Engineered SARS-CoV-2 receptor binding domain improves manufacturability in yeast and immunogenicity in mice

Neil C. Dalvie, Sergio A. Rodriguez-Aponte, Brittany L. Hartwell, Lisa H. Tostanoski, Andrew M. Biedermann, Laura E. Crowell, Kawaljit Kaur, Ozan S. Kumru, Lauren Carter, Jingyou Yu, Aiquan Chang, Katherine McMahan, Thomas Courant, Celia Lebas, Ashley A. Lemnios, Kristen A. Rodrigues, Murillo Silva, Ryan S. Johnston, Christopher A. Naranjo, Mary Kate TraceyJoseph R. Brady, Charles A. Whittaker, Dongsoo Yun, Natalie Brunette, Jing Yang Wang, Carl Walkey, Brooke Fiala, Swagata Kar, Maciel Porto, Megan Lok, Hanne Andersen, Mark G. Lewis, Kerry R. Love, Danielle L. Camp, Judith Maxwell Silverman, Harry Kleanthous, Sangeeta B. Joshi, David B. Volkin, Patrice M. Dubois, Nicolas Collin, Neil P. King, Dan H. Barouch, Darrell J. Irvine, J. Christopher Love

Research output: Contribution to journalArticlepeer-review

25 Scopus citations

Abstract

Global containment of COVID-19 still requires accessible and affordable vaccines for low- and middle-income countries (LMICs). Recently approved vaccines provide needed interventions, albeit at prices that may limit their global access. Subunit vaccines based on recombinant proteins are suited for large-volume microbial manufacturing to yield billions of doses annually, minimizing their manufacturing cost. These types of vaccines are well-established, proven interventions with multiple safe and efficacious commercial examples. Many vaccine candidates of this type for SARS-CoV-2 rely on sequences containing the receptor-binding domain (RBD), which mediates viral entry to cells via ACE2. Here we report an engineered sequence variant of RBD that exhibits high-yield manufacturability, high-affinity binding to ACE2, and enhanced immunogenicity after a single dose in mice compared to the Wuhan-Hu-1 variant used in current vaccines. Antibodies raised against the engineered protein exhibited heterotypic binding to the RBD from two recently reported SARS-CoV-2 variants of concern (501Y.V1/V2). Presentation of the engineered RBD on a designed virus-like particle (VLP) also reduced weight loss in hamsters upon viral challenge.

Original languageEnglish (US)
Article numbere2106845118
JournalProceedings of the National Academy of Sciences of the United States of America
Volume118
Issue number38
DOIs
StatePublished - Sep 21 2021
Externally publishedYes

Bibliographical note

Funding Information:
We thank Prof. Ragahavan Varadarajan of the Indian Institute of Science for kindly providing the RBD sequence for SARS-CoV-2 Wuhan-Hu-1. We thank Laurent Pessaint, Dr. Adrienne Winn, Kamil Radzyminski, Andrew Faudree, Brittany Spence, Melissa Hamilton, and Natalie Figueroa Jones for advice and assistance with hamster studies. We thank Sumi Biswas of SpyBiotech for helpful discussions on SpyTag/SpyCatcher conjugations. We thank the Koch Institute's Robert A. Swanson (1969) Biotechnology Center for technical support. The following reagent was deposited by the Centers for Disease Control and Prevention and obtained through Biodefense and Emerging Infections Research Resources Repository, National Institute of Allergy and Infectious Diseases, NIH: SARS-Related Coronavirus 2, Isolate USAWA1/2020, NR-53780. This work was funded by the Bill & Melinda Gates Foundation (Investment IDs INV-002740, INV-006131, and OPP1156262). This study was also supported in part by the Koch Institute Support (core) Grant P30-CA14051 from the National Cancer Institute (NCI). L.H.T. is an NIH T32 postdoctoral fellow supported by the Multidisciplinary AIDS Training Program (Grant T32 AI007387). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NCI, the NIH, Bill & Melinda Gates Medical Research Institute, or the Bill & Melinda Gates Foundation.

Funding Information:
ACKNOWLEDGMENTS. We thank Prof. Ragahavan Varadarajan of the Indian Institute of Science for kindly providing the RBD sequence for SARS-CoV-2 Wuhan-Hu-1. We thank Laurent Pessaint, Dr. Adrienne Winn, Kamil Radzy-minski, Andrew Faudree, Brittany Spence, Melissa Hamilton, and Natalie Figueroa Jones for advice and assistance with hamster studies. We thank Sumi Biswas of SpyBiotech for helpful discussions on SpyTag/SpyCatcher conjugations. We thank the Koch Institute’s Robert A. Swanson (1969) Biotechnology Center for technical support. The following reagent was deposited by the Centers for Disease Control and Prevention and obtained through Biodefense and Emerging Infections Research Resources Repository, National Institute of Allergy and Infectious Diseases, NIH: SARS-Related Coronavirus 2, Isolate USA-WA1/2020, NR-53780. This work was funded by the Bill & Melinda Gates Foundation (Investment IDs INV-002740, INV-006131, and OPP1156262). This study was also supported in part by the Koch Institute Support (core) Grant P30-CA14051 from the National Cancer Institute (NCI). L.H.T. is an NIH T32 postdoctoral fellow supported by the Multidisciplinary AIDS Training Program (Grant T32 AI007387). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NCI, the NIH, Bill & Melinda Gates Medical Research Institute, or the Bill & Melinda Gates Foundation.

Publisher Copyright:
© 2021 National Academy of Sciences. All rights reserved.

Keywords

  • Manufacturability
  • Pichia pastoris
  • Protein vaccine
  • SARS-CoV-2

PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

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