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Influenza A viruses continuously evolve through antigenic drift and shift, reducing the effectiveness of vaccines that rely primarily on hemagglutinin (HA). Neuraminidase (NA), a surface antigen with greater sequence conservation, has gained attention as a complementary target for broader influenza vaccine design. Using computational analyses of 707 post-2009 A(H1N1)pdm09 NA sequences, we designed two NA-based mRNA vaccine constructs: NA-D1, derived from contemporary H1N1 isolates, and NA-E2, incorporating conserved features shared between H1N1 and H5N1. Mice received prime-boost immunization followed by homologous H1N1 or heterologous H5N1 challenge. Both NA-D1 and NA-E2 induced NA-specific antibody titers and conferred complete protection against homologous H1N1 infection. In contrast, protection against heterologous H5N1 was partial, consistent with lower predicted antigenic similarity between the vaccine constructs and H5N1 NA. Together, these findings demonstrate that NA-based mRNA vaccination can elicit robust homologous protection but offers limited heterologous protection efficacy. Our results support NA as an important complementary antigen for next-generation influenza vaccines and highlight the potential of computationally guided, dual-antigen (HA + NA) strategies to advance the development of broadly protective mRNA vaccines.
Kim et al. (Thu,) studied this question.