Eliciting a single amino acid change by vaccination generates antibody protection against group 1 and group 2 influenza A viruses
Rashmi Ray, Faez Amokrane Nait Mohamed, Daniel P. Maurer, Jiachen Huang, Berk A. Alpay, Larance Ronsard, Zhenfei Xie, Julianna Han, Monica L. Fernández‐Quintero, Quynh Anh Phan, Rebecca L. Ursin, Mya Vu, Kathrin H. Kirsch, Thavaleak Prum, Victoria Rosado, Thalia Bracamonte-Moreno, Vintus Okonkwo, Julia Bals, Caitlin McCarthy, Usha Nair, Masaru Kanekiyo, Andrew B. Ward, Aaron G. Schmidt, Facundo D. Batista, Daniel Lingwood
Abstract
Broadly neutralizing antibodies (bnAbs) targeting the hemagglutinin (HA) stem of influenza A viruses (IAVs) tend to be effective against either group 1 or group 2 viral diversity. In rarer cases, intergroup protective bnAbs can be generated by human antibody paratopes that accommodate the conserved glycan differences between the group 1 and group 2 stems. We applied germline-engaging nanoparticle immunogens to elicit a class of cross-group bnAbs from physiological precursor frequency within a humanized mouse model. Cross-group protection depended on the presence of the human bnAb precursors within the B cell repertoire, and the vaccine-expanded antibodies enriched for an N55T substitution in the CDRH2 loop, a hallmark of the bnAb class. Structurally, this single mutation introduced a flexible fulcrum to accommodate glycosylation differences and could alone enable cross-group protection. Thus, broad IAV immunity can be expanded from the germline repertoire via minimal antigenic input and an exceptionally simple antibody development pathway.