New research may explain why patients with chronic lymphocytic leukemia (CLL) tend to respond poorly to COVID-19 vaccination.

Researchers found that CLL patients experience “progressive deterioration of adaptive immune functions,” even if they have never received CLL treatment.

The researchers also found that CLL patients with seroconversion had non-protective common coronavirus antibodies that cross-react with the SARS-CoV-2 spike protein, which suggests that seroconversion does not signify a protective antibody response in these patients.

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The researchers reported these findings in PLoS Medicine.

For this study, the researchers analyzed plasma samples from 95 CLL patients and 30 healthy volunteers. None of the patients had a prior SARS-CoV-2 infection, and all had received 2 doses of Pfizer-BioNTech’s BNT162b2 vaccine or Moderna’s mRNA-1273 vaccine between December 2020 and June 2021.

Of the patients with CLL, 64% received the BNT162b2 vaccine and 36% received the mRNA-1273 vaccine. Nearly half (47%) of the patients had not received treatment for CLL.

CLL patients were less likely than control individuals to mount antibody responses after vaccination. All control participants had both anti-spike (anti-S) and anti-receptor-binding domain (anti-RBD) antibodies after vaccination, whereas 68% of CLL patients had anti-S antibodies, and 54% had anti-RBD antibodies.

Anti-S antibody titers were significantly lower among CLL patients than among control individuals. Anti-S half-maximal effective concentrations were 23-fold lower among CLL patients (P <.001), and anti-RBD half-maximal effective concentrations were 30-fold lower among CLL patients (P <.001).

CLL patients were less likely to have neutralizing antibodies (NAbs) as well. The NAb response rate in control individuals was 97% for the D614G variant and 93% for the Delta variant. The NAb response rate among CLL patients was 42% against D614G and 38% against Delta.

Median NAb titers for the D614G variant were more than 23-fold lower among CLL patients, and median NAb titers for the Delta variant were more than 17-fold lower among the CLL patients (P <.001 for both comparisons).

Factors that were associated with higher binding and NAb titers among CLL patients were Rai stage 0-II, a serum β2-microglobulin level of 2.4 mg/L or less, having received no prior CLL therapy, undergoing vaccination at least 12 months after anti-CD20 therapy, and having no need for intravenous immunoglobulin (P ≤.04 for all).

The researchers also identified a group of CLL patients (26% of the CLL cohort) who had anti-S binding antibodies but no detectable NAbs. The anti-S binding antibodies primarily reacted with the SARS-CoV-2 S2 subunit.

“Although these antibodies could have been vaccine-induced, it is much more likely that they represent recall responses of preexisting anti-HCoV [human coronavirus] antibodies that cross-react with conserved S2 epitopes,” the researchers wrote. “The latter possibility is reminiscent of antigenic imprinting, which refers to the preferential reactivation of cross-reactive memory B cells from an initial antigenic exposure, rather than the initiation of de novo responses when encountering a new related antigen.”

The researchers also found evidence to suggest that Moderna’s mRNA-1273 vaccine is more beneficial for CLL patients than Pfizer-BioNTech’s BNT162b2 vaccine, a finding that has been reported previously.

The researchers noted, however, that CLL patients and other immunocompromised patients “may benefit from alternative vaccine regimens, which should be evaluated in clinical trials.”


Qin K, Honjo K, Sherrill-Mix S, et al. Exposure of progressive immune dysfunction by SARS-CoV-2 mRNA vaccination in patients with chronic lymphocytic leukemia: A prospective cohort study. PLoS Med. Published online June 29, 2023. doi:10.1371/journal.pmed.1004157

This article originally appeared on Cancer Therapy Advisor