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Patients with cancer are at increased risk of death from COVID-19 and have reduced immune responses to SARS-CoV2 vaccines, necessitating regular boosters. We performed comprehensive chart reviews, surveys of patients attitudes, serology for SARS-CoV-2 antibodies and T cell receptor (TCR) β sequencing for cellular responses on a cohort of 982 cancer patients receiving active cancer therapy accrued between November-3-2020 and Mar-31-2023. We found that 92 · 3% of patients received the primer vaccine, 70 · 8% received one monovalent booster, but only 30 · 1% received a bivalent booster. Booster uptake was lower under age 50, and among African American or Hispanic patients. Nearly all patients seroconverted after 2+ booster vaccinations (>99%) and improved cellular responses, demonstrating that repeated boosters could overcome poor response to vaccination. Receipt of booster vaccinations was associated with a lower risk of all-cause mortality (HR = 0 · 61, p  = 0 · 024). Booster uptake in high-risk cancer patients remains low and strategies to encourage booster uptake are needed., Competing Interests: N.M. holds a consultant or advisory role at Amgen, Kite, Epizyme, TG Therapeutics, ADC Therapeutics, and has research funding from Miltenyi, Teva, and Amgen. J.G. holds a consultant or advisory role at EMD Serono; Elsevier; Exelixis; QED Therapeutics; Natera, Basilea, HalioDx, Eisai, Janssen. O.H. has obtained consulting fees/support meetings/travel/Financial interests in Alkermes, Amgen, Bactonix, Beigene, Bioatla, BMS, Esai, Roche, Genentech, Georgiamune, GigaGen, Grit Bio, GSK, Idera, Immunocore, Incyte, Instilbio, IO Bio, Iovance, Janssen, KSQ, Merck Moderna, Novartis, Obsidian, Pfizer, Regeneron, Sanofi, Seattle Genetics, Tempus, Vial, Zelluna. K.R. holds a consultant or advisory role at Amgen, AstraZeneca, Blueprint, Boehringer Ingelheim, Daiichi Sankyo, EMD Soreno, Genentech, GSK, Janssen, Lilly, Merck KGA, Mirati, Seattle Genetics, Takeda. J.D. holds a consultant or advisory role Kite Pharma and Morphosys. R.V. is on the Speaker’s Bureau for: Amgen, Bristol Myers Squib, Glaxo Smith Klein, Janssen, Karyopharm, and Takeda Pharmaceuticals. A.M. holds a consultant or advisory role at Novartis and Morphosys and has research funding from Amgen and Pfizer., (© 2024 The Authors. Published by Elsevier Inc.)

SARS-CoV-2 vaccines have unquestionably blunted the overall impact of the COVID-19 pandemic, but host factors such as age, sex, obesity, and other co-morbidities can affect vaccine efficacy. We identified individuals in a relatively healthy population of healthcare workers (CORALE study cohort) who had unexpectedly low peak anti-spike receptor binding domain (S-RBD) antibody levels after receiving the BNT162b2 vaccine. Compared to matched controls, "low responders" had fewer spike-specific antibody-producing B cells after the second and third/booster doses. Moreover, their spike-specific T cell receptor (TCR) repertoire had less depth and their CD4 + and CD8 + T cell responses to spike peptide stimulation were less robust. Single cell transcriptomic evaluation of peripheral blood mononuclear cells revealed activation of aging pathways in low responder B and CD4 + T cells that could underlie their attenuated anti-S-RBD antibody production. Premature lymphocyte aging may therefore contribute to a less effective humoral response and could reduce vaccination efficacy., Competing Interests: Authors declare that they have no competing interests., (© 2022 The Author(s).)