| Literature DB >> 33524990 |
Annette B Vogel1, Isis Kanevsky2, Ye Che3, Kena A Swanson2, Alexander Muik1, Mathias Vormehr1, Lena M Kranz1, Kerstin C Walzer1, Stephanie Hein1, Alptekin Güler1, Jakob Loschko2, Mohan S Maddur2, Ayuko Ota-Setlik2, Kristin Tompkins2, Journey Cole4, Bonny G Lui1, Thomas Ziegenhals1, Arianne Plaschke1, David Eisel1, Sarah C Dany1, Stephanie Fesser1, Stephanie Erbar1, Ferdia Bates1, Diana Schneider1, Bernadette Jesionek1, Bianca Sänger1, Ann-Kathrin Wallisch1, Yvonne Feuchter1, Hanna Junginger1, Stefanie A Krumm1, André P Heinen1, Petra Adams-Quack1, Julia Schlereth1, Stefan Schille1, Christoph Kröner1, Ramón de la Caridad Güimil Garcia1, Thomas Hiller1, Leyla Fischer1, Rani S Sellers2, Shambhunath Choudhary2, Olga Gonzalez4, Fulvia Vascotto5, Matthew R Gutman6, Jane A Fontenot7, Shannan Hall-Ursone4, Kathleen Brasky4, Matthew C Griffor3, Seungil Han3, Andreas A H Su1, Joshua A Lees3, Nicole L Nedoma3, Ellene H Mashalidis3, Parag V Sahasrabudhe3, Charles Y Tan2, Danka Pavliakova2, Guy Singh2, Camila Fontes-Garfias8, Michael Pride2, Ingrid L Scully2, Tara Ciolino2, Jennifer Obregon2, Michal Gazi9, Ricardo Carrion4, Kendra J Alfson9, Warren V Kalina2, Deepak Kaushal4, Pei-Yong Shi8, Thorsten Klamp1, Corinna Rosenbaum1, Andreas N Kuhn1, Özlem Türeci1, Philip R Dormitzer2, Kathrin U Jansen2, Ugur Sahin10,11.
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).Entities:
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Year: 2021 PMID： 33524990 DOI： 10.1038/s41586-021-03275-y
Source DB: PubMed Journal: Nature ISSN： 0028-0836 Impact factor: 69.504