Induction of Th1/Th2-Balanced Protection Against SARS-CoV-2 Through Mucosal Delivery of An Adenovirus Vaccine Expressing an Engineered Spike Protein

Abstract

We developed a series of recombinant human type 5 adenoviruses that express the full-length or membrane-truncated spike protein (S) of SARS-CoV-2 (AdCoV2-S or AdCoV2-SdTM, respectively). We tested the immunoprotective efficacy against SARS-CoV-2 via intranasal (i.n.) or subcutaneous (s.c.) immunization in a rodent model following two-dose immunizations. Mucosal delivery of adenovirus (Ad) vaccines could induce anti-SARS-CoV-2 IgG and IgA in the serum and in the mucosal, respectively as indicated by vaginal wash (vw). Serum anti-SARS-CoV-2 IgG but not IgA was induced in the vw by s.c. injection of AdCoV2-S. Intranasal administration of AdCoV2-S was able to induce higher anti-SARS-CoV-2 antibody levels than s.c. injection. Immunization with AdCoV2-SdTM induced a lower antibody response than AdCoV2-S. In addition, the degree of neutralization of clinically isolated SARS-CoV-2 in the serum correlated with the above anti-SARS-CoV-2 responses; the most potent neutralizing activity was observed in the AdCoV2-S i.n. group, and less viral neutralizing activity was observed in response to AdCoV2-S s.c. and AdCoV2dTM i.n. Novelty, S-specific IgG1 which represented Th2-mediated humoral response was dominantly induced in Ad i.n.-immunized serum in contrast to more IgG2a which represented Th1-mediated cellular response found in Ad s.c.-immunized serum. The activation of S-specific IFN-ɣ and IL-4 in Th1 and Th2 cells, respectively, was observed in the AdCoV2s i.n. and s.c. groups, indicating the Th1/Th2-balenced immunity was activated. During the protection study, two doses of i.n. AdCoV2-S or i.n. AdCoV2-SdTM significantly prevented body weight loss and reduced pulmonary viral loads in hamsters. A significant reduction in inflammation in the lungs was observed in AdCoV-S-immunized hamsters following a SARS-CoV-2 challenge. It correlated to Th1 cytokine but no inflammatory cytokines secretions found in i.n. AdCoV-immunized respiratory tract. These results indicate that intranasal delivery of AdCoV2-S vaccines is safe and potent at preventing SARS-CoV-2 infections.