TY - JOUR
T1 - Broadly neutralizing antibodies target a haemagglutinin anchor epitope
AU - Guthmiller, Jenna J.
AU - Han, Julianna
AU - Utset, Henry A.
AU - Li, Lei
AU - Lan, Linda Yu Ling
AU - Henry, Carole
AU - Stamper, Christopher T.
AU - McMahon, Meagan
AU - O’Dell, George
AU - Fernández-Quintero, Monica L.
AU - Freyn, Alec W.
AU - Amanat, Fatima
AU - Stovicek, Olivia
AU - Gentles, Lauren
AU - Richey, Sara T.
AU - de la Peña, Alba Torrents
AU - Rosado, Victoria
AU - Dugan, Haley L.
AU - Zheng, Nai Ying
AU - Tepora, Micah E.
AU - Bitar, Dalia J.
AU - Changrob, Siriruk
AU - Strohmeier, Shirin
AU - Huang, Min
AU - García-Sastre, Adolfo
AU - Liedl, Klaus R.
AU - Bloom, Jesse D.
AU - Nachbagauer, Raffael
AU - Palese, Peter
AU - Krammer, Florian
AU - Coughlan, Lynda
AU - Ward, Andrew B.
AU - Wilson, Patrick C.
N1 - Funding Information:
Acknowledgements We thank all of the volunteers who participated in this study; S. Andrews, R. Ahmed, J. Wrammert and K. Neu for initiating studies on the 2009 MIV, 2010 TIV and 2014 QIV cohorts; C. Mariottini, J. Feser, D. Stadlbauer and A.-K. Palm for their help on the cHA vaccine trial; I. Wilson for fruitful discussion and feedback on experimental design; B. Anderson and H. Turner for assistance with electron microscopy; and the teams at PATH, GSK, Cincinnati Children’s Hospital Medical Center, and Duke University for their work on the cHA vaccine trial (NCT03300050). This project was funded in part by the National Institute of Allergy and Infectious Diseases (NIAID; National Institutes of Health grant numbers K99AI159136 (to J.J.G.), U19AI082724 (to P.C.W.), U19AI109946 (to P.C.W.), U19AI057266 (to P.C.W.), P01AI097092 (to P.P.), R01AI145870-01 (to P.P.), R21AI146529 (to L.C.) and T32AI007244-36 (to J.H.), the NIAID Centers of Excellence for Influenza Research and Surveillance (CEIRS) grant number HHSN272201400005C (to P.C.W.), HHSN272201400008C (to L.C., F.K., A.G.-S. and P.P.), and the NIAID Centers of Excellence for Influenza Research and Response (CEIRR) grant number 75N93019R00028 (to P.C.W., F.K., A.G.-S. and P.P.). This work was also partially supported by the NIAID Collaborative Influenza Vaccine Innovation Centers (CIVIC; 75N93019C00051, to F.K., A.G.-S., P.P., A.B.W. and P.C.W.). The cHA vaccine trial and evaluation of immunity thereafter was funded in part by the Bill and Melinda Gates Foundation (OPP1084518). The findings and conclusions contained within are those of the authors and do not necessarily reflect positions or policies of the Gates Foundation. This study was also funded by the Austrian Science Fund grant number P34518 (to M.L.F.-Q. and K.R.L.).
Funding Information:
We thank all of the volunteers who participated in this study; S. Andrews, R. Ahmed, J. Wrammert and K. Neu for initiating studies on the 2009 MIV, 2010 TIV and 2014 QIV cohorts; C. Mariottini, J. Feser, D. Stadlbauer and A.-K. Palm for their help on the cHA vaccine trial; I. Wilson for fruitful discussion and feedback on experimental design; B. Anderson and H. Turner for assistance with electron microscopy; and the teams at PATH, GSK, Cincinnati Children?s Hospital Medical Center, and Duke University for their work on the cHA vaccine trial (NCT03300050). This project was funded in part by the National Institute of Allergy and Infectious Diseases (NIAID; National Institutes of Health grant numbers K99AI159136 (to J.J.G.), U19AI082724 (to P.C.W.), U19AI109946 (to P.C.W.), U19AI057266 (to P.C.W.), P01AI097092 (to P.P.), R01AI145870-01 (to P.P.), R21AI146529 (to L.C.) and T32AI007244-36 (to J.H.), the NIAID Centers of Excellence for Influenza Research and Surveillance (CEIRS) grant number HHSN272201400005C (to P.C.W.), HHSN272201400008C (to L.C., F.K., A.G.-S. and P.P.), and the NIAID Centers of Excellence for Influenza Research and Response (CEIRR) grant number 75N93019R00028 (to P.C.W., F.K., A.G.-S. and P.P.). This work was also partially supported by the NIAID Collaborative Influenza Vaccine Innovation Centers (CIVIC; 75N93019C00051, to F.K., A.G.-S., P.P., A.B.W. and P.C.W.). The cHA vaccine trial and evaluation of immunity thereafter was funded in part by the Bill and Melinda Gates Foundation (OPP1084518). The findings and conclusions contained within are those of the authors and do not necessarily reflect positions or policies of the Gates Foundation. This study was also funded by the Austrian Science Fund grant number P34518 (to M.L.F.-Q. and K.R.L.).
Publisher Copyright:
© 2021, The Author(s).
PY - 2022/2/10
Y1 - 2022/2/10
N2 - Broadly neutralizing antibodies that target epitopes of haemagglutinin on the influenza virus have the potential to provide near universal protection against influenza virus infection1. However, viral mutants that escape broadly neutralizing antibodies have been reported2,3. The identification of broadly neutralizing antibody classes that can neutralize viral escape mutants is critical for universal influenza virus vaccine design. Here we report a distinct class of broadly neutralizing antibodies that target a discrete membrane-proximal anchor epitope of the haemagglutinin stalk domain. Anchor epitope-targeting antibodies are broadly neutralizing across H1 viruses and can cross-react with H2 and H5 viruses that are a pandemic threat. Antibodies that target this anchor epitope utilize a highly restricted repertoire, which encodes two public binding motifs that make extensive contacts with conserved residues in the fusion peptide. Moreover, anchor epitope-targeting B cells are common in the human memory B cell repertoire and were recalled in humans by an oil-in-water adjuvanted chimeric haemagglutinin vaccine4,5, which is a potential universal influenza virus vaccine. To maximize protection against seasonal and pandemic influenza viruses, vaccines should aim to boost this previously untapped source of broadly neutralizing antibodies that are widespread in the human memory B cell pool.
AB - Broadly neutralizing antibodies that target epitopes of haemagglutinin on the influenza virus have the potential to provide near universal protection against influenza virus infection1. However, viral mutants that escape broadly neutralizing antibodies have been reported2,3. The identification of broadly neutralizing antibody classes that can neutralize viral escape mutants is critical for universal influenza virus vaccine design. Here we report a distinct class of broadly neutralizing antibodies that target a discrete membrane-proximal anchor epitope of the haemagglutinin stalk domain. Anchor epitope-targeting antibodies are broadly neutralizing across H1 viruses and can cross-react with H2 and H5 viruses that are a pandemic threat. Antibodies that target this anchor epitope utilize a highly restricted repertoire, which encodes two public binding motifs that make extensive contacts with conserved residues in the fusion peptide. Moreover, anchor epitope-targeting B cells are common in the human memory B cell repertoire and were recalled in humans by an oil-in-water adjuvanted chimeric haemagglutinin vaccine4,5, which is a potential universal influenza virus vaccine. To maximize protection against seasonal and pandemic influenza viruses, vaccines should aim to boost this previously untapped source of broadly neutralizing antibodies that are widespread in the human memory B cell pool.
UR - http://www.scopus.com/inward/record.url?scp=85121589615&partnerID=8YFLogxK
U2 - 10.1038/s41586-021-04356-8
DO - 10.1038/s41586-021-04356-8
M3 - Article
C2 - 34942633
AN - SCOPUS:85121589615
SN - 0028-0836
VL - 602
SP - 314
EP - 320
JO - Nature
JF - Nature
IS - 7896
ER -