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A self-amplifying mRNA COVID-19 vaccine drives potent and broad immune responses at low doses that protects non-human primates against SARS-CoV-2

Amy R. Rappaport, Sue-Jean Hong, Ciaran D. Scallan, Leonid Gitlin, Arvin Akoopie, Gregory R. Boucher, Milana Egorova, J. Aaron Espinosa, Mario Fidanza, Melissa A. Kachura, Annie Shen, Gloria Sivko, Anne Van Abbema, Robert L. Veres, Karin Jooss
doi: https://doi.org/10.1101/2021.11.08.467773
Amy R. Rappaport
1Gritstone bio, Inc., Emeryville, CA
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Sue-Jean Hong
1Gritstone bio, Inc., Emeryville, CA
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Ciaran D. Scallan
1Gritstone bio, Inc., Emeryville, CA
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Leonid Gitlin
1Gritstone bio, Inc., Emeryville, CA
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Arvin Akoopie
1Gritstone bio, Inc., Emeryville, CA
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Gregory R. Boucher
1Gritstone bio, Inc., Emeryville, CA
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Milana Egorova
1Gritstone bio, Inc., Emeryville, CA
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J. Aaron Espinosa
1Gritstone bio, Inc., Emeryville, CA
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Mario Fidanza
1Gritstone bio, Inc., Emeryville, CA
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Melissa A. Kachura
1Gritstone bio, Inc., Emeryville, CA
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Annie Shen
1Gritstone bio, Inc., Emeryville, CA
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Gloria Sivko
2Battelle Biomedical Research Center, West Jefferson, OH
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Anne Van Abbema
1Gritstone bio, Inc., Emeryville, CA
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Robert L. Veres
1Gritstone bio, Inc., Emeryville, CA
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Karin Jooss
1Gritstone bio, Inc., Emeryville, CA
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  • For correspondence: kjooss@gritstone.com
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Abstract

The coronavirus disease 2019 (COVID-19) pandemic continues to spread globally, highlighting the urgent need for safe and effective vaccines that could be rapidly mobilized to immunize large populations. We report the preclinical development of a self-amplifying mRNA (SAM) vaccine encoding a prefusion stabilized severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike glycoprotein and demonstrate potent cellular and humoral immune responses at low doses in mice and rhesus macaques. The homologous prime-boost vaccination regimen of SAM at 3, 10 and 30 μg induced potent neutralizing antibody titers in rhesus macaques following two SAM vaccinations at all dose levels, with the 10 μg dose generating geometric mean titers (GMT) 48-fold greater than the GMT of a panel of SARS-CoV-2 convalescent human sera. Spike-specific T cell responses were observed at all dose levels. SAM vaccination provided protective efficacy against SARS-CoV-2 challenge as both a homologous prime-boost and as a single boost following ChAd prime, demonstrating reduction of viral replication in both the upper and lower airways. Protection was most effective with a SAM prime-boost vaccination regimen at 10 and 30 μg and with a ChAd/SAM heterologous prime-boost regimen. The SAM vaccine is currently being evaluated in clinical trials as both a homologous prime-boost regimen at low doses and as a boost following heterologous prime.

Competing Interest Statement

ARR, SJH, CDS, LG, AA, GRB, ME, JAE, MF, MAK, AS, AVA, RLV and KJ are stockholders and either current or previous employees at Gritstone bio, Inc. and may be listed as co-inventors on various pending patent applications related to the vaccine platform presented in this study.

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 November 09, 2021.
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A self-amplifying mRNA COVID-19 vaccine drives potent and broad immune responses at low doses that protects non-human primates against SARS-CoV-2
Amy R. Rappaport, Sue-Jean Hong, Ciaran D. Scallan, Leonid Gitlin, Arvin Akoopie, Gregory R. Boucher, Milana Egorova, J. Aaron Espinosa, Mario Fidanza, Melissa A. Kachura, Annie Shen, Gloria Sivko, Anne Van Abbema, Robert L. Veres, Karin Jooss
bioRxiv 2021.11.08.467773; doi: https://doi.org/10.1101/2021.11.08.467773
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A self-amplifying mRNA COVID-19 vaccine drives potent and broad immune responses at low doses that protects non-human primates against SARS-CoV-2
Amy R. Rappaport, Sue-Jean Hong, Ciaran D. Scallan, Leonid Gitlin, Arvin Akoopie, Gregory R. Boucher, Milana Egorova, J. Aaron Espinosa, Mario Fidanza, Melissa A. Kachura, Annie Shen, Gloria Sivko, Anne Van Abbema, Robert L. Veres, Karin Jooss
bioRxiv 2021.11.08.467773; doi: https://doi.org/10.1101/2021.11.08.467773

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