A rationally designed combined intranasal adjuvant drives robust and broad humoral, cellular, and mucosal immune responses to SARS-CoV-2

Abstract Multiple FDA-approved SARS-CoV-2 vaccines have provided excellent protection against severe disease. Despite this, immunity can wane relatively fast, particularly in the elderly and novel viral variants capable of evading infection- and vaccination-induced immunity continue to emerge. Furthermore, while these parenteral vaccines have provided substantial protection, they have been less effective in inducing mucosal immune responses which are critical for effectively blocking viral transmission in vaccinated individuals. As mucosal immune responses are most effectively induced through infection or mucosal immunization, we have developed an intranasal, rationally designed adjuvant integrating a nanoemulsion (NE) that activates TLRs and NLRP3 with an RNA agonist of RIG-I (IVT DI). Through activating this array of receptors, we have shown that the NE/IVT adjuvant better recapitulates the innate immune activation events that occur during natural viral infection, subsequently leading to more tailored and effective downstream adaptive immune responses. The combination adjuvant with various spike protein antigens elicited robust protective humoral, mucosal, and cellular responses to SARS-CoV-2 in mice, with markedly enhanced T H1-biased cellular responses and high virus-neutralizing antibody titers towards both homologous and antigenically distant drift variants of SARS-CoV-2. These results highlight the potential of this adjuvant to improve the immune profile of a variety of SARS-CoV-2 vaccine candidates for use mucosally. This research was supported by R01-AI160706 to P.W. and M.S, and in part by R01-DK130425 to M.S.