Abstract
BACKGROUND: Influenza virus remains a threat to human health, but gaps remain in our knowledge of the humoral correlates of protection against influenza virus A/H3N2, limiting our ability to generate effective, broadly protective vaccines. The role of antibodies against the hemagglutinin (HA) stalk, a highly conserved but immunologically subdominant region, has not been established for influenza virus A/H3N2. METHODS: Household transmission studies were conducted in Managua, Nicaragua, across 3 influenza seasons. Household contacts were tested for influenza virus infection using reverse-transcription polymerase chain reaction. We compared preexisting antibody levels against full-length HA, HA stalk, and neuraminidase (NA) measured by enzyme-linked immunosorbent assay, along with hemagglutination inhibition assay titers, between infected and uninfected participants. RESULTS: A total of 899 individuals participated in household activation, with 329 infections occurring. A 4-fold increase in initial HA stalk titers was independently associated with an 18% decrease in the risk of infection (adjusted odds ratio [aOR], 0.82 [95% confidence interval {CI}, .68-.98]; P = .04). In adults, anti-HA stalk antibodies were independently associated with protection (aOR, 0.72 [95% CI, .54-.95]; P = .02). However, in 0- to 14-year-olds, anti-NA antibodies (aOR, 0.67 [95% CI, .53-.85]; P < .01) were associated with protection against infection, but anti-HA stalk antibodies were not. CONCLUSIONS: The HA stalk is an independent correlate of protection against A/H3N2 infection, though this association is age dependent. Our results support the continued exploration of the HA stalk as a target for broadly protective influenza vaccines but suggest that the relative benefits may depend on age and influenza virus exposure history.