Hemagglutinin Stalk-Specific Fc-Mediated Functions Are Associated with Protection Against Influenza Illness after Seasonal Influenza Vaccination

Background: Future vaccine candidates aim to elicit antibodies against the conserved hemagglutinin stalk domain. Understanding the protective mechanism of these antibodies, which mediate broad neutralization and Fc-mediated functions, following seasonal vaccination is critical. Methods: Plasma samples were obtained from pregnant women with or without HIV-1 enrolled in a randomised trial (138 trivalent inactivated vaccine [TIV] and 145 placebo recipients). Twenty-three influenza cases were confirmed within 6 months postpartum. We measured H1 stalk-specific antibody-dependent cellular phagocytosis (ADCP), complement deposition (ADCD) and cellular cytotoxicity (ADCC) at enrolment and 1-month postvaccination. Results: Lower H1 stalk-specific ADCP and ADCD activity was detected for participants with confirmed influenza compared with individuals without illness 1-month postvaccination. Pre-existing ADCP scores ≥250 reduced the odds of A/H1N1 infection (odds ratio [OR], 0.11; P =. 01) with an 83% likelihood of risk reduction. Following TIV, ADCD scores of ≥25 and ≥15 significantly reduced the odds against A/H1N1 (OR, 0.10; P =. 01) and non-group 1 (OR, 0.06; P =. 0004) influenza virus infections, respectively. These ADCD scores were associated with >84% likelihood of risk reduction. Conclusions: Overall, H1 stalk-specific Fc effector function correlates with protection against influenza illness following influenza vaccination during pregnancy. These findings provide insight into the protective mechanisms of hemagglutinin stalk antibodies.