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^1,2,3, and BNT162b2 is being evaluated in an ongoing global phase II/III trial (NCT04380701 and NCT04368728).

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。