The genetic diversity of influenza A virus is a major obstacle that makes vaccine effectiveness variable and unpredictable. Objectives: Current vaccines induce strain-specific immunity that oftentimes fail to protect against divergent strains. Our previous research explored synthetic centralized consensus (CC) vaccines to minimize immunogen-strain divergence and focused on the viral glycoprotein hemagglutinin. Methods: Recently, emerging evidence of neuraminidase (NA)-mediated immunity has shifted vaccine strategies, prompting our development of a CC NA type 1 (N1CC) vaccine based on ancestral N1 sequences and delivered using a human adenovirus type 5 vector Results: The N1CC vaccine elicited antibody responses with NA inhibition activity and induced NA-specific T-cell responses. In lethal influenza challenge models, N1CC fully protected mice from death against human, swine, and avian influenza H1N1 and H5N1 strains. Conclusions: These findings support NA as a protective immunogen and demonstrate the power and efficacy of a centralized consensus NA design.