Neuraminidase delivered as an APC-targeted DNA vaccine induces protective antibodies against influenza

Conventional influenza vaccines focus on hemagglutinin (HA). However, antibody responses to neuraminidase (NA) have been established as an independent correlate of protection. Here, we introduced the ectodomain of NA into DNA vaccines that, as translated dimeric vaccine proteins, target antigen-presenting cells (APCs). The targeting was mediated by an single-chain variable fragment specific for major histocompatibility complex (MHC) class II, which is genetically linked to NA via a dimerization motif. A single immunization of BALB/c mice elicited strong and long-lasting NA-specific antibodies that inhibited NA enzymatic activity and reduced viral replication. Vaccine-induced NA immunity completely protected against a homologous influenza virus and out-competed NA immunity induced by a conventional inactivated virus vaccine. The protection was mainly mediated by antibodies, although NAspecific T cells also contributed. APC-targeting and antigen bivalency were crucial for vaccine efficacy. The APC-targeted vaccine was potent at low doses of DNA, indicating a dosesparing effect. Similar results were obtained with NA vaccines that targeted different surface molecules on dendritic cells. Interestingly, the protective efficacy of NA as antigen compared favorably with HA and therefore ought to receive more attention in influenza vaccine research.

Automated summary

Conventional influenza vaccines primarily target hemagglutinin (HA), but this study demonstrates the importance of neuraminidase (NA) as an independent correlate of protection. The introduction of NA ectodomain into DNA vaccines, which specifically target antigen-presenting cells (APCs), resulted in the production of strong and long-lasting NA-specific antibodies in mice. These antibodies inhibited NA enzymatic activity, reduced viral replication, and provided complete protection against a homologous influenza virus. The study also found that NA immunity induced by this vaccine outperformed NA immunity induced by a traditional inactivated virus vaccine. Overall, this research highlights the potential of NA as a valuable antigen in influenza vaccine development.