@article{carnell_sars-cov-2_2021,
	title = {{SARS}-{CoV}-2 spike protein stabilized in the closed state induces potent neutralizing responses.},
	copyright = {Copyright © 2021 Carnell et al.. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.},
	issn = {0022-538X, 1098-5514},
	url = {https://jvi.asm.org/content/early/2021/04/28/JVI.00203-21},
	doi = {10.1128/JVI.00203-21},
	abstract = {The majority of SARS-CoV-2 vaccines in use or advanced development are based on the viral spike protein (S) as their immunogen. S is present on virions as pre-fusion trimers in which the receptor binding domain (RBD) is stochastically open or closed. Neutralizing antibodies have been described against both open and closed conformations. The long-term success of vaccination strategies depends upon inducing antibodies that provide long-lasting broad immunity against evolving SARS-CoV-2 strains. Here we have assessed the results of immunization in a mouse model using an S protein trimer stabilized in the closed state to prevent full exposure of the receptor binding site and therefore interaction with receptor. We compared this with other modified S protein constructs, including representatives used in current vaccines. We found that all trimeric S proteins induced a T cell response and long-lived, strongly neutralizing antibody responses against 2019 SARS-CoV-2 and variants of concern B.1.248 and B.1.351. Notably, the protein binding properties of sera induced by the closed spike differed from those induced by standard S protein constructs. Closed S proteins induced more potent neutralizing responses than expected based on the degree to which they inhibit interactions between the RBD and ACE2. These observations suggest that closed spikes recruit different, but equally potent, immune responses than open spikes, and that this is likely to include neutralizing antibodies against conformational epitopes present in the closed conformation. Together with their improved stability and storage properties we suggest that closed spikes may be a valuable component of refined, next-generation vaccines.
Importance
Vaccines in use against SARS-CoV-2 induce immune responses against the spike protein. There is intense interest in whether the antibody response induced by vaccines will be robust against new variants, as well as in next-generation vaccines for use in previously infected or immunized individuals. We assessed the use as an immunogen of a spike protein engineered to be conformationally stabilized in the closed state where the receptor binding site is occluded. Despite occlusion of the receptor binding site, the spike induces potently neutralizing sera against multiple SARS-CoV-2 variants. Antibodies are raised against a different pattern of epitopes to those induced by other spike constructs, preferring conformational epitopes present in the closed conformation. Closed spikes, or mRNA vaccines based on their sequence, can be a valuable component of next generation vaccines.},
	language = {en},
	urldate = {2021-05-12},
	journal = {Journal of Virology},
	author = {Carnell, George W. and Ciazynska, Katarzyna A. and Wells, David A. and Xiong, Xiaoli and Aguinam, Ernest T. and McLaughlin, Stephen H. and Mallery, Donna and Ebrahimi, Soraya and Ceron-Gutierrez, Lourdes and Asbach, Benedikt and Einhauser, Sebastian and Wagner, Ralf and James, Leo C. and Doffinger, Rainer and Heeney, Jonathan L. and Briggs, John A. G.},
	month = may,
	year = {2021},
	pmid = {33963055},
	note = {Publisher: American Society for Microbiology Journals
Section: Vaccines and Antiviral Agents},
	keywords = {Application - Infectious Diseases, Application - Vaccine Development, PEPperCHIP - Standard, PEPperMAP - Epitope Mapping - Linear, SARS-CoV-2},
}

{"_id":"Xav2QGbWxXyyTWX8i","bibbaseid":"carnell-ciazynska-wells-xiong-aguinam-mclaughlin-mallery-ebrahimi-etal-sarscov2spikeproteinstabilizedintheclosedstateinducespotentneutralizingresponses-2021","author_short":["Carnell, G. W.","Ciazynska, K. A.","Wells, D. A.","Xiong, X.","Aguinam, E. T.","McLaughlin, S. H.","Mallery, D.","Ebrahimi, S.","Ceron-Gutierrez, L.","Asbach, B.","Einhauser, S.","Wagner, R.","James, L. C.","Doffinger, R.","Heeney, J. L.","Briggs, J. A. G."],"bibdata":{"bibtype":"article","type":"article","title":"SARS-CoV-2 spike protein stabilized in the closed state induces potent neutralizing responses.","copyright":"Copyright © 2021 Carnell et al.. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.","issn":"0022-538X, 1098-5514","url":"https://jvi.asm.org/content/early/2021/04/28/JVI.00203-21","doi":"10.1128/JVI.00203-21","abstract":"The majority of SARS-CoV-2 vaccines in use or advanced development are based on the viral spike protein (S) as their immunogen. S is present on virions as pre-fusion trimers in which the receptor binding domain (RBD) is stochastically open or closed. Neutralizing antibodies have been described against both open and closed conformations. The long-term success of vaccination strategies depends upon inducing antibodies that provide long-lasting broad immunity against evolving SARS-CoV-2 strains. Here we have assessed the results of immunization in a mouse model using an S protein trimer stabilized in the closed state to prevent full exposure of the receptor binding site and therefore interaction with receptor. We compared this with other modified S protein constructs, including representatives used in current vaccines. We found that all trimeric S proteins induced a T cell response and long-lived, strongly neutralizing antibody responses against 2019 SARS-CoV-2 and variants of concern B.1.248 and B.1.351. Notably, the protein binding properties of sera induced by the closed spike differed from those induced by standard S protein constructs. Closed S proteins induced more potent neutralizing responses than expected based on the degree to which they inhibit interactions between the RBD and ACE2. These observations suggest that closed spikes recruit different, but equally potent, immune responses than open spikes, and that this is likely to include neutralizing antibodies against conformational epitopes present in the closed conformation. Together with their improved stability and storage properties we suggest that closed spikes may be a valuable component of refined, next-generation vaccines. Importance Vaccines in use against SARS-CoV-2 induce immune responses against the spike protein. There is intense interest in whether the antibody response induced by vaccines will be robust against new variants, as well as in next-generation vaccines for use in previously infected or immunized individuals. We assessed the use as an immunogen of a spike protein engineered to be conformationally stabilized in the closed state where the receptor binding site is occluded. Despite occlusion of the receptor binding site, the spike induces potently neutralizing sera against multiple SARS-CoV-2 variants. Antibodies are raised against a different pattern of epitopes to those induced by other spike constructs, preferring conformational epitopes present in the closed conformation. Closed spikes, or mRNA vaccines based on their sequence, can be a valuable component of next generation vaccines.","language":"en","urldate":"2021-05-12","journal":"Journal of Virology","author":[{"propositions":[],"lastnames":["Carnell"],"firstnames":["George","W."],"suffixes":[]},{"propositions":[],"lastnames":["Ciazynska"],"firstnames":["Katarzyna","A."],"suffixes":[]},{"propositions":[],"lastnames":["Wells"],"firstnames":["David","A."],"suffixes":[]},{"propositions":[],"lastnames":["Xiong"],"firstnames":["Xiaoli"],"suffixes":[]},{"propositions":[],"lastnames":["Aguinam"],"firstnames":["Ernest","T."],"suffixes":[]},{"propositions":[],"lastnames":["McLaughlin"],"firstnames":["Stephen","H."],"suffixes":[]},{"propositions":[],"lastnames":["Mallery"],"firstnames":["Donna"],"suffixes":[]},{"propositions":[],"lastnames":["Ebrahimi"],"firstnames":["Soraya"],"suffixes":[]},{"propositions":[],"lastnames":["Ceron-Gutierrez"],"firstnames":["Lourdes"],"suffixes":[]},{"propositions":[],"lastnames":["Asbach"],"firstnames":["Benedikt"],"suffixes":[]},{"propositions":[],"lastnames":["Einhauser"],"firstnames":["Sebastian"],"suffixes":[]},{"propositions":[],"lastnames":["Wagner"],"firstnames":["Ralf"],"suffixes":[]},{"propositions":[],"lastnames":["James"],"firstnames":["Leo","C."],"suffixes":[]},{"propositions":[],"lastnames":["Doffinger"],"firstnames":["Rainer"],"suffixes":[]},{"propositions":[],"lastnames":["Heeney"],"firstnames":["Jonathan","L."],"suffixes":[]},{"propositions":[],"lastnames":["Briggs"],"firstnames":["John","A.","G."],"suffixes":[]}],"month":"May","year":"2021","pmid":"33963055","note":"Publisher: American Society for Microbiology Journals Section: Vaccines and Antiviral Agents","keywords":"Application - Infectious Diseases, Application - Vaccine Development, PEPperCHIP - Standard, PEPperMAP - Epitope Mapping - Linear, SARS-CoV-2","bibtex":"@article{carnell_sars-cov-2_2021,\n\ttitle = {{SARS}-{CoV}-2 spike protein stabilized in the closed state induces potent neutralizing responses.},\n\tcopyright = {Copyright © 2021 Carnell et al.. This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.},\n\tissn = {0022-538X, 1098-5514},\n\turl = {https://jvi.asm.org/content/early/2021/04/28/JVI.00203-21},\n\tdoi = {10.1128/JVI.00203-21},\n\tabstract = {The majority of SARS-CoV-2 vaccines in use or advanced development are based on the viral spike protein (S) as their immunogen. S is present on virions as pre-fusion trimers in which the receptor binding domain (RBD) is stochastically open or closed. Neutralizing antibodies have been described against both open and closed conformations. The long-term success of vaccination strategies depends upon inducing antibodies that provide long-lasting broad immunity against evolving SARS-CoV-2 strains. Here we have assessed the results of immunization in a mouse model using an S protein trimer stabilized in the closed state to prevent full exposure of the receptor binding site and therefore interaction with receptor. We compared this with other modified S protein constructs, including representatives used in current vaccines. We found that all trimeric S proteins induced a T cell response and long-lived, strongly neutralizing antibody responses against 2019 SARS-CoV-2 and variants of concern B.1.248 and B.1.351. Notably, the protein binding properties of sera induced by the closed spike differed from those induced by standard S protein constructs. Closed S proteins induced more potent neutralizing responses than expected based on the degree to which they inhibit interactions between the RBD and ACE2. These observations suggest that closed spikes recruit different, but equally potent, immune responses than open spikes, and that this is likely to include neutralizing antibodies against conformational epitopes present in the closed conformation. Together with their improved stability and storage properties we suggest that closed spikes may be a valuable component of refined, next-generation vaccines.\nImportance\nVaccines in use against SARS-CoV-2 induce immune responses against the spike protein. There is intense interest in whether the antibody response induced by vaccines will be robust against new variants, as well as in next-generation vaccines for use in previously infected or immunized individuals. We assessed the use as an immunogen of a spike protein engineered to be conformationally stabilized in the closed state where the receptor binding site is occluded. Despite occlusion of the receptor binding site, the spike induces potently neutralizing sera against multiple SARS-CoV-2 variants. Antibodies are raised against a different pattern of epitopes to those induced by other spike constructs, preferring conformational epitopes present in the closed conformation. Closed spikes, or mRNA vaccines based on their sequence, can be a valuable component of next generation vaccines.},\n\tlanguage = {en},\n\turldate = {2021-05-12},\n\tjournal = {Journal of Virology},\n\tauthor = {Carnell, George W. and Ciazynska, Katarzyna A. and Wells, David A. and Xiong, Xiaoli and Aguinam, Ernest T. and McLaughlin, Stephen H. and Mallery, Donna and Ebrahimi, Soraya and Ceron-Gutierrez, Lourdes and Asbach, Benedikt and Einhauser, Sebastian and Wagner, Ralf and James, Leo C. and Doffinger, Rainer and Heeney, Jonathan L. and Briggs, John A. G.},\n\tmonth = may,\n\tyear = {2021},\n\tpmid = {33963055},\n\tnote = {Publisher: American Society for Microbiology Journals\nSection: Vaccines and Antiviral Agents},\n\tkeywords = {Application - Infectious Diseases, Application - Vaccine Development, PEPperCHIP - Standard, PEPperMAP - Epitope Mapping - Linear, SARS-CoV-2},\n}\n\n","author_short":["Carnell, G. W.","Ciazynska, K. A.","Wells, D. A.","Xiong, X.","Aguinam, E. 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G."],"key":"carnell_sars-cov-2_2021","id":"carnell_sars-cov-2_2021","bibbaseid":"carnell-ciazynska-wells-xiong-aguinam-mclaughlin-mallery-ebrahimi-etal-sarscov2spikeproteinstabilizedintheclosedstateinducespotentneutralizingresponses-2021","role":"author","urls":{"Paper":"https://jvi.asm.org/content/early/2021/04/28/JVI.00203-21"},"keyword":["Application - Infectious Diseases","Application - Vaccine Development","PEPperCHIP - Standard","PEPperMAP - Epitope Mapping - Linear","SARS-CoV-2"],"metadata":{"authorlinks":{}}},"bibtype":"article","biburl":"https://bibbase.org/zotero/PEPperPAPER","dataSources":["uik5uKfH7ojkHRgZZ","idrrfXaW5AQj5dNMY","NvXC6TpyECRTzBpu8"],"keywords":["application - infectious diseases","application - vaccine development","pepperchip - standard","peppermap - epitope mapping - linear","sars-cov-2"],"search_terms":["sars","cov","spike","protein","stabilized","closed","state","induces","potent","neutralizing","responses","carnell","ciazynska","wells","xiong","aguinam","mclaughlin","mallery","ebrahimi","ceron-gutierrez","asbach","einhauser","wagner","james","doffinger","heeney","briggs"],"title":"SARS-CoV-2 spike protein stabilized in the closed state induces potent neutralizing responses.","year":2021}