SBIR-STTR Award

Development of a vaccine to prevent, or reduce the rate of, HIV infections remains a high priority despite recent setbacks in the field. The lessons from failed and successful experimental programs indicate the need to apply new approaches to HIV vaccine design with the goal of inducing immune responses that are the appropriate type, quality, magnitude and active in the appropriate sites in the body. A promising approach is the use of the Adenovirus (serotype 4) as a vaccine delivery vehicle. The Ad4 virus was a component in the US Military adenovirus vaccine which was formulated for administration in an oral dosage form. Oral delivery should be advantageous for HIV vaccines because this route of administration is more likely to induce mucosal immune responses than parenteral injection and would target the gut mucosal tissues in particular. The Ad4 vaccine vector is replication competent which should drive the induction and expansion of responses that are different, in terms of magnitude and effector functions, than those induced by non-replicating vectors. In this proposal we outline a one year plan to construct and test experimental live Ad4 vectored vaccines. Up to six Ad4 vectored vaccines will be engineered to encode HIV env proteins for the purpose of inducing antibody responses broadly effective against a variety of HIV strains. The vectored vaccines will then be tested in rabbits to assess neutralizing antibody responses that are effective against a range of HIV isolates, and antibody-dependent cell-mediated virus inhibition of HIV. Mucosal vaccine delivery will also be assessed using oral administration. As designed the initial phase of this SBIR program will provide sufficient data to determine the utility of this Ad4 vector system for inducing effective antibody responses and potentially could yield an experimental vaccine suitable for further testing in nonhuman primates and potentially clinical development.

Public Health Relevance:
The development of a safe and protective vaccine against the Human Immunodeficiency Virus (HIV) that causes AIDS has been very difficult. The proposed research will modify an existing adenovirus vaccine, which was used safely in more than 10 million people, so that it expresses HIV proteins and induces an immunological response in animals. This vaccine will have advantages of being live virus vaccine, such as the polio or measles vaccines, which can be taken by mouth without risk of causing HIV infection.

Thesaurus Terms:
Adcc; Aids; Aids Virus; Acquired Immune Deficiency; Acquired Immune Deficiency Syndrome; Acquired Immune Deficiency Syndrome Virus; Acquired Immuno-Deficiency Syndrome; Acquired Immunodeficiency Syndrome; Acquired Immunodeficiency Syndrome Virus; Adenoviridae; Adenoviruses; Administration, Oral; Animals; Antibodies; Antibody -Dependent Cell Cytotoxicity; Antibody Formation; Antibody Production; Antibody Response; Antibody-Dependent Cellular Cytotoxicity; Antigenic Determinants; Armed Forces Personnel; Avian Influenza A Virus; Binding Determinants; Binding Proteins; Buccal Cavity; Caps; Capsules; Cavitas Oris; Cell Cytoxicity, Antibody-Dependent; Cell Membrane Lipids; Cell Membrane; Cell Surface; Cells; Clinical; Clinical Evaluation; Clinical Testing; Clinical Trials; Clinical Trials, Phase I; Clinical Trials, Phase Iii; Clinical Trials, Unspecified; Coupled; Cytoplasmic Membrane; Data; Development; Development Plans; Development And Research; Dosage Forms; Drug Administration, Oral; E Protein; Early-Stage Clinical Trials; Engineering; Engineerings; Ensure; Enteral; Enteric; Envelope Glycoprotein Gp120, Hiv; Envelope Protein; Environment; Epidemic Acute Poliomyelitis; Epitopes; Fowl Plague Virus; Gagging; Gene Products, Env; Genes; Goals; H5 Hemagglutinin; Hiv; Hiv Envelope Protein Gp120; Hiv Vaccine; Hiv/Aids Vaccines; Htlv-Iii; Htlv-Iii Gp120; Head And Neck, Buccal Cavity; Human Immunodeficiency Viruses; Human T-Cell Leukemia Virus Type Iii; Human T-Cell Lymphotropic Virus Type Iii; Human T-Lymphotropic Virus Type Iii; Immune Response; Immune System; Immunization; Immunologic Deficiency Syndrome, Acquired; Immunologic Stimulation; Immunological Stimulation; Immunostimulation; Influenza A Virus, Avian; Influenza Virus, Avian; Injection Of Therapeutic Agent; Injections; Lav-Htlv-Iii; Life; Ligand Binding Protein; Lymphadenopathy-Associated Virus; Mammals, Rabbits; Measles Vaccine; Mediating; Membrane; Membrane Lipids; Military; Military Personnel; Molecular Configuration; Molecular Conformation; Molecular Stereochemistry; Mouth; Mucosa; Mucosal Immune Responses; Mucosal Tissue; Mucous Membrane; Myxovirus Pestis Galli; Oral; Oral Administration; Oral Cavity; Orthomyxovirus Type A, Avian; Oryctolagus Cuniculus; Patients; Phase; Phase 1 Clinical Trials; Phase 3 Clinical Trials; Phase I Clinical Trials; Phase I Study; Phase Iii Clinical Trials; Plasma Membrane; Polio; Poliomyelitis; Poliomyelitis, Acute; Production; Programs (Pt); Programs [publication Type]; Property; Property, Loinc Axis 2; Proteins; R & D; R&D; Rabbit, Domestic; Rabbits; Recombinants; Reflex, Pharyngeal; Reporting; Research; Risk; Route; Sbir; Sbirs (R43/44); Sensitization, Immunologic; Sensitization, Immunological; Series; Serotyping; Site; Small Business Innovation Research; Small Business Innovation Research Grant; Staging; Structure; System; System, Loinc Axis 4; Tm Domain; Tablets; Technology; Testing; Transmembrane Domain; Transmembrane Region; Vaccine Design; Vaccines; Viral Diseases; Viral Gene Products; Viral Gene Proteins; Viral Proteins; Virus; Virus Diseases; Virus-Hiv; Viruses, General; Work; Antibody Biosynthesis; Antibody Dependent Cell Mediated Cytotoxicity; Avian Flu Virus; Base; Bird Flu Virus; Body System, Allergic/Immunologic; Capsule (Pharmacologic); Clinical Investigation; Clinical Test; Conformation; Conformational State; Design; Design And Construction; Designing; Efficacy Trial; Env Antigens; Env Gene Products; Env Polyproteins; Env Protein; Env Protein Gp120, Hiv; Gene Product; Gp120; Gp120 Env Glycoprotein; Gp120(Hiv); Gp160; Host Response; Human Immunodeficiency Virus Vaccine; Immunogenicity; Immunoglobulin Biosynthesis; Immunoresponse; Improved; Intraoral Drug Delivery; Membrane Structure; Mucosal Site; Mucosal Vaccine; Neutralizing Antibody; New Approaches; Non-Human Primate; Nonhuman Primate; Novel Approaches; Novel Strategies; Novel Strategy; Organ System, Allergic/Immunologic; Phase 1 Study; Phase 1 Trial; Phase 3 Study; Phase 3 Trial; Phase I Trial; Phase Iii Trial; Plasmalemma; Plasmid Vaccine; Prevent; Preventing; Programs; Protocol, Phase I; Protocol, Phase Iii; Public Health Relevance; Research And Development; Research Clinical Testing; Response; Study, Phase Iii; Tablet (Pharmacologic); Vaccine Candidate; Vaccine Delivery; Vaccine Development; Vector; Vector Vaccine; Vector-Based Vaccine; Viral Infection; Virus Infection; Virus Protein; Volunteer

Development of a vaccine to prevent, or reduce the rate of, HIV infections remains a high priority despite recent setbacks in the field. The lessons from failed and successful experimental programs indicate the need to apply new approaches to HIV vaccine design with the goal of inducing immune responses that are the appropriate type, quality, magnitude and active in the appropriate sites in the body. A promising approach is the use of the Adenovirus serotype 4 (Ad4) as a vaccine delivery vehicle. The Ad4 virus is a component in the US Military adenovirus vaccine which was formulated for administration in an oral dosage form. Oral delivery should be advantageous for HIV vaccines because this route of administration is more likely to induce mucosal immune responses than parenteral injection and would target the gut mucosal tissues in particular. The Ad4 vaccine vector is replication-competent in humans which should drive the induction and expansion of immune responses that are different, in terms of magnitude and effector functions, than those induced by non- replicating vectors. In Y1, multiple Ad4 vectors will be engineered to express unique antigens including: 1) HIV-1 Env clade C protein for the purpose of inducing antibody responses broadly effective against a variety of HIV strains;2) GBV-C E2 glycoprotein, which may induce antibodies that block HIV-1 cellular attachment;and 3) Gag protein, which may induce T cell responses which promote killing of HIV-1 virus infected cells. Since human adenoviruses such as Ad4 do not replicate in non-human animals, including NHPs, we will also construct analogous replicating Simian adenovirus (SAd7) vectors to allow a direct comparison of the efficacy of Ad4 (non-replicating vector in NHPs) with an analogous replicating vector, SAd7. All vectors will be assessed for immunogenicity in small animals (mice /rabbits) before proceeding to NHP studies in Y2. Once immunogenicity is confirmed in NHPs, we will evaluate their efficacy in an NHP R5 SHIV clade C challenge study. Both antibody (neutralizing and ADCVI) and T cell immune responses (IFN- ) will be determined. Completion of this SBIR program will provide sufficient data to determine the utility of this Ad4 vector system for inducing effective antibody and T cell responses and potentially could yield an experimental vaccine suitable for clinical development.

Public Health Relevance:
The development of a safe and protective vaccine against the Human Immunodeficiency Virus (HIV) that causes AIDS has been very difficult. The proposed research will modify an existing adenovirus vaccine, which was used safely in more than 10 million people, so that it expresses HIV proteins and induces an immunological response in animals. This vaccine will have advantages of being a live virus vaccine, such as the polio or measles vaccines, which can be taken by mouth without risk of causing HIV infection.