Natural gene-encoded affinity for cognate antigen facilitates vaccine-amplification of broadly neutralizing antibodies against influenza virus

Abstract

Abstract B cell receptors display V gene-encoded CDRs and hypervariable CDR3, where the former may harbor innate-like antigen recognition characteristics. To test this in vivo, we deployed transgenic mice containing full human CDRH3 diversity but were constrained to single human VH genes: IGHV1-69*01, a human VH reproducibly used to generate broadly neutralizing antibodies (bnAbs) targeting hemagglutinin stalk of Group 1 influenza A viruses or irrelevant IGHV1-2*02. With this system, we could experimentally evaluate the contribution of V gene encoded CDRs to forming the antibody paratope following immune challenge. Exposure to virus or hemagglutinin vaccine-nanoparticles elicited primary antibody responses targeting the bnAb epitope, but only in IGHV1-69 animals. Repeated exposure amplified off-target responses, however, prime/boost with stalk-only nanoparticle (SS-np) refocused serum antibodies to the target-epitope, expanding the human IGHV1-69 bnAb lineage to elicit prototypic IGHV1-69 Group 1 bnAbs. The bnAb pathway was expanded from a genetically endowed but low frequency population of on target germline B cell precursors (<0.3% of the repertoire). IGHV1-69 therefore endows natural cognate anti-influenza targeting affinity which can be exploited through rational vaccine design to redirect antibodies against an otherwise immunologically silent ‘universal’ flu vaccine target. Remarkably, similar on-target germline B cell levels were seen in human PBMC, suggesting SS-np may elicit bnAbs in humans.