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Title: Structural basis for immunization with postfusion respiratory syncytial virus fusion F glycoprotein (RSV F) to elicit high neutralizing antibody titers

Abstract

Respiratory syncytial virus (RSV), the main cause of infant bronchiolitis, remains a major unmet vaccine need despite more than 40 years of vaccine research. Vaccine candidates based on a chief RSV neutralization antigen, the fusion (F) glycoprotein, have foundered due to problems with stability, purity, reproducibility, and potency. Crystal structures of related parainfluenza F glycoproteins have revealed a large conformational change between the prefusion and postfusion states, suggesting that postfusion F antigens might not efficiently elicit neutralizing antibodies. We have generated a homogeneous, stable, and reproducible postfusion RSV F immunogen that elicits high titers of neutralizing antibodies in immunized animals. The 3.2-{angstrom} X-ray crystal structure of this substantially complete RSV F reveals important differences from homology-based structural models. Specifically, the RSV F crystal structure demonstrates the exposure of key neutralizing antibody binding sites on the surface of the postfusion RSV F trimer. This unanticipated structural feature explains the engineered RSV F antigen's efficiency as an immunogen. This work illustrates how structural-based antigen design can guide the rational optimization of candidate vaccine antigens.

Authors:
; ; ; ; ; ; ;  [1]
  1. (Novartis)
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
INDUSTRY
OSTI Identifier:
1026529
Resource Type:
Journal Article
Resource Relation:
Journal Name: Proc. Natl. Acad. Sci. USA; Journal Volume: 108; Journal Issue: (23) ; 06, 2011
Country of Publication:
United States
Language:
ENGLISH
Subject:
60 APPLIED LIFE SCIENCES; 59 BASIC BIOLOGICAL SCIENCES; ANIMALS; ANTIBODIES; ANTIGENS; CONFORMATIONAL CHANGES; CRYSTAL STRUCTURE; DESIGN; EFFICIENCY; GLYCOPROTEINS; OPTIMIZATION; RESPIRATORY SYSTEM; STABILITY; STRUCTURAL MODELS; VACCINES; VIRUSES

Citation Formats

Swanson, Kurt A., Settembre, Ethan C., Shaw, Christine A., Dey, Antu K., Rappuoli, Rino, Mandl, Christian W., Dormitzer, Philip R., and Carfi, Andrea. Structural basis for immunization with postfusion respiratory syncytial virus fusion F glycoprotein (RSV F) to elicit high neutralizing antibody titers. United States: N. p., 2012. Web. doi:10.1073/pnas.1106536108.
Swanson, Kurt A., Settembre, Ethan C., Shaw, Christine A., Dey, Antu K., Rappuoli, Rino, Mandl, Christian W., Dormitzer, Philip R., & Carfi, Andrea. Structural basis for immunization with postfusion respiratory syncytial virus fusion F glycoprotein (RSV F) to elicit high neutralizing antibody titers. United States. doi:10.1073/pnas.1106536108.
Swanson, Kurt A., Settembre, Ethan C., Shaw, Christine A., Dey, Antu K., Rappuoli, Rino, Mandl, Christian W., Dormitzer, Philip R., and Carfi, Andrea. Tue . "Structural basis for immunization with postfusion respiratory syncytial virus fusion F glycoprotein (RSV F) to elicit high neutralizing antibody titers". United States. doi:10.1073/pnas.1106536108.
@article{osti_1026529,
title = {Structural basis for immunization with postfusion respiratory syncytial virus fusion F glycoprotein (RSV F) to elicit high neutralizing antibody titers},
author = {Swanson, Kurt A. and Settembre, Ethan C. and Shaw, Christine A. and Dey, Antu K. and Rappuoli, Rino and Mandl, Christian W. and Dormitzer, Philip R. and Carfi, Andrea},
abstractNote = {Respiratory syncytial virus (RSV), the main cause of infant bronchiolitis, remains a major unmet vaccine need despite more than 40 years of vaccine research. Vaccine candidates based on a chief RSV neutralization antigen, the fusion (F) glycoprotein, have foundered due to problems with stability, purity, reproducibility, and potency. Crystal structures of related parainfluenza F glycoproteins have revealed a large conformational change between the prefusion and postfusion states, suggesting that postfusion F antigens might not efficiently elicit neutralizing antibodies. We have generated a homogeneous, stable, and reproducible postfusion RSV F immunogen that elicits high titers of neutralizing antibodies in immunized animals. The 3.2-{angstrom} X-ray crystal structure of this substantially complete RSV F reveals important differences from homology-based structural models. Specifically, the RSV F crystal structure demonstrates the exposure of key neutralizing antibody binding sites on the surface of the postfusion RSV F trimer. This unanticipated structural feature explains the engineered RSV F antigen's efficiency as an immunogen. This work illustrates how structural-based antigen design can guide the rational optimization of candidate vaccine antigens.},
doi = {10.1073/pnas.1106536108},
journal = {Proc. Natl. Acad. Sci. USA},
number = (23) ; 06, 2011,
volume = 108,
place = {United States},
year = {Tue Feb 07 00:00:00 EST 2012},
month = {Tue Feb 07 00:00:00 EST 2012}
}