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The Dual-Antigen Ad5 COVID-19 Vaccine Delivered as an Intranasal Plus Subcutaneous Prime Elicits Th1 Dominant T-Cell and Humoral Responses in CD-1 Mice

Adrian Rice, Mohit Verma, Annie Shin, Lise Zakin, Peter Sieling, Shiho Tanaka, Joseph Balint, Kyle Dinkins, Helty Adisetiyo, Brett Morimoto, Justin Taft, View ORCID ProfileRoosheel Patel, Sofija Buta, Marta Martin-Fernandez, Dusan Bogunovic, Patricia Spilman, Elizabeth Gabitzsch, Jeffrey T. Safrit, Shahrooz Rabizadeh, Kayvan Niazi, View ORCID ProfilePatrick Soon-Shiong
doi: https://doi.org/10.1101/2021.03.22.436476
Adrian Rice
1ImmunityBio, Inc., 9920 Jefferson Blvd, Culver City, CA 90232, USA
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Mohit Verma
1ImmunityBio, Inc., 9920 Jefferson Blvd, Culver City, CA 90232, USA
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Annie Shin
1ImmunityBio, Inc., 9920 Jefferson Blvd, Culver City, CA 90232, USA
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Lise Zakin
1ImmunityBio, Inc., 9920 Jefferson Blvd, Culver City, CA 90232, USA
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Peter Sieling
1ImmunityBio, Inc., 9920 Jefferson Blvd, Culver City, CA 90232, USA
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Shiho Tanaka
1ImmunityBio, Inc., 9920 Jefferson Blvd, Culver City, CA 90232, USA
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Joseph Balint
1ImmunityBio, Inc., 9920 Jefferson Blvd, Culver City, CA 90232, USA
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Kyle Dinkins
1ImmunityBio, Inc., 9920 Jefferson Blvd, Culver City, CA 90232, USA
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Helty Adisetiyo
1ImmunityBio, Inc., 9920 Jefferson Blvd, Culver City, CA 90232, USA
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Brett Morimoto
1ImmunityBio, Inc., 9920 Jefferson Blvd, Culver City, CA 90232, USA
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Justin Taft
2Center for Inborn Errors of Immunity, Icahn School of Medicine at Mount Sinai, 1 Gustave Lane, Levy Place, New York, NY 10029-5674, USA
3Department of Pediatrics, Icahn School of Medicine at Mount Sinai, 1 Gustave Lane, Levy Place, New York, NY 10029-5674, USA
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Roosheel Patel
2Center for Inborn Errors of Immunity, Icahn School of Medicine at Mount Sinai, 1 Gustave Lane, Levy Place, New York, NY 10029-5674, USA
3Department of Pediatrics, Icahn School of Medicine at Mount Sinai, 1 Gustave Lane, Levy Place, New York, NY 10029-5674, USA
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Sofija Buta
2Center for Inborn Errors of Immunity, Icahn School of Medicine at Mount Sinai, 1 Gustave Lane, Levy Place, New York, NY 10029-5674, USA
3Department of Pediatrics, Icahn School of Medicine at Mount Sinai, 1 Gustave Lane, Levy Place, New York, NY 10029-5674, USA
4Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave Lane, Levy Place, New York, NY 10029-5674, USA
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Marta Martin-Fernandez
2Center for Inborn Errors of Immunity, Icahn School of Medicine at Mount Sinai, 1 Gustave Lane, Levy Place, New York, NY 10029-5674, USA
3Department of Pediatrics, Icahn School of Medicine at Mount Sinai, 1 Gustave Lane, Levy Place, New York, NY 10029-5674, USA
4Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave Lane, Levy Place, New York, NY 10029-5674, USA
5Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave Lane, Levy Place, New York, NY 10029-5674, USA
6Department of Microbiology, Icahn School of Medicine at Mount Sinai, 1 Gustave Lane, Levy Place, New York, NY 10029-5674, USA
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Dusan Bogunovic
2Center for Inborn Errors of Immunity, Icahn School of Medicine at Mount Sinai, 1 Gustave Lane, Levy Place, New York, NY 10029-5674, USA
3Department of Pediatrics, Icahn School of Medicine at Mount Sinai, 1 Gustave Lane, Levy Place, New York, NY 10029-5674, USA
4Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave Lane, Levy Place, New York, NY 10029-5674, USA
5Mindich Child Health and Development Institute, Icahn School of Medicine at Mount Sinai, 1 Gustave Lane, Levy Place, New York, NY 10029-5674, USA
6Department of Microbiology, Icahn School of Medicine at Mount Sinai, 1 Gustave Lane, Levy Place, New York, NY 10029-5674, USA
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Patricia Spilman
1ImmunityBio, Inc., 9920 Jefferson Blvd, Culver City, CA 90232, USA
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Elizabeth Gabitzsch
1ImmunityBio, Inc., 9920 Jefferson Blvd, Culver City, CA 90232, USA
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Jeffrey T. Safrit
1ImmunityBio, Inc., 9920 Jefferson Blvd, Culver City, CA 90232, USA
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Shahrooz Rabizadeh
1ImmunityBio, Inc., 9920 Jefferson Blvd, Culver City, CA 90232, USA
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Kayvan Niazi
1ImmunityBio, Inc., 9920 Jefferson Blvd, Culver City, CA 90232, USA
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Patrick Soon-Shiong
1ImmunityBio, Inc., 9920 Jefferson Blvd, Culver City, CA 90232, USA
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  • ORCID record for Patrick Soon-Shiong
  • For correspondence: Patrick@NantWorks.com
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ABSTRACT

In response to the need for an efficacious, thermally-stable COVID-19 vaccine that can elicit both humoral and cell-mediated T-cell responses, we have developed a dual-antigen human adenovirus serotype 5 (hAd5) COVID-19 vaccine in formulations suitable for subcutaneous (SC), intranasal (IN), or oral delivery. The vaccine expresses both the SARS-CoV-2 spike (S) and nucleocapsid (N) proteins using an hAd5 platform with E1, E2b, and E3 sequences deleted (hAd5[E1-, E2b-, E3-]) that is effective even in the presence of hAd5 immunity. In the vaccine, S is modified (S-Fusion) for enhanced cell-surface display to elicit humoral responses and N is modified with an Enhanced T-cell Stimulation Domain (N-ETSD) to direct N to the endosomal/lysosomal pathway to increase MHC I and II presentation. Initial studies using subcutaneous (SC) prime and SC boost vaccination of CD-1 mice demonstrated that the hAd5 S-Fusion + N-ETSD vaccine elicits T-helper cell 1 (Th1) dominant T-cell and humoral responses to both S and N. We then compared SC to IN prime vaccination with either an SC or IN boost post-SC prime and an IN boost after IN prime. These studies reveal that IN prime/IN boost is as effective at generating Th1 dominant humoral responses to both S and N as the other combinations, but that the SC prime with either an IN or SC boost elicits greater T cell responses. In a third study to assess the power of the two routes of delivery when used together, we used a combined SC plus IN prime with or without a boost and found the combined prime alone to be as effective as the combined prime with either an SC or IN boost in generating both humoral and T-cell responses. The findings here in CD-1 mice demonstrate that combined SC and IN prime-only delivery has the potential to provide broad immunity – including mucosal immunity – against SARS-CoV-2 and supports further testing of this delivery approach in additional animal models and clinical trials.

Competing Interest Statement

All authors with an ImmunityBio affiliation have a role in the development of the vaccine described.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted March 23, 2021.
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The Dual-Antigen Ad5 COVID-19 Vaccine Delivered as an Intranasal Plus Subcutaneous Prime Elicits Th1 Dominant T-Cell and Humoral Responses in CD-1 Mice
Adrian Rice, Mohit Verma, Annie Shin, Lise Zakin, Peter Sieling, Shiho Tanaka, Joseph Balint, Kyle Dinkins, Helty Adisetiyo, Brett Morimoto, Justin Taft, Roosheel Patel, Sofija Buta, Marta Martin-Fernandez, Dusan Bogunovic, Patricia Spilman, Elizabeth Gabitzsch, Jeffrey T. Safrit, Shahrooz Rabizadeh, Kayvan Niazi, Patrick Soon-Shiong
bioRxiv 2021.03.22.436476; doi: https://doi.org/10.1101/2021.03.22.436476
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The Dual-Antigen Ad5 COVID-19 Vaccine Delivered as an Intranasal Plus Subcutaneous Prime Elicits Th1 Dominant T-Cell and Humoral Responses in CD-1 Mice
Adrian Rice, Mohit Verma, Annie Shin, Lise Zakin, Peter Sieling, Shiho Tanaka, Joseph Balint, Kyle Dinkins, Helty Adisetiyo, Brett Morimoto, Justin Taft, Roosheel Patel, Sofija Buta, Marta Martin-Fernandez, Dusan Bogunovic, Patricia Spilman, Elizabeth Gabitzsch, Jeffrey T. Safrit, Shahrooz Rabizadeh, Kayvan Niazi, Patrick Soon-Shiong
bioRxiv 2021.03.22.436476; doi: https://doi.org/10.1101/2021.03.22.436476

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