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This content will become publicly available on July 13, 2016

Title: Vaccine-elicited antibody that neutralizes H5N1 influenza and variants binds the receptor site and polymorphic sites

Antigenic drift of circulating seasonal influenza viruses necessitates an international vaccine effort to reduce the impact on human health. A critical feature of the seasonal vaccine is that it stimulates an already primed immune system to diversify memory B cells to recognize closely related, but antigenically distinct, influenza glycoproteins (hemagglutinins). Influenza pandemics arise when hemagglutinins to which no preexisting adaptive immunity exists acquire the capacity to infect humans. Hemagglutinin 5 is one subtype to which little preexisting immunity exists and is only a few acquired mutations away from the ability to transmit efficiently between ferrets, and possibly humans. In this paper, we describe the structure and molecular mechanism of neutralization by H5.3, a vaccine-elicited antibody that neutralizes hemagglutinin 5 viruses and variants with expanded host range. H5.3 binds in the receptor-binding site, forming contacts that recapitulate many of the sialic acid interactions, as well as multiple peripheral interactions, yet is not sensitive to mutations that alter sialic acid binding. H5.3 is highly specific for a subset of H5 strains, and this specificity arises from interactions to the periphery of the receptor-binding site. Finally, H5.3 is also extremely potent, despite retaining germ line-like conformational flexibility.
Authors:
 [1] ;  [2] ;  [2] ;  [2] ;  [3] ;  [4]
  1. Vanderbilt Univ. School of Medicine, Nashville, TN (United States). Dept. of Pathology, Microbiology and Immunology
  2. Vanderbilt Univ. School of Medicine, Nashville, TN (United States). Vanderbilt Vaccine Center
  3. Vanderbilt Univ. School of Medicine, Nashville, TN (United States). Dept. of Pathology, Microbiology and Immunology. Vanderbilt Vaccine Center
  4. Vanderbilt Univ. School of Medicine, Nashville, TN (United States). Dept. of Pathology, Microbiology and Immunology. Dept. of Pharmacology. Center for Structural Biology
Publication Date:
OSTI Identifier:
1214868
Grant/Contract Number:
AC02-06CH11357; R01 AI106002; R21 AI092268; HHSN272200900047C; HDTRA1-10-1-0067; 085P1000817; T32 GM008320; RR026915
Type:
Accepted Manuscript
Journal Name:
Proceedings of the National Academy of Sciences of the United States of America
Additional Journal Information:
Journal Volume: 112; Journal Issue: 30; Journal ID: ISSN 0027-8424
Publisher:
National Academy of Sciences, Washington, DC (United States)
Research Org:
Vanderbilt Univ. School of Medicine, Nashville, TN (United States)
Sponsoring Org:
USDOE Office of Science (SC), Basic Energy Sciences (BES) (SC-22); National Inst. of Health (NIH) (United States); Defense Threat Reduction Agency (DTRA) (United States); Michigan Economic Development Corporation (United States); Michigan Technology Tri-Corridor (United States)
Country of Publication:
United States
Language:
ENGLISH
Subject:
60 APPLIED LIFE SCIENCES; structural biology; immunity; antigen recognition; affinity maturation; influenza