tetano
Editor, Senior Moderator
J Virol
. 2021 Aug 11;JVI0059221.
doi: 10.1128/JVI.00592-21. Online ahead of print.
A methyltransferase-defective VSV-based SARS-CoV-2 vaccine candidate provides complete protection against SARS-CoV-2 infection in hamsters
Mijia Lu[SUP] 1 [/SUP], Yuexiu Zhang[SUP] 1 [/SUP], Piyush Dravid[SUP] 2 [/SUP], Anzhong Li[SUP] 1 [/SUP], Cong Zeng[SUP] 1 [/SUP], Mahesh K C[SUP] 2 [/SUP], Sheetal Trivedi[SUP] 2 [/SUP], Himanshu Sharma[SUP] 2 [/SUP], Supranee Chaiwatpongsakorn[SUP] 2 [/SUP], Ashley Zani[SUP] 3 [/SUP], Adam Kenney[SUP] 3 [/SUP], Chuanxi Cai[SUP] 4 [/SUP], Chengjin Ye[SUP] 5 [/SUP], Xueya Liang[SUP] 1 [/SUP], Jianming Qiu[SUP] 6 [/SUP], Luis Martinez-Sobrido[SUP] 5 [/SUP], Jacob S Yount[SUP] 3 [/SUP], Prosper N Boyaka[SUP] 1 7 [/SUP], Shan-Lu Liu[SUP] 1 3 8 7 [/SUP], Mark E Peeples[SUP] 2 9 7 [/SUP], Amit Kapoor[SUP] 2 9 7 [/SUP], Jianrong Li[SUP] 1 7 [/SUP]
Affiliations
Abstract
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 the uncertainties of 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), S1, or its receptor binding domain (RBD). All these recombinant viruses grew to high titers in mammalian cells despite high attenuation in cell culture. 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. Syrian golden hamsters immunized with mtdVSV-S triggered SARS-CoV-2 specific NAbs that were higher than convalescent plasma from convalescent 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. Significance Viral mRNA cap methyltransferase (MTase) is essential for mRNA stability, protein translation, and innate immune evasion. Thus, viral mRNA cap MTase activity is a novel target for development of live attenuated or live vectored vaccine candidates. Here, we developed a panel of MTase-defective recombinant 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 antibody (Nabs) and Th1-biased immune responses in mice. Syrian golden hamsters immunized with mtdVSV-S triggered SARS-CoV-2 specific NAbs that were higher than convalescent plasma from COVID-19 recovered 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.
. 2021 Aug 11;JVI0059221.
doi: 10.1128/JVI.00592-21. Online ahead of print.
A methyltransferase-defective VSV-based SARS-CoV-2 vaccine candidate provides complete protection against SARS-CoV-2 infection in hamsters
Mijia Lu[SUP] 1 [/SUP], Yuexiu Zhang[SUP] 1 [/SUP], Piyush Dravid[SUP] 2 [/SUP], Anzhong Li[SUP] 1 [/SUP], Cong Zeng[SUP] 1 [/SUP], Mahesh K C[SUP] 2 [/SUP], Sheetal Trivedi[SUP] 2 [/SUP], Himanshu Sharma[SUP] 2 [/SUP], Supranee Chaiwatpongsakorn[SUP] 2 [/SUP], Ashley Zani[SUP] 3 [/SUP], Adam Kenney[SUP] 3 [/SUP], Chuanxi Cai[SUP] 4 [/SUP], Chengjin Ye[SUP] 5 [/SUP], Xueya Liang[SUP] 1 [/SUP], Jianming Qiu[SUP] 6 [/SUP], Luis Martinez-Sobrido[SUP] 5 [/SUP], Jacob S Yount[SUP] 3 [/SUP], Prosper N Boyaka[SUP] 1 7 [/SUP], Shan-Lu Liu[SUP] 1 3 8 7 [/SUP], Mark E Peeples[SUP] 2 9 7 [/SUP], Amit Kapoor[SUP] 2 9 7 [/SUP], Jianrong Li[SUP] 1 7 [/SUP]
Affiliations
- PMID: 34379509
- DOI: 10.1128/JVI.00592-21
Abstract
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 the uncertainties of 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), S1, or its receptor binding domain (RBD). All these recombinant viruses grew to high titers in mammalian cells despite high attenuation in cell culture. 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. Syrian golden hamsters immunized with mtdVSV-S triggered SARS-CoV-2 specific NAbs that were higher than convalescent plasma from convalescent 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. Significance Viral mRNA cap methyltransferase (MTase) is essential for mRNA stability, protein translation, and innate immune evasion. Thus, viral mRNA cap MTase activity is a novel target for development of live attenuated or live vectored vaccine candidates. Here, we developed a panel of MTase-defective recombinant 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 antibody (Nabs) and Th1-biased immune responses in mice. Syrian golden hamsters immunized with mtdVSV-S triggered SARS-CoV-2 specific NAbs that were higher than convalescent plasma from COVID-19 recovered 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.