Despite the availability of effective anti-retroviral drugs, there are still about 38 million people living with HIV-1 infection and about 1.5 million people became newly infected just in 2020. A vaccine is critically needed to stop the AIDS pandemic. Induction of broadly neutralizing antibodies (bnAbs) against HIV-1 is the utmost critical goal towards the development of a protective AIDS vaccine. In this R43 Phase I SBIR proposal, we will evaluate a novel "Antibody- Stabilized, Epitope Presentation" (ASEP) vaccine strategy to elicit 10E8-like bnAbs against HIV-1. 10E8, a bnAb isolated from an HIV-1-infected patient that targets the membrane proximal external region (MPER) of HIV-1 gp41, has been shown to neutralize ~98% of all HIV-1 isolates tested. Developing immunogens and/or establishing vaccine strategies that can induce 10E8-like bnAbs would be a major milestone towards AIDS vaccine development. Thus, our proposal is highly significant and, if successful, this project will have great impact in the AIDS vaccine field and immunogens we generate will be commercially valuable. The major innovation and the focus of this proposal is our ASEP vaccine strategy, in which precisely defined immune complexes are used as immunogens. This proposal is founded on three scientific premises. (1) A vaccine that can induce high titers of 10E8-like bnAbs will be protective against HIV-1 infections. (2) Although short peptides are good for focusing antibody responses, they are not ideal B-cell immunogens because they are highly flexible and can exist in many different conformations. (3) The conformation of a peptide can be fixed into a rigid structure when it is bound to an antibody. The primary objective of this Phase I R43 feasibility study is to demonstrate MPER/Antibody immune complexes can be used to elicit 10E8-like bnAbs against HIV-1. Successful completion of this study would overcome a critical roadblock towards development of a protective AIDS vaccine.
Public Health Relevance Statement: PROJECT NARRATIVE Antibodies that can neutralize (block) HIV-1 infection are important components of the body's immune system. The critical roadblock to AIDS vaccine development is the difficulty in eliciting neutralizing antibodies that are broadly reactive against many different variants of the virus. It is believed that preventing a critical step of virus entry into host cells is the best strategy to develop an AIDS vaccine. However, this has been a significant scientific challenge during the past four decades. The major goal of this proposal is to generate novel vaccine candidates that can train the body's immune system to produce antibodies that can block fusion of viral and cellular membranes. Thus, successful completion of proposed studies will overcome a critical roadblock to AIDS vaccine development.
Project Terms: Acquired Immunodeficiency Syndrome; AIDS; Acquired Immune Deficiency; Acquired Immune Deficiency Syndrome; Acquired Immuno-Deficiency Syndrome; Acquired Immunologic Deficiency Syndrome; Amino Acids; aminoacid; Antibodies; Monoclonal Antibodies; Clinical Treatment Moab; mAbs; Antigen-Antibody Complex; Immune Complex; Epitopes; Antigenic Determinants; Binding Determinants; Antigens; immunogen; B-Lymphocytes; B blood cells; B cell; B cells; B-Cells; B-cell; Cells; Cell Body; Crystallization; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Face; faces; facial; Feasibility Studies; Genes; Goals; Government; HIV-1; HIV-I; HIV1; Human Immunodeficiency Virus Type 1; Human immunodeficiency virus 1; Human; Modern Man; Immune system; allergic/immunologic body system; allergic/immunologic organ system; Infection; Iowa; Lead; Pb element; heavy metal Pb; heavy metal lead; Transgenic Mice; Molecular Conformation; Molecular Configuration; Molecular Stereochemistry; conformation; conformational state; Mus; Mice; Mice Mammals; Murine; Persons; Patients; Peptides; Research Proposals; Testing; Universities; Vaccines; Vaccinia virus; Poxvirus officinale; recombinant vaccinia virus; Virus; NF1 gene; NF-1; NF-1 Protein; NF-1 encoded protein; NF1; NF1 GRP; NF1 Protein; NF1-GAP-Related Protein; Neurofibromatosis 1 Genes; Neurofibromatosis Type 1 Gene Product; Neurofibromatosis Type 1 Protein; Neurofibromin; Neurofibromin 1; neurofibromatosis type 1 gene; neurofibromatosis type 1 protein/gene; nf 1 Genes; AIDS Vaccines; AIDS vaccine; Chimeric Proteins; Chimera Protein; Fusion Protein; Surface; Phase; Variant; Variation; Evaluation; Training; Complex; Side; neutralizing antibody; Viral; membrane structure; Membrane; a-helix; alpha helix; Antiretroviral Agents; anti-retroviral; antiretroviral; Anti-Retroviral Agents; synergism; Structure; novel; novel technologies; new technology; gp160; preventing; prevent; Length; Affinity; Cellular Membrane; Scaffolding Protein; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; AIDS vaccine development; Immunologics; Immunochemical Immunologic; Immunologic; Immunological; Immunologically; Development; developmental; pandemic disease; pandemic; neutralizing monoclonal antibodies; neutralizing mAb; innovation; innovate; innovative; C-terminal; Peptide antibodies; novel vaccines; new vaccines; next generation vaccines; commercialization; vaccine candidate; flexibility; flexible; phase 1 study; Phase I Study; Antibody Response; nanomolar; nano-molar; Immunize; vaccine strategy
