Differential T follicular helper cell responses induced by candidate HIV vaccine strategies utilizing ALVAC versus Ad5 vectors

Abstract

Abstract The development of a safe and effective vaccine against Human Immunodeficiency Virus (HIV) remains a major priority in global health research. Several candidate HIV vaccines have undergone late-stage clinical trials in recent years, several of which utilized non-replicating viral vectors based on canarypox (ALVAC) or human adenovirus (Ad5.) Thus far, the only trial to show moderate (31.2%) efficacy in preventing HIV infection is the RV144 trial, which utilized an ALVAC prime/protein boost strategy. Subsequent analyses showed that protection from HIV infection correlated with the production of IgG3 antibodies directed against the highly conserved V1V2 loop of the HIV envelope (Env) protein, and was abrogated by the production of Env-specific serum IgA antibodies. Although the ineffective Ad5-based vaccines also induced strong Env-specific antibody responses, they failed to induce protective IgG3 and/or V1V2-specific antibodies. To better understand the mechanisms underlying the differential antibody profiles generated by these two vectors, we measured the frequency and functional phenotype of follicular T helper-like cells found in the peripheral blood of vaccine recipients (pTfh). We found that subjects who received an ALVAC prime/protein boost vaccine regimen had higher levels of Env-specific pTfh cells than subjects who received a DNA prime/Ad5 boost regimen, and that these pTfh cells have enhanced ability to induce B cell activation and class switching compared to those found in Ad5-based vaccine recipients. We hypothesize that the higher frequency and functionality of these ALVAC-induced pTfh cells contributes to the uniquely protective antibody response generated by ALVAC prime/protein boost vaccination.