Balancing the influenza neuraminidase and hemagglutinin responses by exchanging the vaccine virus backbone

Virions are a common antigen source for many viral vaccines. One limitation to using virions is that the antigen abundance is determined by the content of each protein in the virus. This caveat especially applies to viral-based influenza vaccines where the low abundance of the neuraminidase (NA) surface antigen remains a bottleneck for improving the NA antibody response. Here, we used the WHO recommended H1N1 antigens (2019-2020 season) in a systematic analysis to demonstrate that the NA to hemagglutinin (HA) ratio in virions can be improved by exchanging the viral backbone internal genes, thereby preserving the antigens. The purified inactivated virions with higher NA content show a more spherical morphology, a different balance between the HA receptor binding and NA receptor release functions, and induce a better NA inhibitory antibody response in mice. These results indicate that influenza viruses support a range of ratios for a given NA and HA pair that can be utilized to produce viral-based influenza vaccines with increased NA content which can elicit more balanced inhibitory antibody responses to NA and HA.