Development of effective SARS-CoV-2 vaccines to induce potent and long-lasting immunity and to provide cross-reactive protection against emerging variants remains a high priority. We recently reported a live-attenuated SARS-CoV-2 vaccine candidate with re-engineered viral transcription regulator sequences and deleted open-reading-frames (ORF) 3, 6, 7, and 8 (Δ3678) is highly attenuated in mice and hamsters and vaccination with Δ3678 SARS-CoV-2 protect hamsters from wild-type virus challenge and transmission. Here we report that a single dose intranasal vaccination with the Δ3678 SARS-CoV-2 live attenuated vaccine candidate induced strong SARS-CoV-2-specific systemic and mucosal humoral and T cell-mediated immune responses at one-month post-vaccination and day 4 post wild-type virus challenge, which are at similar levels to those infected with wild-type virus. High titer of SARS-CoV-2-specific IgG and IgA were detected in sera and BAL of vaccinated mice respectively. Furthermore, mice vaccinated with the Δ3678 vaccine showed markedly diminished viral loads and tissue inflammation in the lung following wild-type SARS-CoV-2 challenge. In summary, our results suggest that the Δ3678 SARS-CoV-2 live attenuated vaccine protects mice from wild-type SARS-CoV-2 infection by induction of protective mucosal and systemic cell-mediated and humoral responses.

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