Novel sialoglycan linkage for constructing adjuvant-protein conjugate as potent vaccine for COVID-19.

Self-adjuvanting protein vaccines have been proved to be highly immunogenic with efficient codelivery of adjuvant and antigen. Current protein vaccines with built-in adjuvants are all modified at the peptide backbone of antigen protein, which could not achieve minor epitope interference and adjuvant multivalency at the same time. Herein, we developed a new conjugate strategy to construct effective adjuvant-protein vaccine with adjuvant cluster effect and minimal epitope interference. The toll-like receptor 7 agonist (TLR7a) is covalently conjugated on the terminal sialoglycans of SARS-CoV-2-S1 protein, leading to intracellular release of the small-molecule stimulators with greatly reduced risks of systemic toxicity. The resulting TLR7a-S1 conjugate elicited strong activation of immune cells in vitro , and potent antibody and cellular responses with a significantly enhanced Th1-bias in vivo. TLR7a-S1-induced antibody also effectively cross-neutralized all variants of concern. This sialoglycoconjugation approach to construct protein conjugate vaccines will have more applications to combat SARS-CoV-2 and other diseases. A new conjugating strategy was developed to construct effective self-adjuvanting protein vaccines through sialoglycoconjugation. The resulting adjuvant-glycoprotein conjugate (TLR7a-S1) induced effective anti-virus humoral and cellular immunity. [Display omitted] • TLR7a-S1 conjugate vaccine was developed by a novel sialoglycoconjugation approach. • Sialic acids on the glycoprotein were used as linkage sites for conjugating adjuvants onto antigens. • The conjugated TLR7a reduces potential toxicities by impeding its diffusion to the whole body. • TLR7a-S1 elicited potent antibody and cellular responses with a significantly enhanced Th1-bias. [ABSTRACT FROM AUTHOR]