Protective Effects of Influenza B Neuraminidase Antibodies Against Symptomatic Influenza Virus Infection

Background Influenza vaccines are designed to induce hemagglutinin-inhibiting (HAI) antibodies rather than neuraminidase-inhibiting (NAI) antibodies; therefore, NAI antibodies' protective effects need further investigation. Neuraminidase-inhibiting antibodies' protective effects, independent of HAI antibodies, have been demonstrated for influenza A viruses, but not influenza B viruses (IBVs).Methods Employing H6NB reassortant virus targets, we evaluated NAI antibodies' protective effects against IBV in sera from a prospective influenza vaccine effectiveness study among healthcare personnel (HCP) in Israel. Antibody titers against B/Brisbane/60/2008 and B/Phuket/3073/2013 were quantified by HAI and NAI assays. Matched NAI and HAI antibody titers from baseline and postvaccination sera were analyzed for the 2017-2018 influenza season.Results Laboratory-confirmed IBV infection was recorded in 64/262 HCP and influenza vaccination in 187/262 HCP. Vaccination did not consistently elicit rising NAI titers against vaccine strain B/Brisbane, with a geometric mean fold rise of 1.1 (95% CI: .9-1.3). However, comparing baseline NAI titers, geometric mean titer ratios were 1.50 (95% CI: 1.0-2.1) times higher against B/Brisbane and 2.5 (95% CI: 1.7-3.6) times higher against circulating B/Phuket in vaccinated versus unvaccinated HCP. Each 2-fold rise in NAI antibody titers reduced the hazard of symptomatic infection by 42% (95% CI: 36%-48%) against B/Phuket and 23% (95% CI: 13%-33%) against B/Brisbane, adjusting for HAI titers.Conclusions Neuraminidase-inhibiting antibodies were a strong correlate of protection against symptomatic IBV infection, with protective effects independent of those from HAI antibodies. These findings suggest that the use and standardization of neuraminidase content in influenza vaccines could provide broader protection against influenza.In a prospective healthcare personnel cohort during the 2017-2018 influenza season, neuraminidase-inhibiting antibodies demonstrated protective effects, independent of hemagglutinin-inducing antibodies, against symptomatic influenza B virus infection. Research supports standardizing neuraminidase content in influenza vaccines may increase vaccine-induced protection against influenza.