Identification of an Optimized Receptor-Binding Domain Subunit Vaccine against SARS-CoV-2
Hong Yu, Liam J. Worrall, Thorsten Berger, Martin Petric, Bryan H. Lin, Marija Vuckovic, Craig S. Robb, Quan Le, Calem Kenward, Chuanbin Dai, Andrew Wakeham, Shaofeng Liu, Bryan Snow, Chantal Tobin, Patrick Budylowski, Furkan Guvenc, Annick You-Ten, Jillian Haight, Jennifer Silvester, Rashim Pal Singh, Sang Kyun Ahn, Azmiri Sultana, Betty Poon, Jessica Lam, Natasha Christie-Holmes, Mario Ostrowski, Scott D. Gray-Owen, Shawn Kubli, Tak Mak, Natalie C. J. Strynadka, Robert C. Brunham- Immunology
- Immunology and Allergy
Abstract
Current vaccine efforts to combat SARS-CoV-2 are focused on the whole spike protein administered as mRNA, viral vector, or protein subunit. However, the SARS-CoV-2 receptor-binding domain (RBD) is the immunodominant portion of the spike protein, accounting for 90% of serum neutralizing activity. In this study, we constructed several versions of RBD and together with aluminum hydroxide or DDA (dimethyldioctadecylammonium bromide)/TDB (d-(+)-trehalose 6,6′-dibehenate) adjuvant evaluated immunogenicity in mice. We generated human angiotensin-converting enzyme 2 knock-in mice to evaluate vaccine efficacy in vivo following viral challenge. We found that 1) subdomain (SD)1 was essential for the RBD to elicit maximal immunogenicity; 2) RBDSD1 produced in mammalian HEK cells elicited better immunogenicity than did protein produced in insect or yeast cells; 3) RBDSD1 combined with the CD4 Th1 adjuvant DDA/TDB produced higher neutralizing Ab responses and stronger CD4 T cell responses than did aluminum hydroxide; 4) addition of monomeric human Fc receptor to RBDSD1 (RBDSD1Fc) significantly enhanced immunogenicity and neutralizing Ab titers; 5) the Beta version of RBDSD1Fc provided a broad range of cross-neutralization to multiple antigenic variants of concern, including Omicron; and 6) the Beta version of RBDSD1Fc with DDA/TDB provided complete protection against virus challenge in the knock-in mouse model. Thus, we have identified an optimized RBD-based subunit vaccine suitable for clinical trials.