Alexandra A. M. Fischer, Martin Corcoran, Philip J.M. Brouwer, Mark Chernyshev, Rebecca A. Gillespie, Andrea Nicoletto, Johannes R. Loeffler, James A. Ferguson, Ioannis Zygouras, Pradeepa Pushparaj, Alesandra J. Rodriguez, Sanjana Narang, Marit J. van Gils, Xaquín Castro Dopico, Masaru Kanekiyo, Andrew B. Ward, Julianna Han, Gunilla B. Karlsson Hedestam
The regular emergence of influenza strains with pandemic potential necessitates vaccines that elicit protective immune responses across genetically diverse human populations. A critical but understudied factor is how germline-encoded variation in immunoglobulin genes shapes the development of neutralizing antibodies. Here, by combining personalized immunoglobulin genotyping with high-throughput paired-chain antibody sequencing from influenza A hemagglutinin (HA)-binding B cells across four donors, using a technique we developed called individualized single-cell analysis of paired expressed antigen receptors (ISCAPE), we demonstrate that B cell responses to HA are highly individual. We identified a common IGHV2-70 polymorphism that impaired the function of a class of neutralizing HA head-directed antibodies. Furthermore, we described HA central stem-targeting broadly neutralizing antibodies that utilize IGHD3-3 recombined with diverse IGHV genes, expanding the known repertoire of stem antibodies and highlighting antibody gene usage population restrictions. We suggest that multi-donor repertoire studies, coupled with personalized immunoglobulin genotyping, can uncover germline-encoded functional variations and help mitigate population vulnerabilities in vaccine design.