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Title: Design and Characterization of Epitope-Scaffold Immunogens That Present the Motavizumab Epitope from Respiratory Syncytial Virus

Abstract

Respiratory syncytial virus (RSV) is a major cause of respiratory tract infections in infants, but an effective vaccine has not yet been developed. An ideal vaccine would elicit protective antibodies while avoiding virus-specific T-cell responses, which have been implicated in vaccine-enhanced disease with previous RSV vaccines. We propose that heterologous proteins designed to present RSV-neutralizing antibody epitopes and to elicit cognate antibodies have the potential to fulfill these vaccine requirements, as they can be fashioned to be free of viral T-cell epitopes. Here we present the design and characterization of three epitope-scaffolds that present the epitope of motavizumab, a potent neutralizing antibody that binds to a helix-loop-helix motif in the RSV fusion glycoprotein. Two of the epitope-scaffolds could be purified, and one epitope-scaffold based on a Staphylococcus aureus protein A domain bound motavizumab with kinetic and thermodynamic properties consistent with the free epitope-scaffold being stabilized in a conformation that closely resembled the motavizumab-bound state. This epitope-scaffold was well folded as assessed by circular dichroism and isothermal titration calorimetry, and its crystal structure (determined in complex with motavizumab to 1.9 {angstrom} resolution) was similar to the computationally designed model, with all hydrogen-bond interactions critical for binding to motavizumab preserved. Immunization ofmore » mice with this epitope-scaffold failed to elicit neutralizing antibodies but did elicit sera with F binding activity. The elicitation of F binding antibodies suggests that some of the design criteria for eliciting protective antibodies without virus-specific T-cell responses are being met, but additional optimization of these novel immunogens is required.« less

Authors:
; ; ; ; ; ;  [1];  [2]
  1. (UWASH)
  2. (
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
FOREIGNNIH
OSTI Identifier:
1040898
Resource Type:
Journal Article
Resource Relation:
Journal Name: J. Mol. Biol.; Journal Volume: 409; Journal Issue: (5) ; 06, 2011
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; ANTIBODIES; CALORIMETRY; CRYSTAL STRUCTURE; DESIGN; DICHROISM; DISEASES; KINETICS; MICE; OPTIMIZATION; PROTEINS; RESOLUTION; STAPHYLOCOCCUS; THERMODYNAMIC PROPERTIES; TITRATION; VACCINES

Citation Formats

McLellan, Jason S., Correia, Bruno E., Chen, Man, Yang, Yongping, Graham, Barney S., Schief, William R., Kwong, Peter D., and NIH). Design and Characterization of Epitope-Scaffold Immunogens That Present the Motavizumab Epitope from Respiratory Syncytial Virus. United States: N. p., 2012. Web. doi:10.1016/j.jmb.2011.04.044.
McLellan, Jason S., Correia, Bruno E., Chen, Man, Yang, Yongping, Graham, Barney S., Schief, William R., Kwong, Peter D., & NIH). Design and Characterization of Epitope-Scaffold Immunogens That Present the Motavizumab Epitope from Respiratory Syncytial Virus. United States. doi:10.1016/j.jmb.2011.04.044.
McLellan, Jason S., Correia, Bruno E., Chen, Man, Yang, Yongping, Graham, Barney S., Schief, William R., Kwong, Peter D., and NIH). Thu . "Design and Characterization of Epitope-Scaffold Immunogens That Present the Motavizumab Epitope from Respiratory Syncytial Virus". United States. doi:10.1016/j.jmb.2011.04.044.
@article{osti_1040898,
title = {Design and Characterization of Epitope-Scaffold Immunogens That Present the Motavizumab Epitope from Respiratory Syncytial Virus},
author = {McLellan, Jason S. and Correia, Bruno E. and Chen, Man and Yang, Yongping and Graham, Barney S. and Schief, William R. and Kwong, Peter D. and NIH)},
abstractNote = {Respiratory syncytial virus (RSV) is a major cause of respiratory tract infections in infants, but an effective vaccine has not yet been developed. An ideal vaccine would elicit protective antibodies while avoiding virus-specific T-cell responses, which have been implicated in vaccine-enhanced disease with previous RSV vaccines. We propose that heterologous proteins designed to present RSV-neutralizing antibody epitopes and to elicit cognate antibodies have the potential to fulfill these vaccine requirements, as they can be fashioned to be free of viral T-cell epitopes. Here we present the design and characterization of three epitope-scaffolds that present the epitope of motavizumab, a potent neutralizing antibody that binds to a helix-loop-helix motif in the RSV fusion glycoprotein. Two of the epitope-scaffolds could be purified, and one epitope-scaffold based on a Staphylococcus aureus protein A domain bound motavizumab with kinetic and thermodynamic properties consistent with the free epitope-scaffold being stabilized in a conformation that closely resembled the motavizumab-bound state. This epitope-scaffold was well folded as assessed by circular dichroism and isothermal titration calorimetry, and its crystal structure (determined in complex with motavizumab to 1.9 {angstrom} resolution) was similar to the computationally designed model, with all hydrogen-bond interactions critical for binding to motavizumab preserved. Immunization of mice with this epitope-scaffold failed to elicit neutralizing antibodies but did elicit sera with F binding activity. The elicitation of F binding antibodies suggests that some of the design criteria for eliciting protective antibodies without virus-specific T-cell responses are being met, but additional optimization of these novel immunogens is required.},
doi = {10.1016/j.jmb.2011.04.044},
journal = {J. Mol. Biol.},
number = (5) ; 06, 2011,
volume = 409,
place = {United States},
year = {Thu Jun 28 00:00:00 EDT 2012},
month = {Thu Jun 28 00:00:00 EDT 2012}
}