Cited by 333Respiratory viral infections researchSARS-CoV-2 and COVID-19 Researchvaccines and immunoinformatics approaches

A proof of concept for structure-based vaccine design targeting RSV in humans

Crank, Michelle C., Ruckwardt, Tracy J., Chen, Man, Morabito, Kaitlyn M., Phung, Emily, Costner, Pamela J., Holman, LaSonji A., Hickman, Somia P. +43 more·2019·Science

Abstract

Building a better RSV vaccine: Respiratory syncytial virus (RSV) causes severe respiratory disease, especially in infants and the elderly. However, attempts to produce effective human vaccines have largely been unsuccessful. Structure-based design has been used to generate an RSV fusion glycoprotein stabilized in its prefusion conformation (DS-Cav1). This immunogen is highly effective in mice and macaques. Crank et al. now report the results of a phase I vaccine clinical trial using the stabilized prefusion DS-Cav1 molecule. Four weeks after immunization, these vaccines elicited substantially more high-quality antibody titers than those typically generated using earlier RSV immunogens. The findings provide a proof of concept for how structural biology can contribute to precision vaccine design. Science , this issue p. 505

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Crossref · 10.1126/science.aav9033

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  • S-2P conformational stability translates into greater immunogenicity, based on preservation of neutralization-sensitive epitopes and improved protein expression.

    “Moreover, S-2P conformational stability translates into greater immunogenicity,27-29 based on preservation of neutralization-sensitive epitopes at the apex of the prefusion molecule, as shown for respiratory syncytial virus F glycoprotein,30 and improved protein expression,27 which is particularly advantageous for gene-based antigen delivery.”

    From An mRNA Vaccine against SARS-CoV-2 — Preliminary Report (2020) · cites this paper as [30]

  • Newfound structural insights into F protein conformation have revealed that vaccinating against the prefusion conformation elicits superior neutralizing antibody response.

    “Although some candidates have failed clinical trials owing to insufficient neutralizing antibody titres174, newfound structural insights into F protein conformation have revealed that vaccinating against the prefusion conformation elicits superior neutralizing antibody response175–178.”
  • Insight into the atomic-level structure of the RSV F protein allowed stable expression of the pre-F protein, leading to strongly enhanced immune responses and providing proof of concept for structure-based vaccine design.

    “insight into the atomic-level structure of the protein has allowed for stable expression of the pre-F protein, leading to strongly enhanced immune responses and providing a proof of concept for structure-based vaccine design132,133”

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Authors
Crank, M. C., Ruckwardt, T. J., Chen, M., Morabito, K. M., Phung, E., Costner, P. J., Holman, L. A., Hickman, S. P., Berkowitz, N. M., Gordon, I. J., Yamshchikov, G. V., Gaudinski, M. R., Kumar, A., Chang, L. A., Moin, S. M., Hill, J. P., DiPiazza, A. T., Schwartz, R. M., Kueltzo, L., Cooper, J. W., Chen, P., Stein, J. A., Carlton, K., Gall, J. G., Nason, M. C., Kwong, P. D., Chen, G. L., Mascola, J. R., McLellan, J. S., Ledgerwood, J. E., Graham, B. S., the VRC 317 Study Team, Novik, L., Saunders, J., Mendoza, F., Whalen, W., Eshun, A., Cunningham, J., Wang, X., Hicks, R., Sitar, S., Hendel, C. S., Ola, A., Requilman, L., Tran, C., Nguyen, T., Williams, P., Boyd, C., Trofmenko, O., Carter, C., & Widge, A.
Affiliations
  • National Institutes of Health (US)
  • The University of Texas at Austin (US)
Corresponding author
  • Crank, Michelle C.
  • Ruckwardt, Tracy J.
  • Chen, Man
  • Graham, Barney S.
Venue
Science
Published
2019-08-02
Volume
365
Issue
6452
Pages
505-509
ISSN
  • 0036-8075 (ISSN-L)
  • 1095-9203
OpenAlex
W2964965456
Cited by
333
References
32
Citations by year
2026: 30 · 2025: 54 · 2024: 48 · 2023: 47 · 2022: 40 · 2021: 55 · 2020: 47 · 2019: 12
FWCI
29.36
Type
journal article
Language
en
Open access
closed
Locations
  • Science (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • National Institute of Allergy and Infectious Diseases (Intramural Funding)
  • Bill and Melinda Gates Foundation (OPP1147555)
Topics
  • Health Sciences › Medicine › Epidemiology › Respiratory viral infections research
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
Keywords
respiratory syncytial virus, RSV F glycoprotein, structure-based vaccine design, subunit vaccine, neutralizing antibodies, protein engineering
MeSH terms
Immunogenicity, Vaccine, Adolescent, Adult, Antibodies, Viral, Humans, Middle Aged, Viral Fusion Proteins, Respiratory Syncytial Virus, Human, Respiratory Syncytial Virus Infections, Epitope Mapping, Respiratory Syncytial Virus Vaccines, Young Adult, Antibodies, Neutralizing

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