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

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 118; no. 38; pp. 1 - 9
• Main Authors: Dalvie, Neil C., Rodriguez-Aponte, Sergio A., Hartwell, Brittany L., Tostanoski, Lisa H., Biedermann, Andrew M., Crowell, Laura E., Kaur, Kawaljit, Kumru, Ozan S., Carter, Lauren, Yu, Jingyou, Chang, Aiquan, McMahan, Katherine, Courant, Thomas, Lebas, Celia, Lemnios, Ashley A., Rodrigues, Kristen A., Silva, Murillo, Johnston, Ryan S., Naranjo, Christopher A., Tracey, Mary Kate, Brady, Joseph R., Whittaker, Charles A., Yun, Dongsoo, Brunette, Natalie, Wang, Jing Yang, Walkey, Carl, Fiala, Brooke, Kar, Swagata, Porto, Maciel, Lok, Megan, Andersen, Hanne, Lewis, Mark G., Love, Kerry R., Camp, Danielle L., Silverman, Judith Maxwell, Kleanthous, Harry, Joshi, Sangeeta B., Volkin, David B., Dubois, Patrice M., Collin, Nicolas, King, Neil P., Barouch, Dan H., Irvine, Darrell J., Love, J. Christopher
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 21.09.2021
• Subjects: ACE2; Angiotensin-converting enzyme 2; Animals; Antibodies; Antibodies, Viral - immunology; Antigens, Viral; Binding; Binding Sites; Biological Sciences; COVID-19; COVID-19 - prevention & control; COVID-19 - virology; COVID-19 Vaccines - economics; COVID-19 Vaccines - immunology; Domains; Hamsters; Humans; Immunogenicity; Immunogenicity, Vaccine; Manufacturability; Mice; Mice, Inbred BALB C; Microorganisms; Models, Molecular; Physical Sciences; Production costs; Protein Binding; Protein Conformation; Protein Engineering - methods; Proteins; Receptors; Saccharomycetales - metabolism; SARS-CoV-2 - metabolism; Severe acute respiratory syndrome coronavirus 2; Spike Glycoprotein, Coronavirus - genetics; Vaccines; Vaccines, Subunit; Viral diseases; Virus-like particles; Weight loss; Weight reduction; Yeast; SARS-CoV-2; Pichia pastoris; manufacturability; protein vaccine
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.2106845118

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.