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. Clinical Trials Registration. NCT01306669 and NCT01306682 (ClinicalTrials.gov).