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Vaccination with SARS-CoV-2 Spike Protein and AS03 Adjuvant Induces Rapid Anamnestic Antibodies in the Lung and Protects Against Virus Challenge in Nonhuman Primates

Joseph R. Francica, Barbara J. Flynn, Kathryn E. Foulds, Amy T. Noe, Anne P. Werner, Ian N. Moore, Matthew Gagne, Timothy S. Johnston, Courtney Tucker, Rachel L. Davis, Britta Flach, Sarah O’Connell, Shayne F. Andrew, Evan Lamb, Dillon R. Flebbe, Saule T. Nurmukhambetova, Mitzi M. Donaldson, John-Paul M. Todd, Alex Lee Zhu, Caroline Atyeo, Stephanie Fischinger, Matthew J Gorman, Sally Shin, Venkata Viswanadh Edara, Katharine Floyd, Lilin Lai, Alida Tylor, Elizabeth McCarthy, Valerie Lecouturier, Sophie Ruiz, Catherine Berry, Timothy Tibbitts, Hanne Andersen, Anthony Cook, Alan Dodson, Laurent Pessaint, Alex Van Ry, Marguerite Koutsoukos, Cindy Gutzeit, I-Ting Teng, Tongqing Zhou, Dapeng Li, Barton F. Haynes, Peter D. Kwong, Adrian McDermott, Mark G. Lewis, Tong Ming Fu, Roman Chicz, Robbert van der Most, Kizzmekia S. Corbett, Mehul S. Suthar, Galit Alter, Mario Roederer, Nancy J. Sullivan, Daniel C. Douek, Barney S. Graham, Danilo Casimiro, Robert A. Seder
doi: https://doi.org/10.1101/2021.03.02.433390
Joseph R. Francica
1Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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Barbara J. Flynn
1Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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Kathryn E. Foulds
1Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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Amy T. Noe
1Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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Anne P. Werner
1Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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Ian N. Moore
1Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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Matthew Gagne
1Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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Timothy S. Johnston
1Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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Courtney Tucker
1Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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Rachel L. Davis
1Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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Britta Flach
1Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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Sarah O’Connell
1Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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Shayne F. Andrew
1Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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Evan Lamb
1Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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Dillon R. Flebbe
1Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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Saule T. Nurmukhambetova
1Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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Mitzi M. Donaldson
1Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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John-Paul M. Todd
1Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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Alex Lee Zhu
2Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA
3PhD program in Immunology and Virology, University of Duisburg-Essen, Essen, Germany
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Caroline Atyeo
2Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA
4PhD program in Virology, Division of Medical Sciences, Harvard University, Boston, MA, USA
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Stephanie Fischinger
2Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA
3PhD program in Immunology and Virology, University of Duisburg-Essen, Essen, Germany
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Matthew J Gorman
2Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA
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Sally Shin
2Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA
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Venkata Viswanadh Edara
5Centers for Childhood Infections and Vaccines; Children’s Healthcare of Atlanta and Emory University, Department of Pediatrics, Atlanta, GA, 30329, USA
6Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30329, USA
7Yerkes National Primate Research Center, Atlanta, GA 30329, USA
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Katharine Floyd
5Centers for Childhood Infections and Vaccines; Children’s Healthcare of Atlanta and Emory University, Department of Pediatrics, Atlanta, GA, 30329, USA
6Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30329, USA
7Yerkes National Primate Research Center, Atlanta, GA 30329, USA
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Lilin Lai
5Centers for Childhood Infections and Vaccines; Children’s Healthcare of Atlanta and Emory University, Department of Pediatrics, Atlanta, GA, 30329, USA
6Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30329, USA
7Yerkes National Primate Research Center, Atlanta, GA 30329, USA
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Alida Tylor
1Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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Elizabeth McCarthy
1Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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Valerie Lecouturier
8Sanofi Pasteur, Marcy l’Etoile, France
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Sophie Ruiz
8Sanofi Pasteur, Marcy l’Etoile, France
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Catherine Berry
8Sanofi Pasteur, Marcy l’Etoile, France
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Timothy Tibbitts
9Sanofi Pasteur, 38 Sidney Street, Cambridge, MA 02139, USA
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Hanne Andersen
10Bioqual, Inc., Rockville, MD, USA
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Anthony Cook
10Bioqual, Inc., Rockville, MD, USA
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Alan Dodson
10Bioqual, Inc., Rockville, MD, USA
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Laurent Pessaint
10Bioqual, Inc., Rockville, MD, USA
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Alex Van Ry
10Bioqual, Inc., Rockville, MD, USA
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Marguerite Koutsoukos
11GSK, Wavre, Belgium
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Cindy Gutzeit
12GSK, Rixensart, Belgium
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I-Ting Teng
1Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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Tongqing Zhou
1Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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Dapeng Li
13Duke Human Vaccine Institute, Duke University, Durham, NC 27708, USA
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Barton F. Haynes
13Duke Human Vaccine Institute, Duke University, Durham, NC 27708, USA
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Peter D. Kwong
1Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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Adrian McDermott
1Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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Mark G. Lewis
10Bioqual, Inc., Rockville, MD, USA
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Tong Ming Fu
9Sanofi Pasteur, 38 Sidney Street, Cambridge, MA 02139, USA
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Roman Chicz
9Sanofi Pasteur, 38 Sidney Street, Cambridge, MA 02139, USA
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Robbert van der Most
12GSK, Rixensart, Belgium
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Kizzmekia S. Corbett
1Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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Mehul S. Suthar
5Centers for Childhood Infections and Vaccines; Children’s Healthcare of Atlanta and Emory University, Department of Pediatrics, Atlanta, GA, 30329, USA
6Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30329, USA
7Yerkes National Primate Research Center, Atlanta, GA 30329, USA
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Galit Alter
2Ragon Institute of MGH, MIT, and Harvard, Cambridge, MA 02139, USA
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Mario Roederer
1Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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Nancy J. Sullivan
1Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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Daniel C. Douek
1Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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Barney S. Graham
1Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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Danilo Casimiro
9Sanofi Pasteur, 38 Sidney Street, Cambridge, MA 02139, USA
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Robert A. Seder
1Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA
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  • For correspondence: rseder@mail.nih.gov
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Abstract

Adjuvanted soluble protein vaccines have been used extensively in humans for protection against various viral infections based on their robust induction of antibody responses. Here, soluble prefusion-stabilized spike trimers (preS dTM) from the severe acute respiratory syndrome coronavirus (SARS-CoV-2) were formulated with the adjuvant AS03 and administered twice to nonhuman primates (NHP). Binding and functional neutralization assays and systems serology revealed that NHP developed AS03-dependent multi-functional humoral responses that targeted multiple spike domains and bound to a variety of antibody FC receptors mediating effector functions in vitro. Pseudovirus and live virus neutralizing IC50 titers were on average greater than 1000 and significantly higher than a panel of human convalescent sera. NHP were challenged intranasally and intratracheally with a high dose (3×106 PFU) of SARS-CoV-2 (USA-WA1/2020 isolate). Two days post-challenge, vaccinated NHP showed rapid control of viral replication in both the upper and lower airways. Notably, vaccinated NHP also had increased spike-specific IgG antibody responses in the lung as early as 2 days post challenge. Moreover, vaccine-induced IgG mediated protection from SARS-CoV-2 challenge following passive transfer to hamsters. These data show that antibodies induced by the AS03-adjuvanted preS dTM vaccine are sufficient to mediate protection against SARS-CoV-2 and support the evaluation of this vaccine in human clinical trials.

Competing Interest Statement

All authors have declared the following interests: VL, TB, CB, SR, TMF, DC, RC are Sanofi Pasteur employees and may hold stock. MK, RvdM, and CG are employees of the GSK group of companies and report ownership of GSK shares.

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under a CC0 license.
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Vaccination with SARS-CoV-2 Spike Protein and AS03 Adjuvant Induces Rapid Anamnestic Antibodies in the Lung and Protects Against Virus Challenge in Nonhuman Primates
Joseph R. Francica, Barbara J. Flynn, Kathryn E. Foulds, Amy T. Noe, Anne P. Werner, Ian N. Moore, Matthew Gagne, Timothy S. Johnston, Courtney Tucker, Rachel L. Davis, Britta Flach, Sarah O’Connell, Shayne F. Andrew, Evan Lamb, Dillon R. Flebbe, Saule T. Nurmukhambetova, Mitzi M. Donaldson, John-Paul M. Todd, Alex Lee Zhu, Caroline Atyeo, Stephanie Fischinger, Matthew J Gorman, Sally Shin, Venkata Viswanadh Edara, Katharine Floyd, Lilin Lai, Alida Tylor, Elizabeth McCarthy, Valerie Lecouturier, Sophie Ruiz, Catherine Berry, Timothy Tibbitts, Hanne Andersen, Anthony Cook, Alan Dodson, Laurent Pessaint, Alex Van Ry, Marguerite Koutsoukos, Cindy Gutzeit, I-Ting Teng, Tongqing Zhou, Dapeng Li, Barton F. Haynes, Peter D. Kwong, Adrian McDermott, Mark G. Lewis, Tong Ming Fu, Roman Chicz, Robbert van der Most, Kizzmekia S. Corbett, Mehul S. Suthar, Galit Alter, Mario Roederer, Nancy J. Sullivan, Daniel C. Douek, Barney S. Graham, Danilo Casimiro, Robert A. Seder
bioRxiv 2021.03.02.433390; doi: https://doi.org/10.1101/2021.03.02.433390
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Vaccination with SARS-CoV-2 Spike Protein and AS03 Adjuvant Induces Rapid Anamnestic Antibodies in the Lung and Protects Against Virus Challenge in Nonhuman Primates
Joseph R. Francica, Barbara J. Flynn, Kathryn E. Foulds, Amy T. Noe, Anne P. Werner, Ian N. Moore, Matthew Gagne, Timothy S. Johnston, Courtney Tucker, Rachel L. Davis, Britta Flach, Sarah O’Connell, Shayne F. Andrew, Evan Lamb, Dillon R. Flebbe, Saule T. Nurmukhambetova, Mitzi M. Donaldson, John-Paul M. Todd, Alex Lee Zhu, Caroline Atyeo, Stephanie Fischinger, Matthew J Gorman, Sally Shin, Venkata Viswanadh Edara, Katharine Floyd, Lilin Lai, Alida Tylor, Elizabeth McCarthy, Valerie Lecouturier, Sophie Ruiz, Catherine Berry, Timothy Tibbitts, Hanne Andersen, Anthony Cook, Alan Dodson, Laurent Pessaint, Alex Van Ry, Marguerite Koutsoukos, Cindy Gutzeit, I-Ting Teng, Tongqing Zhou, Dapeng Li, Barton F. Haynes, Peter D. Kwong, Adrian McDermott, Mark G. Lewis, Tong Ming Fu, Roman Chicz, Robbert van der Most, Kizzmekia S. Corbett, Mehul S. Suthar, Galit Alter, Mario Roederer, Nancy J. Sullivan, Daniel C. Douek, Barney S. Graham, Danilo Casimiro, Robert A. Seder
bioRxiv 2021.03.02.433390; doi: https://doi.org/10.1101/2021.03.02.433390

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