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Single-dose respiratory mucosal delivery of next-generation viral-vectored COVID-19 vaccine provides robust protection against both ancestral and variant strains of SARS-CoV-2

Sam Afkhami, Michael R. D’Agostino, Ali Zhang, Hannah D. Stacey, Art Marzok, Alisha Kang, Ramandeep Singh, Jegarubee Bavananthasivam, Gluke Ye, Xiangqian Luo, Fuan Wang, Jann C. Ang, Anna Zganiacz, Uma Sankar, Natallia Kazhdan, Joshua F. E. Koenig, Allyssa Phelps, Manel Jordana, Yonghong Wan, Karen L. Mossman, Mangalakumari Jeyanathan, Amy Gillgrass, Maria Fe C. Medina, Fiona Smaill, Brian D. Lichty, Matthew S. Miller, Zhou Xing
doi: https://doi.org/10.1101/2021.07.16.452721
Sam Afkhami
1McMaster Immunology Research Centre, M. G. DeGroote Institute for Infectious Disease Research & Department of Medicine, McMaster University, Hamilton, ON, L8S 4K1, Canada
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Michael R. D’Agostino
3McMaster Immunology Research Centre, M. G. DeGroote Institute for Infectious Disease Research & Department of Biochemistry & Biomedical Sciences, McMaster University, Hamilton, ON, L8S 4K1, Canada
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Ali Zhang
3McMaster Immunology Research Centre, M. G. DeGroote Institute for Infectious Disease Research & Department of Biochemistry & Biomedical Sciences, McMaster University, Hamilton, ON, L8S 4K1, Canada
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Hannah D. Stacey
3McMaster Immunology Research Centre, M. G. DeGroote Institute for Infectious Disease Research & Department of Biochemistry & Biomedical Sciences, McMaster University, Hamilton, ON, L8S 4K1, Canada
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Art Marzok
3McMaster Immunology Research Centre, M. G. DeGroote Institute for Infectious Disease Research & Department of Biochemistry & Biomedical Sciences, McMaster University, Hamilton, ON, L8S 4K1, Canada
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Alisha Kang
1McMaster Immunology Research Centre, M. G. DeGroote Institute for Infectious Disease Research & Department of Medicine, McMaster University, Hamilton, ON, L8S 4K1, Canada
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Ramandeep Singh
1McMaster Immunology Research Centre, M. G. DeGroote Institute for Infectious Disease Research & Department of Medicine, McMaster University, Hamilton, ON, L8S 4K1, Canada
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Jegarubee Bavananthasivam
1McMaster Immunology Research Centre, M. G. DeGroote Institute for Infectious Disease Research & Department of Medicine, McMaster University, Hamilton, ON, L8S 4K1, Canada
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Gluke Ye
1McMaster Immunology Research Centre, M. G. DeGroote Institute for Infectious Disease Research & Department of Medicine, McMaster University, Hamilton, ON, L8S 4K1, Canada
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Xiangqian Luo
1McMaster Immunology Research Centre, M. G. DeGroote Institute for Infectious Disease Research & Department of Medicine, McMaster University, Hamilton, ON, L8S 4K1, Canada
4Department of Pediatric Otolaryngology, Shenzhen Hospital, Southern Medical University, Shenzhen, China
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Fuan Wang
1McMaster Immunology Research Centre, M. G. DeGroote Institute for Infectious Disease Research & Department of Medicine, McMaster University, Hamilton, ON, L8S 4K1, Canada
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Jann C. Ang
3McMaster Immunology Research Centre, M. G. DeGroote Institute for Infectious Disease Research & Department of Biochemistry & Biomedical Sciences, McMaster University, Hamilton, ON, L8S 4K1, Canada
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Anna Zganiacz
1McMaster Immunology Research Centre, M. G. DeGroote Institute for Infectious Disease Research & Department of Medicine, McMaster University, Hamilton, ON, L8S 4K1, Canada
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Uma Sankar
1McMaster Immunology Research Centre, M. G. DeGroote Institute for Infectious Disease Research & Department of Medicine, McMaster University, Hamilton, ON, L8S 4K1, Canada
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Natallia Kazhdan
1McMaster Immunology Research Centre, M. G. DeGroote Institute for Infectious Disease Research & Department of Medicine, McMaster University, Hamilton, ON, L8S 4K1, Canada
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Joshua F. E. Koenig
1McMaster Immunology Research Centre, M. G. DeGroote Institute for Infectious Disease Research & Department of Medicine, McMaster University, Hamilton, ON, L8S 4K1, Canada
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Allyssa Phelps
1McMaster Immunology Research Centre, M. G. DeGroote Institute for Infectious Disease Research & Department of Medicine, McMaster University, Hamilton, ON, L8S 4K1, Canada
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Manel Jordana
1McMaster Immunology Research Centre, M. G. DeGroote Institute for Infectious Disease Research & Department of Medicine, McMaster University, Hamilton, ON, L8S 4K1, Canada
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Yonghong Wan
1McMaster Immunology Research Centre, M. G. DeGroote Institute for Infectious Disease Research & Department of Medicine, McMaster University, Hamilton, ON, L8S 4K1, Canada
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Karen L. Mossman
1McMaster Immunology Research Centre, M. G. DeGroote Institute for Infectious Disease Research & Department of Medicine, McMaster University, Hamilton, ON, L8S 4K1, Canada
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Mangalakumari Jeyanathan
1McMaster Immunology Research Centre, M. G. DeGroote Institute for Infectious Disease Research & Department of Medicine, McMaster University, Hamilton, ON, L8S 4K1, Canada
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Amy Gillgrass
1McMaster Immunology Research Centre, M. G. DeGroote Institute for Infectious Disease Research & Department of Medicine, McMaster University, Hamilton, ON, L8S 4K1, Canada
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Maria Fe C. Medina
1McMaster Immunology Research Centre, M. G. DeGroote Institute for Infectious Disease Research & Department of Medicine, McMaster University, Hamilton, ON, L8S 4K1, Canada
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Fiona Smaill
5Department of Pathology and Molecular Medicine & M. G. DeGroote Institute for Infectious Disease Research, McMaster University, Hamilton, ON, L8S 4K1, Canada
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Brian D. Lichty
1McMaster Immunology Research Centre, M. G. DeGroote Institute for Infectious Disease Research & Department of Medicine, McMaster University, Hamilton, ON, L8S 4K1, Canada
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  • For correspondence: xingz@mcmaster.ca mmiller@mcmaster.ca lichtyb@mcmaster.ca
Matthew S. Miller
3McMaster Immunology Research Centre, M. G. DeGroote Institute for Infectious Disease Research & Department of Biochemistry & Biomedical Sciences, McMaster University, Hamilton, ON, L8S 4K1, Canada
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  • For correspondence: xingz@mcmaster.ca mmiller@mcmaster.ca lichtyb@mcmaster.ca
Zhou Xing
1McMaster Immunology Research Centre, M. G. DeGroote Institute for Infectious Disease Research & Department of Medicine, McMaster University, Hamilton, ON, L8S 4K1, Canada
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  • For correspondence: xingz@mcmaster.ca mmiller@mcmaster.ca lichtyb@mcmaster.ca
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Summary

The emerging SARS-CoV-2 variants of concern (VOC) increasingly threaten the effectiveness of current first-generation COVID-19 vaccines that are administered intramuscularly and are designed to only target the spike protein. There is thus a pressing need to develop next-generation vaccine strategies to provide more broad and long-lasting protection. By using adenoviral vectors (Ad) of human and chimpanzee origin, we developed Ad-vectored trivalent COVID-19 vaccines expressing Spike-1, Nucleocapsid and RdRp antigens and evaluated them following single-dose intramuscular or intranasal immunization in murine models. We show that respiratory mucosal immunization, particularly with chimpanzee Ad-vectored vaccine, is superior to intramuscular immunization in induction of the three-arm immunity, consisting of local and systemic antibody responses, mucosal tissue-resident memory T cells, and mucosal trained innate immunity. We further show that single-dose intranasal immunization provides robust protection against not only the ancestral strain of SARS-CoV-2, but also two emerging VOC, B.1.1.7 and B.1.351. Our findings indicate that single-dose respiratory mucosal delivery of an Ad-vectored multivalent vaccine represents an effective next-generation COVID-19 vaccine strategy against current and future VOC. This strategy has great potential to be used not only to boost first-generation vaccine-induced immunity but also to expand the breadth of protective T cell immunity at the respiratory mucosa.

Competing Interest Statement

The authors have declared no competing interest.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted July 19, 2021.
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Single-dose respiratory mucosal delivery of next-generation viral-vectored COVID-19 vaccine provides robust protection against both ancestral and variant strains of SARS-CoV-2
Sam Afkhami, Michael R. D’Agostino, Ali Zhang, Hannah D. Stacey, Art Marzok, Alisha Kang, Ramandeep Singh, Jegarubee Bavananthasivam, Gluke Ye, Xiangqian Luo, Fuan Wang, Jann C. Ang, Anna Zganiacz, Uma Sankar, Natallia Kazhdan, Joshua F. E. Koenig, Allyssa Phelps, Manel Jordana, Yonghong Wan, Karen L. Mossman, Mangalakumari Jeyanathan, Amy Gillgrass, Maria Fe C. Medina, Fiona Smaill, Brian D. Lichty, Matthew S. Miller, Zhou Xing
bioRxiv 2021.07.16.452721; doi: https://doi.org/10.1101/2021.07.16.452721
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Single-dose respiratory mucosal delivery of next-generation viral-vectored COVID-19 vaccine provides robust protection against both ancestral and variant strains of SARS-CoV-2
Sam Afkhami, Michael R. D’Agostino, Ali Zhang, Hannah D. Stacey, Art Marzok, Alisha Kang, Ramandeep Singh, Jegarubee Bavananthasivam, Gluke Ye, Xiangqian Luo, Fuan Wang, Jann C. Ang, Anna Zganiacz, Uma Sankar, Natallia Kazhdan, Joshua F. E. Koenig, Allyssa Phelps, Manel Jordana, Yonghong Wan, Karen L. Mossman, Mangalakumari Jeyanathan, Amy Gillgrass, Maria Fe C. Medina, Fiona Smaill, Brian D. Lichty, Matthew S. Miller, Zhou Xing
bioRxiv 2021.07.16.452721; doi: https://doi.org/10.1101/2021.07.16.452721

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