Early clonal dominance at priming sets the trajectory for broad HIV serum neutralization

Abstract

Germline-targeting vaccines aim to elicit HIV-1 broadly neutralizing antibodies (bnAbs), but determinants of serum bnAb induction remain unclear. We previously showed that Q23-APEX-GT2 primes diverse V2-apex bnAb precursors in outbred rhesus macaques (RMs). To assess their maturation into authentic bnAbs, we infected immunized RMs with CAP256.SU SHIV. Four of six developed heterologous serum neutralization breadth, with one neutralizing ~70% of viruses tested. Early autologous neutralization and B-cell priming efficiency post-prime correlated with post-infection breadth. Longitudinal lineage tracing in lymph-nodes and blood revealed that recruitment and expansion of diverse long-CDRH3 V2-apex B-cell precursors, followed by early dominance of one or two clones, predicted serum breadth. Structural analyses showed that non-neutralizing lineages failed despite cross-reactive Env binding, owing to unfavorable V2-apex approach angles and limited glycan engagement. Together, these findings identify priming efficiency and early clonal dominance as key determinants of serum bnAb induction and provide a framework for HIV vaccine design.