Enhancing HIV-1 vaccines by altering vaccine dose

PROJECT SUMMARY: Developing a vaccine against HIV is thus a research priority, but it has been difficult in part because vaccines have not been able to generate sufficient antiviral immunity able to prevent infection. Our prior research using Ad5-vectored vaccines show that vaccine prime fractionation improves vaccine-elicited immune responses,

especially neutralizing antibody responses. We have shown that a prime with a low dose (LD) of vaccine, followed by a booster with a standard dose (SD) of vaccine, results in more potent induction of immune responses, relative to priming and boosting with the same SD. These results with Ad5 beg the question of

whether vaccine fractionation can also improve other vaccine platforms, and whether such initial “micro-dosing” approach can be utilized to develop more effective HIV vaccines. To answer this question, our proposal will have 2 Specific Aims: Specific Aim 1. To evaluate whether vaccine fractionation improves the immunogenicity of Ad26- and

mRNA-based HIV vaccines in mice. Our prior data using an Ad5-SIV vector vaccine show that priming mice with a LD of vaccine, followed by boosting with a SD of vaccine results in superior immune responses relative to priming and boosting with the same SD. These data provide a rationale for testing whether the same

immunological effects occur with other HIV/SIV vaccines in mice, including Ad26 and mRNA. Specific Aim 2. To evaluate the safety, immunogenicity, and efficacy of fractionated HIV vaccines in macaques. In this aim we will extend our findings to macaques and determine whether vaccine fractionation improves the immunogenicity and protective efficacy of HIV vaccines.

Our overarching hypothesis is that HIV vaccines can be improved by reducing the priming dose. This hypothesis is based on our recent published data, as well as a recent vaccine trial (ChAdOx1 nCoV-19) in which the prime dose was accidentally reduced to half and shown to confer higher protection upon boosting, relative

to standard prime dose upon boosting. Taken together, our studies will provide a framework for developing more effective vaccines against HIV and other infectious diseases and may warrant a re-evaluation of current vaccine dosing schemes.