The Durability of Antibody Responses of Two Doses of High-Dose Relative to Two Doses of Standard-Dose Inactivated Influenza Vaccine in Pediatric Hematopoietic Cell Transplant Recipients: A Multi-Center Randomized Controlled Trial

Abstract

Abstract Background Our previous study established a 2-dose regimen of high-dose trivalent influenza vaccine (HD-TIV) to be immunogenically superior compared to a 2-dose regimen of standard-dose quadrivalent influenza vaccine (SD-QIV) in pediatric allogeneic hematopoietic cell transplant (HCT) recipients. However, the durability of immunogenicity and the role of time post-HCT at immunization as an effect modifier are unknown. Methods This phase II, multi-center, double-blinded, randomized controlled trial compared HD-TIV to SD-QIV in children 3–17 years old who were 3–35 months post-allogeneic HCT, with each formulation administered twice, 28–42 days apart. Hemagglutination inhibition (HAI) titers were measured at baseline, 28–42 days following each dose, and 138–222 days after the second dose. Using linear mixed effects models, we estimated adjusted geometric mean HAI titer ratios (aGMR: HD-TIV/SD-QIV) to influenza antigens. Early and late periods were defined as 3–5 and 6–35 months post-HCT, respectively. Results During 3 influenza seasons (2016–2019), 170 participants were randomized to receive HD-TIV (n = 85) or SD-QIV (n = 85). HAI titers maintained significant elevations above baseline for both vaccine formulations, although the relative immunogenic benefit of HD-TIV to SD-QIV waned during the study. A 2-dose series of HD-TIV administered late post-HCT was associated with higher GMTs compared to the early post-HCT period (late group: A/H1N1 aGMR = 2.16, 95% confidence interval [CI] = [1.14–4.08]; A/H3N2 aGMR = 3.20, 95% CI = [1.60–6.39]; B/Victoria aGMR = 1.91, 95% CI = [1.01–3.60]; early group: A/H1N1 aGMR = 1.03, 95% CI = [0.59–1.80]; A/H3N2 aGMR = 1.23, 95% CI = [0.68–2.25]; B/Victoria aGMR = 1.06, 95% CI = [0.56–2.03]). Conclusions Two doses of HD-TIV were more immunogenic than SD-QIV, especially when administered ≥6 months post-HCT. Both groups maintained higher titers compared to baseline throughout the season. Clinical Trials Registration NCT02860039.