TY - JOUR
T1 - Conserved epitope on influenza-virus hemagglutinin head defined by a vaccine-induced antibody
AU - Raymond, Donald D.
AU - Bajic, Goran
AU - Ferdman, Jack
AU - Suphaphiphat, Pirada
AU - Settembre, Ethan C.
AU - Moody, M. Anthony
AU - Schmidt, Aaron G.
AU - Harrison, Stephen C.
N1 - Funding Information:
ACKNOWLEDGMENTS. We thank Giuseppe Del Giudice, Oretta Finco, Philip Dormitzer, and Shaun Stewart for their participation in earlier stages of this project; Thomas Kepler for assistance with Clonalyst; and Barton Haynes for advice and support. The research was supported by National Institutes of Health (NIH) Grant P01 AI089618. X-ray diffraction data were collected on Northeastern Collaborative Access Team beamline 24 ID-C (Advanced Photon Source), funded by NIH Grant P41 GM103403. The Pilatus 6M detector on 24-ID-C is funded by an NIH Office of Research Infrastructure Programs High-End Instrumentation Grant (S10 RR029205). This research used resources of the Advanced Photon Source, a US Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract DE-AC02-06CH11357. S.C.H. is an Investigator at the Howard Hughes Medical Institute.
PY - 2018/1/2
Y1 - 2018/1/2
N2 - Circulating influenza viruses evade neutralization in their human hosts by acquiring escape mutations at epitopes of prevalent antibodies. A goal for next-generation influenza vaccines is to reduce escape likelihood by selectively eliciting antibodies recognizing conserved surfaces on the viral hemagglutinin (HA). The receptor-binding site (RBS) on the HA “head” and a region near the fusion peptide on the HA “stem” are two such sites. We describe here a human antibody clonal lineage, designated CL6649, members of which bind a third conserved site (“lateral patch”) on the side of the H1-subtype, HA head. A crystal structure of HA with bound Fab6649 shows the conserved antibody footprint. The site was invariant in isolates from 1977 (seasonal) to 2012 (pdm2009); antibodies in CL6649 recognize HAs from the entire period. In 2013, human H1 viruses acquired mutations in this epitope that were retained in subsequent seasons, prompting modification of the H1 vaccine component in 2017. The mutations inhibit Fab6649 binding. We infer from the rapid spread of these mutations in circulating H1 influenza viruses that the previously subdominant, conserved lateral patch had become immunodominant for individuals with B-cell memory imprinted by earlier H1 exposure. We suggest that introduction of the pdm2009 H1 virus, to which most of the broadly prevalent, neutralizing antibodies did not bind, conferred a selective advantage in the immune systems of infected hosts to recall of memory B cells that recognized the lateral patch, the principal exposed epitope that did not change when pdm2009 displaced previous seasonal H1 viruses.
AB - Circulating influenza viruses evade neutralization in their human hosts by acquiring escape mutations at epitopes of prevalent antibodies. A goal for next-generation influenza vaccines is to reduce escape likelihood by selectively eliciting antibodies recognizing conserved surfaces on the viral hemagglutinin (HA). The receptor-binding site (RBS) on the HA “head” and a region near the fusion peptide on the HA “stem” are two such sites. We describe here a human antibody clonal lineage, designated CL6649, members of which bind a third conserved site (“lateral patch”) on the side of the H1-subtype, HA head. A crystal structure of HA with bound Fab6649 shows the conserved antibody footprint. The site was invariant in isolates from 1977 (seasonal) to 2012 (pdm2009); antibodies in CL6649 recognize HAs from the entire period. In 2013, human H1 viruses acquired mutations in this epitope that were retained in subsequent seasons, prompting modification of the H1 vaccine component in 2017. The mutations inhibit Fab6649 binding. We infer from the rapid spread of these mutations in circulating H1 influenza viruses that the previously subdominant, conserved lateral patch had become immunodominant for individuals with B-cell memory imprinted by earlier H1 exposure. We suggest that introduction of the pdm2009 H1 virus, to which most of the broadly prevalent, neutralizing antibodies did not bind, conferred a selective advantage in the immune systems of infected hosts to recall of memory B cells that recognized the lateral patch, the principal exposed epitope that did not change when pdm2009 displaced previous seasonal H1 viruses.
KW - Affinity maturation
KW - B-cell memory
KW - Hemagglutinin
KW - Influenza vaccine
UR - http://www.scopus.com/inward/record.url?scp=85040202194&partnerID=8YFLogxK
U2 - 10.1073/pnas.1715471115
DO - 10.1073/pnas.1715471115
M3 - Article
C2 - 29255041
AN - SCOPUS:85040202194
SN - 0027-8424
VL - 115
SP - 168
EP - 173
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 - 1
ER -