ChAdOx1‐S adenoviral vector vaccine applied intranasally elicits superior mucosal immunity compared to the intramuscular route of vaccination

COVID-19 vaccines prevent severe forms of the disease, but do not warrant complete pro-tection against breakthrough infections. This could be due to suboptimal mucosal immu-nity at the site of virus entry, given that all currently approved vaccines are administeredvia the intramuscular route. In this study, we assessed humoral and cellular immuneresponses in BALB/c mice after intranasal and intramuscular immunization with adenovi-ral vector ChAdOx1-S expressing full- length Spike protein of SARS-CoV-2. We showed thatboth routes of vaccination induced a potent IgG antibody response, as well as robust neu- tralizing capacity, but intranasal vaccination elicited a superior IgA antibody titer in thesera and in the respiratory mucosa. Bronchoalveolar lavage from intranasally immunizedmice efficiently neutralized SARS-CoV-2, which has not been the case in intramuscularlyimmunized group. Moreover, substantially higher percentages of epitope- specific CD8 Tcells exhibiting a tissue resident phenotype were found in the lungs of intranasally immu-nized animals. Finally, both intranasal and intramuscular vaccination with ChAdOx1- Sefficiently protected the mice after the challenge with recombinant herpesvirus express-ing the Spike protein. Our results demonstrate that intranasal application of adenoviralvector ChAdOx1-S induces superior mucosal immunity and therefore could be a promis-ing strategy for putting the COVID-19 pandemic under control.