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Peer-reviewedCC BY 4.0PLOS Biology

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

  • Katrine E. Dailey1
  • Yiquan Wang2
  • Qi Wen Teo3
  • Chaoyang Wang4
  • Huibin Lv5
  • Ruipeng Lei
  • Meixuan Tong
  • Lucia A. Rodriguez
  • Letianchu Wang
  • Nicholas C. Wu
5 affiliations
  1. 1Department of Biochemistry, University of Illinois Urbana-Champaign, Urbana, Illinois, United States of America
  2. 2Department of Infectious Diseases and Immunology, University of Florida, Gainesville, Florida, United States of America
  3. 3Carl R. Woese Institute for Genomic Biology, University of Illinois Urbana-Champaign, Urbana, Illinois, United States of America
  4. 4Center for Biophysics and Quantitative Biology, University of Illinois Urbana-Champaign, Urbana, Illinois, United States of America
  5. 5Carle Illinois College of Medicine, University of Illinois Urbana-Champaign, Urbana, Illinois, United States of America
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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.

Broadly neutralizing flu antibodies able to recognize both influenza A and B viruses are exceptionally rare. This study shows that mutations which preserve or improve binding to one flu virus can weaken recognition of others, constraining antibody cross-reactive breadth.

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Cite

BibTeXRIS
BibTeX
@article{dailey2026epistasis,
  title = {{Epistasis and pleiotropy constrain the evolution of cross-reactive breadth in a broadly neutralizing influenza antibody}},
  author = {Katrine E. Dailey and Yiquan Wang and Qi Wen Teo and Chaoyang Wang and Huibin Lv and Ruipeng Lei and Meixuan Tong and Lucia A. Rodriguez and Letianchu Wang and Nicholas C. Wu},
  journal = {PLOS Biology},
  year = {2026},
  month = sep,
  doi = {10.1371/journal.pbio.3004021},
  url = {https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3004021},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Epistasis and pleiotropy constrain the evolution of cross-reactive breadth in a broadly neutralizing influenza antibody
AU  - Katrine E. Dailey
AU  - Yiquan Wang
AU  - Qi Wen Teo
AU  - Chaoyang Wang
AU  - Huibin Lv
AU  - Ruipeng Lei
AU  - Meixuan Tong
AU  - Lucia A. Rodriguez
AU  - Letianchu Wang
AU  - Nicholas C. Wu
PY  - 2026
DA  - 2026/09/28
JO  - PLOS Biology
DO  - 10.1371/journal.pbio.3004021
UR  - https://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.3004021
AB  - 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.  Broadly neutralizing flu antibodies able to recognize both influenza A and B viruses are exceptionally rare. This study shows that mutations which preserve or improve binding to one flu virus can weaken recognition of others, constraining antibody cross-reactive breadth.
SN  - 1545-7885
ER  -