces a protective immunogenic response in the animal or a mammal (e.g., human) and stimulates both mucosal and systemic immune responses similar to those of the natural infection.
  • that response includes the production of killer T-cell (TC or CTL) responses, helper T-cell (TH) responses, macrophages (MP), and specific antibody production in an inoculated subject.
  • Antigens of the invention may also be obtained or derived from the sequences of a pathogen such as, for example, multiple or combined epitopes of the proteins and/or polypeptides of bacteria, for example, but not limited to Streptococcus, Pseudomonas, Mycobacterium such as M. tuberculosis, Shigella, Campylobacter, Salmonella, Haemophilus influenza, Chlamydophila pneumonia, Corynebacterium diphtheriae, Clostridium tetani, Mycoplasma pneumonia, Staphylococcus aureus, Moraxella catarrhalis, Legionella pneumophila, Bordetella pertussis, Escherichia coli, such as E.
  • a pathogen such as, for example, multiple or combined epitopes of the proteins and/or polypeptides of bacteria, for example, but not limited to Streptococcus, Pseudomonas, Mycobacterium such as M. tuber
  • Exemplary parasites from which sequences may be obtained or derived include but are not limited to Plasmodium such as Plasmodium falciparum and Trypanosoma.
  • Exemplary fungi include, but are not limited to Aspergillus fumigatus or Aspergillus flavus.
  • viruses include, but are not limited to arena viruses, bunyaviruses, coronaviruses, filoviruses, Hepadna viruses, herpes viruses, orthomyxoviruses, parvoviruses, picornaviruses, papillomaviruses, reoviruses, retroviruses, rhabdoviruses, and togaviruses.
  • the virus epitopes are obtained or derived from sequences of Influenza viruses (e.g., the paramyxoviruses).
  • Antigens as disclosed herein include “composite” antigens, which are engineered, artificially created antigens made from two or more epitopes, such that the resulting composite antigen has physical and/or chemical properties that differ from or are additive of the individual epitopes.
  • the composite antigen when exposed to the immune system of a mammal or an animal, is capable of simultaneously generating an immunological response to each of the constituent epitope of the composite and preferably to a greater degree (e.g., as measurable from a cellular or humoral response to an identified pathogen) than the individual epitopes.
  • the composite antigen provides the added function of generating a protective immunological response in a mammal or an animal when used as a vaccine and against each of the constituent epitopes.
  • the composite has the additional function of providing protection against not only the pathogens from which the constituents were derived, but related pathogens as well.
  • These related pathogenic organisms may be strains or serotypes of the same species of organism, or different species of the same genus of organism, or different organisms entirely that are only related by a common epitope.
  • Composite antigens or peptides may contain composite epitopes that represent two or more epitopes with epitope sequences only similar to the epitope sequences from which they were derived.
  • Epitopes are regions obtained or derived from a protein or peptide of a pathogen that elicit a robust immunological response when administered to a mammal or an animal. Preferably, that robust response provides the subject with an immunological protection against developing disease from exposure to the pathogen.
  • a preferred example is a composite epitope, which is one artificially created from a combination of two or more highly conserved, although not identical, amino acid sequences of two or more different, but otherwise related pathogens.
  • the pathogens may be of the same type, but of a different strain, serotype, or species or other relation.
  • the composite epitope contains the conserved region that is in common between the related epitopes, and also contains the variable regions which differ.
  • sequences of a composite epitope that represents a combination of two conserved, but not identical sequences may be illustrated as follows: Sequence of Epitope 1 ...AAAAABAAAAA... Sequence of Epitope 2 ...AAAAACAAAAA... Composite Epitope ...AAAAABCAAAAA... wherein, “A” represents the amino acids in common between the two highly conserved epitopes, “B” and “C” represent the amino acids that differ, respectively, between two epitopes, each of “A”,”“B” and “C” can be any amino acid and any number of amino acids.
  • the conserved region contains about 20 or less amino acids on each side of the variable amino acids, preferably about 15 or less, preferably about 10 or less, preferably about 8 or less, preferably about 6 or less, and more preferably about 4 or less.
  • the amino acids that vary between two similar, but not identical conserved regions are 5 or less, preferably 4 or less, preferably 3 or less, preferably 2 or less, and more preferably only 1.
  • a “composite epitope,” similar to the composite antigen, is an engineered, artificially created single epitope made from two or more constituent epitopes, such that the resulting composite epitope has physical and/or chemical properties that differ from or are additive of the constituent epitopes.
  • the composite epitope when exposed to the immune system of a mammal or an animal, is capable of simultaneously generating an immunological response to each of the constituent epitopes of the composite and preferably to a greater degree than that achieved by either of the constituent epitopes individually.
  • the composite epitope provides the added function of generating a protective immunological response in a patient when used as a vaccine and against each of the constituent epitopes.
  • the composite has the additional function of providing protection against not only the pathogens from which the constituents were derived, but related pathogens as well.
  • These related pathogenic organisms may be strains or serotypes of the same species of organism, or different species of the same genus of organism, or different organisms entirely that are only related by a common epitope.
  • Composite epitopes of the invention are entirely artificial molecules that do not otherwise exist in nature and to which an immune system has not been otherwise exposed.
  • these conserved immunological regions that are combined as a composite epitope represent immunologically responsive regions of proteins and/or polypeptides that are highly conserved between related pathogens.
  • a vaccine can be developed from a single composite epitope, in many instances the most effective vaccine may be developed from multiple, different composite epitopes.
  • Composite antigens of the invention may contain one or more epitopes or composite epitopes, which may include and/or one or more known epitopes to provide an effective vaccine. Although composite antigens may comprise a single composite epitope, a composite antigen would not comprise only a single known epitope.
  • the immunological response achieved from a vaccination with a composite antigen, or group of composite antigens provides protection against infection caused by the original strains from which the sequence of the composite antigen was derived and also provides immunological protection against other strains, serotypes and/or species that share one or more of the general conserved regions represented in the composite antigen.
  • the resulting immune response achieved from a vaccination with a composite antigen is more broadly protective than can be achieved from a conventional single antigen vaccination against multiple strains, serotypes, and species or otherwise related pathogens regardless of antigenic drift that may take place in the evolution of the pathogen.
  • vaccines developed from composite antigens of the invention avoid any need for repeated or annual vaccinations, the associated complications and expenses of manufacture, and the elevated risks to the subject. These vaccines are useful to treat individual animals, mammals, and populations or either, thereby preventing infection and mortality and subsequently infections in mammals including pandemics. Such vaccines are also useful to compliment conventional vaccines.
  • the composite antigen preferably comprises a single chain of amino acids with a sequence derived from one or more epitopes or a plurality of epitopes, that may be the same or different.
  • Epitope sequences may be repeated consecutively and uninterrupted along a composite sequence or interspersed among other sequences that may be single or a few amino acids as spacers or sequences that encode peptides (collectively spacers), and may be nonimmunogenic or immunogenic and capable of inducing a cellular (T cell) or humoral (B cell) immune response in an animal or a mammal.
  • T-cell stimulating antigens include, for example, tetanus toxin, tetanus toxin heavy chain proteins, diphtheria toxoid (e.g., recombinantly engineered or purified CRM197), tetanus toxoid, Pseudomonas exoprotein A, Pseudomonas aeruginosa toxoid, Bordetella pertusis toxoid, Clostridium perfringens toxoid, Escherichia coli heat-labile toxin B subunit, Neisseria meningitidis outer membrane complex, Hemophilus influenzae protein D, Flagellin Fli C, Horseshoe crab Haemocyanin, and fragments, derivatives, and modifications thereof.
  • diphtheria toxoid e.g., recombinantly engineered or purified CRM197
  • tetanus toxoid Pse
  • Peptides sequence from unrelated microbes may be combined into a single composite antigen.
  • viral sequences of selected immunoresponsive peptides may be interspersed with conserved sequences or epitopes selected from other microbes, such as, for example, bacteria such as S. pneumococcus, P. auriginosa or S. aureus.
  • Preferred viral proteins, from which preferred epitopes may be selected include, but are not limited to the influenza virus proteins HA, NA, and M2e, and/or coronavirus proteins spike (S), envelope (E), membrane (M), and nucleocapsid (N).
  • An epitope of the composite antigen may be of any sequence and size, but is preferable composed of natural amino acids or mimetopes and is more than 5 but less than 100 amino acids in length, preferably less than 80, preferably less than 70, preferably less than 60, preferably less than 50, preferably less than 40, preferably less than 30, preferably between 5 and 25 amino acids in length, preferably between 8 and 20 amino acids in length, and more preferably between 5 and 15 amino acids in length.
  • Composite antigens preferably contain any number of composite and/or other epitopes. The most effective number of epitopes of a composite antigen against a particular pathogen, pathogen family, or group of pathogens may be determined by one skilled in the art from the disclosures of this application and using routine testing procedures.
  • Composite antigens may be effective with one epitope, preferably with 2 or more, 3 or more 4 or more, 5 or more or greater.
  • composite antigens may include one or more spacers between epitopes which may be sequences of antigenic regions derived from the same or from one or more different pathogens, or sequences that serve as immunological primers or that otherwise provide a boost to the immune system. That boost may be generated from a sequence of amino acids that are known to stimulate the immune system, either directly or as an adjuvant.
  • Preferred adjuvants comprise analgesic adjuvants, inorganic compounds such as alum, aluminum hydroxide, aluminum phosphate, calcium phosphate hydroxide, mineral oil such as paraffin oil, bacterial products such as killed bacteria Bordetella pertussis, Mycobacterium bovis, toxoids, nonbacterial organics such as squalene, detergents (Quil A), plant saponins such as Quillaja, soybean, Polygala senega, cytokines such as IL-1, IL-2, IL-12, Freund's complete adjuvant, Freund's incomplete adjuvant, food-based oil, Adjuvant 65, which is a product based on peanut oil, and derivatives, modifications and combinations thereof.
  • inorganic compounds such as alum, aluminum hydroxide, aluminum phosphate, calcium phosphate hydroxide, mineral oil such as paraffin oil, bacterial products such as killed bacteria Bordetella pertussis, Mycobacterium bovis, toxoids, nonbacterial organics such
  • Preferred adjuvants include, for example, AS01 (Adjuvant System 01) which comprises TLR4 ligand, 3-O-desacyl-4’- monophosphoryl lipid A (MPL), and a saponin, QS-21, AS01b which is a component of the adjuvant Shingrix, ALF (Army Liposome Formulation) which comprises liposomes containing saturated phospholipids, cholesterol, and/or monophosphoryl lipid A (MPLA) as an immunostimulant.
  • ALF has a safety and a strong potency.
  • ALF modifications and derivatives include, for example, ALF adsorbed to aluminum hydroxide (ALFA), ALF containing QS21 saponin (ALFQ), and ALFQ adsorbed to aluminum hydroxide (ALFQA).
  • a preferred adjuvant formulation comprises a liposome, saponin, lipid A, squalene, unilamellar liposomes having a liposome bilayer that comprises at least one phosphatidylcholine (PC) and/or phosphatidylglycerol (PG), as phospholipids, which may be dimyristoyl phosphatidylcholine (DMPC), dipalmitoyl phosphatidylcholine (DPPC), distearyl phosphatidylcholine (DSPC), dimyristoyl phosphatidylglycerol (DMPG), dipalmitoyl phosphatidylglycerol (DPPG), and/or distearyl phosphatidylglycerol (DSPG
  • the mole ratio of the cholesterol to the phospholipids is greater than about 50:50 and also that the unilamellar liposomes have a median diameter size in micrometer range as detected by light scattering analysis.
  • Additional preferred adjuvants are disclosed in U.S. Patent No. 10,434,167, which issued October 8, 2019, the entirety of which is incorporated by reference herein.
  • composite antigens useful to generate an immunological response against influenza virus comprise epitopes of HA, M, and/or NA proteins, and/or new epitopes derived from similar conserved regions of different serotypes and strains of influenza virus, and/or from the S protein of coronavirus.
  • composite antigens containing epitopes of proteins of Mycobacterium tuberculosis and Clostridium tetani, and/or new epitopes derived from similar conserved regions of different serotypes of these bacteria.
  • Another form of the antigen comprises a contiguous sequence of one or more epitopes, which may comprise composite and/or known epitopes, from one or more pathogens in a sequence that does not exist naturally and must be artificially constructed.
  • a contiguous sequence of the invention contains one or more composite epitopes, which is a combination of the sequences of the conserved regions of epitopes that are common to multiple pathogens plus those amino acids that differ between the two conserved regions.
  • a composite antigen of the invention contain a plurality of repeated epitopes and, optionally, epitopes conjugated with linker regions between or surrounding each epitope, and the plurality of epitopes be the same or different.
  • Preferred linkers include amino acid sequences of antigenic regions of the same or of different pathogens, or amino acids sequences that aid in the generation of an immune response.
  • Preferred examples include, but are not limited to, any of the various antigenic regions of bacteria such as, but not limited to tuberculosis and virus such as, but not limited to influenza and coronavirus. It is also preferred that composite antigens contain epitopes that generate a mucosal and/or systemic immune responses similar to that produced from a natural infection.
  • Another embodiment of the invention is directed to method of immunizing mammals or animals with the immunogenic compositions of the invention.
  • the vaccines of the invention are less susceptible to variation of antigenicity due to antigenic shift of pathogens which reduces or eliminates the need for annual or repeated vaccination to maintain protection of the mammal or animal populations against potential outbreaks of infection from, for example, new bacterial strain or viral isolates.
  • the vaccines of the invention generally and advantageously provide increased safety considerations, both in their manufacture and administration (due in part to a substantially decreased need for repeated administration), a relatively long shelf life in part due to minimized need to reformulate due to strain-specific shift and drift, an ability to target immune responses with high specificity for particular microbial epitopes, and an ability to prepare a single vaccine that is effective against multiple pathogens, each of which may be a different but know strain or species of the same pathogen.
  • the invention encompasses antigenic compositions, methods of making such compositions, and methods for their use in the prevention, treatment, management, and/or prophylaxis of an infection.
  • compositions disclosed herein, as well as methods employing them find particular use in the treatment or prevention of viral, bacterial, parasitic and/or fungal pathogenesis and infection using immunogenic compositions and methods superior to conventional treatments presently available in the art.
  • These methods can prevent or control infections, such as, for example, an outbreak of viral, parasitic, fungal or bacterial infection, preferably but not limited to an influenza virus, coronavirus, and/or a tuberculosis bacterial infection, in a selected population of animals or mammals.
  • the method includes at least the step of providing an immunologically effective amount of one or more of the disclosed immunogenic or vaccine compositions to a susceptible or an at-risk animals of a population, for a time sufficient to prevent, reduce, lessen, alleviate, control, or delay the outbreak of such an infection in the general population.
  • the administration is performed into the water or food supply, or as an aerosol into a closed or semi- closed environment where the animals are maintained, even temporarily maintained.
  • Another embodiment of the invention is directed to an immunogenic composition comprising nucleic acid sequences that encode protective antigens and/or epitopes against a pathogen.
  • the sequences can be incorporated into a viral vector, such as NDV, or another viral vector suitable for the animal population or a mammal.
  • Preferred pathogens include, but are not limited to bacteria, viruses, parasites, fungi and viruses.
  • antigens contain a conserved region derived from an influenza virus subtypes (e.g., influenza viruses with varying HA or NA compositions, such as H1N1, H5N1, H3N2, and H2N2).
  • influenza virus subtypes e.g., influenza viruses with varying HA or NA compositions, such as H1N1, H5N1, H3N2, and H2N2.
  • Epitopes of conserved regions on NA or HA may also confer cross- subtype immunity.
  • conserved epitopes on NA(N1) may confer enhanced immunity to H5N1 and H1N1.
  • influenza A subtypes and/or strains within a subtype preferably these are at least about 80 percent, more preferably at least about 90 percent, more preferably at least about 95 percent identical, more preferably at least about 96 percent identical, more preferably at least about 97 percent identical, more preferably at least about 98 percent identical, more preferably at least about 99 percent identical, and even more preferably 100 percent identical (invariant).
  • at least one peptide sequence within the composite antigen is also conserved on homologous proteins (e.g., protein subunits) of at least two viral particles, preferably influenza particles.
  • Proteins of influenza virus include, for example, expressed proteins in the virus structure, such as HA, NA, protein polymerases (PB1, PB2, PA), matrix proteins (M1, M2), and nucleoprotein (“NP”).
  • the conserved peptide sequences are conserved on at least two or more of the M1, M2, HA, NA, or one or more polymerase proteins.
  • a selected sequence in the M1 and M2 proteins of the H5N1 influenza virus corresponds to the M1 and M2 proteins found in other H5N1 particles, and to the same sequence in the M1 and M2 proteins of the H3N2 influenza virus.
  • sequences from HA and NA are found across many influenza strains and many subtypes (e.g., HA and NA sequences are conserved across H5N1 and H1N1).
  • the sequences are derived from a conserved sequence present within variants or strains (viral isolates expressing substantially the same HA and NA proteins, but wherein the HA and NA protein amino acid sequences show some minor drift), of a single influenzavirus subtype and more preferably across at least two influenzavirus subtypes, e.g., subtypes of influenza A virus.
  • Peptide or polypeptide that includes at least one conserved epitope sequence which may also comprise one or more repeats of the same or a different epitope sequence, each of which is conserved across a plurality of homologous proteins that is conserved in a population of bacterial or viral strains or serotypes, and a pharmaceutically acceptable carrier.
  • at least one epitopic sequence is repeated at least once, preferably at least twice times, more preferably at least three times.
  • the at least one epitopic sequence is repeated four or more times.
  • the sequences are identical with the sequences in the homologous protein subunits of at least two circulating viral isolates.
  • Compositions may include a pharmaceutically acceptable carrier.
  • Peptide sequences preferably include sequences derived from genome (i.e., RNA) segment 7 of the influenza virus, while in a more preferred embodiment, the sequences include at least portions of the M1 and M2 proteins. In other preferred embodiments, the sequences include sequences expressed from genome segments encoding the HA or NA proteins. Such sequences are less affected by subtype drift and more broadly protective against infections.
  • Antigens may include one or more T-cell stimulating epitopes, such as diphtheria toxoid, tetanus toxoid, a polysaccharide, a lipoprotein, or a derivative or any combination thereof (including fragments or variants thereof).
  • the at least one repeated sequence of the composite antigen is contained within the same molecule as the T-cell stimulating epitopes.
  • the at least one repeated sequence of the composite antigen may be contained within the same polypeptide as the T-cell stimulating epitopes, may be conjugated thereto, or may be associated in other ways.
  • one or more T-cell stimulating epitopes are positioned at either the N-Terminus or the C-Terminus (or both) of the antigen.
  • the composite antigens, with or without associated T-cell stimulating epitopes may include one or more polysaccharides or portions thereof.
  • At least one sequence of a composite antigen is conjugated to one or more polysaccharides.
  • one or more polysaccharides are conjugated to other portions of the composite antigen.
  • Certain embodiments of the present invention are selected from polysaccharide vaccines, protein-polysaccharide conjugate vaccines, or combinations thereof.
  • Composite antigens of the invention may be synthesizing by in vitro chemical synthesis, solid-phase protein synthesis, and in vitro (cell-free) protein translation, or recombinantly engineered and expressed in bacterial cells, fungi, insect cells, mammalian cells, virus particles, yeast, and the like.
  • a composite antigen may include one of the following elements: at least one repeated epitope; at least one T-cell epitope; at least one polysaccharide (sugars); at least one structural component; or a combination thereof.
  • the one structural component may include one or more of: at least one linker segment; at least one sugar-binding moiety; at least one nucleotide-binding moiety; at least one protein-binding moiety; at least one enzymatic moiety; or a combination thereof.
  • the invention encompasses methods of preparing an immunogenic composition, preferably a pharmaceutical composition, more preferably a vaccine, wherein a target antigen of the present invention is associated with a pharmaceutically acceptable diluent, excipient, or carrier, and may be used with most any adjuvant, such as, for example, ALFQ, ALFQA, ALFA, AS01, AS01b, and/or combinations, derivatives, and modifications thereof.
  • a relatively small number of conservative or neutral substitutions e.g., 1 or 2 may be made within the sequence of the composite antigen or epitope sequences disclosed herein, without substantially altering the immunological response to the peptide.
  • the substitution of one or more amino acids in a particular peptide may in fact serve to enhance or otherwise improve the ability of the peptide to elicit a systemic response in an animal or a mammal that has been provided with a composition that comprises the modified peptide, or a polynucleotide that encodes the peptide.
  • Suitable substitutions may generally be identified using computer programs and the effect of such substitutions may be confirmed based on the reactivity of the modified peptide with antisera and/or T-cells.
  • a peptide for use in the disclosed diagnostic and therapeutic methods may comprise a primary amino acid sequence in which one or more amino acid residues are substituted by one or more replacement amino acids, such that the ability of the modified peptide to react with antigen-specific antisera and/or T-cell lines or clones is not significantly less than that for the unmodified peptide.
  • preferred peptide variants are those that contain one or more conservative substitutions.
  • a “conservative substitution” is one in which an amino acid is substituted for another amino acid that has similar properties, such that one skilled in the art of peptide chemistry would expect the secondary structure and hydropathic nature of the peptide to be substantially unchanged.
  • Amino acid substitutions may generally be made on the basis of similarity in polarity, charge, solubility, hydrophobicity, hydrophilicity and/or the amphipathic nature of the residues.
  • negatively charged amino acids include aspartic acid and glutamic acid
  • positively charged amino acids include lysine and arginine
  • amino acids with uncharged polar head groups having similar hydrophilicity values include leucine, isoleucine and valine; glycine and alanine; asparagine and glutamine; and serine, threonine, phenylalanine and tyrosine.
  • amino acid substitutions that represent a conservative change include: (1) replacement of one or more Ala, Pro, Gly, Glu, Asp, Gln, Asn, Ser, or Thr; residues with one or more residues from the same group; (2) replacement of one or more Cys, Ser, Tyr, or Thr residues with one or more residues from the same group; (3) replacement of one or more Val, Ile, Leu, Met, Ala, or Phe residues with one or more residues from the same group; (4) replacement of one or more Lys, Arg, or His residues with one or more residues from the same group; and (5) replacement of one or more Phe, Tyr, Trp, or His residues with one or more residues from the same group.
  • a variant may also, or alternatively, contain non-conservative changes, for example, by substituting one of the amino acid residues from group (1) with an amino acid residue from group (2), group (3), group (4), or group (5).
  • Variants may also (or alternatively) be modified by, for example, the deletion or addition of amino acids that have minimal influence on the immunogenicity, secondary structure and hydropathic nature of the peptide.
  • Epitopes may be arranged in any order relative to one another in the composite sequence which may be with or without spacers.
  • the number of spacer amino acids between two or more of the epitopic sequences can be of any practical range, including, for example, from 1 or 2 amino acids to 3, 4, 5, 6, 7, 8, 9, or even 10 or more amino acids between adjacent epitopes.
  • polynucleotides including DNA, RNA (e.g., cRNA, mRNA), and PNA (peptide nucleic acid) constructs that encode the composite sequences of the invention.
  • RNA e.g., cRNA, mRNA
  • PNA peptide nucleic acid
  • These polynucleotides may be single-stranded (coding or antisense) or double-stranded, and may be DNA (genomic, cDNA or synthetic) or RNA molecules. Additional coding or non-coding sequences may, but need not, be present within a polynucleotide of the present invention, and a polynucleotide may, but need not, be linked to other molecules and/or support materials.
  • nucleotide sequences that encode a given primary amino acid sequence.
  • Some of these polynucleotides bear minimal homology to the nucleotide sequence of any native gene. Nonetheless, polynucleotides that vary due to differences in codon usage are specifically contemplated by the present invention.
  • Polynucleotides that encode an immunogenic peptide may generally be used for production of the peptide, in vitro or in vivo. Any polynucleotide may be further modified to increase stability in vivo.
  • a nucleic acid vaccine of the invention contains the genetic sequence of a composite antigen as cRNA or mRNA, or DNA, plus other necessary sequences that provide for the expression of the composite antigen in cells.
  • nucleic acid vaccines By injecting the mammal with the genetically engineered nucleic acid, the composite antigen is produced in or preferably on cells, which the mammal’s immune system recognizes and thereby generates a humoral or cellular response to the composite antigen, and therefore the pathogen.
  • Nucleic acid vaccines have a number of advantages over conventional vaccines, including the ability to induce a more general and complete immune response in the mammal. Accordingly, nucleic acid vaccines can be used to protect an animal or a mammal against disease caused from many different pathogenic organisms of viral, bacterial, and parasitic origin as well as certain tumors.
  • Nucleic acid vaccines typically comprise a viral or bacterial nucleic acid (e.g., cRNA, mRNA, DNA) that encodes an antigen contained in vectors or plasmids that have been genetically modified to transcribe and translate the composite antigenic sequences into specific protein sequences derived from a pathogen.
  • the nucleic acid vaccine is administered and the cellular machinery transcribed and/or translates the nucleic acid into the antigens which produce an immune response.
  • the antigens being non-natural and unrecognized by the mammalian immune system, are processed by cells and the processed proteins, preferably the epitopes, displayed on cell surfaces.
  • nucleic acid vaccines of the invention are preferably codon optimized for expression in the animal (or mammal) of interest.
  • codon optimization involves selecting a desired codon usage bias (the frequency of occurrence of synonymous codons in coding DNA) for the particular cell type so that the desired peptide sequence is expressed.
  • Compositions of the invention may contain composite antigens and epitopes, composite sequences, and/or RNA and/or DNA vaccines.
  • Composition may include adjuvants such as, for example, ALFQ, ALFQA, ALFA, AS01, AS01b, and/or combinations, derivatives, and modifications thereof.
  • the formulation of pharmaceutically-acceptable excipients and carrier solutions is well known to those of ordinary skill in the art, as is the development of suitable dosing and treatment regimens for using the particular compositions described herein in a variety of treatment regimens.
  • the amount of immunogenic composition(s) and the time needed for the administration of such immunogenic composition(s) will be within the purview of the ordinary-skilled artisan having benefit of the present teachings.
  • the administration of a therapeutically-effective, pharmaceutically-effective, and/or prophylactically-effective amount of the disclosed immunogenic compositions may be achieved by a single administration.
  • the immunogenic compositions and vaccines of the present invention preferably contain an adjuvant such as ALFQ and may be given by IM, SQ, Intradermal or intranasal administration or in a manner compatible with the dosage formulation, and in such an amount as will be prophylactically or therapeutically effective and preferably immunogenic.
  • the quantity to be administered depends on the subject to be treated, including, e.g., the capacity of the immune system to mount an immune response, and the degree of protection desired.
  • Suitable dosage ranges may be on the order of several hundred micrograms ( ⁇ g) of active ingredient per animal or mammal with a preferred range from about 0.1 ⁇ g to 2000 ⁇ g (even though higher amounts, such as, e.g., in the range of about 1 to about 10 mg are also contemplated), such as in the range from about 0.5 ⁇ g to 1000 ⁇ g, preferably in the range from about 1 ⁇ g to about 500 ⁇ g and especially in the range from about 10 ⁇ g to about 100 ⁇ g.
  • Suitable regimens for initial administration and booster shots are also variable but are typified by an initial administration followed by optional but preferred subsequent inoculations or other periodic administrations.
  • An effective dose comprises amounts the range of about 1 ⁇ g to about 1 mg total protein or target antigen per animal or mammal.
  • the vaccine dosage range is about 0.1 ⁇ g to about 10 mg per animal or mammal.
  • Precise dosages may be determined by assessing the immunogenicity of the conjugate produced in the appropriate host so that an immunologically effective dose is delivered.
  • An immunologically effective dose is one that stimulates the immune system of the animal or mammal to establish an immune response to the immunogenic composition or vaccine.
  • a level of immunological memory sufficient to provide long-term protection against disease caused by microbial infection is obtained.
  • the immunogenic compositions or vaccines of the invention may be preferably formulated with an adjuvant.
  • long-term it is preferably meant over a period of time of at least about 6 months, over at least about 1 year, over at least about 2 to 5 or even at least about 2 to about 10 years or longer.
  • sequences include composite sequences as well as sequences of interest that can be combined to form composite sequences: Influenza Virus SEQ ID NO 1 DWSGYSGSFVQHPELTGLD (N1 sequence; H1 N5) SEQ ID NO 2 ETPIRNE (M2e epitope) SEQ ID NO 3 FVIREPFISCSHLEC SEQ ID NO 4 GNFIAP (HA epitope; Pep 1) SEQ ID NO 5 GNLIAP (HA epitope; Pep 2) SEQ ID NO 6 GNLFIAP (composite sequence of SEQ ID NOs 4 and 5; Pep 3) SEQ ID NO 7 GNLIFAP (composite sequence of SEQ ID NOs 4 and 5) SEQ ID NO 8 HYEECSCY (NA epitope; Pep 10) SEQ ID NO 9 LLTEVETPIR (highly conserved region M1/M2e) SEQ ID NO 10 LLTEVETPIRN (highly conserved region M1/M2e) SEQ ID NO 11 LLTEVETPIRNE (highly conserved
  • SEQ ID NO 22 IWGIVHHP (composite of SEQ ID NOs. 19 and 20) SEQ ID NO 23 KSCINRCFYVELIRGR (N3 conserved epitope) SEQ ID NO 24 LLTEVETPIRNESLLTEVETPIRNEWG (M2e epitope) SEQ ID NO 25 LLTEVETPIRNEW (M2e epitope) SEQ ID NO 26 LLTEVETPIRNEWG (M2e epitope) SEQ ID NO 27 LTEVETPIRNE (M2e epitope) SEQ ID NO 28 LTEVETPIRNEW (M2e epitope) SEQ ID NO 29 LTEVETPIRNEWG (M2e epitope) SEQ ID NO 30 MSLLTEVET (M2e epitope) SEQ ID NO 31 MSLLTEVETP (M2e epitope) SEQ ID NO 32 MSLLTEVETPI (M2e epitope) SEQ ID NO 33 MSLLTEVETPIR (M2e epitope) SEQ ID NO
  • SEQ ID NO 110 SLDQINVTFLDLEYEMKKLEESY (coronavirus spike protein conserved epitope (SP)) SEQ ID NO 111 SLDQINVTFLDLEYEMKKLEESYQYIKANSKFIGITE (tetanus toxoid T cell epitope + SP) SEQ ID NO 112 WDYPKCDRA (polymerase conserved epitope (POL)) SEQ ID NO 113 WDYPKCDRAQYIKANSKFIGITE (POL + tetanus T cell epitope) SEQ ID NO 114 WDYPKCDRASLDQINVTFLDLEYEMKKLEESYQYIKANSKFIGITE (Cor POL + SP + Tet) SEQ ID NO 115 WDYPKCDRATEVETPIRNEHYEECSCYQYIKANSKFIGITE Cor POL.

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Abstract

L'invention concerne des compositions comprenant un acide nucléique qui code pour un peptide ou un peptide qui induit une réponse immunitaire chez un animal ou un mammifère qui est protecteur contre une infection par un ou plusieurs pathogènes. De plus, l'invention concerne des vaccins comprenant des compositions et un procédé de traitement et de prévention d'une infection chez des animaux et des mammifères tels que des êtres humains.
EP22763831.9A 2021-03-04 2022-02-28 Vaccins pour le traitement et la prévention d'infections zoonotiques Pending EP4301406A4 (fr)

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