Abstract

The RSV F glycoprotein is a key target for vaccine-induced neutralizing antibody. Our hypothesis is that understanding the mechanism of antibody neutralization will be facilitated by defining the structure of F and the structure of epitopes associated with neutralization. This will allow novel antigen design. Characterizing the chemistry and post-translational modifications in F will also promote improved vaccine antigen design. We have advanced our stabilized prefusion F protein into clinical evaluation in a Phase 1 clinical trial, VRC 317. In this trial, we are evaluating safety, tolerability, and immunogenicity of our stabilized prefusion F protein (DS-Cav1) with or with alum adjuvant in healthy adults. In addition to neutralizing antibodies, the induction of both protective, disease-sparing CD8+ T cell responses are desirable in a vaccine candidate. These studies include evaluation of gene and vector-based vaccines expressing either the stabilized Pre-F protein or the wildtype F protein to vaccination with soluble Pre-F protein. We are also working with collaborators to assess immunogenicity of other vectors expressing our stabilized Pre-F protein.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIAAI005129-03
Application #
9789630
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2018
Total Cost
Indirect Cost

  Institution

Name
Niaid Extramural Activities
Department
Type
DUNS #
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State
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  Publications

Graham, Barney S (2017) Vaccine development for respiratory syncytial virus. Curr Opin Virol 23:107-112
Leemans, A; De Schryver, M; Van der Gucht, W et al. (2017) Antibody-Induced Internalization of the Human Respiratory Syncytial Virus Fusion Protein. J Virol 91:
Liang, Bo; Ngwuta, Joan O; Surman, Sonja et al. (2017) Improved Prefusion Stability, Optimized Codon Usage, and Augmented Virion Packaging Enhance the Immunogenicity of Respiratory Syncytial Virus Fusion Protein in a Vectored-Vaccine Candidate. J Virol 91:
Zhao, Min; Zheng, Zi-Zheng; Chen, Man et al. (2017) Discovery of a Prefusion Respiratory Syncytial Virus F-Specific Monoclonal Antibody That Provides Greater In Vivo Protection than the Murine Precursor of Palivizumab. J Virol 91:
Graham, Barney S (2016) Vaccines against respiratory syncytial virus: The time has finally come. Vaccine 34:3535-41
Liang, Bo; Ngwuta, Joan O; Herbert, Richard et al. (2016) Packaging and Prefusion Stabilization Separately and Additively Increase the Quantity and Quality of Respiratory Syncytial Virus (RSV)-Neutralizing Antibodies Induced by an RSV Fusion Protein Expressed by a Parainfluenza Virus Vector. J Virol 90:10022-10038
Boyington, Jeffrey C; Joyce, M Gordon; Sastry, Mallika et al. (2016) Structure-Based Design of Head-Only Fusion Glycoprotein Immunogens for Respiratory Syncytial Virus. PLoS One 11:e0159709
Joyce, M Gordon; Zhang, Baoshan; Ou, Li et al. (2016) Iterative structure-based improvement of a fusion-glycoprotein vaccine against RSV. Nat Struct Mol Biol 23:811-820
Francica, Joseph R; Lynn, Geoffrey M; Laga, Richard et al. (2016) Thermoresponsive Polymer Nanoparticles Co-deliver RSV F Trimers with a TLR-7/8 Adjuvant. Bioconjug Chem 27:2372-2385
Graham, Barney S; Modjarrad, Kayvon; McLellan, Jason S (2015) Novel antigens for RSV vaccines. Curr Opin Immunol 35:30-8

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