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Background: The optimal timing of vaccination with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines after cellular therapy is incompletely understood. The objectives of this study are to determine whether humoral and cellular responses after SARS-CoV-2 vaccination differ if initiated <4 months versus 4-12 months after cellular therapy., Methods: We conducted a multicenter, prospective, observational study at 30 cancer centers in the United States. SARS-CoV-2 vaccination was administered as part of routine care. We obtained blood prior to and after vaccinations at up to 5 time points and tested for SARS-CoV-2 spike (anti-S) IgG in all participants and neutralizing antibodies for Wuhan D614G, Delta B.1.617.2, and Omicron B.1.1.529 strains, as well as SARS-CoV-2-specific T-cell receptors, in a subgroup., Results: We enrolled 466 allogeneic hematopoietic cell transplantation (HCT) (n = 231), autologous HCT (n = 170), and chimeric antigen receptor T-cell (CAR-T-cell) therapy (n = 65) recipients between April 2021 and June 2022. Humoral and cellular responses did not significantly differ among participants initiating vaccinations <4 months versus 4-12 months after cellular therapy. Anti-S IgG ≥2500 U/mL was correlated with high neutralizing antibody titers and attained by the last time point in 70%, 69%, and 34% of allogeneic HCT, autologous HCT, and CAR-T-cell recipients, respectively. SARS-CoV-2-specific T-cell responses were attained in 57%, 83%, and 58%, respectively. Pre-cellular therapy SARS-CoV-2 infection or vaccination and baseline B-cell count were key predictors of post-cellular therapy immunity., Conclusions: These data support mRNA SARS-CoV-2 vaccination prior to, and reinitiation 3 to 4 months after, cellular therapies with allogeneic HCT, autologous HCT, and CAR-T-cell therapy., Competing Interests: Potential conflicts of interest . J. A. H—research funding: AlloVir, Geovax, Merck; consulting: Pfizer, Gilead, Moderna, Geovax, AlloVir. J. H. Y.—research funding: AlloVir, Ansun, Cidara, F2G, GSK, NobelPharma, Pulmocide, Scynexis, Shire/Takeda. L. W. L.—employment and equity holder in Adaptive Biotechnologies Corporation. M. V. D.—research funding: Janssen, Roche/Genentech. R. N.—consulting: Ono Pharmaceutical, Jazz Pharmaceuticals, Bluebird Bio, Omeros Pharmaceutical, Sanofi, Pfizer. J. M.—consulting: Evision, Kite, Allovir, Bristol Myers Squibb, Novartis, CRISPR, Nektar, Caribiou Bio, Sana Technologies, Legend Biotech. S. D.—research funding: MSK Leukemia SPORE Career Enhancement Program and MSK Gerstner Physician Scholar program. J. J. A.—employment: National Marrow Donor Program; Advisory Board: AscellaHealth, Takeda. M. H.—research support/funding: Takeda Pharmaceutical Company, ADC Therapeutics, Spectrum Pharmaceuticals, Astellas Pharma; consultancy: Incyte Corporation, MorphoSys, SeaGen, Gamida Cell, Novartis, Legend Biotech, Kadmon, ADC Therapeutics, Omeros, AbbVie, Caribou, CRISPR, Genmab, Kite; Speaker’s Bureau: Sanofi Genzyme, AstraZeneca, BeiGene, ADC Therapeutics, Kite; Data Monitoring Committee: Myeloid Therapeutics, Inc. M. L. R.—research funding from Jazz Pharmaceuticals and Atara Bio-Pharma; employment by IQVIA Biotech and Kura Oncology; stock in Kura Oncology. M. M. H.—research funding from Astellas Pharma, CSL Behring, Incyte, Sanofi; consultancy: Sobi, Inc. M.-A. P.—honoraria from Adicet, Allogene, Allovir, Caribou Biosciences, Celgene, Bristol-Myers Squibb, Equilium, Exevir, ImmPACT Bio, Incyte, Karyopharm, Kite/Gilead, Merck, Miltenyi Biotec, MorphoSys, Nektar Therapeutics, Novartis, Omeros, OrcaBio, Sanofi, Syncopation, VectivBio AG, and Vor Biopharma; he serves on Data and Safety Monitoring Boards (DSMBs) for Cidara Therapeutics and Sellas Life Sciences, and the scientific advisory board of NexImmune; he has ownership interests in NexImmune, Omeros, and OrcaBio; he has received institutional research support for clinical trials from Allogene, Incyte, Kite/Gilead, Miltenyi Biotec, Nektar Therapeutics, and Novartis. 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., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

The anti-spike T-cell and antibody responses to SARS-CoV-2 mRNA vaccines in patients with B-cell malignancies were examined in a real-world setting. A next-generation sequencing (NGS)-based molecular assay was used to assess SARS-CoV-2-specific T-cell responses. After the second dose, 58% (166/284) of seropositive and 45% (99/221) of seronegative patients display anti-spike T cells. The percentage of patients who displayed T-cell response was higher among patients receiving mRNA-1273 vaccines compared with those receiving BNT162b2 vaccines. After the third vaccination, 40% (137/342) of patients seroconverted, although only 22% displayed sufficient antibody levels associated with the production of neutralizing antibodies. 97% (717/738) of patients who were seropositive before the third dose had markedly elevated anti-spike antibody levels. Anti-spike antibody levels, but not T-cell responses, were depressed by B cell-directed therapies. Vaccinated patients with B-cell malignancies with a poor response to SARS-CoV-2 vaccines may remain vulnerable to COVID-19 infections., Significance: This study represents the first investigation of SARS-CoV-2-specific immune responses to vaccination in a patient registry using an NGS-based method for T-cell receptor repertoire-based analysis combined with anti-spike antibody assessments. Vaccinated patients with B cell-derived hematologic malignancies are likely at higher risk of infection or severe COVID-19. This article is highlighted in the In This Issue feature, p. 476., (©2022 The Authors; Published by the American Association for Cancer Research.)

Patients with hematologic malignancies are particularly vulnerable to COVID-19 infections, and upon a pooled data analysis of 24 publications, there is evidence that they have suboptimal antibody responses to COVID-19 vaccination and boosters. To provide them the needed additional protection from COVID-19, it is imperative to achieve a 100% full immunization rate in health care workers and adult caretakers, and to foster research to test higher doses and repeated rounds of COVID-19 vaccines and the use of passive immune prophylaxis and therapy., (©2021 American Association for Cancer Research.)