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BNT162b vaccines protect rhesus macaques from SARS-CoV-2
Nature ( IF 50.5 ) Pub Date : 2021-02-01 , DOI: 10.1038/s41586-021-03275-y
Annette B Vogel 1 , Isis Kanevsky 2 , Ye Che 3 , Kena A Swanson 2 , Alexander Muik 1 , Mathias Vormehr 1 , Lena M Kranz 1 , Kerstin C Walzer 1 , Stephanie Hein 1 , Alptekin Güler 1 , Jakob Loschko 2 , Mohan S Maddur 2 , Ayuko Ota-Setlik 2 , Kristin Tompkins 2 , Journey Cole 4 , Bonny G Lui 1 , Thomas Ziegenhals 1 , Arianne Plaschke 1 , David Eisel 1 , Sarah C Dany 1 , Stephanie Fesser 1 , Stephanie Erbar 1 , Ferdia Bates 1 , Diana Schneider 1 , Bernadette Jesionek 1 , Bianca Sänger 1 , Ann-Kathrin Wallisch 1 , Yvonne Feuchter 1 , Hanna Junginger 1 , Stefanie A Krumm 1 , André P Heinen 1 , Petra Adams-Quack 1 , Julia Schlereth 1 , Stefan Schille 1 , Christoph Kröner 1 , Ramón de la Caridad Güimil Garcia 1 , Thomas Hiller 1 , Leyla Fischer 1 , Rani S Sellers 2 , Shambhunath Choudhary 2 , Olga Gonzalez 4 , Fulvia Vascotto 5 , Matthew R Gutman 6 , Jane A Fontenot 7 , Shannan Hall-Ursone 4 , Kathleen Brasky 4 , Matthew C Griffor 3 , Seungil Han 3 , Andreas A H Su 1 , Joshua A Lees 3 , Nicole L Nedoma 3 , Ellene H Mashalidis 3 , Parag V Sahasrabudhe 3 , Charles Y Tan 2 , Danka Pavliakova 2 , Guy Singh 2 , Camila Fontes-Garfias 8 , Michael Pride 2 , Ingrid L Scully 2 , Tara Ciolino 2 , Jennifer Obregon 2 , Michal Gazi 9 , Ricardo Carrion 4 , Kendra J Alfson 9 , Warren V Kalina 2 , Deepak Kaushal 4 , Pei-Yong Shi 8 , Thorsten Klamp 1 , Corinna Rosenbaum 1 , Andreas N Kuhn 1 , Özlem Türeci 1 , Philip R Dormitzer 2 , Kathrin U Jansen 2 , Ugur Sahin 1, 5
Affiliation  

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 USA1,2,3, and BNT162b2 is being evaluated in an ongoing global phase II/III trial (NCT04380701 and NCT04368728).



中文翻译:


BNT162b 疫苗可保护恒河猴免受 SARS-CoV-2 感染



迫切需要一种安全有效的 COVID-19 疫苗,其数量足以为大量人群提供免疫。在此,我们报告了两种候选疫苗(BNT162b1 和 BNT162b2)的临床前开发,它们含有核苷修饰的信使 RNA,编码源自 SARS-CoV-2 刺突糖蛋白 (S) 的免疫原,配制在脂质纳米颗粒中。 BNT162b1 编码可溶性、分泌性三聚化受体结合域(称为 RBD-foldon)。 BNT162b2 编码全长跨膜 S 糖蛋白,通过用脯氨酸替换两个残基(S(K986P/V987P);以下称为 S(P2)(也称为 P2 S))锁定其融合前构象。 RBD-foldon 中灵活连接的 RBD 以高亲和力与人 ACE2 结合。大约 20% 的 S(P2) 三聚体处于两个 RBD“向下”、一个 RBD“向上”状态。在小鼠中,肌注剂量的任一候选疫苗都会引发剂量依赖性抗体反应,具有高病毒进入抑制滴度和强烈的 T-helper-1 CD4 +和 IFNγ + CD8 + T 细胞反应。使用 BNT162b 候选物对恒河猴 ( Macaca mulatta ) 进行初免-加强疫苗接种,可引发 SARS-CoV-2 中和几何平均滴度,该滴度是一组 SARS-CoV-2 恢复期人类血清滴度的 8.2-18.2 倍。候选疫苗可保护猕猴免受 SARS-CoV-2 的攻击;特别是,BNT162b2 可以保护下呼吸道免受病毒 RNA 的影响,并且没有显示出疾病增强的证据。两种候选药物正在德国和美国1,2,3 的I 期试验中接受评估,BNT162b2 正在正在进行的全球 II/III 期试验(NCT04380701 和 NCT04368728)中接受评估。

更新日期:2021-02-01
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