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Combinatorial mRNA vaccination enhances protection against SARS-CoV-2 delta variant

Renee L. Hajnik, Jessica A. Plante, Yuejin Liang, Mohamad-Gabriel Alameh, Jinyi Tang, Chaojie Zhong, Awadalkareem Adam, Dionna Scharton, Grace H. Rafael, Yang Liu, Nicholas C. Hazell, Jiaren Sun, Lynn Soong, Pei-Yong Shi, Tian Wang, Jie Sun, Drew Weissman, Scott C. Weaver, Kenneth S. Plante, Haitao Hu
doi: https://doi.org/10.1101/2021.12.08.471664
Renee L. Hajnik
1Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA 77555
9Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA 77555
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Jessica A. Plante
1Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA 77555
2Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA 77555
3World Reference Center for Emerging Viruses and Arboviruses, University of Texas Medical Branch, Galveston, TX, USA 77555
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Yuejin Liang
1Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA 77555
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Mohamad-Gabriel Alameh
4Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA 19104
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Jinyi Tang
5Division of Pulmonary and Critical Medicine, Department of Medicine, Mayo Clinic, Rochester, MN, USA 55905
6Carter Immunology Center, University of Virginia, Charlottesville, VA, USA 22908
7Division of Infectious Disease and International Health, Department of Medicine, University of Virginia, Charlottesville, VA, USA 22908
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Chaojie Zhong
1Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA 77555
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Awadalkareem Adam
1Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA 77555
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Dionna Scharton
1Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA 77555
3World Reference Center for Emerging Viruses and Arboviruses, University of Texas Medical Branch, Galveston, TX, USA 77555
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Grace H. Rafael
1Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA 77555
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Yang Liu
8Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA 77555
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Nicholas C. Hazell
1Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA 77555
9Department of Pathology, University of Texas Medical Branch, Galveston, TX, USA 77555
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Jiaren Sun
1Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA 77555
2Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA 77555
10Sealy Institute for Vaccine Sciences, University of Texas Medical Branch, Galveston, TX, USA 77555
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Lynn Soong
1Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA 77555
2Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA 77555
10Sealy Institute for Vaccine Sciences, University of Texas Medical Branch, Galveston, TX, USA 77555
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Pei-Yong Shi
2Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA 77555
8Department of Biochemistry and Molecular Biology, University of Texas Medical Branch, Galveston, TX, USA 77555
10Sealy Institute for Vaccine Sciences, University of Texas Medical Branch, Galveston, TX, USA 77555
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Tian Wang
1Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA 77555
2Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA 77555
10Sealy Institute for Vaccine Sciences, University of Texas Medical Branch, Galveston, TX, USA 77555
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Jie Sun
5Division of Pulmonary and Critical Medicine, Department of Medicine, Mayo Clinic, Rochester, MN, USA 55905
6Carter Immunology Center, University of Virginia, Charlottesville, VA, USA 22908
7Division of Infectious Disease and International Health, Department of Medicine, University of Virginia, Charlottesville, VA, USA 22908
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Drew Weissman
4Department of Medicine, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA 19104
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Scott C. Weaver
1Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA 77555
2Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA 77555
3World Reference Center for Emerging Viruses and Arboviruses, University of Texas Medical Branch, Galveston, TX, USA 77555
10Sealy Institute for Vaccine Sciences, University of Texas Medical Branch, Galveston, TX, USA 77555
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Kenneth S. Plante
1Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA 77555
2Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA 77555
3World Reference Center for Emerging Viruses and Arboviruses, University of Texas Medical Branch, Galveston, TX, USA 77555
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  • For correspondence: haihu@UTMB.edu ksplante@utmb.edu
Haitao Hu
1Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA 77555
2Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA 77555
10Sealy Institute for Vaccine Sciences, University of Texas Medical Branch, Galveston, TX, USA 77555
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  • For correspondence: haihu@UTMB.edu ksplante@utmb.edu
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Abstract

Emergence of SARS-CoV-2 variants of concern (VOC), including the highly transmissible delta strain, has posed challenges to current COVID-19 vaccines that principally target the viral spike protein (S). Here, we report a nucleoside-modified mRNA vaccine that expresses the more conserved viral nucleoprotein (mRNA-N). We show that mRNA-N alone was able to induce a modest but significant control of SARS-CoV-2 in mice and hamsters. Critically, by combining mRNA-N with the clinically approved S-expressing mRNA vaccine (mRNA-S-2P), we found that combinatorial mRNA vaccination (mRNA-S+N) led to markedly enhanced protection against the SARS-CoV-2 delta variant compared to mRNA-S. In a hamster model, we demonstrated that while mRNA-S alone elicited significant control of the delta strain in the lungs (∼45-fold reduction in viral loads compared to un-vaccinated control), its effectiveness in the upper respiratory tract was weak, whereas combinatorial mRNA-S+N vaccination induced markedly more robust control of the delta variant infection in the lungs (∼450-fold reduction) as well as in the upper respiratory tract (∼20-fold reduction). Immune analyses indicated that induction of N-specific immunity as well as augmented S-specific T-cell response and neutralizing antibody activity were collectively associated the enhanced protection against SARS-CoV-2 delta strain by combinatorial mRNA vaccination. These findings suggest that the combined effects of protection in the lungs and upper respiratory tract could both reduce the risk of severe disease as well as of infection and transmission.

Competing Interest Statement

H.H. has filed a patent application on the vaccine approach described in this manuscript.

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Combinatorial mRNA vaccination enhances protection against SARS-CoV-2 delta variant
Renee L. Hajnik, Jessica A. Plante, Yuejin Liang, Mohamad-Gabriel Alameh, Jinyi Tang, Chaojie Zhong, Awadalkareem Adam, Dionna Scharton, Grace H. Rafael, Yang Liu, Nicholas C. Hazell, Jiaren Sun, Lynn Soong, Pei-Yong Shi, Tian Wang, Jie Sun, Drew Weissman, Scott C. Weaver, Kenneth S. Plante, Haitao Hu
bioRxiv 2021.12.08.471664; doi: https://doi.org/10.1101/2021.12.08.471664
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Combinatorial mRNA vaccination enhances protection against SARS-CoV-2 delta variant
Renee L. Hajnik, Jessica A. Plante, Yuejin Liang, Mohamad-Gabriel Alameh, Jinyi Tang, Chaojie Zhong, Awadalkareem Adam, Dionna Scharton, Grace H. Rafael, Yang Liu, Nicholas C. Hazell, Jiaren Sun, Lynn Soong, Pei-Yong Shi, Tian Wang, Jie Sun, Drew Weissman, Scott C. Weaver, Kenneth S. Plante, Haitao Hu
bioRxiv 2021.12.08.471664; doi: https://doi.org/10.1101/2021.12.08.471664

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