Cited by 384Respiratory viral infections researchSARS-CoV-2 and COVID-19 ResearchVirology and Viral Diseases

A highly stable prefusion RSV F vaccine derived from structural analysis of the fusion mechanism

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Krarup, Anders, Truan, Daphné, Furmanova-Hollenstein, Polina, Bogaert, Lies, Bouchier, Pascale, Bisschop, Ilona J. M., Widjojoatmodjo, Myra N., Zahn, Roland +3 more·2015·Nature Communications

Abstract

Respiratory syncytial virus (RSV) causes acute lower respiratory tract infections and is the leading cause of infant hospitalizations. Recently, a promising vaccine antigen based on the RSV fusion protein (RSV F) stabilized in the native prefusion conformation has been described. Here we report alternative strategies to arrest RSV F in the prefusion conformation based on the prevention of hinge movements in the first refolding region and the elimination of proteolytic exposure of the fusion peptide. A limited number of unique mutations are identified that stabilize the prefusion conformation of RSV F and dramatically increase expression levels. This highly stable prefusion RSV F elicits neutralizing antibodies in cotton rats and induces complete protection against viral challenge. Moreover, the structural and biochemical analysis of the prefusion variants suggests a function for p27, the excised segment that precedes the fusion peptide in the polypeptide chain.

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  • 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.”

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Authors
Krarup, A., Truan, D., Furmanova-Hollenstein, P., Bogaert, L., Bouchier, P., Bisschop, I. J. M., Widjojoatmodjo, M. N., Zahn, R., Schuitemaker, H., McLellan, J. S., & Langedijk, J. P. M.
Affiliations
  • Janssen (Netherlands) (NL)
  • Dartmouth College (US)
Corresponding author
Langedijk, Johannes P. M.
Venue
Nature Communications
Published
2015-09-03
Volume
6
Issue
1
Pages
8143-8143
ISSN
2041-1723 (ISSN-L)
OpenAlex
W2178271040
Cited by
383
References
38
Citations by year
2026: 37 · 2025: 51 · 2024: 58 · 2023: 35 · 2022: 27 · 2021: 28 · 2020: 32 · 2019: 35 · 2018: 30 · 2017: 26 · 2016: 22 · 2015: 2
FWCI
20.91
Type
journal article
Language
en
Open access
Locations
  • Nature Communications (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • RePEc: Research Papers in Economics (submittedVersion)
Funders
  • U.S. Department of Energy (DE‐ AC02‐06CH11357, AC02‐06CH11357, DEAC-02-98CH10886, No. DE-AC02-98CH10886, contract DE-AC02-06CH11357, -AC02-98 CH 10886, 06CH11357, DE-AC02-)
  • University of Chicago (DE-AC02-06CH11357)
  • National Institute of General Medical Sciences (GM0080, Y01 GM000080, DE-AC02-06CH11357)
  • Biological and Environmental Research (DEAC0206CH11357, DE-AC02-98CH10886)
  • Argonne National Laboratory (DE- AC02-06-CH11357, DE-AC02, AC02–06CH11357, 06CH11357, DE-AC02- 98CH10886, under contract DE-AC02-06CH11357)
  • Brookhaven National Laboratory (AC-02-98CH10886, DE-AC02- 98CH10886, DE-AC-02-06CH11357)
Topics
  • Health Sciences › Medicine › Epidemiology › Respiratory viral infections research
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
  • Health Sciences › Medicine › Epidemiology › Virology and Viral Diseases
Keywords
respiratory syncytial virus, RSV F protein, prefusion conformation, vaccine antigens, fusion mechanism, hinge region, fusion peptide, p27, neutralizing antibodies, Sigmodon hispidus, structural analysis
MeSH terms
Animals, Antigens, Viral, Crystallization, Electrophoresis, Polyacrylamide Gel, Enzyme-Linked Immunosorbent Assay, Microscopy, Electron, Mutation, Protein Conformation, Respiratory Syncytial Viruses, Viral Fusion Proteins, Blotting, Western, Sigmodontinae, Respiratory Syncytial Virus Infections, Crystallography, X-Ray, Respiratory Syncytial Virus Vaccines, Mice, Antibodies, Neutralizing

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