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Patients with non–Hodgkin lymphoma and chronic lymphocytic leukemia (NHL/CLL) elicit inadequate antibody responses after initial SARS-CoV-2 vaccination and remain at high risk of severe COVID-19 disease. We investigated IgG, IgA, and IgM responses after booster vaccination against recent SARS-CoV-2 variants including Omicron BA.5 in 67 patients. Patients had lower fold increase and total anti-spike binding titers after booster than healthy individuals. Antibody responses negatively correlated with recent anti-CD20 therapy and low B-cell numbers. Antibodies generated after booster demonstrated similar binding properties against SARS-CoV-2 variants compared with those generated by healthy controls with lower binding against Omicron variants. Importantly, 43% of patients showed anti-Omicron BA.1 neutralizing antibodies after booster and all these patients also had anti-Omicron BA.5 neutralizing antibodies. Patients with NHL/CLL demonstrated inferior antibody responses after booster vaccination, particularly against Omicron variants. Prioritization of prophylactic and treatment agents and vaccination of patients and close contacts with updated vaccine formulations are essential. Significance: Limited data exist on antibody responses against current SARS-CoV-2 variants after booster vaccination in patients with NHL/CLL. We showed inferior antibody responses against Omicron variants after booster vaccination in these patients but some generated anti-Omicron titers. This stresses the importance of vaccinating patients with updated formulations.

Patients with multiple myeloma (MM) mount suboptimal neutralizing antibodies (nAb) following 2 doses of SARS-CoV-2 mRNA vaccines. Currently, circulating SARS-CoV-2 variants of concern (VOC) carry the risk of breakthrough infections. We evaluated immune recognition of current VOC including BA.1, BA.2, and BA.5 in 331 racially representative patients with MM following 2 or 3 doses of mRNA vaccines. The third dose increased nAbs against WA1 in 82%, but against BA variants in only 33% to 44% of patients. Vaccine-induced nAbs correlated with receptor-binding domain (RBD)–specific class-switched memory B cells. Vaccine-induced spike-specific T cells were detected in patients without seroconversion and cross-recognized variant-specific peptides but were predominantly CD4+ T cells. Detailed clinical/immunophenotypic analysis identified features correlating with nAb/B/T-cell responses. Patients who developed breakthrough infections following 3 vaccine doses had lower live-virus nAbs, including against VOC. Patients with MM remain susceptible to SARS-CoV-2 variants following 3 vaccine doses and should be prioritized for emerging approaches to elicit variant-nAb and CD8+ T cells.Significance:Three doses of SARS-CoV-2 mRNA vaccines fail to yield detectable VOC nAbs in nearly 60% and spike-specific CD8+ T cells in >80% of myeloma patients. Patients who develop breakthrough infections following vaccination have low levels of live-virus nAb.This article is highlighted in the In This Issue feature, p. 101

PURPOSE To examine COVID-19 mRNA vaccine–induced binding and neutralizing antibody responses in patients with non–small-cell lung cancer (NSCLC) to SARS-CoV-2 614D (wild type [WT]) strain and variants of concern after the primary 2-dose and booster vaccination. METHODS Eighty-two patients with NSCLC and 53 healthy volunteers who received SARS-CoV-2 mRNA vaccines were included in the study. Blood was collected longitudinally, and SARS-CoV-2–specific binding and neutralizing antibody responses were evaluated by Meso Scale Discovery assay and live virus Focus Reduction Neutralization Assay, respectively. RESULTS A majority of patients with NSCLC generated binding and neutralizing antibody titers comparable with the healthy vaccinees after mRNA vaccination, but a subset of patients with NSCLC (25%) made poor responses, resulting in overall lower (six- to seven-fold) titers compared with the healthy cohort ( P = < .0001). Although patients age > 70 years had lower immunoglobulin G titers ( P = < .01), patients receiving programmed death-1 monotherapy, chemotherapy, or a combination of both did not have a significant impact on the antibody response. Neutralizing antibody titers to the B.1.617.2 (Delta), B.1.351 (Beta), and in particular, B.1.1.529 (Omicron) variants were significantly lower ( P = < .0001) compared with the 614D (WT) strain. Booster vaccination led to a significant increase ( P = .0001) in the binding and neutralizing antibody titers to the WT and Omicron variant. However, 2-4 months after the booster, we observed a five- to seven-fold decrease in neutralizing titers to WT and Omicron viruses. CONCLUSION A subset of patients with NSCLC responded poorly to the SARS-CoV-2 mRNA vaccination and had low neutralizing antibodies to the B.1.1.529 Omicron variant. Booster vaccination increased binding and neutralizing antibody titers to Omicron, but antibody titers declined after 3 months. These data highlight the concern for patients with cancer given the rapid spread of SARS-CoV-2 Omicron variant.