The comparison of two SARS-CoV-2 spike protein antigens in TLR-adjuvanted subunit vaccines

Abstract Adjuvanted subunit vaccines offer improved safety and efficacy over whole inactivated or live attenuated vaccines by incorporating recombinant proteins with highly selective innate immune activators. Selection of an antigen in subunit vaccines can alter immune responses, making it an important consideration. For severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the spike (S)-protein aids in receptor recognition and membrane fusion. Previous studies of SARS-CoV-2 and the closely related SARS-CoV-1 define the receptor binding domain (RBD) portion of the S-protein as the target of most neutralizing antibodies (nAbs). Here the recombinant full spike trimer (FST) and the isolated recombinant RBD are compared as antigens in an adjuvanted subunit vaccine. Induction of Th1-biased CD4+ and CD8+ cellular responses are believed to be important for durable antiviral immunity. Therefore, we used synthetic agonists of the toll-like receptor (TLR)4 or TLR7/8 as vaccine adjuvants for their ability to promote Th1 cellular immunity. We found that a TLR4 agonist was effective at adjuvanting both RBD and FST, while a TLR7/8 ligand provided superior adaptive immune responses with FST. In addition, increased induction of nAbs were demonstrated when vaccinating mice with FST. Thus, we find that early selection and optimization of adjuvant and antigen combinations is critical for the induction of humoral (including nABs) and cell-mediated immunity to SARS-CoV-2 antigens.