BNT162b vaccines protect rhesus macaques from SARS-CoV-2

Vogel, Annette B.; Kanevsky, Isis; Che, Ye; Swanson, Kena A.; Muik, Alexander; Vormehr, Mathias; Kranz, Lena M.; Walzer, Kerstin C.; Hein, Stephanie; Güler, Alptekin; Loschko, Jakob; Maddur, Mohan S.; Ota-Setlik, Ayuko; Tompkins, Kristin; Cole, Journey; Lui, Bonny G.; Ziegenhals, Thomas; Plaschke, Arianne; Eisel, David; Dany, Sarah C.; Fesser, Stephanie; Erbar, Stephanie; Bates, Ferdia; Schneider, Diana; Jesionek, Bernadette; Sänger, Bianca; Wallisch, Ann-Kathrin; Feuchter, Yvonne; Junginger, Hanna; Krumm, Stefanie A.; Heinen, André P.; Adams-Quack, Petra; Schlereth, Julia; Schille, Stefan; Kröner, Christoph; de la Caridad Güimil Garcia, Ramón; Hiller, Thomas; Fischer, Leyla; Sellers, Rani S.; Choudhary, Shambhunath; Gonzalez, Olga; Vascotto, Fulvia; Gutman, Matthew R.; Fontenot, Jane A.; Hall-Ursone, Shannan; Brasky, Kathleen; Griffor, Matthew C.; Han, Seungil; Su, Andreas A. H.; Lees, Joshua A.

doi:10.1038/s41586-021-03275-y

Cited by 694SARS-CoV-2 and COVID-19 ResearchAnimal Virus Infections Studiesvaccines and immunoinformatics approaches

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BNT162b vaccines protect rhesus macaques from SARS-CoV-2

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Vogel, Annette B., Kanevsky, Isis, Che, Ye, Swanson, Kena A., Muik, Alexander, Vormehr, Mathias, Kranz, Lena M., Walzer, Kerstin C., Hein, Stephanie, Güler, Alptekin, Loschko, Jakob, Maddur, Mohan S., Ota-Setlik, Ayuko, Tompkins, Kristin, Cole, Journey, Lui, Bonny G., Ziegenhals, Thomas, Plaschke, Arianne, Eisel, David, Dany, Sarah C., Fesser, Stephanie, Erbar, Stephanie, Bates, Ferdia, Schneider, Diana, Jesionek, Bernadette, Sänger, Bianca, Wallisch, Ann-Kathrin, Feuchter, Yvonne, Junginger, Hanna, Krumm, Stefanie A., Heinen, André P., Adams-Quack, Petra, Schlereth, Julia, Schille, Stefan, Kröner, Christoph, de la Caridad Güimil Garcia, Ramón, Hiller, Thomas, Fischer, Leyla, Sellers, Rani S., Choudhary, Shambhunath, Gonzalez, Olga, Vascotto, Fulvia, Gutman, Matthew R., Fontenot, Jane A., Hall-Ursone, Shannan, Brasky, Kathleen, Griffor, Matthew C., Han, Seungil, Su, Andreas A. H., Lees, Joshua A., Nedoma, Nicole L., Mashalidis, Ellene H., Sahasrabudhe, Parag V., Tan, Charles Y., Pavliakova, Danka, Singh, Guy, Fontes-Garfias, Camila, Pride, Michael, Scully, Ingrid L., Ciolino, Tara, Obregon, Jennifer, Gazi, Michal, Carrion, Ricardo, Alfson, Kendra J., Kalina, Warren V., Kaushal, Deepak, Shi, Pei-Yong, Klamp, Thorsten, Rosenbaum, Corinna, Kuhn, Andreas N., Türeci, Özlem, Dormitzer, Philip R., Jansen, Kathrin U., Sahin, Ugur·2021·Nature

DOI 10.1038/s41586-021-03275-y

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Abstract

A safe and effective vaccine against COVID-19 is urgently needed in quantities that are sufficient to immunize large populations. Here we report the preclinical development of two vaccine candidates (BNT162b1 and BNT162b2) that contain nucleoside-modified messenger RNA that encodes immunogens derived from the spike glycoprotein (S) of SARS-CoV-2, formulated in lipid nanoparticles. BNT162b1 encodes a soluble, secreted trimerized receptor-binding domain (known as the RBD-foldon). BNT162b2 encodes the full-length transmembrane S glycoprotein, locked in its prefusion conformation by the substitution of two residues with proline (S(K986P/V987P); hereafter, S(P2) (also known as P2 S)). The flexibly tethered RBDs of the RBD-foldon bind to human ACE2 with high avidity. Approximately 20% of the S(P2) trimers are in the two-RBD 'down', one-RBD 'up' state. In mice, one intramuscular dose of either candidate vaccine elicits a dose-dependent antibody response with high virus-entry inhibition titres and strong T-helper-1 CD4+ and IFNγ+CD8+ T cell responses. Prime-boost vaccination of rhesus macaques (Macaca mulatta) with the BNT162b candidates elicits SARS-CoV-2-neutralizing geometric mean titres that are 8.2-18.2× that of a panel of SARS-CoV-2-convalescent human sera. The vaccine candidates protect macaques against challenge with SARS-CoV-2; in particular, BNT162b2 protects the lower respiratory tract against the presence of viral RNA and shows no evidence of disease enhancement. Both candidates are being evaluated in phase I trials in Germany and the USA 1-3, and BNT162b2 is being evaluated in an ongoing global phase II/III trial (NCT04380701 and NCT04368728).

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BNT162b2 was chosen as the pivotal candidate based on all data from the two phase-I/II trials and non-human primate challenge studies.
“BNT162b2 was selected as pivotal candidate on the basis of the totality of data obtained in the two phase-I/II trials and challenge studies in non-human primates 2,18 .”
From BNT162b2 vaccine induces neutralizing antibodies and poly-specific T cells in humans (2021) · cites this paper as [18]
The Discussion (page not available) says BNT162b2 was selected for further clinical testing largely because it was better tolerated than BNT162b1 while showing comparable immunogenicity in clinical trials, and because its full-length spike offered broader T-cell epitopes. The paper reports macaque challenge studies, but does not say their results were a basis for that selection or characterize the decision as based on the totality of data from two phase-I/II trials. (LLM, conf=0.85)
Experimental — accuracy not yet measured
BNT162b2 encodes the full-length SARS-CoV-2 spike protein stabilized in its prefusion conformation.
“BNT162b2 encodes full-length SARS-CoV-2 S stabilized in the prefusion conformation 18 .”
From BNT162b2 vaccine induces neutralizing antibodies and poly-specific T cells in humans (2021) · cites this paper as [18]
Neutralizing antibody titres induced by CV2CoV in this study appear similar to those reported for other mRNA vaccines in macaques.
“The neutralizing antibody titres induced by CV2CoV in this study also appear to be similar to those reported for other mRNA vaccines in macaques27,28.”
From Optimization of non-coding regions for a non-modified mRNA COVID-19 vaccine (2022) · cites this paper as [28]
Neutralizing antibody titres induced by BNT162b2 in our study were comparable to those reported for BNT162b2 in a prior study.
“Moreover, the neutralizing antibody titres induced by BNT162b2 in our study (Fig. 2e) were comparable to those reported for BNT162b2 in a prior study28.”
From Optimization of non-coding regions for a non-modified mRNA COVID-19 vaccine (2022) · cites this paper as [28]
In preclinical studies, one intramuscular injection of BNT162b1 or BNT162b2 was sufficient to elicit an inhibitory antibody response with high titers as well as CD4+ helper and CD8+ cytotoxic T cell responses.
“In preclinical studies, one i.m. injection of BNT162b1 or BNT162b2 was sufficient to elicit an inhibitory antibody response with high titers as well as CD4+ helper and CD8+ cytotoxic T cell responses.107”
From COVID-19 mRNA vaccines: Platforms and current developments (2022) · cites this paper as [107]

Two injections of BNT162b2 administered to rhesus macaques elicited SARS-CoV-2 neutralizing antibody titers 8.2- to 18.2-fold higher than in convalescent human sera.
“Two injections of BNT162b2 administered to rhesus macaques elicited SARS-CoV-2 neutralizing antibody titers 8.2- to 18.2-fold higher than in convalescent human sera.107”
From COVID-19 mRNA vaccines: Platforms and current developments (2022) · cites this paper as [107]
The pseudovirus-neutralization test (pVNT) has been shown to be in close concordance with live SARS-CoV-2-neutralization assays.
“a pseudovirus-neutralization test (pVNT) that has been shown to be in close concordance with live SARS-CoV-2–neutralization assays (17, 18)”
From Neutralization of SARS-CoV-2 Omicron by BNT162b2 mRNA vaccine–elicited human sera (2022) · cites this paper as [18]
The study used two orthogonal test systems: a pseudovirus-neutralization test and a live SARS-CoV-2-neutralization test.
“we used two orthogonal test systems: a pseudovirus-neutralization test (pVNT) that has been shown to be in close concordance with live SARS-CoV-2–neutralization assays (17, 18), as well as a live SARS-CoV-2–neutralization test (VNT).”
From Neutralization of SARS-CoV-2 Omicron by BNT162b2 mRNA vaccine–elicited human sera (2022) · cites this paper as [18]
In rhesus macaques, two 100 μg doses of BNT162b2 delivered 21 days apart elicited neutralizing antibody titres 10.2-18.0 times higher than convalescent patient serum and strong CD4+ and CD8+ T cell responses.
“In preclinical studies in rhesus macaques, two 100 μg doses of BNT162b2 delivered 21 days apart elicited neutralizing antibody titres 10.2–18.0 times higher than convalescent patient serum as well as strong CD4+ and CD8+ T cell responses122.”
From mRNA vaccines for infectious diseases: principles, delivery and clinical translation (2021) · cites this paper as [122]
COVID-19 mRNA vaccines consist of synthetic mRNA strands encoding the SARS-CoV-2 Spike glycoprotein, packaged in lipid nanoparticles to deliver mRNA to cells.
“The COVID-19 mRNA vaccines represent a new class of vaccine products, which consist of synthetic mRNA strands encoding the SARS-CoV-2 Spike glycoprotein, packaged in lipid nanoparticles to deliver mRNA to cells.”
From The dawn of mRNA vaccines: the COVID-19 case (2021) · cites this paper as [48]
In non-human primate viral challenge experiments, both mRNA vaccines produced rapid viral control in the upper and lower airways.
“Supported by evidence obtained in viral challenge experiments in non-human primates that both vaccines produced rapid viral control in the upper and lower airways”
From The dawn of mRNA vaccines: the COVID-19 case (2021) · cites this paper as [48]

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BackgroundInfluential
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Authors: Vogel, A. B., Kanevsky, I., Che, Y., Swanson, K. A., Muik, A., Vormehr, M., Kranz, L. M., Walzer, K. C., Hein, S., Güler, A., Loschko, J., Maddur, M. S., Ota-Setlik, A., Tompkins, K., Cole, J., Lui, B. G., Ziegenhals, T., Plaschke, A., Eisel, D., Dany, S. C., Fesser, S., Erbar, S., Bates, F., Schneider, D., Jesionek, B., Sänger, B., Wallisch, A.-K., Feuchter, Y., Junginger, H., Krumm, S. A., Heinen, A. P., Adams-Quack, P., Schlereth, J., Schille, S., Kröner, C., de la Caridad Güimil Garcia, R., Hiller, T., Fischer, L., Sellers, R. S., Choudhary, S., Gonzalez, O., Vascotto, F., Gutman, M. R., Fontenot, J. A., Hall-Ursone, S., Brasky, K., Griffor, M. C., Han, S., Su, A. A. H., Lees, J. A., Nedoma, N. L., Mashalidis, E. H., Sahasrabudhe, P. V., Tan, C. Y., Pavliakova, D., Singh, G., Fontes-Garfias, C., Pride, M., Scully, I. L., Ciolino, T., Obregon, J., Gazi, M., Carrion, R., Alfson, K. J., Kalina, W. V., Kaushal, D., Shi, P.-Y., Klamp, T., Rosenbaum, C., Kuhn, A. N., Türeci, Ö., Dormitzer, P. R., Jansen, K. U., & Sahin, U.
Affiliations: BioNTech (Germany) (DE)
Pfizer (United States) (US)
Texas Biomedical Research Institute (US)
Johannes Gutenberg University Mainz (DE)
The University of Texas Medical Branch at Galveston (US)
ORCID: Vogel, Annette B.
Kanevsky, Isis
Che, Ye
Swanson, Kena A.
Muik, Alexander
Vormehr, Mathias
Kranz, Lena M.
Güler, Alptekin
Maddur, Mohan S.
Tompkins, Kristin
Lui, Bonny G.
Ziegenhals, Thomas
Eisel, David
Erbar, Stephanie
Bates, Ferdia
Sänger, Bianca
Wallisch, Ann-Kathrin
Heinen, André P.
Schille, Stefan
Sellers, Rani S.
Choudhary, Shambhunath
Vascotto, Fulvia
Fontenot, Jane A.
Hall-Ursone, Shannan
Griffor, Matthew C.
Han, Seungil
Lees, Joshua A.
Nedoma, Nicole L.
Mashalidis, Ellene H.
Sahasrabudhe, Parag V.
Tan, Charles Y.
Fontes-Garfias, Camila
Pride, Michael
Scully, Ingrid L.
Carrion, Ricardo
Alfson, Kendra J.
Kaushal, Deepak
Shi, Pei-Yong
Kuhn, Andreas N.
Türeci, Özlem
Dormitzer, Philip R.
Jansen, Kathrin U.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2021-02-01
Volume: 592
Issue: 7853
Pages: 283-289
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/s41586-021-03275-y
OpenAlex: W3126657865
Cited by: 694
References: 60
Citations by year: 2026: 58 · 2025: 84 · 2024: 114 · 2023: 110 · 2022: 183 · 2021: 144
FWCI: 43.67
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
RePEc: Research Papers in Economics (submittedVersion)
Funders: Pfizer
National Institutes of Health (U42OD010442)
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: BNT162b2, COVID-19 vaccines, SARS-CoV-2, mRNA vaccines, nucleoside-modified mRNA, lipid nanoparticles, spike protein, receptor binding domain, prime-boost vaccination, rhesus monkeys, neutralizing antibodies, T cell response, disease enhancement, lower respiratory tract
MeSH terms: COVID-19, SARS-CoV-2, COVID-19 Vaccines, mRNA Vaccines, BNT162 Vaccine, COVID-19 Serotherapy, Aging, Animals, Antibodies, Viral, Antigens, Viral, Cell Line, Clinical Trials as Topic, Disease Models, Animal, Female, Humans, Immunization, Passive, Macaca mulatta, Male, Mice, Inbred BALB C, Models, Molecular, Respiratory System, RNA, Viral, Solubility, T-Lymphocytes, Vaccination, Vaccines, Synthetic, Internationality, Mice, Protein Multimerization, Antibodies, Neutralizing, Spike Glycoprotein, Coronavirus

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BNT162b vaccines protect rhesus macaques from SARS-CoV-2

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