HIV vaccine swarms for PWID

PROJECT SUMMARY/ABSTRACT: More than 80 million people have become infected with HIV since the start of the epidemic, and people who inject drugs (PWID) are particularly affected by this disease. Developing an HIV vaccine has been challenging in great part because of the high variability of HIV. Thus, we propose that an effective HIV vaccine would need to encode diverse antigens to capture the natural sequence diversity of HIV exposures. During mucosal transmission, the mucosa can offer partial protection against HIV by acting as a natural barrier, reducing the number of founder viruses that can cause infection. In contrast, during intravenous transmission, the virus enters directly into the circulation without any mucosal protection, leading to infection by many viral quasispecies. Therefore, developing a vaccine to prevent intravenous HIV transmission is strikingly more difficult. For an HIV vaccine to protect PWID against intravenous transmission, it would need to elicit high levels of immune responses to rapidly clear the multiple viral strains that are injected after needle use. Here, we will develop novel polyvalent vaccines encoding highly diverse HIV envelope sequences, derived from HIV+ PWID. In addition, we will utilize a vaccine dose fractionation regimen that elicits 19-fold superior neutralizing antibody responses compared to conventional vaccine regimens. We will determine whether the vaccines expressing diverse envelope sequences confer superior protection against intravenous HIV challenges in animal models. These studies may provide a rationale for a future clinical trial to evaluate the efficacy of polyvalent HIV vaccines, referred to as vaccine swarms, in PWID. Taken together, our overarching hypothesis is that HIV vaccines for PWID can be more effective by: 1) incorporating multiple antigenic sequences present during a natural HIV infection; and, 2) utilizing a more immunogenic vaccine dose regimen. These studies can provide a framework for developing more effective vaccines against other variable pathogens besides HIV, including HCV, which disproportionately affects PWID.