Epistasis and pleiotropy constrain the evolution of cross-reactive breadth in a broadly neutralizing influenza antibody.

Authors

Katrine E Dailey, Yiquan Wang, Qi Wen Teo, Chaoyang Wang, Huibin Lv, Ruipeng Lei, Meixuan Tong, Lucia A Rodriguez, Letianchu Wang, Nicholas C Wu

Published in

PLoS biology. Volume 24. Issue 9. Pages e3004021. Sep 28, 2026. Epub Sep 28, 2026.

Abstract

The highly conserved influenza virus hemagglutinin (HA) stem domain is a major target for broadly neutralizing antibodies (bnAbs). However, despite being discovered more than a decade ago, the IGHV1-69-encoded CR9114 remains the only HA stem bnAb that cross-reacts with both influenza A and B viruses. To investigate the constraints on the breadth evolution of CR9114, this study performs four deep mutational scanning experiments to compare the binding affinity landscapes of the germline and somatic CR9114 against H1 HA, H3 HA, and influenza B virus HA. Many mutations that minimally affect or even improve the H1 HA binding are detrimental for binding to H3 HA and influenza B virus HA. We further reveal the prevalence of epistasis in IGHV1-69 HA stem bnAbs. Overall, our findings provide a mechanistic explanation for the scarcity of HA stem bnAbs with cross-reactivity against both influenza A and B viruses, and have important implications for developing broadly protective influenza vaccines.

PMID:
42804473
Bibliographic data and abstract were imported from PubMed on 29 Sep 2026.

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