Saturday, April 20, 2024
4/20/2024
A broad consensus regarding HIV vaccine development calls for engineering antigens that elicit production of antibodies like the known Broadly Neutralizing (BN) Monoclonal Antibodies (MAbs). Two Env BN MAb binding sites, the Membrane Proximal External Region (MPER) and Fusion Peptide (FP), are attractive targets because they are linear peptides. We developed a new, low cost, globally appropriate vaccine platform: Killed Whole Cell (KWC) Genome-Reduced E. coli (grEc), with vaccine antigens expressed on bacterial surfaces using Gram- autotransporters. Using synthetic biology, testable vaccine candidates can be made in ~3 wks for ~$50 each. Vaccines made with the platform will cost ~$1/dose, can be produced in existing factories globally, and have forgiving cold chain requirements. We made coronavirus FP vaccines using the KWC grEc platform and showed clinical efficacy in an animal model. We propose to make KWC grEc HIV vaccines targeting MPER and FP. Our preliminary data show that we can express HIV MPER and FP Ags with this approach and elicit HIV neutralizing sera in mice using an MPER-derived Ag. We hypothesize that the KWC grEc platform, targeting MPER and FP, will yield safe, effective, low cost, globally appropriate HIV vaccines. In PHASE 1, Aim 1, we will synthesize DNAs encoding MPER and FP Ags, employing bioengineering strategies to enhance Ag exposure and antigenicity. We will clone these DNAs into our expression plasmid and transform into grEc to make KWC candidate vaccines. Using highly neutralizing and relatively non-neutralizing MAbs, we will test candidate vaccines, selecting those that show the best difference in binding neutralizing vs. less neutralizing MAbs for in vivo testing. In Aim 2, we will vaccinate mice to assess vaccine immunogenicity, comparing the different candidate vaccines, alone and in combination, to identify the best vaccines and dose/route/adjuvant using ELISAs, ELIspot assays, and PhenoSense neutralization assays against a representative panel of viruses. Decision Gate to progress to Phase 2: Production of a single or combination vaccine that elicits sera in vaccinated mice yielding an IC50 >100 in the PhenoSense neutralization assay for =75% of mice immunized, for =75% of HIV-1 Env reference strains, while sera from control immunized mice (mice immunized with bacteria not expressing viral antigen) show no neutralization above baseline control. In PHASE 2 we will, in Aim 3, conduct a non-human primate (NHP) model study to assess the safety, immunogenicity, and ability to elicit a neutralizing Ab response by the vaccines. We expect that our vaccines will induce specific HIV Ag-binding Abs, HIV antigen-specific T cell responses, and BN neutralizing Ab responses in NHP, implying that the vaccine will be safe and effective in humans. KWC vaccines have a long history, are inexpensive to make, and can be produced globally in existing facilities, we anticipate that our work can be quickly translated into safe and effective, inexpensive, globally appropriate, prophylactic HIV vaccines.
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