In this preprint, Hassan et al. show that local immunization with the ChAd-SARS-CoV-2-S vaccine, based on a chimpanzee adenovirus, confers sterilizing protection in mice engineered to express human ACE2. Intramuscular delivery of ChAd-SARS-CoV-2-S protected against lung pathology but did not clear the infection of the upper respiratory tract after SARS-CoV-2 challenge. However, when administered intranasally, it induced local neutralizing antibody and T cell responses that provided superior protection to both the upper and lower respiratory tract, with no signs of viral replication 8 days post viral challenge. The presence of tissue-resident memory T cells in the lung suggested long-lasting protection. This work illustrates the importance of the delivery route to vaccine effectivity.