The Development and Assessment of Immune Responses in Plasmid DNA, VSV-Vectored, and Virus-Like Particle HIV Vaccinations in Murine Models

Our previous macaque immunization study demonstrated that vaccinations with the Vesicular Stomatitis Virus (VSV)-vectored HIV vaccine (VSVXN2∆G/CDO-EBOVGP+HIV-1 Codon-optimized A74_Env-EC/SIV_Env-TMCT) in Rhesus macaques provided protection to 50% of the animals against low-dose challenges with SHIVenv_SF162P infection, making it an effective vaccine candidate. Building on these findings, my project was designed to assess 1) various vaccine vectors: VSV, virus-like particle (VLP), and DNA; 2) immunogens: transmitted founder strain A74 N425 wild type and N425K mutant; and 3) conformational changes: vaccines with or without CD4 mimetic interaction, to identify the best vaccine candidate. We also investigated the mechanisms by which these vaccines elicit humoral and cellular immune responses in mice by assessing antibody levels in sera and evaluating the phenotypes and functions of memory cell development in immunized mice. My results suggest that both VLP and VSV-vectored HIV vaccinations robustly induce humoral responses by eliciting HIV-specific memory B cells, while VSV-vectored HIV vaccination activates cellular responses by significantly increasing CD8+ memory T cells. DNA vaccine provided inferior immune responses, compared with VLP vaccination in mice. Furthermore, vaccination with VLP K425 primed with the CD4 mimetic elicited memory B cells targeting the CD4 binding site and V3 loop, which were previously buried inside the closed Env conformation. This finding suggests that removing the conformational mask enables access to concealed, highly conserved epitopes of HIV, eliciting memory cells targeting the virus's vulnerabilities. By directing immune cells towards highly conserved epitopes through the unmasking of the envelope's conformational epitopes, this vaccine strategy of conformational changes may explain why the VSV-HIV A74 K425 vaccine introduced potent protective effects in macaques and could provide valuable insights for human HIV vaccine design.