The persistent emergence of COVID-19 variants and recurrent waves of infection worldwide underscores the urgent need for vaccines that effectively reduce viral transmission and prevent infections. Current intramuscular (IM) COVID-19 vaccines inadequately protect the upper respiratory mucosa. In response, we have developed a nonadjuvanted, interferon-armed SARS-CoV-2 fusion protein vaccine with IM priming and intranasal (IN) boost sequential immunization. Our study showed that this sequential vaccination strategy of the IM+IN significantly enhances both upper respiratory and systemic antiviral immunity in a mouse model, characterized by the rapid increase in systemic and mucosal T and B cell responses, particularly the mucosal IgA antibody response. The IN boost triggered a swift secondary immune response, rapidly inducing antigen-specific IgA+ B cells. Further BCR-seq analysis indicated that these IgA+ B cells primarily arise through direct class switching from pre-existing IgG+ B cells in draining lymph nodes. Notably, our clinical studies reveal that the IN boost after IM vaccination elicited a robust systemic IgA antibody response in humans, as measured in serum. Thus, our cytokine-armed protein vaccine presents a promising strategy for inducing rapid and potent mucosal protection against respiratory viral infections.