Abstract:
:A safe and effective vaccine against COVID-19 is urgently needed in quantities sufficient to immunise large populations. We report the preclinical development of two BNT162b vaccine candidates, which contain lipid-nanoparticle (LNP) formulated nucleoside-modified mRNA encoding SARS-CoV-2 spike glycoprotein-derived immunogens. BNT162b1 encodes a soluble, secreted, trimerised receptor-binding domain (RBD-foldon). BNT162b2 encodes the full-length transmembrane spike glycoprotein, locked in its prefusion conformation (P2 S). The flexibly tethered RBDs of the RBD-foldon bind ACE2 with high avidity. Approximately 20% of the P 2S trimers are in the two-RBD 'down,' one-RBD 'up' state. In mice, one intramuscular dose of either candidate elicits a dose-dependent antibody response with high virus-entry inhibition titres and strong TH1 CD4+ and IFNγ+ CD8+ T-cell responses. Prime/boost vaccination of rhesus macaques with BNT162b candidates elicits SARS-CoV-2 neutralising geometric mean titres 8.2 to 18.2 times that of a SARS-CoV-2 convalescent human serum panel. The vaccine candidates protect macaques from SARS-CoV-2 challenge, with BNT162b2 protecting the lower respiratory tract from the presence of viral RNA and with no evidence of disease enhancement. Both candidates are being evaluated in phase 1 trials in Germany and the United States1-3. BNT162b2 is being evaluated in an ongoing global, pivotal Phase 2/3 trial (NCT04380701, NCT04368728).
journal_name
Naturejournal_title
Natureauthors
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,Batesdoi
10.1038/s41586-021-03275-ysubject
Has Abstractpub_date
2021-02-01 00:00:00eissn
0028-0836issn
1476-4687pii
10.1038/s41586-021-03275-ypub_type
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