Influenza vaccine responses differ between young children previously exposed to influenza antigens via infection versus vaccination

BACKGROUND: Annual influenza vaccination is recommended for young children with limited understanding of how this may imprint influenza immunity. We conducted a pilot study to examine whether early life exposure to influenza through vaccination versus infection affects subsequent vaccination responses. METHODS: Nineteen children aged 6-60 months were enrolled at two Australian hospitals during 2019-2021. Plasma was collected before and after vaccination for up to three successive years to measure antibody titres by hemagglutinination (HA) and neuraminidase (NA) inhibiting (HI, NI) assays and ELISA. Medical records and seropositivity (HI titre ≥40) at enrolment were used to classify seven children as having prior vaccination(s) and eight as having prior influenza A(H3N2) infection. Others had mixed, no, or unclear prior exposures. Post-vaccination antibody titres and seroconversion (HI fold-rise ≥4) were compared across the two main prior exposure groups. RESULTS: Here we show that post-vaccination HI and NI antibody titres and titre-rises against A(H3N2) are far higher among children classified as having had prior A(H3N2) infection compared to prior vaccination; 8/8 versus 3/7 seroconverted, respectively. A(H3N2) HA-stem binding antibody titres are modest but rise more after vaccination among children classified as having had prior A(H3N2) infection. A(H1N1)-reactive antibody responses are not significantly different between groups. CONCLUSIONS: These results suggest that for priming subsequent vaccine antibody responses against A(H3N2), infection may be superior to vaccination.