Germline-Encoded Affinity for Cognate Antigen Enables Vaccine Amplification of a Human Broadly Neutralizing Response against Influenza Virus

Abstract

Antibody paratopes are formed by hypervariable complementarity-determining regions (CDRH3s) and variable gene-encoded CDRs. The latter shows biased usage in human broadly neutralizing antibodies (bnAbs) against both HIV and influenza virus, suggesting the existence of gene-endowed targeting solutions that may be amenable to pathway amplification. To test this, we generated transgenic mice with human CDRH3 diversity but simultaneously constrained to individual user-defined human immunoglobulin variable heavy chain (V H ) genes, including IGHV1-69, which shows biased usage in human bnAbs targeting the hemagglutinin stalk of Group 1 influenza A viruses. Sequential immunization with a stalk-only hemagglutinin nanoparticle elicited Group 1 bnAbs, but only in IGHV1-69 mice. This V H -endowed response required minimal affinity maturation, was elicited alongside pre-existing influenza immunity, and when IGHV1-69 B cells were diluted to match the frequency measured in humans. These results indicate that the human repertoire could in principle support germline-encoded bnAb elicitation using a single recombinant hemagglutinin immunogen. Human broadly neutralizing antibodies (bnAbs) against influenza virus can be biased for VH-gene usage, suggesting gene-encoded development pathways. Sangesland et al. show that human IGHV1-69 B cell receptors impart natural affinity for a ‘universal’ vaccine target, enabling rapid bnAb responses in mice that were elicited using a rationally designed influenza immunogen.