COVID-19 Vaccine Failure in Chronic Lymphocytic Leukemia and Monoclonal B-Lymphocytosis; Humoral and Cellular Immunity

Abstract

Chronic lymphocytic leukemia (CLL) is associated with immunocompromise and high risk of severe COVID-19 disease and mortality. Monoclonal B-Lymphocytosis (MBL) patients also have immune impairment. We evaluated humoral and cellular immune responses in 181 patients with CLL (160) and MBL (21) to correlate failed seroconversion (<50AU/mL SARS-CoV-2 II IgG assay, antibody to spike protein, Abbott Diagnostics) following each of 2 vaccine doses with clinical and laboratory parameters. Following first and second doses, 79.2% then 45% of CLL, and 50% then 9.5% of MBL respectively remained seronegative, indicating 2 vaccine doses are crucial. There was significant association between post-dose 2 antibody level with pre-vaccination reduced IgM (p<0.0001), IgG2 (p<0.035), IgG3 (p<0.046), and CLL therapy within 12 months (p<0.001) in univariate analysis. By multivariate analysis, reduced IgM (p<0.0002) and active therapy (p<0.0002) retained significance. There was no significant correlation with age, gender, CLL duration, IgG, IgA or lymphocyte subsets. Anti-spike protein levels varied widely and were lower in CLL, than MBL, and both lower than normal donors. Neutralization activity showed anti-spike levels <1000AU/mL were usually negative for both an early viral clade and the contemporary Delta variant. There were 72.9% of CLL and 53.3% of MBL who failed to reach anti-spike levels >1000AU/mL. In a representative subset of 32 CLL patients, 80% had normal T-cell responses by IFNγ and IL-2 FluoroSpot assay. Failed seroconversion occurred in 36.6%% of treatment-naive patients, 52.9% treatment-naive with reduced IgM, 78.1% on therapy, and 85.7% on ibrutinib. Vaccination failure is very common in CLL, including early-stage disease.6 Key Novel FindingsComparison CLL vs MBL vs normal-45% of CLL and 9.5% of MBL fail to seroconvert with 2 doses of COVID-19 vaccineNeutralization assay-SARS CoV-2 IgG levels <1000 AU/mL rarely associated with neutralization activity.COVID-19-specific T-cell function by FluoroSpot IFN-g and IL-2 productionIgG, A, M class and IgG subclass: correlations by univariate and multivariate analysis-IgM (OR 7.29 p<0.0001), IgG2 and IgG3 subclass univariate significanceCorrelation with therapy – ICT, targeted therapies, and those on Ig replacementHigh risk of vaccination failure for all CLL, including early-stage disease, and MBLKey PointsCLL and MBL show significantly impaired anti-spike antibody, viral neutralization, with cellular immune response to COVID-19 vaccinationFailure to seroconvert is associated with low IgM, IgG2, IgG3, and recent therapy; many CLL and MBL patients remain COVID-19 vulnerable

COVID‐19 vaccine response in chronic lymphocytic leukaemia is more than just seroconversion

“…This study from Shen et al 1 is an important contribution to our understanding about COVID-19 vaccine responses in patients with CLL and MBL. It also leads to new questions that warrant further investigation.…”

“…5 SARS-CoV-2-specific T cells are likely an important part of immunological memory, providing long-term protection against COVID-19. 6 To investigate the T-cell response to COVID-19 vaccination, Shen et al 1 evaluated the presence of interferon gamma and interleukin 2 producing T cells after stimulation with spike protein peptide pool. While antibody and cellular immune responses are generally co-ordinated in healthy individuals, 7 no association between spike-specific T cells, anti-spike antibody, and neutralising activity was observed in this study.…”

“…Shen et al 1 identified several factors associated with seroconversion. In line with previous reports, 4 most patients treated with Bruton tyrosine kinase inhibitor or anti-CD20 monoclonal antibodies did not develop anti-spike antibodies.…”

“…Commentary on Shen et al 1 . ‘COVID‐19 vaccine failure in chronic lymphocytic leukaemia and monoclonal B‐lymphocytosis: humoral and cellular immunity’.…”

“…SARS‐CoV‐2‐specific T cells are likely an important part of immunological memory, providing long‐term protection against COVID‐19 6 . To investigate the T‐cell response to COVID‐19 vaccination, Shen et al 1 . evaluated the presence of interferon gamma and interleukin 2 producing T cells after stimulation with spike protein peptide pool.…”