Isolation of genetically diverse influenza antibodies highlights the role of IG germline gene variation and informs the design of population-comprehensive vaccine strategies.

The regular emergence of influenza strains with pandemic potential creates a strong incentive to develop vaccines that stimulate protective responses across all human populations. A critical consideration is how variation in the human immunoglobulin (IG) loci influences B cell recognition of viral epitopes and elicitation of neutralizing antibodies. Here, we applied personalized IG germline genotyping and high-throughput sequencing of paired antibody chains from influenza A virus hemagglutinin (HA)-binding B cells to demonstrate that the response to HA is highly individual. We show that a germline-encoded polymorphism in IGHV2-70 alters the functionality of the LPAF-a class of neutralizing antibodies, and we describe HA stem-targeting broadly neutralizing antibodies (bNAbs) that use germline IGHV genes other than the population-restricted IGHV genes used by many previously known stem bNAbs. Our results demonstrate that the approach used here can be used to discover and avert population vulnerabilities arising from IG gene variation when designing HA-based influenza vaccines aimed for the global human population.