ABSTRACT
B-cell chronic lymphocytic leukaemia (CLL) is associated with immune suppression and patients are at increased risk following SARS-CoV-2 infection. The Chronic Lymphocytic Leukaemia-Vaccine Response (CLL-VR) study was designed to assess immune responses following the introduction of Covid-19 vaccination in UK. Five hundred patients with CLL were recruited nationally through NHS and charity communications. Phlebotomy blood samples were taken from local patients ( n = 100) and dried blood spot samples were collected via post from participants across the UK ( n = 400). Ninety-six age-matched control subjects were also recruited locally. Samples were taken at 2-3 weeks following the first, second and third primary vaccine doses. Antibody and cellular responses against spike protein, and neutralising antibody titre to delta and omicron variant, were measured. Total serum immunoglobulin level was also determined. Responses were analysed according to clinical history, serum immunoglobulin level and vaccine type received. Donors with a clinical or serological history of prior natural infection were excluded from the analysis. Twenty percent (70/353) of participants developed a measurable antibody response after the first vaccination and this increased to 67% (323/486) following the second dose and 80% (202/254) after a third dose. The response rate in healthy controls plateaued at 100% after only two doses. The magnitude of the antibody response was also 3.7-fold lower following the second vaccine compared to controls ( n = 244;490 vs. 1821 U/ml, p < 0.0001) but increased markedly to 3114 U/ ml after third dose ( n = 51). No difference was observed in relation to the initial vaccine platform received. Multivariate analysis on 486 participants showed that BTKi therapy, history of recurrent infection and low serum antibody levels of IgA or IgM were independent prognostic markers for poor antibody response. Among participants with a detectable antibody response, a marked reduction in the ability to neutralise the delta and omicron variants of concern was noted compared to healthy controls following both the second and third dose of vaccine. Cellular responses were assessed following the second vaccine by IFN-g ELISPOT ( n = 91). Patients who had received the ChAdOx1 vaccine had similar levels to controls ( p = 0.39), while those who had received BNT162b2 had lower levels ( p < 0.0001). Five patients with poor spike-specific antibody responses to vaccination subsequently developed breakthrough infection with SARS-CoV-2 delta variant. Antibody responses and neutralisation remained poor following recovery from infection although T-cell responses were strong and only one patient required hospital admission. CLL-VR is the largest vaccine study conducted in patients with CLL and reveals diminished but comparable antibody responses to both the ChAdOx1 and BNT162b2 vaccines with some improvement following third primary dose of mRNA vaccine. In contrast T-cell responses following second dose are greater in those who received ChAdOx1 platform. Low neutralising activity against the delta and omicron variants highlights an ongoing risk for this vulnerable population despite repeated vaccination and reveals the need for alternative approaches to protection including prophylactic monoclonal antibody therapy..
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.