Multiple tandem copies of conserved gp41 epitopes incorporated in gag virus-like particles elicit systemic and mucosal antibodies in an optimized heterologous vector delivery regimen

Induction of neutralizing antibodies to prevent HIV infection, especially at the mucosa, is a critical goal of future vaccines. In this study, we have designed chimeric HIV-gag virus-like particles (VLPs) that contain multiple copies of the two highly conserved gp41 membrane-proximal external region (MPER) epitopes, ELDKWA and NWFDIT, with the objective of generating high titers of MPER-specific antibodies. We have shown that the implementation of optimized vector design, delivery regimens and appropriate delivery methods is critical to significantly increase epitope-specific antibody titers. One goal of the methods that were tested and employed was to generate high levels of mucosal MPER-specific antibodies, as mucosal immune induction could play a key role in preventing HIV infection. We also tested a design strategy that incorporated multiple repeats of the MPER epitopes within gag, which significantly increased specific antibody titers, systemically and mucosally. This alternative design strategy and the implementation of optimized heterologous immunization regimens can serve to ‘immuno-focus’ and significantly increase epitope-specific titers.