Ad26 vector-based COVID-19 vaccine encoding a prefusion-stabilized SARS-CoV-2 Spike immunogen induces potent humoral and cellular immune responses.
Ad26 vector-based COVID-19 vaccine encoding a prefusion-stabilized SARS-CoV-2 Spike immunogen induces potent humoral and cellular immune responses.
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DOI：
10.1038/s41541-020-00243-x
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发表时间：
2020
期刊：
影响因子：
9.2
通讯作者：
Schuitemaker H
中科院分区：
文献类型：
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作者：
Bos R;Rutten L;van der Lubbe JEM;Bakkers MJG;Hardenberg G;Wegmann F;Zuijdgeest D;de Wilde AH;Koornneef A;Verwilligen A;van Manen D;Kwaks T;Vogels R;Dalebout TJ;Myeni SK;Kikkert M;Snijder EJ;Li Z;Barouch DH;Vellinga J;Langedijk JPM;Zahn RC;Custers J;Schuitemaker H
迫切需要针对COVID-19的病原体SARS-CoV-2开发有效的预防干预措施。SARS-CoV-2的病毒表面刺突（S）蛋白是预防措施的关键目标，因为它对病毒复制周期至关重要，也是中和抗体的主要目标。我们评估了先前显示用于其他基于冠状病毒S蛋白的疫苗的成功设计元素，例如，融合前稳定取代和异源信号肽，用于选择基于S的SARS-CoV-2候选疫苗。体外表征表明，引入稳定取代（即，弗林蛋白酶切割位点突变和S2的铰链区中的两个连续脯氨酸）增加了中和与非中和抗体结合的比率，提示S蛋白的融合前构象。此外，野生型信号肽最适合于天然折叠蛋白质所需的正确切割。这些观察结果转化为小鼠中的上级免疫原性，其中编码具有野生型信号肽的膜结合稳定S蛋白的Ad 26载体引发了有效的中和体液免疫和细胞免疫，其极化为Th 1 IFN-γ。这种优化的基于Ad 26载体的SARS-CoV-2疫苗，称为Ad26.COV2.S，目前正在I期临床试验中进行评估（ClinicalTrials.gov标识符：NCT 04436276）。
Development of effective preventative interventions against SARS-CoV-2, the etiologic agent of COVID-19 is urgently needed. The viral surface spike (S) protein of SARS-CoV-2 is a key target for prophylactic measures as it is critical for the viral replication cycle and the primary target of neutralizing antibodies. We evaluated design elements previously shown for other coronavirus S protein-based vaccines to be successful, e.g., prefusion-stabilizing substitutions and heterologous signal peptides, for selection of a S-based SARS-CoV-2 vaccine candidate. In vitro characterization demonstrated that the introduction of stabilizing substitutions (i.e., furin cleavage site mutations and two consecutive prolines in the hinge region of S2) increased the ratio of neutralizing versus non-neutralizing antibody binding, suggestive for a prefusion conformation of the S protein. Furthermore, the wild-type signal peptide was best suited for the correct cleavage needed for a natively folded protein. These observations translated into superior immunogenicity in mice where the Ad26 vector encoding for a membrane-bound stabilized S protein with a wild-type signal peptide elicited potent neutralizing humoral immunity and cellular immunity that was polarized towards Th1 IFN-γ. This optimized Ad26 vector-based vaccine for SARS-CoV-2, termed Ad26.COV2.S, is currently being evaluated in a phase I clinical trial (ClinicalTrials.gov Identifier: NCT04436276).