Immunogenicity and Safety of Third, Fourth, and Subsequent COVID-19 Vaccine Doses in Recipients of Hematopoietic Cell Transplantation and Cellular Therapy.

Recipients of hematopoietic cell transplantation (HCT) and immune effector cellular (IEC) therapies are particularly vulnerable to infectious complications after treatment. Given the ongoing transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), developing vaccination strategies that optimize and sustain protective immunity in this high-risk immunocompromised population remains important. The present study was conducted to assess the humoral immune response engendered by SARS-CoV-2 vaccination following HCT or IEC therapy, as measured by anti-spike (anti-S) antibody levels based on dried blood spot (DBS) testing. A prospective study of COVID-19 vaccination in participants with hematologic malignancies was conducted between August 2021 and January 2023 across 12 sites in Canada. Participants were followed longitudinally and provided finger-prick DBS cards at specific intervals based on vaccination. A high-throughput enzyme-linked immunosorbent assay was performed to detect serum antibodies against nucleocapsid (N) and spike (S) proteins after the third, fourth, and fifth doses. Descriptive statistics were used to summarize participants' characteristics. Logistic regression was used to model differences in anti-S seropositivity by the number of vaccine doses and clinical risk factors. We obtained 1115 samples from 267 unique participants with a history of allogeneic (allo)-HCT, autologous (auto)-HCT, or IEC therapy. Anti-S antibodies were detected in 75.7% of participants after the third vaccine dose (84 of 111 DBS samples), 82.9% after the fourth dose (107 of 129 samples), and 94.8% after the fifth dose (55 of 58 samples). The proportion of anti-S-positive participants in the allo-HCT subgroup was 93.1%, 97.1% and 94.4% at post-doses 3, 4, and 5, respectively; in contrast, respective auto-HCT proportions were 79.2%, 81.6%, and 97.4%. Seropositivity generally increased from pre-dose to post-dose 3, 4 and/or 5 within the cohort and in the auto-HCT and allo-HCT subgroups. IEC had low overall vaccine immunity at all doses examined, although the sample size was small. For post-auto-HCT recipients, anti-S positivity in patients with lymphoma and plasma cell dyscrasias who received anti-CD20 and anti-CD38 therapies, respectively, was notably reduced, although vaccine immunity could still be improved with additional vaccine doses. This prospective cohort study demonstrates that humoral immune responses could be safely enhanced in HCT recipients after the third and subsequent doses of the COVID-19 vaccine. Although exposure to anti-CD20 and anti-CD38 therapies negatively impacted antibody responses to the COVID-19 vaccine, additional vaccine doses still could improve humoral immunity. © 2025 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc.