%0 Journal Article
%T Eliciting a single amino acid change by vaccination generates antibody protection against group 1 and group 2 influenza A viruses.
%A Ray R
%A Nait Mohamed FA
%A Maurer DP
%A Huang J
%A Alpay BA
%A Ronsard L
%A Xie Z
%A Han J
%A Fernandez-Quintero M
%A Phan QA
%A Ursin RL
%A Vu M
%A Kirsch KH
%A Prum T
%A Rosado VC
%A Bracamonte-Moreno T
%A Okonkwo V
%A Bals J
%A McCarthy C
%A Nair U
%A Kanekiyo M
%A Ward AB
%A Schmidt AG
%A Batista FD
%A Lingwood D
%J Immunity
%V 57
%N 5
%D 2024 May 14
%M 38670113
%F 43.474
%R 10.1016/j.immuni.2024.03.022
%X 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.