Heavy-chain CDR3-engineered B cells facilitate in vivo evaluation of HIV-1 vaccine candidates

V2-glycan/apex broadly neutralizing antibodies (bNAbs) recognize a closed quaternary epitope of the HIV-1 envelope glycoprotein (Env). This closed structure is necessary to elicit apex antibodies and useful to guide maturation of other bNAb classes. To compare candidate antigens designed to maintain this conformation, apex-specific responses were monitored in mice engrafted with B cells expressing the HCDR3 of the apex bNAb VRC26.25. Engineered B cells class-switched and affinity-matured, guiding improvement of VRC26.25 itself. We found that previously described soluble Env (SOSIP) variants differed significantly in their ability to raise apex responses. A transmembrane SOSIP (SOSIP-TM) delivered as an mRNA-lipid nanoparticle elicited more potent neutralizing responses than any multimerized SOSIP protein. Importantly, SOSIP-TM elicited neutralizing sera from a diverse B-cell repertoire engineered with the predicted VRC26.25 HCDR3 progenitor. Our data show that HCDR3-edited B cells facilitate efficient in vivo comparisons of Env antigens and highlight the potential of an HCDR3-focused vaccine approach.