Generation of potent cellular and humoral immunity against SARS-CoV-2 antigens via conjugation to a polymeric glyco-adjuvant

Gray, Laura T.; Raczy, Michal M.; Briquez, Priscilla S.; Marchell, Tiffany M.; Alpar, Aaron T.; Wallace, Rachel P.; Volpatti, Lisa R.; Sasso, Maria Stella; Cao, Shijie; Nguyen, Mindy; Mansurov, Aslan; Budina, Erica; Watkins, Elyse A.; Solanki, Ani; Mitrousis, Nikolaos; Reda, Joseph W.; Yu, Shann S.; Tremain, Andrew C.; Wang, Ruyi; Nicolaescu, Vlad; Furlong, Kevin; Dvorkin, Steve; Manicassamy, Balaji; Randall, Glenn; Wilson, D. Scott; Kwissa, Marcin; Swartz, Melody A.; Hubbell, Jeffrey A.

The SARS-CoV-2 virus has caused an unprecedented global crisis, and curtailing its spread requires an effective vaccine which elicits a diverse and robust immune response. We have previously shown that vaccines made of a polymeric glyco-adjuvant conjugated to an antigen were effective in triggering such a response in other disease models and hypothesized that the technology could be adapted to create an effective vaccine against SARS-CoV-2. The core of the vaccine platform is the copolymer p(Man-TLR7), composed of monomers with pendant mannose or a toll-like receptor 7 (TLR7) agonist. Thus, p(Man-TLR7) is designed to target relevant antigen-presenting cells (APCs) via mannose-binding receptors and then activate TLR7 upon endocytosis. The p(Man-TLR7) construct is amenable to conjugation to protein antigens such as the Spike protein of SARS-CoV-2, yielding Spike-p(Man-TLR7). Here, we demonstrate Spike-p(Man-TLR7) vaccination elicits robust antigen-specific cellular and humoral responses in mice. In adult and elderly wild-type mice, vaccination with Spike-p(Man-TLR7) generates high and long-lasting titers of anti-Spike IgGs, with neutralizing titers exceeding levels in convalescent human serum. Interestingly, adsorbing Spike-p(Man-TLR7) to the depot-forming adjuvant alum amplified the broadly neutralizing humoral responses to levels matching those in mice vaccinated with formulations based off of clinically-approved adjuvants. Additionally, we observed an increase in germinal center B cells, antigen-specific antibody secreting cells, activated T follicular helper cells, and polyfunctional Th1-cytokine producing CD4(+) and CD8(+) T cells. We conclude that Spike-p(Man-TLR7) is an attractive, next-generation subunit vaccine candidate, capable of inducing durable and robust antibody and T cell responses.