BNT162b vaccines protect rhesus macaques from SARS-CoV-2
BNT162b vaccines protect rhesus macaques from SARS-CoV-2
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DOI：
10.1038/s41586-021-03275-y
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发表时间：
2021-02-01
期刊：
影响因子：
64.8
通讯作者：
Sahin, Ugur
中科院分区：
文献类型：
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作者：
Vogel, Annette B.;Kanevsky, Isis;Sahin, Ugur
目前迫切需要一种安全有效的COVID-19疫苗，其数量足以使大量人群免疫。在这里，我们报告了两种候选疫苗（BNT 162 b1和BNT 162 b2）的临床前开发，这些候选疫苗含有核苷修饰的信使RNA，编码来自SARS-CoV-2的刺突糖蛋白（S）的免疫原，配制在脂质纳米颗粒中。BNT 162 b1编码一个可溶性的、分泌性的三聚化受体结合结构域（称为RBD-折叠子）。BNT 162 b2编码全长跨膜S糖蛋白，通过用脯氨酸取代两个残基而锁定在其融合前构象（S（K986 P/V987 P）;此后，S（P2）（也称为P2 S））。RBD-折叠子的柔性拴系的RBD以高亲合力结合人ACE 2。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，一剂肌肉注射任一候选疫苗均可激发剂量依赖性抗体应答，具有高病毒进入抑制滴度和强T辅助细胞-1 CD 4（+）和IFN γ（+）CD 8（+）T细胞应答。用BNT 162 b候选物对恒河猴（Macaca mulatta）进行初免-加强免疫，使得SARS-CoV-2中和的几何平均滴度是一组SARS-CoV-2恢复期人血清的8.2- 18.2倍。候选疫苗保护猕猴免受SARS-CoV-2的攻击;特别是，BNT 162 b2保护下呼吸道免受病毒RNA的存在，并且没有显示出疾病增强的证据。这两种候选药物正在德国和美国的I期试验中进行评价1 -3，BNT 162 b2正在进行的全球II/III期试验（NCT 04380701和NCT 04368728）中进行评价。
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 IFN gamma(+)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 8.2-18.2x 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).