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An AAV-based, room-temperature-stable, single-dose COVID-19 vaccine provides durable immunogenicity and protection in non-human primates

Nerea Zabaleta, Wenlong Dai, Urja Bhatt, Cécile Hérate, Pauline Maisonnasse, Jessica A. Chichester, Julio Sanmiguel, Reynette Estelien, Kristofer T. Michalson, Cheikh Diop, Dawid Maciorowski, Nathalie Dereuddre Bosquet, Mariangela Cavarelli, Anne-Sophie Gallouët, Thibaut Naninck, Nidhal Kahlaoui, Julien Lemaitre, Wenbin Qi, Elissa Hudspeth, Allison Cucalon, Cecilia D. Dyer, M. Betina Pampena, James J. Knox, Regina C. LaRocque, Richelle C. Charles, Dan Li, Maya Kim, Abigail Sheridan, Nadia Storm, Rebecca I. Johnson, Jared Feldman, Blake M. Hauser, Vanessa Contreras, Romain Marlin, Raphaël Ho Tsong Fang, Catherine Chapon, Sylvie van der Werf, Eric Zinn, Aisling Ryan, Dione T. Kobayashi, Ruchi Chauhan, Marion McGlynn, Edward T. Ryan, Aaron G. Schmidt, Brian Price, Anna Honko, Anthony Griffiths, Sam Yaghmour, Robert Hodge, Michael R. Betts, Mason W. Freeman, James M. Wilson, Roger Le Grand, Luk H. Vandenberghe

Cell Host & Microbe, Volume 29, Issue 9, 2021, Pages 1437-1453

Abstract:

The SARS-CoV-2 pandemic has affected more than 185 million people worldwide resulting in over 4 million deaths. To contain the pandemic, there is a continued need for safe vaccines that provide durable protection at low and scalable doses and can be deployed easily. Here, AAVCOVID-1, an adeno-associated viral (AAV), spike-gene-based vaccine candidate demonstrates potent immunogenicity in mouse and non-human primates following a single injection and confers complete protection from SARS-CoV-2 challenge in macaques. The AAVCOVID vector has no relevant pre-existing immunity in humans and does not elicit cross-reactivity to common AAVs used in gene therapy. Vector genome persistence and expression wanes following injection. The single low-dose requirement, high-yield manufacturability, and 1-month stability for storage at room temperature may make this technology well suited to support effective immunization campaigns for emerging pathogens on a global scale.

In this study, the AAVCOVID candidates were produced at larger scale via standard AAV production processes by Novartis Gene Therapies, following their stablished protocol with only minimal modifications to adjust to the AAVrh32.33 technology. Briefly, AC1 and AC3 were produced via three plasmid transfection. After cell lysis and lysate clarification, tangential flow filtration (TFF) was conducted to achieve volume reduction. The TFF retentate was next enriched for AAV particles on a cation exchange chromatography column (BIA Separations, Sartorius). The eluate was concentrated, and buffer exchanged through an additional TFF step, before CsCl ultracentrifugation to separate genome containing versus empty AAV particles. Finally, formulation was achieved through TFF before bulk drug substance was filtered.

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