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Clinical Trial
. 2023 Dec 15;77(12):1723-1732.
doi: 10.1093/cid/ciad458.

Comparison of Two High-Dose Versus Two Standard-Dose Influenza Vaccines in Adult Allogeneic Hematopoietic Cell Transplant Recipients

Lora D Thomas  1 , Einas Batarseh  2 , Lubna Hamdan  2 , Zaid Haddadin  2 , Daniel Dulek  2 , Spyros Kalams  2 , Laura S Stewart  3 , Anna L Stahl  2 , Herdi Rahman  2 , Justin Z Amarin  2 , Haya Hayek  2 , Michael Ison  4 , Edgar T Overton  5 , Steven A Pergam  6 , Andrew J Spieker  7 , Natasha B Halasa  2 ; Adult HCT Flu Study
Collaborators, Affiliations
Clinical Trial

Comparison of Two High-Dose Versus Two Standard-Dose Influenza Vaccines in Adult Allogeneic Hematopoietic Cell Transplant Recipients

Lora D Thomas et al. Clin Infect Dis. .

Abstract

Background: Adult hematopoietic cell transplant (HCT) recipients are at high risk for influenza-related morbidity and mortality and have suboptimal influenza vaccine immune responses compared to healthy adults, particularly within 2 years of transplant.

Methods: This phase II, double-blind, multicenter randomized controlled trial compared 2 doses of high-dose trivalent (HD-TIV) to 2 doses of standard-dose quadrivalent (SD-QIV) influenza vaccine administered 1 month apart in adults 3-23 months post-allogeneic HCT. Hemagglutinin antibody inhibition (HAI) titers were measured at baseline, 4 weeks following each vaccine dose, and approximately 7 months post-second vaccination. Injection-site and systemic reactions were assessed for 7 days post-vaccination. The primary immunogenicity comparison was geometric mean HAI titer (GMT) at visit 3 (4 weeks after the second dose); we used linear mixed models to estimate adjusted GMT ratios (aGMRs) comparing HD-TIV/SD-QIV for each antigen.

Results: We randomized 124 adults; 64 received SD-QIV and 60 received HD-TIV. Following the second vaccination, HD-TIV was associated with higher GMTs compared to SD-QIV for A/H3N2 (aGMR = 2.09; 95% confidence interval [CI]: [1.19, 3.68]) and B/Victoria (aGMR = 1.61; 95% CI: [1.00, 2.58]). The increase was not statistically significant for A/H1N1 (aGMR = 1.16; 95% CI: [0.67, 2.02]). There was a trend to more injection-site reactions for HD-TIV after the second vaccination compared to SD-QIV (50% vs 33%; adjusted odds ratio [aOR] = 4.53; 95% CI: [0.71, 28.9]), whereas systemic reactions were similar between groups with both injections.

Conclusions: Adult allogeneic HCT recipients who received 2 doses of HD-TIV produced higher HAI antibody responses for A/H3N2 and B/Victoria compared with 2 doses of SD-QIV, with comparable injection-site or systemic reactions.

Keywords: hematopoietic cell transplant; influenza vaccine.

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Conflict of interest statement

Potential conflicts of interest. M. I. has received research support, paid to Northwestern University, from GlaxoSmithKline and reports grant number UL1TR001422, which supported the author and the research capacity used for this project; payment for consultation from Adagio, ADMA Biologics, Adamis, AlloVir, Atea, Cidara, Genetech, Invivyd, Inc, Roche, Janssen, Shionogi, Takeda, Telaris, and Viracor Eurofins; royalties from UpToDate, and is a paid member of an independent data monitoring committee for Adamis, AlloVir, Merck, Sequiris/CSL, Takeda and Talaris. He also reports a role as Chair of ISIRV AVG and as Editor-in-Chief of Transplant Infectious Disease. All conflicts were ended effective 4 December 2022 except for UpToDate. S. A. P. receives research support from Global Life Technologies, Inc, and he participates in clinical trials with F2G, Symbio, and Cidarra. He also reports that Sanofi Pasteur supplied vaccines and hemagglutination titers for this study. N. B. H. has formerly received grant funding from SANOFI and Quidel. She currently receives funding from Merck for an investigator-initiated grant. D. D. reports that Eurofins-Viracor provided assay performance for investigator-initiated research on cytomegalovirus (no payments made); consulting fees paid to author from Horizon Pharmaceuticals. S. K. reports that Sanofi Pasteur supplied vaccines and hemagglutination titers for this study. A. J. S reports participation on a Data Safety Monitoring Board or Advisory Board for Integrated Health Services to reduce opioid use while managing chronic pain and the effect and contribution of a perioperative ketamine infusion in an established enhanced recovery pathway. H. H. reports VIPER T32 grant. E. T. O. reports grants or contracts paid to institution from ViiV Healthcare, Gilead Sciences, and Janssen. L. D. T. reports Sanofi Pasteur supplied vaccines and hemagglutination titers for this study. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Figures

Graphical abstract
Graphical abstract
This graphical abstract is also available at Tidbit: https://tidbitapp.io/tidbits/comparison-of-two-high-dose-versus-two-standard-dose-influenza-vaccines-in-adult-allogeneic-hematopoietic-cell-transplant-recipients-17b01d1d-6b7c-486f-9645-5d38dbbfeabd
Figure 1.
Figure 1.
Enrollment, randomization, and vaccine status. A total of 134 participants were consented, among whom 124 were subsequently randomized and vaccinated. Among the 64 participants randomized to receive SD-QIV, 59 (92%) received both doses; among the 60 participants randomized to receive HD-TIV, 59 (98%) received both doses. Abbreviations: HD-TIV, high-dose trivalent; SD-QIV, standard-dose quadrivalent.
Figure 2.
Figure 2.
Fold-rises by vaccine group and dose. Depiction of titer fold-rises from baseline (visit 1, prior to the first dose), shown by randomization group (SD-QIV and HD-TIV) for each antigen and each follow-up visit. The estimated GMFR and 95% confidence intervals are depicted in black. Visit 2 titers are measured at a target window of 28–42 d following the first dose (prior to the second dose), visit 3 titers are measured at a target window of 28–42 d following the second dose, and visit 4 titers are measured at a target window of 124–236 d following the visit 3. Furthermore, B/Yamagata was not included in HD-TIV. Abbreviations: GMFR, geometric mean fold-rise; HD-TIV, high-dose trivalent; SD-QIV, standard-dose quadrivalent.
Figure 3.
Figure 3.
Injection-site and systemic reaction frequencies. Displayed are the relative frequencies of each injection site and systemic reaction type for each vaccine group (SD-QIV vs HD-TIV) following each dose. Reactions were further graded according to a mild/moderate/severe toxicity scale (grades 1 through 3, respectively), which are additionally marked by shading. Abbreviations: HD-TIV, high-dose trivalent; SD-QIV, standard-dose quadrivalent.
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