Abstract

Broadly neutralizing antibodies (bNAbs) against HIV-1 Env have redefined prospects for biomedical prevention, 
offering long-acting, mechanism-based protection complementary to antiretroviral pre-exposure prophylaxis 
(PrEP). This review synthesized recent mechanistic, translational, and clinical evidence on bNAbs for HIV 
prevention and appraises barriers to implementation. The purpose was to provide clinicians, translational scientists, 
and policymakers a critical, up-to-date assessment of where bNAb-based prevention stands and what is needed for 
impact at population scale. Literature was identified by searching PubMed/MEDLINE, Embase, and Web of Science 
(January 2010–September 2025) using terms related to “HIV,” “broadly neutralizing antibody,” “PrEP,” “clinical 
trial,” “Fc engineering,” and “vectored immunoprophylaxis,” prioritizing randomized trials, large cohort analyses, 
systematic reviews, and seminal mechanistic studies. The AMP efficacy trials showed overall null efficacy of VRC01 
but strong efficacy (~75%) against viruses with in-vitro sensitivity (IC80 <1 μg/mL), validating neutralization 
sensitivity as a correlate of protection and motivating more potent/longer-acting antibodies and combinations. 
Next-generation CD4bs, V3-glycan, V2-apex, and MPER bNAbs with LS or related FcRn-enhancing substitutions 
achieved prolonged half-life, enabling quarterly to semiannual dosing; dual/triple regimens broaden coverage and 
curb escape, and trispecifics and AAV-vectored delivery are advancing. Remaining gaps included scalable sensitivity 
assays or genotypic predictors to guide selection, manufacturing cost and cold-chain constraints, and comparative 
effectiveness versus long-acting small-molecule PrEP. In conclusion, bNAb prevention was biologically validated 
with promising pharmacologic refinements; clinical implementation will hinge on rational antibody selection, 
simplified diagnostics, and cost-efficient delivery systems aligned with global PrEP programs.