Current HIV Research - Online First

Developing an effective HIV-1 vaccine remains a critical global health challenge, hindered by the virus’s high genetic diversity, immune evasion strategies, and structural complexity of its Envelope (Env) glycoprotein. Broadly neutralizing antibodies (bNAbs), capable of targeting conserved Env epitopes, offer a promising path for vaccine design. Germline-Targeting (GT) strategies have emerged as a promising approach to engage naive B cell precursors that have the potential to mature into bNAb-producing cells. Advances in GT have enabled the design of immunogens capable of recruiting specific bNAb precursors in animal models and early clinical trials. Despite these successes, achieving neutralization breadth requires sequential immunizations with tailored boosting strategies to guide B cell maturation. Studies underscore the importance of using immunogens that mimic native Env structures while modulating glycosylation patterns to focus immune responses. Emerging approaches, such as membrane-bound presentation and mRNA delivery, hold the potential for enhancing immunogen effectiveness and rapid pre-clinical and in human screening to identify combinations of immunogens that foster bNAb lineages. This review seeks to synthesize key developments in GT strategies for HIV-1 vaccines, highlighting the design and implementation of immunogens that drive bNAb precursor maturation. It aims to underscore the importance of integrating structural insights, immunogen sequence design, and delivery methods to enhance the induction of bNAbs, offering direction for future research to address existing gaps and optimize vaccine efficacy.

This article discusses how the RV144 Phase 3 HIV-1 vaccine trial conducted over 15 years ago impacted the subsequent direction of research intended to create and evaluate vaccines with potentially greater efficacy. Follow-on Phase 2b and Phase 3 trials directly or indirectly inspired by the modest efficacy reported for the RV144 trial have not shown any significant protection against HIV-1 acquisition. No credibly protective new immunogens have emerged from the Correlates of Protection (CoP) or Risk (CoR) analyses conducted after RV144-inspired studies in either humans or various macaque models. Notably, the RV144 trial did not induce neutralizing antibodies (NAbs), only non-NAbs. However, only NAbs have been shown to be protective in macaque models. One possible but underappreciated explanation for the outcome of the RV144 trial could be trained innate immune responses against the non-HIV-1 canarypox virus vector antigens, considering the placebo group only received saline. In this article, the author outlines how monkey model research based directly or indirectly on the RV144 trial could still yield useful information on the possible role of trained immunity in short-term vaccine protection. However, non-human primate research, in general, should now focus on testing new immunogens that have a reasonable chance of inducing NAbs in humans, rather than expending more resources on CoP/CoR studies inspired by the RV144 trial and its follow-ups.

Controversy exists around the relative merits of Fc functions in controlling or preventing HIV-1 infection. Proponents point to general correlations of Fc functions with control of HIV, indicating that non-neutralizing antibodies could force immune escape, as observed in the early experiments with Fc mutants of the b12-neutralizing monoclonal antibody. Nay-sayers point to the primary role of neutralization in the control of HIV, the general failure of vaccine trials including antibodies with Fc functions, and the lack of additional benefit with newer broadly neutralizing Ab, such as PGT121. The truth may lie somewhere in between and there are lessons to be learned from the utility of Fc functions in other viral infections. In general, however, the additional benefit of Fc function over and above robust anti-HIV neutralizing antibodies may be modest. The intense primary research focus on delivering and inducing potent and broadly neutralizing antibodies, regardless of their Fc function potential, is justified.