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Title: Conserved epitope on influenza-virus hemagglutinin head defined by a vaccine-induced antibody

Journal Article · · Proceedings of the National Academy of Sciences of the United States of America
 [1];  [2];  [3];  [3];  [3];  [4];  [2];  [5]
  1. Harvard Medical School, Boston, MA (United States); Broad Inst., Cambridge, MA (United States)
  2. Harvard Medical School, Boston, MA (United States)
  3. Seqirus, Cambridge, MA (United States)
  4. Duke Univ. Medical School, Durham, NC (United States)
  5. Harvard Medical School, Boston, MA (United States); Howard Hughes Medical Inst., Boston, MA (United States)
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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.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States)
Sponsoring Organization:
USDOE Office of Science (SC), Basic Energy Sciences (BES). Scientific User Facilities Division; National Institutes of Health (NIH)
Grant/Contract Number:
AC02-06CH11357; P01 AI089618; P41 GM103403; S10 RR029205
OSTI ID:
1417383
Journal Information:
Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, Issue 1; ISSN 0027-8424
Publisher:
National Academy of SciencesCopyright Statement
Country of Publication:
United States
Language:
ENGLISH
Citation Metrics:
Cited by: 85 works
Citation information provided by
Web of Science

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Cited By (17)

B cell epitopes in the intrinsically disordered regions of neuraminidase and hemagglutinin proteins of H5N1 and H9N2 avian influenza viruses for peptide‐based vaccine development journal May 2019
A naturally protective epitope of limited variability as an influenza vaccine target journal September 2018
Mosaic nanoparticle display of diverse influenza virus hemagglutinins elicits broad B cell responses journal February 2019
Passive immunization with influenza haemagglutinin specific monoclonal antibodies journal July 2018
Universal Influenza Virus Vaccines That Target the Conserved Hemagglutinin Stalk and Conserved Sites in the Head Domain journal April 2019
Dynamic Perspectives on the Search for a Universal Influenza Vaccine journal April 2019
Sera from Individuals with Narrowly Focused Influenza Virus Antibodies Rapidly Select Viral Escape Mutations In Ovo journal July 2018
Timescales of influenza A/H3N2 antibody dynamics journal August 2018
Potent anti-influenza H7 human monoclonal antibody induces separation of hemagglutinin receptor-binding head domains journal February 2019
The Quest for a Truly Universal Influenza Vaccine journal October 2019
Extra-Neutralizing FcR-Mediated Antibody Functions for a Universal Influenza Vaccine journal March 2019
The Hard Way towards an Antibody-Based HIV-1 Env Vaccine: Lessons from Other Viruses journal April 2018
Boosting subdominant neutralizing antibody responses with a computationally designed epitope-focused immunogen journal February 2019
Boosting subdominant neutralizing antibody responses with a computationally designed epitope-focused immunogen text January 2019
Structural Insights for Anti-Influenza Vaccine Design journal January 2019
Recombinant Influenza Vaccines: Saviors to Overcome Immunodominance journal January 2020
Neutralizing Anti-Hemagglutinin Monoclonal Antibodies Induced by Gene-Based Transfer Have Prophylactic and Therapeutic Effects on Influenza Virus Infection journal June 2018

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Related Subjects

60 APPLIED LIFE SCIENCES
influenza vaccine
hemagglutinin
B-cell memory
affinity maturation