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Heterologous COVID-19 vaccine boosters have not been evaluated for patients with hematological malignancies. A Novavax booster was administered for 56 individuals with hematological malignancies who had received a primary COVID-19 series and prior boosters with mRNA vaccines only. Blood specimens were obtained at baseline (pre-vaccine), 28 days, and 168 days after vaccination with the Novavax booster. The median fold change of anti-Spike IgG was 1.02 (IQR 0.79, 1.3) between baseline and Day 28. Circulating Spike protein-specific B cells increased 1.4-fold at Day 28 (p < 0.05). Increases in antibody and T cell responses were modest without significance, with a waning of humoral and cellular responses at 168 days after vaccination.