A broadly generalizable stabilization strategy for sarbecovirus fusion machinery vaccines
Open accessPublished version of a preprint
Abstract
Evolution of SARS-CoV-2 alters the antigenicity of the immunodominant spike (S) receptor-binding domain and N-terminal domain, undermining the efficacy of vaccines and antibody therapies. To overcome this challenge, we set out to develop a vaccine focusing antibody responses on the highly conserved but metastable S 2 subunit, which folds as a spring-loaded fusion machinery. We describe a strategy for prefusion-stabilization and high yield recombinant production of SARS-CoV-2 S 2 trimers with native structure and antigenicity. We demonstrate that our design strategy is broadly generalizable to sarbecoviruses, as exemplified with the SARS-CoV-1 (clade 1a) and PRD-0038 (clade 3) S 2 subunits. Immunization of mice with a prefusion-stabilized SARS-CoV-2 S 2 trimer elicits broadly reactive sarbecovirus antibodies and neutralizing antibody titers of comparable magnitude against Wuhan-Hu-1 and the immune evasive XBB.1.5 variant. Vaccinated mice were protected from weight loss and disease upon challenge with XBB.1.5, providing proof-of-principle for fusion machinery sarbecovirus vaccines.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Highly accurate protein structure prediction with AlphaFold
Jumper, J., Evans, R., Pritzel, A., Green, T., Figurnov, M., Ronneberger, O., Tunyasuvunakool, K., Bates, R., Žídek, A., Potapenko, A., et al. (2021) · Nature · doi:10.1038/s41586-021-03819-2 · Cited by 43,764 · see citing works
Omicron escapes the majority of existing SARS-CoV-2 neutralizing antibodies
Cao, Y., Wang, J., Jian, F., Xiao, T., Song, W., Yisimayi, A., Huang, W., Li, Q., Wang, P., An, R., et al. (2022) · Nature · doi:10.1038/s41586-021-04385-3 · Cited by 2,006 · see citing works
Immunogenicity and structures of a rationally designed prefusion MERS-CoV spike antigen
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., et al. (2017) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1707304114 · Cited by 1,073 · see citing works
N-terminal domain antigenic mapping reveals a site of vulnerability for SARS-CoV-2
McCallum, M., De Marco, A., Lempp, F. A., Tortorici, M. A., Pinto, D., Walls, A. C., Beltramello, M., Chen, A., Liu, Z., Zatta, F., et al. (2021) · Cell · doi:10.1016/j.cell.2021.03.028 · Cited by 901 · cited 1× · see citing works
“Conversely, the S N-terminal domain (NTD) is mostly targeted by variant-speci fi c neutralizing antibodies 6,19,20 .”
Self-citationA Bivalent Omicron-Containing Booster Vaccine against Covid-19
Chalkias, S., Harper, C., Vrbicky, K., Walsh, S. R., Essink, B., Brosz, A., McGhee, N., Tomassini, J. E., Chen, X., Chang, Y., et al. (2022) · New England Journal of Medicine · doi:10.1056/nejmoa2208343 · Cited by 627 · see citing works
Unexpected Receptor Functional Mimicry Elucidates Activation of Coronavirus Fusion
Walls, A. C., Xiong, X., Park, Y.-J., Tortorici, M. A., Snijder, J., Quispe, J., Cameroni, E., Gopal, R., Dai, M., Lanzavecchia, A., et al. (2019) · Cell · doi:10.1016/j.cell.2018.12.028 · Cited by 582 · see citing works
Self-citationStructural basis of SARS-CoV-2 Omicron immune evasion and receptor engagement
McCallum, M., Czudnochowski, N., Rosen, L. E., Zepeda, S. K., Bowen, J. E., Walls, A. C., Hauser, K., Joshi, A., Stewart, C., Dillen, J. R., et al. (2022) · Science · doi:10.1126/science.abn8652 · Cited by 535 · cited 1× · see citing works
“The sarbe-covirus S 2 subunit prefusion-stabilization strategy presented here represents a key step in this direction due to the much higher conservation of the S 2 subunit relative to the S 1 subunit among SARS-CoV-2 variants and other sarbecoviruses 14,41,51 .”
Self-citationUltrapotent human antibodies protect against SARS-CoV-2 challenge via multiple mechanisms
Tortorici, M. A., Beltramello, M., Lempp, F. A., Pinto, D., Dang, H. V., Rosen, L. E., McCallum, M., Bowen, J., Minola, A., Jaconi, S., et al. (2020) · Science · doi:10.1126/science.abe3354 · Cited by 510 · see citing works
Self-citationSARS-CoV-2 immune evasion by the B.1.427/B.1.429 variant of concern
McCallum, M., Bassi, J., De Marco, A., Chen, A., Walls, A. C., Di Iulio, J., Tortorici, M. A., Navarro, M.-J., Silacci-Fregni, C., Saliba, C., et al. (2021) · Science · doi:10.1126/science.abi7994 · Cited by 412 · cited 1× · see citing works
“Conversely, the S N-terminal domain (NTD) is mostly targeted by variant-speci fi c neutralizing antibodies 6,19,20 .”
Self-citationGreaney, A. J., Loes, A. N., Gentles, L. E., Crawford, K. H. D., Starr, T. N., Malone, K. D., Chu, H. Y., & Bloom, J. D. (2021) · Science Translational Medicine · doi:10.1126/scitranslmed.abi9915 · Cited by 244 · see citing works
Flagged first, then by citations
- Authors
- Lee, J., Stewart, C., Schäfer, A., Leaf, E. M., Park, Y.-J., Asarnow, D., Powers, J. M., Treichel, C., Sprouse, K. R., Corti, D., Baric, R., King, N. P., & Veesler, D.
- Affiliations
- University of Washington (US)
- University of North Carolina at Chapel Hill (US)
- Howard Hughes Medical Institute (US)
- Vir Biotechnology (Switzerland) (CH)
- Corresponding author
- Veesler, David
- ORCID
- Venue
- Nature Communications
- Published
- 2024-06-28
- Volume
- 15
- Issue
- 1
- Pages
- 5496-5496
- ISSN
- 2041-1723 (ISSN-L)
- PMC
- PMC11214633
- OpenAlex
- W4400146025
- Cited by
- 23
- References
- 10
- Citations by year
- 2026: 8 · 2025: 12 · 2024: 3
- FWCI
- 7.90
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- Nature Communications (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Howard Hughes Medical Institute
- Topics
- 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
- Life Sciences › Agricultural and Biological Sciences › Animal Science and Zoology › Animal Virus Infections Studies
- Keywords
- SARS-CoV-2, recombinant protein expression, SARS-CoV-1, XBB.1.5 variant, neutralizing antibodies, broadly reactive antibodies, antigenic drift
- MeSH terms
- COVID-19, SARS-CoV-2, COVID-19 Vaccines, Animals, Antibodies, Viral, Female, Humans, Mice, Inbred BALB C, Mice, Antibodies, Neutralizing, Spike Glycoprotein, Coronavirus
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
