Structural basis for immunization with postfusion respiratory syncytial virus fusion F glycoprotein (RSV F) to elicit high neutralizing antibody titers
Open accessAbstract
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-Å 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.
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The F protein of RSV is a conserved target of neutralizing antibodies and a promising antigen for RSV vaccine development.
“The F protein of RSV is a conserved target of neutralizing antibodies and a promising antigen for RSV vaccine development (29).”
From Nonviral delivery of self-amplifying RNA vaccines (2012) · cites this paper as [29]
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Self-citation
- Authors
- Swanson, K. A., Settembre, E. C., Shaw, C. A., Dey, A. K., Rappuoli, R., Mandl, C. W., Dormitzer, P. R., & Carfi, A.
- Affiliations
- Novartis Vaccines and Diagnostics, Cambridge, MA 02139
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2011-05-17
- Volume
- 108
- Issue
- 23
- Pages
- 9619-9624
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3111287
- OpenAlex
- W2140898182
- Cited by
- 285
- References
- 42
- Citations by year
- 2026: 12 · 2025: 11 · 2024: 17 · 2023: 14 · 2022: 16 · 2021: 19 · 2020: 15 · 2019: 26 · 2018: 12 · 2017: 23 · 2016: 22 · 2015: 33 · 2014: 25 · 2013: 19 · 2012: 17
- FWCI
- 15.67
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Novartis Institutes for BioMedical Research
- Argonne National Laboratory
- 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 glycoprotein, neutralizing antibodies, vaccine immunogen design, X-ray crystal structure, antibody binding sites
- MeSH terms
- Palivizumab, Amino Acid Sequence, Animals, Antibodies, Monoclonal, Antibodies, Viral, Binding Sites, Antibody, Circular Dichroism, Humans, Immunization, Infant, Mice, Inbred BALB C, Microscopy, Electron, Models, Molecular, Molecular Sequence Data, Respiratory Syncytial Viruses, Viral Fusion Proteins, Sigmodontinae, Sequence Homology, Amino Acid, Protein Structure, Secondary, Protein Structure, Tertiary, Respiratory Syncytial Virus Infections, Crystallography, X-Ray, Mice, Protein Multimerization, Antibodies, Neutralizing, Antibodies, Monoclonal, Humanized
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