Germline-Targeting Strategies to Induce bNAbs against HIV-1

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.