Mucosal vaccination with long-form TSLP induces migratory cDC1-mediated adaptive immunity against SARS-CoV-2 infection.

A combination of vaccination strategies will potentially be required for effective control of the virus pandemic. We report that mice intranasally immunized with commercial severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) subunit vaccines enriched with the human thymic stromal lymphopoietin (TSLP) variant, long-form TSLP (lfTSLP), but not the short-isoform TSLP (sfTSLP), induced robust antigen-specific systemic and mucosal antibody production. The adjuvant-enhancing activity of lfTSLP in mice requires functional TSLP receptor signals in migratory type 1 conventional dendritic cells (cDC1s). Furthermore, lfTSLP acts on migratory cDC1s to enhance T follicular helper (Tfh) cell and germinal center (GC) B cell responses. Intranasal vaccination with lfTSLP elicits long-lasting immunogenicity and protection against the challenge of wild-type SARS-CoV-2 and the B.1.617.2 variant in mice. Our study provides insights into the adjuvant role of lfTSLP, which is critical in enhancing migratory cDC1-mediated GC responses to improve vaccine efficacy. IMPORTANCE: Adjuvants are indispensable components of subunit vaccines, and the development of adjuvants capable of inducing powerful systemic and mucosal immune responses is critical for enhancing the efficacy of viral vaccines. This study reveals that the human long-form thymic stromal lymphopoietin (lfTSLP) induces antigen-specific systemic IgG and mucosal IgA antibody production with sustained immunogenicity. Mechanistically, lfTSLP enhances germinal center reactions by preferentially activating migratory type 1 conventional dendritic cells (cDC1s). These findings uncover a previously unrecognized mechanism underlying the adjuvant activity of lfTSLP, which enhances vaccine-induced adaptive immunity and confers protection against SARS-CoV-2 infection. These findings indicate that the application of lfTSLP as an adjuvant should be encouraged in the rational design and development of viral vaccines.