PROJECT SUMMARY/ABSTRACT 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.