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A Methyltransferase-Defective Vesicular Stomatitis Virus-Based SARS-CoV-2 Vaccine Candidate Provides Complete Protection against SARS-CoV-2 Infection in Hamsters.
J Virol. 2021 09 27; 95(20):e0059221.JV

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 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.

Authors+Show Affiliations

Department of Veterinary Biosciences, The Ohio State Universitygrid.261331.4, Columbus, Ohio, USA.Department of Veterinary Biosciences, The Ohio State Universitygrid.261331.4, Columbus, Ohio, USA.Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.Department of Veterinary Biosciences, The Ohio State Universitygrid.261331.4, Columbus, Ohio, USA.Department of Veterinary Biosciences, The Ohio State Universitygrid.261331.4, Columbus, Ohio, USA.Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA.Department of Microbial Infection and Immunity, College of Medicine, The Ohio State Universitygrid.261331.4, Columbus, Ohio, USA.Department of Microbial Infection and Immunity, College of Medicine, The Ohio State Universitygrid.261331.4, Columbus, Ohio, USA.Department of Surgery, College of Medicine, The Ohio State Universitygrid.261331.4, Columbus, Ohio, USA.Texas Biomedical Research Institutegrid.250889.e, San Antonio, Texas, USA.Department of Veterinary Biosciences, The Ohio State Universitygrid.261331.4, Columbus, Ohio, USA.Department of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Centergrid.412016.0, Kansas City, Kansas, USA.Texas Biomedical Research Institutegrid.250889.e, San Antonio, Texas, USA.Department of Microbial Infection and Immunity, College of Medicine, The Ohio State Universitygrid.261331.4, Columbus, Ohio, USA.Department of Veterinary Biosciences, The Ohio State Universitygrid.261331.4, Columbus, Ohio, USA. Infectious Disease Institute, The Ohio State Universitygrid.261331.4, Columbus, Ohio, USA.Department of Veterinary Biosciences, The Ohio State Universitygrid.261331.4, Columbus, Ohio, USA. Department of Microbial Infection and Immunity, College of Medicine, The Ohio State Universitygrid.261331.4, Columbus, Ohio, USA. Center for Retrovirus Research, The Ohio State Universitygrid.261331.4, Columbus, Ohio, USA. Infectious Disease Institute, The Ohio State Universitygrid.261331.4, Columbus, Ohio, USA.Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA. Department of Pediatrics, College of Medicine, The Ohio State Universitygrid.261331.4, Columbus, Ohio, USA. Infectious Disease Institute, The Ohio State Universitygrid.261331.4, Columbus, Ohio, USA.Center for Vaccines and Immunity, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA. Department of Pediatrics, College of Medicine, The Ohio State Universitygrid.261331.4, Columbus, Ohio, USA. Infectious Disease Institute, The Ohio State Universitygrid.261331.4, Columbus, Ohio, USA.Department of Veterinary Biosciences, The Ohio State Universitygrid.261331.4, Columbus, Ohio, USA. Infectious Disease Institute, The Ohio State Universitygrid.261331.4, Columbus, Ohio, USA.

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

34379509

Citation

Lu, Mijia, et al. "A Methyltransferase-Defective Vesicular Stomatitis Virus-Based SARS-CoV-2 Vaccine Candidate Provides Complete Protection Against SARS-CoV-2 Infection in Hamsters." Journal of Virology, vol. 95, no. 20, 2021, pp. e0059221.
Lu M, Zhang Y, Dravid P, et al. A Methyltransferase-Defective Vesicular Stomatitis Virus-Based SARS-CoV-2 Vaccine Candidate Provides Complete Protection against SARS-CoV-2 Infection in Hamsters. J Virol. 2021;95(20):e0059221.
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, J. S., Boyaka, P. N., Liu, S. L., ... Li, J. (2021). A Methyltransferase-Defective Vesicular Stomatitis Virus-Based SARS-CoV-2 Vaccine Candidate Provides Complete Protection against SARS-CoV-2 Infection in Hamsters. Journal of Virology, 95(20), e0059221. https://doi.org/10.1128/JVI.00592-21
Lu M, et al. A Methyltransferase-Defective Vesicular Stomatitis Virus-Based SARS-CoV-2 Vaccine Candidate Provides Complete Protection Against SARS-CoV-2 Infection in Hamsters. J Virol. 2021 09 27;95(20):e0059221. PubMed PMID: 34379509.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A Methyltransferase-Defective Vesicular Stomatitis Virus-Based SARS-CoV-2 Vaccine Candidate Provides Complete Protection against SARS-CoV-2 Infection in Hamsters. AU - Lu,Mijia, AU - Zhang,Yuexiu, AU - Dravid,Piyush, AU - Li,Anzhong, AU - Zeng,Cong, AU - Kc,Mahesh, AU - Trivedi,Sheetal, AU - Sharma,Himanshu, AU - Chaiwatpongsakorn,Supranee, AU - Zani,Ashley, AU - Kenney,Adam, AU - Cai,Chuanxi, AU - Ye,Chengjin, AU - Liang,Xueya, AU - Qiu,Jianming, AU - Martinez-Sobrido,Luis, AU - Yount,Jacob S, AU - Boyaka,Prosper N, AU - Liu,Shan-Lu, AU - Peeples,Mark E, AU - Kapoor,Amit, AU - Li,Jianrong, Y1 - 2021/08/11/ PY - 2021/8/12/pubmed PY - 2021/10/9/medline PY - 2021/8/11/entrez KW - SARS-CoV-2 KW - VSV KW - mRNA cap methyltransferase KW - vaccine SP - e0059221 EP - e0059221 JF - Journal of virology JO - J Virol VL - 95 IS - 20 N2 - 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. SN - 1098-5514 UR - https://www.unboundmedicine.com/medline/citation/34379509/A_Methyltransferase_Defective_Vesicular_Stomatitis_Virus_Based_SARS_CoV_2_Vaccine_Candidate_Provides_Complete_Protection_against_SARS_CoV_2_Infection_in_Hamsters_ L2 - https://journals.asm.org/doi/10.1128/JVI.00592-21?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -