TY - JOUR
T1 - Influenza chimeric hemagglutinin structures in complex with broadly protective antibodies to the stem and trimer interface
AU - Zhu, Xueyong
AU - Han, Julianna
AU - Sun, Weina
AU - Puente-Massaguer, Eduard
AU - Yu, Wenli
AU - Palese, Peter
AU - Krammer, Florian
AU - Ward, Andrew B.
AU - Wilson, Ian A.
N1 - Funding Information:
ACKNOWLEDGMENTS. We thank Henry Tien for automated robotic crystal screening, and Bill Anderson, Hannah Turner, and Charles Bowman for running the electron microscopy suite computational resources at The Scripps Research Institute. The work was supported in part by NIH National Institute of Allergy and Infectious Diseases (NIAID) Collaborative Influenza Vaccine Innovation Centers Contract 75N93109C00051 (to I.A.W., A.B.W., P.P., and F.K.). The work was also partially funded by NIH Centers of Excellence for Influenza Research and Response 75N93021C00014 (to P.P. and F.K.), and NIAID Grants P01 AI097092-07 (to P.P.) and AI145870-03 (to P.P.). J.H. was funded by NIAID 2 T32 AI007244-36. X-ray diffraction data were collected at the Advanced Photon Source (APS) beamline 23ID-B (GM/CA CAT) and the Stanford Synchrotron Radiation Lightsource (SSRL) beamline 12-2. GM/CA CAT is funded in whole or in part with federal funds from the National Cancer Institute (Y1-CO-1020) and the National Institute of General Medical Sciences (NIGMS) (Y1-GM-1104). Use of the APS was supported by the US Department of Energy (DOE), Basic Energy Sciences, Office of Science, under Contract DE-AC02-06CH11357. The SSRL is a Directorate of SLAC National Accelerator Laboratory and an Office of Science User Facility operated for the US DOE of Science by Stanford University. The SSRL Structural Molecular Biology Program is supported by the DOE Office of Biological and Environmental Research, and by the NIH, NIGMS (including P41GM103393), and the National Center for Research Resources (NCRR) (P41RR001209). The contents of this publication are solely the responsibility of the authors and do not necessarily represent the official views of NIAID, NIGMS, NCRR, or NIH.
Publisher Copyright:
Copyright © 2022 the Author(s).
PY - 2022/5/24
Y1 - 2022/5/24
N2 - Influenza virus hemagglutinin (HA) has been the primary target for influenza vaccine development. Broadly protective antibodies targeting conserved regions of the HA unlock the possibility of generating universal influenza immunity. Two group 2 influenza A chimeric HAs, cH4/3 and cH15/3, were previously designed to elicit antibodies to the conserved HA stem. Here, we show by X-ray crystallography and negative-stain electron microscopy that a broadly protective antistem antibody can stably bind to cH4/3 and cH15/3 HAs, thereby validating their potential as universal vaccine immunogens. Furthermore, flexibility was observed in the head domain of the chimeric HA structures, suggesting that antibodies could also potentially interact with the head interface epitope. Our structural and binding studies demonstrated that a broadly protective antihead trimeric interface antibody could indeed target the more open head domain of the cH15/3 HA trimer. Thus, in addition to inducing broadly protective antibodies against the conserved HA stem, chimeric HAs may also be able to elicit antibodies against the conserved trimer interface in the HA head domain, thereby increasing the vaccine efficacy.
AB - Influenza virus hemagglutinin (HA) has been the primary target for influenza vaccine development. Broadly protective antibodies targeting conserved regions of the HA unlock the possibility of generating universal influenza immunity. Two group 2 influenza A chimeric HAs, cH4/3 and cH15/3, were previously designed to elicit antibodies to the conserved HA stem. Here, we show by X-ray crystallography and negative-stain electron microscopy that a broadly protective antistem antibody can stably bind to cH4/3 and cH15/3 HAs, thereby validating their potential as universal vaccine immunogens. Furthermore, flexibility was observed in the head domain of the chimeric HA structures, suggesting that antibodies could also potentially interact with the head interface epitope. Our structural and binding studies demonstrated that a broadly protective antihead trimeric interface antibody could indeed target the more open head domain of the cH15/3 HA trimer. Thus, in addition to inducing broadly protective antibodies against the conserved HA stem, chimeric HAs may also be able to elicit antibodies against the conserved trimer interface in the HA head domain, thereby increasing the vaccine efficacy.
KW - HA trimer interface
KW - X-ray crystallography
KW - chimeric influenza hemagglutinin
KW - negative-stain electron microscopy
KW - stem
KW - universal vaccine design
UR - http://www.scopus.com/inward/record.url?scp=85130864165&partnerID=8YFLogxK
U2 - 10.1073/pnas.2200821119
DO - 10.1073/pnas.2200821119
M3 - Article
C2 - 35594401
AN - SCOPUS:85130864165
SN - 0027-8424
VL - 119
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 21
M1 - e2200821119
ER -