Efficacy and immunogenicity of high-dose influenza vaccine in older adults by age, comorbidities, and frailty

Background: A randomized trial demonstrated that a high-dose inactivated influenza vaccine (IIV-HD) was 24.2% more efficacious than a standard-dose vaccine (IIV-SD) against laboratory-confirmed influenza illness in adults ≥65 years. To evaluate the consistency of IIV-HD benefits, supplemental analyses explored efficacy and immunogenicity by baseline characteristics of special interest. Methods: Double-blind, randomized, active-controlled, multicenter trial. Adults ≥65 years were randomized 1:1 to receive IIV-HD or IIV-SD and followed for 6-8 months postvaccination for the occurrence of influenza. One third of participants were randomly selected to provide sera for measurement of hemagglutination inhibition antibody (HAI) titers. Efficacy (IIV-HD vs. IIV-SD) against laboratory-confirmed, protocol-defined influenza-like illness (PD-ILI) and HAI geometric mean titer (GMT) ratios (IIV-HD/IIV-SD) were evaluated by age, and number of high-risk comorbid and frailty conditions. Results: Efficacy (95% confidence intervals) of IIV-HD relative to IIV-SD against laboratory-confirmed PD-ILI was 19.7% (0.4%; 35.4%) for participants 65-74 years, 32.4% (8.1%; 50.6%) for those ≥75 years, 22.1% (3.9%; 37.0%) for participants with ≥1 high-risk comorbidity, 23.6% (-3.2%; 43.6%) for those with ≥2 high-risk comorbidities, 27.5% (0.4%; 47.4%) for persons with 1 frailty condition, 23.9% (-9.0%; 47.2%) for those with 2 frailty conditions, and 16.0% (-16.3%; 39.4%) for those with ≥3 frailty conditions. There was no evidence of vaccine efficacy heterogeneity within age, comorbidity, and frailty strata (. P-values 0.351, 0.875, and 0.838, respectively). HAI GMT ratios were significantly higher among IIV-HD recipients for all strains and across all subgroups. Conclusions: Estimates of relative efficacy consistently favored IIV-HD over IIV-SD. There was no significant evidence that baseline age, comorbidity, or frailty modified the efficacy of IIV-HD relative to IIV-SD. IIV-HD significantly improved HAI responses for all strains and in all subgroups. IIV-HD is likely to provide benefits beyond IIV-SD for adults ≥65 years, irrespective of age and presence of comorbid or frailty conditions.