Antibody responses after first and second Covid-19 vaccination in patients with chronic lymphocytic leukaemia

Abstract

B-cell chronic lymphocytic leukaemia (CLL) is associated with immunosuppression and patients are at increased clinical risk following SARS-CoV-2 infection. Covid-19 vaccines offer the potential for protection against severe infection but relatively little is known regarding the profile of the antibody response following first or second vaccination. We studied spike-specific antibody responses following first and/or second Covid-19 vaccination in 299 patients with CLL compared with healthy donors. 286 patients underwent extended interval (10-12 week) vaccination. 154 patients received the BNT162b2 mRNA vaccine and 145 patients received ChAdOx1. Blood samples were taken either by venepuncture or as dried blood spots on filter paper. Spike-specific antibody responses were detectable in 34% of patients with CLL after one vaccine (n = 267) compared to 94% in healthy donors with antibody titres 104-fold lower in the patient group. Antibody responses increased to 75% after second vaccine (n = 55), compared to 100% in healthy donors, although titres remained lower. Multivariate analysis showed that current treatment with BTK inhibitors or IgA deficiency were independently associated with failure to generate an antibody response after the second vaccine. This work supports the need for optimisation of vaccination strategy in patients with CLL including the potential utility of booster vaccines.

Fig. 1. Infographic of study design and collection.

Samples were collected from patients who had undergone dual vaccination with either an ‘extended interval’ (n = 286) or ‘standard interval’ regimen (n = 13). Antibody levels in serum samples obtained by phlebotomy or in eluates from dried blood spot samples were assessed at the indicated timepoints.

Fig. 2. Antibody responses in patients with CLL following first Covid-19 vaccine.

A Antibody responses to SARS-COV19 Spike following first vaccine in sera from healthy donors (HD) and patients with CLL, as measured by Roche assay. Red indicates those previously exposed (PE) to SARS-CoV-2 (median HD 41.6 vs CLL 0.4 (104 fold change)); cut off for positivity at 0.8 shown by dotted line. B Antibody responses to SARS-CoV-2 Spike in patients with CLL following first vaccine, by management stage, as measured by Roche (Total patients; Watch and Wait (W+W); Previous Chemo-immunotherapy but not on active therapy (pCI); Bruton Tyrosine Kinase therapy (BTKi); Venetoclax therapy (Ven); Treatment planned (TP). C Bar chart to show the percentage response after first vaccine in healthy donors and CLL measured by Roche. D Antibody responses to SARS-CoV-2 Spike from DBS in healthy donors (HD) and patients with CLL, as measured by The Binding Site (TBS) assay using DBS eluates (median 1 vs 0.5; p < 0.0001; (cut off positivity shown at 1). E Antibody responses to SARS-CoV-2 Spike in patients with CLL following first vaccine, by management stage, as measured by TBS using DBS eluates (Kruskal–Wallis p = 0.0054; post hoc Dunn’s analysis p < 0.0056 W+W vs BTKi). F Bar chart to show the percentage response after first vaccine in HD and CLL measured by TBS using DBS eluates.

Fig. 3. Antibody responses in patients with CLL following second Covid-19 vaccine.

A Antibody responses to SARS-CoV-2 Spike following second vaccine in sera from healthy donors (HD) and patients with CLL, as measured by Roche assay. No donors had evidence of previous exposure (cut off for positivity at 0.8 indicated by dotted line). B Dot plot of antibody responses to SARS-CoV-2 Spike in patient with CLL following second vaccine, by management stage is shown, (W+W watch and wait; PCi previous chemo-immunotherapy but not on active therapy) as measured by Roche. C Bar chart to show the percentage response after second vaccine in HD and CLL measured by Roche. D Antibody responses to SARS-CoV-2 spike following second vaccine in healthy donors (HD) and patients with CLL, as measured by TBS assay (cut off for positivity indicated by the dotted line at a ratio of 1). E Antibody responses to SARS-CoV-2 Spike in patient with CLL following second vaccine, by management stage, DBS testing and analysed by TBS assay (Kruskal–Wallis p < 0.0045 and Dunn’s analysis for BTKi therapy and W+W p = 0.03). Watch and Wait (W+W); Previous Chemo-immunotherapy but not on active therapy (pCI); Bruton Tyrosine Kinase therapy (BTKi); Treatment planned (TP). F Bar chart to show the percentage response after second vaccine in HD and CLL measured by TBS assay using DBS eluates.

Fig. 4. Determinants of Covid-19 vaccine response in patients with CLL.

A Paired analysis of antibody responses to SARS-CoV-2 Spike in healthy donors (HD) and patients with CLL after first and second vaccine (Analysis by TBS ELISA, HD median post 1^st and 2^nd vaccine 1.0 & 5.8 vs CLL median 0.5 & 3.0, respectively) with cut off for positivity shown by dotted line ratio = 1). B Dot plot showing antibody responses to second vaccine in patients with CLL taking a Bruton Tyrosine Kinase inhibitor (BTKi) and those not on BTKi (median BTKi 0.6 vs No BTKi 3.2 p = 0.0002) as measured by TBS assay. C Correlation between antibody response to SARS-CoV-2 following second vaccine and serum immunoglobulin. Antibody levels were measured by TBS ELISA and shown against total serum IgA (p = 0.0004; r = 0.43, IgA deficiency (0.8 g/L) is highlighted in blue); total serum IgG (p = 0.02; r = 0.29, IgG deficiency (6 g/L) highlighted in blue) and total serum IgM (p = 0.01, r = 0.334, IgM deficiency (<0.5 g/L) highlighted in blue). D Infographic of patients with CLL according to the presence or absence of antibody response following double vaccination according to disease characteristics (n = 55).