Mucosal subunit vaccines against SARS CoV-2

With the emergence of SARS-CoV-2 variants with mutations in the Spike protein, there remains an urgent need for vaccines that are both effective against variants and that generate long-lived mucosal immunity. Generation of durable cell-mediated and humoral immunity is critical for optimal naturally occurring and vaccine-induced protection against respiratory pathogens, including SARS-CoV-2, and includes IFN-γ and IL-17 producing tissue- resident memory T (TRM) cells, T follicular helper (TFH) cells, germinal center (GC) and memory B cells, that contribute to the production of pathogen-specific neutralizing antibodies. Most currently approved vaccines are adjuvanted with alum, which is a strong adjuvant that elicits TH2 skewed cellular and humoral responses, associated with short-lived immunity to intracellular respiratory pathogens. Experimental adjuvants that generate TH1 and TH17 driven systemic and mucosal responses, provide effective and long-lived protection against infection. Bordetella Colonization Factor A (BcfA) is an adjuvant that elicits strong TH1 and TH17 responses and has the unique ability to attenuate the detrimental TH2 responses primed by alum. Polyfunctional IL-21 and IFN-γ (TFH1 cells) or IL-21 and IL-17 (TFH17 cells) cells are important for generation of effective antibodies against viral respiratory pathogens. The TH1/TH17 skewing properties of BcfA may promote the differentiation and function of these specialized TFH cell populations. Mucosal vaccination is a more effective means of generating tissue-resident memory that is not generated by parenterally administered alum-adjuvanted vaccines. A prime-pull regimen (systemic priming and intranasal booster) generates mucosal responses to vaccines containing TH1/TH17 skewing adjuvants and provides superior protection. We will test the overarching hypothesis that a BcfA/alum-adjuvanted subunit SARS CoV-2 vaccine containing S, M and N proteins, delivered via a heterologous prime-pull immunization regimen will reduce SARS-CoV-2 infection of the mouse respiratory tract and elicit long-lived systemic and mucosal TH1/TH17 driven immune responses.