A Methyltransferase-Defective Vesicular Stomatitis Virus-Based SARS-CoV-2 Vaccine Candidate Provides Complete Protection against SARS-CoV-2 Infection in Hamsters.
A Methyltransferase-Defective Vesicular Stomatitis Virus-Based SARS-CoV-2 Vaccine Candidate Provides Complete Protection against SARS-CoV-2 Infection in Hamsters.
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DOI：
10.1128/jvi.00592-21
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发表时间：
2021-09-27
影响因子：
5.4
通讯作者：
Li J
中科院分区：
文献类型：
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作者：
Lu M;Zhang Y;Dravid P;Li A;Zeng C;Kc M;Trivedi S;Sharma H;Chaiwatpongsakorn S;Zani A;Kenney A;Cai C;Ye C;Liang X;Qiu J;Martinez-Sobrido L;Yount JS;Boyaka PN;Liu SL;Peeples ME;Kapoor A;Li J
当前由严重急性呼吸道综合征冠状病毒2型（SARS-CoV-2）引起的2019年冠状病毒病（COVID-19）大流行导致了巨大的经济和健康负担。尽管全球SARS-CoV-2疫苗接种活动已经开始，但由于目前批准的疫苗存在不确定性，例如保护的持久性，对变异株的交叉保护以及长期生产和储存的成本，因此需要探索其他候选疫苗。在这项研究中，我们开发了一个甲基转移酶缺陷型重组水泡性口炎病毒（mtdVSV）为基础的SARS-CoV-2疫苗候选人。我们产生了表达SARS-CoV-2全长刺突（S）蛋白S1或其受体结合结构域（RBD）的mtdVSV。尽管在细胞培养物中高度减毒，但所有这些重组病毒在哺乳动物细胞中均生长至高滴度。用mtdVSV载体高效表达SARS-CoV-2S蛋白及其截短片段。这些基于mtdVSV的候选疫苗在免疫活性小鼠和免疫受损小鼠中均完全减毒。在这些构建体中，mtdVSV-S在小鼠中诱导高水平的SARS-CoV-2特异性中和抗体（NAb）和Th 1偏向的T细胞免疫应答。在叙利亚金仓鼠中，由mtdVSV-S触发的SARS-CoV-2特异性NAb的血清水平高于COVID-19康复患者恢复期血浆中的NAb水平。此外，用mtdVSV-S免疫的仓鼠完全保护免于SARS-CoV-2在肺和鼻甲组织中的复制、细胞因子风暴和肺病理学。总的来说，我们的数据表明，表达SARS-CoV-2 S蛋白的mtdVSV是一种安全和高效的抗SARS-CoV-2感染的候选疫苗。重要性病毒mRNA帽甲基转移酶（MTase）对于mRNA稳定性、蛋白质翻译和先天性免疫逃避是必不可少的。因此，病毒mRNA帽MTase活性是用于开发活减毒或活载体疫苗候选物的极好靶标。在这里，我们开发了一组MTase缺陷型重组水泡性口炎病毒（mtdVSV）为基础的SARS-CoV-2候选疫苗表达全长S，S1，或几个版本的RBD。这些基于mtdVSV的候选疫苗在细胞培养物中生长至高滴度，并且在免疫活性小鼠和免疫受损小鼠中完全减毒。在这些候选疫苗中，mtdVSV-S在小鼠中诱导高水平的SARS-CoV-2特异性中和抗体（Nabs）和Th 1偏向的免疫应答。用mtdVSV-S免疫的叙利亚金仓鼠触发的SARS-CoV-2特异性NAb水平高于COVID-19康复患者恢复期血浆中的水平。此外，mtdVSV-S免疫的仓鼠对SARS-CoV-2攻击完全保护。因此，mtdVSV是一种安全、高效的SARS-CoV-2疫苗载体。
The current pandemic of coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to dramatic economic and health burdens. Although the worldwide SARS-CoV-2 vaccination campaign has begun, exploration of other vaccine candidates is needed due to uncertainties with the current approved vaccines, such as durability of protection, cross-protection against variant strains, and costs of long-term production and storage. In this study, we developed a methyltransferase-defective recombinant vesicular stomatitis virus (mtdVSV)-based SARS-CoV-2 vaccine candidate. We generated mtdVSVs expressing SARS-CoV-2 full-length spike (S) protein, S1, or its receptor-binding domain (RBD). All of these recombinant viruses grew to high titers in mammalian cells despite high attenuation in cell culture. The SARS-CoV-2 S protein and its truncations were highly expressed by the mtdVSV vector. These mtdVSV-based vaccine candidates were completely attenuated in both immunocompetent and immunocompromised mice. Among these constructs, mtdVSV-S induced high levels of SARS-CoV-2-specific neutralizing antibodies (NAbs) and Th1-biased T-cell immune responses in mice. In Syrian golden hamsters, the serum levels of SARS-CoV-2-specific NAbs triggered by mtdVSV-S were higher than the levels of NAbs in convalescent plasma from recovered COVID-19 patients. In addition, hamsters immunized with mtdVSV-S were completely protected against SARS-CoV-2 replication in lung and nasal turbinate tissues, cytokine storm, and lung pathology. Collectively, our data demonstrate that mtdVSV expressing SARS-CoV-2 S protein is a safe and highly efficacious vaccine candidate against SARS-CoV-2 infection. IMPORTANCE Viral mRNA cap methyltransferase (MTase) is essential for mRNA stability, protein translation, and innate immune evasion. Thus, viral mRNA cap MTase activity is an excellent target for development of live attenuated or live vectored vaccine candidates. Here, we developed a panel of MTase-defective recombinant vesicular stomatitis virus (mtdVSV)-based SARS-CoV-2 vaccine candidates expressing full-length S, S1, or several versions of the RBD. These mtdVSV-based vaccine candidates grew to high titers in cell culture and were completely attenuated in both immunocompetent and immunocompromised mice. Among these vaccine candidates, mtdVSV-S induces high levels of SARS-CoV-2-specific neutralizing antibodies (Nabs) and Th1-biased immune responses in mice. Syrian golden hamsters immunized with mtdVSV-S triggered SARS-CoV-2-specific NAbs at higher levels than those in convalescent plasma from recovered COVID-19 patients. Furthermore, hamsters immunized with mtdVSV-S were completely protected against SARS-CoV-2 challenge. Thus, mtdVSV is a safe and highly effective vector to deliver SARS-CoV-2 vaccine.
DOI：
10.1084/jem.67.2.201
发表时间：
1938-01-31
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Sabin AB;Olitsky PK
通讯作者：
Olitsky PK