1. BNT162b vaccines protect rhesus macaques from SARS-CoV-2.
- Author
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Vogel AB, Kanevsky I, Che Y, Swanson KA, Muik A, Vormehr M, Kranz LM, Walzer KC, Hein S, Güler A, Loschko J, Maddur MS, Ota-Setlik A, Tompkins K, Cole J, Lui BG, Ziegenhals T, Plaschke A, Eisel D, Dany SC, Fesser S, Erbar S, Bates F, Schneider D, Jesionek B, Sänger B, Wallisch AK, Feuchter Y, Junginger H, Krumm SA, Heinen AP, Adams-Quack P, Schlereth J, Schille S, Kröner C, de la Caridad Güimil Garcia R, Hiller T, Fischer L, Sellers RS, Choudhary S, Gonzalez O, Vascotto F, Gutman MR, Fontenot JA, Hall-Ursone S, Brasky K, Griffor MC, Han S, Su AAH, Lees JA, Nedoma NL, Mashalidis EH, Sahasrabudhe PV, Tan CY, Pavliakova D, Singh G, Fontes-Garfias C, Pride M, Scully IL, Ciolino T, Obregon J, Gazi M, Carrion R Jr, Alfson KJ, Kalina WV, Kaushal D, Shi PY, Klamp T, Rosenbaum C, Kuhn AN, Türeci Ö, Dormitzer PR, Jansen KU, and Sahin U
- Subjects
- Aging immunology, Animals, Antibodies, Neutralizing immunology, Antibodies, Viral immunology, Antigens, Viral chemistry, Antigens, Viral genetics, Antigens, Viral immunology, BNT162 Vaccine, COVID-19 blood, COVID-19 therapy, COVID-19 virology, COVID-19 Vaccines administration & dosage, COVID-19 Vaccines chemistry, COVID-19 Vaccines genetics, Cell Line, Clinical Trials as Topic, Female, Humans, Immunization, Passive, Internationality, Macaca mulatta immunology, Macaca mulatta virology, Male, Mice, Mice, Inbred BALB C, Models, Molecular, Protein Multimerization, RNA, Viral analysis, Respiratory System immunology, Respiratory System virology, SARS-CoV-2 chemistry, SARS-CoV-2 genetics, Solubility, Spike Glycoprotein, Coronavirus chemistry, Spike Glycoprotein, Coronavirus genetics, Spike Glycoprotein, Coronavirus immunology, T-Lymphocytes immunology, Vaccination, Vaccines, Synthetic administration & dosage, Vaccines, Synthetic chemistry, Vaccines, Synthetic genetics, Vaccines, Synthetic immunology, COVID-19 Serotherapy, mRNA Vaccines, COVID-19 immunology, COVID-19 prevention & control, COVID-19 Vaccines immunology, Disease Models, Animal, SARS-CoV-2 immunology
- 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 USA1-3 , and BNT162b2 is being evaluated in an ongoing global phase II/III trial (NCT04380701 and NCT04368728).- Published
- 2021
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