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Immunogenicity and structures of a rationally designed prefusion MERS-CoV spike antigen
Open accessAbstract
Middle East respiratory syndrome coronavirus (MERS-CoV) is a lineage C betacoronavirus that since its emergence in 2012 has caused outbreaks in human populations with case-fatality rates of ∼36%. As in other coronaviruses, the spike (S) glycoprotein of MERS-CoV mediates receptor recognition and membrane fusion and is the primary target of the humoral immune response during infection. Here we use structure-based design to develop a generalizable strategy for retaining coronavirus S proteins in the antigenically optimal prefusion conformation and demonstrate that our engineered immunogen is able to elicit high neutralizing antibody titers against MERS-CoV. We also determined high-resolution structures of the trimeric MERS-CoV S ectodomain in complex with G4, a stem-directed neutralizing antibody. The structures reveal that G4 recognizes a glycosylated loop that is variable among coronaviruses and they define four conformational states of the trimer wherein each receptor-binding domain is either tightly packed at the membrane-distal apex or rotated into a receptor-accessible conformation. Our studies suggest a potential mechanism for fusion initiation through sequential receptor-binding events and provide a foundation for the structure-based design of coronavirus vaccines.
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“Immune responses are improved by introducing two consecutive proline residues (2P), which are known to retain the full-length S protein in the prefusion conformation.64,65”
From COVID-19 mRNA vaccines: Platforms and current developments (2022) · cites this paper as [64]
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“Both vaccines encode the same full-length, pre-fusion stabilized severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike protein13,14 and are encapsulated in lipid nanoparticles (LNPs) with identical composition.”
From Optimization of non-coding regions for a non-modified mRNA COVID-19 vaccine (2022) · cites this paper as [13]
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“Stabilizing coronavirus spike proteins by substituting two prolines at the top of heptad repeat 1 prevents structural rearrangements of the fusion (S2) subunit.”
From An mRNA Vaccine against SARS-CoV-2 — Preliminary Report (2020) · cites this paper as [27]
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“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 [27]
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Metadata
- Authors
- Pallesen, J., Wang, N., Corbett, K. S., Wrapp, D., Kirchdoerfer, R. N., Turner, H. L., Cottrell, C. A., Becker, M. M., Wang, L., Shi, W., Kong, W.-P., Andres, E. L., Kettenbach, A. N., Denison, M. R., Chappell, J. D., Graham, B. S., Ward, A. B., & McLellan, J. S.
- Affiliations
- Scripps Research Institute (US)
- Dartmouth College (US)
- National Institute of Allergy and Infectious Diseases (US)
- Vanderbilt University Medical Center (US)
- Vanderbilt University (US)
- Corresponding author
- Pallesen, Jesper
- Wang, Nianshuang
- Corbett, Kizzmekia S.
- Ward, Andrew B.
- McLellan, Jason S.
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2017-08-14
- Volume
- 114
- Issue
- 35
- Pages
- E7348-E7357
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC5584442
- OpenAlex
- W2750464792
- Cited by
- 1,073
- References
- 89
- Citations by year
- 2026: 48 · 2025: 75 · 2024: 98 · 2023: 127 · 2022: 174 · 2021: 275 · 2020: 220 · 2019: 31 · 2018: 17 · 2017: 6
- FWCI
- 57.66
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- OSTI OAI (U.S. Department of Energy Office of Scientific and Technical Information) (submittedVersion)
- Funders
- HHS | NIH | National Institute of Allergy and Infectious Diseases (R01AI127521)
- HHS | NIH | National Institute of General Medical Sciences (P20GM113132)
- Division of Intramural Research, National Institute of Allergy and Infectious Diseases (AI005125)
- Topics
- Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
- Life Sciences › Agricultural and Biological Sciences › Animal Science and Zoology › Animal Virus Infections Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › vaccines and immunoinformatics approaches
- Keywords
- MERS-CoV, spike protein, structure-based vaccine design, neutralizing antibodies, receptor binding domain, receptor recognition, membrane fusion mechanism, coronavirus vaccines
- MeSH terms
- Animals, Antibodies, Viral, Coronaviridae, Humans, Immunoglobulin G, Mice, Inbred BALB C, Protein Binding, Protein Conformation, Receptors, Virus, Structure-Activity Relationship, Vaccination, Viral Vaccines, Coronavirus Infections, Crystallography, X-Ray, Immunity, Humoral, Antibodies, Neutralizing, Spike Glycoprotein, Coronavirus, Middle East Respiratory Syndrome Coronavirus
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