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Background: Immune response to COVID-19 vaccine is diminished in patients with hematologic malignancy. There is limited data regarding response to vaccine doses in these patients., Purpose: To quantify the humoral immune response engendered by 4th and subsequent doses of SARS-CoV-2 vaccination as measured by anti-Spike (anti-S) antibody levels, based on dried blood spot (DBS) testing, in patients with hematologic malignancies. Anti-S binds to the spike protein of the SARS-CoV-2 virus and is indicative of vaccine immunogenicity., Methods: We conducted a prospective study of hematologic malignancies between August 2021 and January 2023 at 12 sites across Canada. Participants were followed longitudinally and submitted finger-prick DBS cards at set intervals associated with vaccination. Samples were processed via high throughput ELISA assay to detect serum antibodies against nucleocapsid (N) and spike (S) proteins., Results: We obtained 3071 samples on 790 unique patients. Of these, 372 unique participants with 1840 samples had anti-S results available post-4th, 5th or 6th COVID-19 vaccine dose and were included for analysis. Three hundred thirty-three patients of the 372 participants submitted a DBS sample post 4th dose. Of these, 257 patients (77.2%) had a positive anti-S antibody. A total of 198 patients had paired samples pre- and post-dose 4, of which 59 (29.7%) had a negative anti-S antibody pre-dose 4. Of these, 20 (33.4%) developed positive anti-S antibody post-dose 4. One hundred forty-nine patients submitted a DBS sample post-dose 5. Of these, 135 patients (90.6%) had positive anti-S antibody. A total of 52 had paired samples pre- and post-dose 5. Six (8.7%) had a negative anti-S antibody pre-dose 5, of which two (33.3%) developed positive anti-S antibody post-dose 5. Of these 372 patients, 123 (34%) reported COVID-19 infection and 4 (1%) had a COVID-19 related hospitalization. There were no reported deaths from COVID-19., Conclusions: This prospective cohort study showed that humoral immune response improved with subsequent doses of COVID-19 vaccines., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [C. Arianne Buchan reports financial support was provided by Public Health Agency of Canada - Canadian Immunization Task Force. Sita Bhella reports a relationship with Gilead Sciences Inc that includes: consulting or advisory and travel reimbursement. Annette E. Hay reports a relationship with Roche that includes: funding grants. Annette E. Hay reports a relationship with AbbVie Inc that includes: funding grants. Annette E. Hay reports a relationship with Seattle Genetics that includes: funding grants. Annette E. Hay reports a relationship with Merck that includes: funding grants. Annette E. Hay reports a relationship with Janssen that includes: funding grants. Annette E. Hay reports a relationship with Incyte that includes: funding grants. Annette E. Hay reports a relationship with Karyopharm that includes: funding grants. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper]., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)