A Methyltransferase-Defective Vesicular Stomatitis Virus-Based SARS-CoV-2 Vaccine Candidate Provides Complete Protection against SARS-CoV-2 Infection in Hamsters
Mijia Lu, Yuexiu Zhang, Piyush Dravid, Anzhong Li, Cong Zeng, Mahesh KC, Sheetal Trivedi, Himanshu Sharma, Supranee Chaiwatpongsakorn, Ashley Zani, Adam D. Kenney, Chuanxi Cai, Chengjin Ye, Xueya Liang, Jianming Qiu, Luis Martínez‐Sobrido, Jacob S. Yount, Prosper N. Boyaka, Shan‐Lu Liu, Mark E. Peeples, Amit Kapoor, Jiànróng Lǐ
Abstract
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.