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Single Immunization with Recombinant ACAM2000 Vaccinia Viruses Expressing the Spike and the Nucleocapsid Proteins Protects Hamsters against SARS-CoV-2-Caused Clinical Disease.
J Virol. 2022 05 11; 96(9):e0038922.JV

Abstract

Increasing cases of SARS-CoV-2 breakthrough infections from immunization with current spike protein-based COVID-19 vaccines highlight the need to develop alternative vaccines using different platforms and/or antigens. In this study, we expressed SARS-CoV-2 spike and nucleocapsid proteins based on a novel vaccinia virus (VACV) ACAM2000 platform (rACAM2000). In this platform, the vaccinia virus host range and immunoregulatory gene E3L was deleted to make the virus attenuated and to enhance innate immune responses, and another host range gene, K3L, was replaced with a poxvirus ortholog gene, taterapox virus 037 (TATV037), to make virus replication competent in both hamster and human cells. Following a single intramuscular immunization, the rACAM2000 coexpressing the spike and nucleocapsid proteins induced significantly improved protection against SARS-CoV-2 challenge in comparison to rACAM2000 expressing the individual proteins in a hamster model, as shown by reduced weight loss and shorter recovery time. The protection was associated with reduced viral loads, increased neutralizing antibody titer, and reduced neutrophil-to-lymphocyte ratio. Thus, our study demonstrates that rACAM2000 expressing a combination of the spike and nucleocapsid antigens is a promising COVID-19 vaccine candidate, and further studies will investigate if the rACAM2000 vaccine candidate can induce a long-lasting immunity against infection by SARS-CoV-2 variants of concern. IMPORTANCE Continuous emergence of SARS-CoV-2 variants which cause breakthrough infection from the immunity induced by current spike protein-based COVID-19 vaccines highlights the need for new generations of vaccines that will induce long-lasting immunity against a wide range of the variants. To this end, we investigated the protective efficacy of the recombinant COVID-19 vaccine candidates based on a novel VACV ACAM2000 platform, in which an immunoregulatory gene, E3L, was deleted and both the SARS-CoV-2 spike (S) and nucleocapsid (N) antigens were expressed. Thus, it is expected that the vaccine candidate we constructed should be more immunogenic and safer. In the initial study described in this work, we demonstrated that the vaccine candidate expressing both the S and N proteins is superior to the constructs expressing an individual protein (S or N) in protecting hamsters against SARS-CoV-2 challenge after a single-dose immunization, and further investigation against different SARS-CoV-2 variants will warrant future clinical evaluations.

Authors+Show Affiliations

Zoonotic Disease and Special Pathogens Division, National Microbiology Laboratory, Public Health Agency of Canadagrid.415368.d, Winnipeg, Manitoba, Canada.Viral Diseases Division, National Microbiology Laboratory, Public Health Agency of Canadagrid.415368.d, Winnipeg, Manitoba, Canada.Zoonotic Disease and Special Pathogens Division, National Microbiology Laboratory, Public Health Agency of Canadagrid.415368.d, Winnipeg, Manitoba, Canada.Zoonotic Disease and Special Pathogens Division, National Microbiology Laboratory, Public Health Agency of Canadagrid.415368.d, Winnipeg, Manitoba, Canada.National Centre for Foreign Animal Diseases, Canadian Food Inspection Agencygrid.418040.9, Winnipeg, Manitoba, Canada.Zoonotic Disease and Special Pathogens Division, National Microbiology Laboratory, Public Health Agency of Canadagrid.415368.d, Winnipeg, Manitoba, Canada.National Centre for Foreign Animal Diseases, Canadian Food Inspection Agencygrid.418040.9, Winnipeg, Manitoba, Canada.Zoonotic Disease and Special Pathogens Division, National Microbiology Laboratory, Public Health Agency of Canadagrid.415368.d, Winnipeg, Manitoba, Canada.Zoonotic Disease and Special Pathogens Division, National Microbiology Laboratory, Public Health Agency of Canadagrid.415368.d, Winnipeg, Manitoba, Canada.Viral Diseases Division, National Microbiology Laboratory, Public Health Agency of Canadagrid.415368.d, Winnipeg, Manitoba, Canada.Viral Diseases Division, National Microbiology Laboratory, Public Health Agency of Canadagrid.415368.d, Winnipeg, Manitoba, Canada.Viral Diseases Division, National Microbiology Laboratory, Public Health Agency of Canadagrid.415368.d, Winnipeg, Manitoba, Canada.Centre for Biologics Evaluation, Biologic and Radiopharmaceutical Drugs Directorate, HPFB, Health Canadagrid.57544.37 and WHO Collaborating Centre for Standardization and Evaluation of Biologicals, Ottawa, Ontario, Canada. Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.Viral Diseases Division, National Microbiology Laboratory, Public Health Agency of Canadagrid.415368.d, Winnipeg, Manitoba, Canada.Zoonotic Disease and Special Pathogens Division, National Microbiology Laboratory, Public Health Agency of Canadagrid.415368.d, Winnipeg, Manitoba, Canada. Department of Medical Microbiology, College of Medicine, University of Manitobagrid.21613.37, Winnipeg, Manitoba, Canada.Viral Diseases Division, National Microbiology Laboratory, Public Health Agency of Canadagrid.415368.d, Winnipeg, Manitoba, Canada. Department of Medical Microbiology, College of Medicine, University of Manitobagrid.21613.37, Winnipeg, Manitoba, Canada.Zoonotic Disease and Special Pathogens Division, National Microbiology Laboratory, Public Health Agency of Canadagrid.415368.d, Winnipeg, Manitoba, Canada. Department of Medical Microbiology, College of Medicine, University of Manitobagrid.21613.37, Winnipeg, Manitoba, Canada.Centre for Biologics Evaluation, Biologic and Radiopharmaceutical Drugs Directorate, HPFB, Health Canadagrid.57544.37 and WHO Collaborating Centre for Standardization and Evaluation of Biologicals, Ottawa, Ontario, Canada. Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.Zoonotic Disease and Special Pathogens Division, National Microbiology Laboratory, Public Health Agency of Canadagrid.415368.d, Winnipeg, Manitoba, Canada. Department of Medical Microbiology, College of Medicine, University of Manitobagrid.21613.37, Winnipeg, Manitoba, Canada.Viral Diseases Division, National Microbiology Laboratory, Public Health Agency of Canadagrid.415368.d, Winnipeg, Manitoba, Canada. Department of Medical Microbiology, College of Medicine, University of Manitobagrid.21613.37, Winnipeg, Manitoba, Canada.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

35412347

Citation

Deschambault, Yvon, et al. "Single Immunization With Recombinant ACAM2000 Vaccinia Viruses Expressing the Spike and the Nucleocapsid Proteins Protects Hamsters Against SARS-CoV-2-Caused Clinical Disease." Journal of Virology, vol. 96, no. 9, 2022, pp. e0038922.
Deschambault Y, Lynch J, Warner B, et al. Single Immunization with Recombinant ACAM2000 Vaccinia Viruses Expressing the Spike and the Nucleocapsid Proteins Protects Hamsters against SARS-CoV-2-Caused Clinical Disease. J Virol. 2022;96(9):e0038922.
Deschambault, Y., Lynch, J., Warner, B., Tierney, K., Huynh, D., Vendramelli, R., Tailor, N., Frost, K., Sajesh, B., LeBlanc, K., Layne, C., Lin, L., Tamming, L., Beniac, D., Booth, S., Carpenter, M., Safronetz, D., Li, X., Kobasa, D., & Cao, J. (2022). Single Immunization with Recombinant ACAM2000 Vaccinia Viruses Expressing the Spike and the Nucleocapsid Proteins Protects Hamsters against SARS-CoV-2-Caused Clinical Disease. Journal of Virology, 96(9), e0038922. https://doi.org/10.1128/jvi.00389-22
Deschambault Y, et al. Single Immunization With Recombinant ACAM2000 Vaccinia Viruses Expressing the Spike and the Nucleocapsid Proteins Protects Hamsters Against SARS-CoV-2-Caused Clinical Disease. J Virol. 2022 05 11;96(9):e0038922. PubMed PMID: 35412347.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Single Immunization with Recombinant ACAM2000 Vaccinia Viruses Expressing the Spike and the Nucleocapsid Proteins Protects Hamsters against SARS-CoV-2-Caused Clinical Disease. AU - Deschambault,Yvon, AU - Lynch,Jessie, AU - Warner,Bryce, AU - Tierney,Kevin, AU - Huynh,Denise, AU - Vendramelli,Robert, AU - Tailor,Nikesh, AU - Frost,Kathy, AU - Sajesh,Babu, AU - LeBlanc,Kyle, AU - Layne,Christine, AU - Lin,Lisa, AU - Tamming,Levi, AU - Beniac,Daniel, AU - Booth,Stephanie, AU - Carpenter,Michael, AU - Safronetz,David, AU - Li,Xuguang, AU - Kobasa,Darwyn, AU - Cao,Jingxin, Y1 - 2022/04/12/ PY - 2022/4/13/pubmed PY - 2022/5/18/medline PY - 2022/4/12/entrez KW - ACAM2000 KW - COVID-19 KW - E3L KW - K3L KW - SARS-CoV-2 KW - hamster KW - nucleocapsid KW - spike KW - vaccine KW - vaccinia SP - e0038922 EP - e0038922 JF - Journal of virology JO - J Virol VL - 96 IS - 9 N2 - Increasing cases of SARS-CoV-2 breakthrough infections from immunization with current spike protein-based COVID-19 vaccines highlight the need to develop alternative vaccines using different platforms and/or antigens. In this study, we expressed SARS-CoV-2 spike and nucleocapsid proteins based on a novel vaccinia virus (VACV) ACAM2000 platform (rACAM2000). In this platform, the vaccinia virus host range and immunoregulatory gene E3L was deleted to make the virus attenuated and to enhance innate immune responses, and another host range gene, K3L, was replaced with a poxvirus ortholog gene, taterapox virus 037 (TATV037), to make virus replication competent in both hamster and human cells. Following a single intramuscular immunization, the rACAM2000 coexpressing the spike and nucleocapsid proteins induced significantly improved protection against SARS-CoV-2 challenge in comparison to rACAM2000 expressing the individual proteins in a hamster model, as shown by reduced weight loss and shorter recovery time. The protection was associated with reduced viral loads, increased neutralizing antibody titer, and reduced neutrophil-to-lymphocyte ratio. Thus, our study demonstrates that rACAM2000 expressing a combination of the spike and nucleocapsid antigens is a promising COVID-19 vaccine candidate, and further studies will investigate if the rACAM2000 vaccine candidate can induce a long-lasting immunity against infection by SARS-CoV-2 variants of concern. IMPORTANCE Continuous emergence of SARS-CoV-2 variants which cause breakthrough infection from the immunity induced by current spike protein-based COVID-19 vaccines highlights the need for new generations of vaccines that will induce long-lasting immunity against a wide range of the variants. To this end, we investigated the protective efficacy of the recombinant COVID-19 vaccine candidates based on a novel VACV ACAM2000 platform, in which an immunoregulatory gene, E3L, was deleted and both the SARS-CoV-2 spike (S) and nucleocapsid (N) antigens were expressed. Thus, it is expected that the vaccine candidate we constructed should be more immunogenic and safer. In the initial study described in this work, we demonstrated that the vaccine candidate expressing both the S and N proteins is superior to the constructs expressing an individual protein (S or N) in protecting hamsters against SARS-CoV-2 challenge after a single-dose immunization, and further investigation against different SARS-CoV-2 variants will warrant future clinical evaluations. SN - 1098-5514 UR - https://www.unboundmedicine.com/medline/citation/35412347/Single_Immunization_with_Recombinant_ACAM2000_Vaccinia_Viruses_Expressing_the_Spike_and_the_Nucleocapsid_Proteins_Protects_Hamsters_against_SARS_CoV_2_Caused_Clinical_Disease_ DB - PRIME DP - Unbound Medicine ER -