Immunogenicity and safety of high-dose versus standard-dose quadrivalent inactivated influenza vaccine in patients living with HIV: a randomized controlled trial

Influenza remains a major cause of morbidity in people living with HIV (PLWH), and despite recommendations for annual vaccination with the standard-dose (SD) quadrivalent inactivated influenza vaccine (IIV4), immune responses are often suboptimal in this population. To address this gap, we conducted a randomized, single-blinded, controlled trial to compare the immunogenicity and safety of the high-dose (HD) IIV4 (60 μg, Efluelda, Sanofi) with the SD IIV4 (15 μg, Vaxigrip Tetra, Sanofi). Vaccinations were administered between August and December 2023, and seroprotection (SP) was defined as a hemagglutination-inhibition antibody titer ≥1:40 at one month post-vaccination. Adverse events (AEs) were actively monitored. Of 110 participants enrolled, 103 were included in the per-protocol analysis (52 HD; 51 SD). The mean age was 49.6 years, 63.1% were male, and the median CD4 count was 555 cells/mm 3 . Most participants were virologically suppressed (93.2%), and more than half were receiving integrase inhibitor–based antiretroviral regimens (57.3%). Overall, 50.5% of participants achieved SP to all four vaccine strains. The HD group demonstrated significantly higher overall SP compared with the SD group (61.5% vs. 39.2%, p = 0.02). In strain-specific analyses, a significantly higher seroprotection rate was observed for A/H3N2 (76.9% vs. 52.9%, p = 0.01). In multivariable logistic regression, receipt of HD IIV4 (OR 2.7, 95% CI 1.9–6.1, p = 0.02) and female sex (OR 2.5, 95% CI 1.1–5.9, p = 0.04) were independently associated with SP against all strains. AEs were reported in 55.8% of HD and 58.8% of SD recipients ( p = 0.75), most commonly local reactions, with no severe vaccine-related events observed. In conclusion, HD IIV4 enhanced immunogenicity against the vaccine A/H3N2 strain compared with SD IIV4, without increasing the risk of adverse events compared to SD IIV4. These findings suggest that HD IIV4 may enhance immunogenicity in PLWH and warrant further investigation in studies evaluating clinical effectiveness (TCTR20230501002).