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Background: Patients with chronic lymphocytic leukemia (CLL) have reduced seroconversion rates and lower binding antibody (Ab) and neutralizing antibody (NAb) titers than healthy individuals following Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) mRNA vaccination. Here, we dissected vaccine-mediated humoral and cellular responses to understand the mechanisms underlying CLL-induced immune dysfunction. Methods and findings: We performed a prospective observational study in SARS-CoV-2 infection-naïve CLL patients (n = 95) and healthy controls (n = 30) who were vaccinated between December 2020 and June 2021. Sixty-one CLL patients and 27 healthy controls received 2 doses of the Pfizer-BioNTech BNT162b2 vaccine, while 34 CLL patients and 3 healthy controls received 2 doses of the Moderna mRNA-1273 vaccine. The median time to analysis was 38 days (IQR, 27 to 83) for CLL patients and 36 days (IQR, 28 to 57) for healthy controls. Testing plasma samples for SARS-CoV-2 anti-spike and receptor-binding domain Abs by enzyme-linked immunosorbent assay (ELISA), we found that all healthy controls seroconverted to both antigens, while CLL patients had lower response rates (68% and 54%) as well as lower median titers (23-fold and 30-fold; both p < 0.001). Similarly, NAb responses against the then prevalent D614G and Delta SARS-CoV-2 variants were detected in 97% and 93% of controls, respectively, but in only 42% and 38% of CLL patients, who also exhibited >23-fold and >17-fold lower median NAb titers (both p < 0.001). Interestingly, 26% of CLL patients failed to develop NAbs but had high-titer binding Abs that preferentially reacted with the S2 subunit of the SARS-CoV-2 spike. Since these patients were also seropositive for endemic human coronaviruses (HCoVs), these responses likely reflect cross-reactive HCoV Abs rather than vaccine-induced de novo responses. CLL disease status, advanced Rai stage (III-IV), elevated serum beta-2 microglobulin levels (β2m >2.4 mg/L), prior therapy, anti-CD20 immunotherapy (<12 months), and intravenous immunoglobulin (IVIg) prophylaxis were all predictive of an inability to mount SARS-CoV-2 NAbs (all p ≤ 0.03). T cell response rates determined for a subset of participants were 2.8-fold lower for CLL patients compared to healthy controls (0.05, 95% CI 0.01 to 0.27, p < 0.001), with reduced intracellular IFNγ staining (p = 0.03) and effector polyfunctionality (p < 0.001) observed in CD4+ but not in CD8+ T cells. Surprisingly, in treatment-naïve CLL patients, BNT162b2 vaccination was identified as an independent negative risk factor for NAb generation (5.8, 95% CI 1.6 to 27, p = 0.006). CLL patients who received mRNA-1273 had 12-fold higher (p < 0.001) NAb titers and 1.7-fold higher (6.5, 95% CI 1.3 to 32, p = 0.02) response rates than BNT162b2 vaccinees despite similar disease characteristics. The absence of detectable NAbs in CLL patients was associated with reduced naïve CD4+ T cells (p = 0.03) and increased CD8+ effector memory T cells (p = 0.006). Limitations of the study were that not all participants were subjected to the same immune analyses and that pre-vaccination samples were not available. Conclusions: CLL pathogenesis is characterized by a progressive loss of adaptive immune functions, including in most treatment-naïve patients, with preexisting memory being preserved longer than the capacity to mount responses to new antigens. In addition, higher NAb titers and response rates identify mRNA-1273 as a superior vaccine for CLL patients. In a prospective cohort study, Kai Qin and colleagues investigate underlying mechanisms of immune dysfunction in CLL, by measuring humoral and cellular immune responses to SARS-CoV-2 mRNA vaccination in patients with varying degrees of disease progression. Author summary: Why was this study done?: Chronic lymphocytic leukemia (CLL) patients are immunocompromised, have a high risk of acquiring life-threatening infections, and generally respond poorly to vaccination. CLL patients also have low seroconversion rates and binding antibody (Ab) and neutralizing antibody (NAb) titers following Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) mRNA vaccination. To probe the underlying mechanisms of immune dysfunction in CLL, we studied both humoral and cellular immune responses to SARS-CoV-2 mRNA vaccination in patients with varying degrees of disease progression. What did the researchers do and find?: We enrolled SARS-CoV-2 infection-naive healthy participants (n = 30) and CLL patients (n = 95) who received either 2 doses of the Pfizer-BioNTech BNT162b2 or the Moderna mRNA-1273 vaccine. We found spike-binding Abs and NAbs in 100% and 97% of healthy controls, respectively, but in only 68% and 42% of CLL patients, who also had much lower titers. T cell responses were found in 91% of healthy controls compared to 33% of CLL patients. Approximately 26% of CLL patients who lacked SARS-CoV-2 NAbs preferentially reacted with the S2 subunit of the SARS-CoV-2 spike, suggesting cross-reactivity with preexisting common coronavirus Abs. mRNA-1273 induced higher NAb response rates and titers than BNT162b2 in treatment-naïve CLL vaccinees despite similar disease progression. What do these findings mean?: Dissection of SARS-CoV-2 vaccine-induced humoral and cellular responses revealed a progressive deterioration of adaptive immune functions, even in CLL patients who had never received therapy. The "seroconversion" of over a quarter of CLL vaccinees likely reflects the presence of non-protective common coronavirus Abs that cross-react with the SARS-CoV-2 spike protein. Higher Ab response rates and NAb titers indicate that mRNA-1273 may be more beneficial for CLL patients. CLL patients and other immunocompromised populations may benefit from alternative vaccine regimens, which should be evaluated in clinical trials. [ABSTRACT FROM AUTHOR]