Hemagglutinin- and neuraminidase-targeting antibody responses after receipt of egg-based inactivated or recombinant influenza vaccines among adults aged 18–64 years

INTRODUCTION: Antibodies to hemagglutinin (HA) and neuraminidase (NA) are independent surrogates of protection from influenza yet only HA content is standardized in vaccines. Egg-based inactivated influenza vaccines (IIV) contain HA and NA from egg-adapted viruses. Recombinant influenza vaccines (RIV) solely include HA without egg-adapted modifications. Humoral responses to both HA and NA can provide valuable insights into vaccine effectiveness. METHODS: In a randomized trial comparing 2022-2023 quadrivalent RIV and standard dose (SD) IIV among adults aged 18-64 years, a subgroup of participants had sera collected pre-vaccination, 1-, and 6-months post-vaccination. Neutralization titers were determined for both cell- and egg-based vaccine reference viruses and representative circulating viruses using single cycle replication-based IRINA. NA-inhibiting responses to N1 and N2 were evaluated using ELLA; ELISA was used to measure N2-binding response. RESULTS: Anti-HA responses to cell-based type A and B/Yamagata viruses were two-fold higher among RIV versus SD-IIV recipients; the difference in response to cell-based B/Victoria virus was not statistically significant. Compared to responses to cell-based vaccine viruses, post-vaccination sera reacted comparably to circulating viruses, except to A(H1N1)pdm09 (2-6-fold reduction). Compared to HI antibodies, neutralizing antibodies waned faster to most vaccine viruses. SD-IIV recipients showed no rise in NA-inhibiting antibodies to mammalian cell-grown viruses. Conversely, there was a ≥ 4-fold rise in ELLA GMTs to N1 (13%) and N2 (37%) antigens that were prepared in eggs, despite no changes in NA sequences. Baseline egg/cell titer ratios were 1.3 for N1 and 4.2 for N2 antigens, and they increased by approximately 2-fold after vaccination in SD-IIV but not RIV recipients. CONCLUSION: HA-targeting antibody responses were more robust in RIV-recipients. SD-IIV did not elicit meaningful NA-inhibiting antibody responses to viruses grown in mammalian cells but did boost antibodies to egg-grown viruses. Sourcing NA antigens from cell-grown viruses should be considered when assessing humoral responses to vaccination.