Impaired neutralisation of SARS-CoV-2 delta variant in vaccinated patients with B cell chronic lymphocytic leukaemia

Abstract

Background: Immune suppression is a clinical feature of chronic lymphocytic leukaemia (CLL), and patients show increased vulnerability to SARS-CoV-2 infection and suboptimal antibody responses.

Method: We studied antibody responses in 500 patients following dual COVID-19 vaccination to assess the magnitude, correlates of response, stability and functional activity of the spike-specific antibody response with two different vaccine platforms.

Results: Spike-specific seroconversion post-vaccine was seen in 67% of patients compared to 100% of age-matched controls. Amongst responders, titres were 3.7 times lower than the control group. Antibody responses showed a 33% fall over the next 4 months. The use of an mRNA (n = 204) or adenovirus-based (n = 296) vaccine platform did not impact on antibody response. Male gender, BTKi therapy, prophylactic antibiotics use and low serum IgA/IgM were predictive of failure to respond. Antibody responses after CD20-targeted immunotherapy recovered 12 months post treatment. Post-vaccine sera from CLL patients with Spike-specific antibody response showed markedly reduced neutralisation of the SARS-CoV-2 delta variant compared to healthy controls. Patients with previous natural SARS-CoV-2 infection showed equivalent antibody levels and function as healthy donors after vaccination.

Conclusions: These findings demonstrate impaired antibody responses following dual COVID-19 vaccination in patients with CLL and further define patient risk groups. Furthermore, humoural protection against the globally dominant delta variant is markedly impaired in CLL patients and indicates the need for further optimisation of immune protection in this patient cohort.

Keywords: Antibody; CLL; COVID; Leukaemia; SARS-CoV-2; Vaccination.

Fig. 1

Prevalence and titre of SARS-CoV-2 spike-specific antibody response in patients with CLL following dual COVID-19 vaccination. A Proportion of donors who develop a positive antibody response following dual vaccination. HD = Healthy donors; CLL = CLL-VR patient cohort. B (i) Antibody titres in participants with a positive antibody response. Donors with serological evidence of previous natural SARS-CoV-2 infection (previous exposure; PE) were excluded (p =  < 0.0001). (ii) Antibody titres in CLL patients in relation to history of previous natural exposure (PE) or no previous exposure (NPE) (p < 0.0001). Cut off for positive response is indicated by dotted line). (iii) Antibody titres in paired serum samples from patients with CLL following first and second vaccine. Red lines indicate patients with PE. C (i) Proportion of patients with CLL who develop a positive antibody response following dual vaccination with either the BNT162b2 or ChAdOx1 vaccine. (ii) Antibody titres in CLL patients in relation to vaccine subtype

Fig. 2

SARS-CoV-2 spike-specific antibody responses after vaccination in patients with CLL in relation to stage of disease. A Infographic to show the proportion of patients who develop an antibody response after COVID-19 vaccination in relation to disease stage and management (n = 484). B (i) Proportion of patients on BTKi therapy who develop a positive antibody response by line of therapy (p = 0.07) and (ii) in relation to current or previous BTKi therapy (p = NS). (iii) The proportion of patients with a positive antibody response who had received an anti-CD20 therapy within 12 months or longer (p = 0.008). C (i) Antibody titres in CLL patients who develop an positive antibody response (n = 244). Antibody titres do not vary across the disease course. (Untreated; Treatment planned (TP); Bruton Tyrosine Kinase therapy (BTKi); BCL-2 inhibitor (BCL-2); Previous Chemo-immunotherapy but not on active therapy (pCI). (ii). Antibody titres in relation to ‘time since diagnosis’ in patients who develop an antibody response and are on expectant ‘watch and wait’ management (r =  − 0.25; p = 0.0008). (iii) Antibody titres are broadly maintained at 4 months after vaccination. Serial titres at 5-weeks after first vaccine, 2–3 weeks after second vaccine and 4-months (range 3–8) after second vaccine (n = 56) (p = 0.0006 Wilcoxon paired analysis between 2nd and 3rd bleed time point)

Fig. 3

Post-vaccine neutralisation of live Wuhan virus and Delta variant. A (i) Maximum neutralisation of live virus using post-vaccine sera from healthy donors (HD; n = 94) and patients with CLL (n = 94) (p < 0.0001 Kruskal–Wallis). (ii) Maximum neutralisation in 53 CLL patients with a positive spike-specific antibody response following second vaccine (p < 0.0001). (iii) Maximum neutralisation using post-vaccine sera in HD and patients with serological evidence of previous natural infection with SARS-CoV-2. B Correlation between ND50 value against Wuhan virus or delta variant and spike-specific antibody titre in HD (Wuhan r = 0.80 and Delta r = 0.77; p < 0.0001) and CLL patients with a positive antibody response (Wuhan r = 0.60 and for Delta r = 0.61; p =  < 0.0001)