Recombinant measles virus expressing prefusion spike protein stabilized by six rather than two prolines is more efficacious against SARS-CoV-2 infection.
Recombinant measles virus expressing prefusion spike protein stabilized by six rather than two prolines is more efficacious against SARS-CoV-2 infection.
复制标题
表达由六个而不是两个脯氨酸稳定的融合前刺突蛋白的重组麻疹病毒对 SARS-CoV-2 感染更有效。
DOI：
10.1002/jmv.28687
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发表时间：
2023
影响因子：
12.7
通讯作者：
Li,Jianrong
中科院分区：
文献类型：
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作者：
Zhang,Yuexiu;Lu,Mijia;Thongpan,Ilada;Xu,Jiayu;Kc,Mahesh;Dravid,Piyush;Trivedi,Sheetal;Sharma,Himanshu;Liang,Xueya;Kapoor,Amit;Peeples,MarkE;Li,Jianrong
麻疹病毒（MeV）因其高安全性和有效性以及诱导长效免疫力而成为针对多种病原体的疫苗的绝佳载体平台。在COVID-19大流行早期，开发了表达由两个脯氨酸稳定的灌注前全长刺突蛋白（TMV-083）的重组MeV（rMeV），并在1期和1/2期临床试验中进行了测试，但由于免疫原性不足和成人血清转化率低而停止。在这里，我们比较了表达由两个脯氨酸稳定的可溶性预融合蛋白（preS）蛋白（rMeV-preS-2P）的rMeV与表达由六个脯氨酸稳定的可溶性preS蛋白（rMeV-preS-6P）的rMeV的免疫原性。我们发现，在细胞培养物中，rMeV-preS-6P 的 preS 表达量大约是 rMeV-preS-2P 的五倍。重要的是，在 IFNAR−/− 小鼠中，rMeV-preS-6P 诱导的血清免疫球蛋白 G 和中和抗体分别比 rMeV-preS-2P 多 30-60 倍和 6 倍。用 rMeV-preS-6P 免疫的 IFNAR−/− 小鼠完全免受小鼠适应性 SARS-CoV-2 的攻击，而用 rMeV-preS-2P 免疫的小鼠则得到部分保护。此外，用 rMeV-preS-6P 免疫的仓鼠完全免受 SARS-CoV-2 Delta 变体的攻击。我们的结果表明，rMeV-preS-6P 明显比 rMeV-preS-2P 更有效，凸显了使用 preS-6P 作为抗原开发 SARS-CoV-2 疫苗的价值。
Measles virus (MeV) has been an excellent vector platform for delivering vaccines against many pathogens because of its high safety and efficacy, and induction of long‐lived immunity. Early in the COVID‐19 pandemic, a recombinant MeV (rMeV) expressing the prefusion full‐length spike protein stabilized by two prolines (TMV‐083) was developed and tested in phase 1 and 1/2 clinical trials but was discontinued because of insufficient immunogenicity and a low seroconversion rate in adults. Here, we compared the immunogenicity of rMeV expressing a soluble prefusion spike (preS) protein stabilized by two prolines (rMeV‐preS‐2P) with a rMeV expressing a soluble preS protein stabilized by six prolines (rMeV‐preS‐6P). We found that rMeV‐preS‐6P expressed approximately five times more preS than rMeV‐preS‐2P in cell culture. Importantly, rMeV‐preS‐6P induced 30‐60 and six times more serum immunoglobulin G and neutralizing antibody than rMeV‐preS‐2P, respectively, in IFNAR−/−mice. IFNAR−/−mice immunized with rMeV‐preS‐6P were completely protected from challenge with a mouse‐adapted SARS‐CoV‐2, whereas those immunized with rMeV‐preS‐2P were partially protected. In addition, hamsters immunized with rMeV‐preS‐6P were completely protected from the challenge with a Delta variant of SARS‐CoV‐2. Our results demonstrate that rMeV‐preS‐6P is significantly more efficacious than rMeV‐preS‐2P, highlighting the value of using preS‐6P as the antigen for developing vaccines against SARS‐CoV‐2.