Humoral and cellular immune responses on SARS-CoV-2 vaccines in patients with anti-CD20 therapies: a systematic review and meta-analysis of 1342 patients

Abstract

Background: Immune responses on SARS-CoV-2 vaccination in patients receiving anti-CD20 therapies are impaired but vary considerably. We conducted a systematic review and meta-analysis of the literature on SARS-CoV-2 vaccine induced humoral and cell-mediated immune response in patients previously treated with anti-CD20 antibodies.

Methods: We searched PubMed, Embase, Medrxiv and SSRN using variations of search terms 'anti-CD20', 'vaccine' and 'COVID' and included original studies up to 21 August 2021. We excluded studies with missing data on humoral or cell-mediated immune response, unspecified methodology of response testing, unspecified timeframes between vaccination and blood sampling or low number of participants (≤3). We excluded individual patients with prior COVID-19 or incomplete vaccine courses. Primary endpoints were humoral and cell-mediated immune response rates. Subgroup analyses included time since anti-CD20 therapy, B cell depletion and indication for anti-CD20 therapy. We used random-effects models of proportions.

Findings: Ninety studies were assessed. Inclusion criteria were met by 23 studies comprising 1342 patients. Overall rate of humoral response was 0.40 (95% CI 0.35 to 0.47). Overall rate of cell-mediated immune responses was 0.71 (95% CI 0.57 to 0.87). A time interval >6 months since last anti-CD20 therapy was associated with higher humoral response rates with 0.63 (95% CI 0.53 to 0.72) versus <6 months 0.2 (95% CI 0.03 to 0.43); p=0<01. Similarly, patients with circulating B cells more frequently showed humoral responses. Anti-CD20-treated kidney transplant recipients showed lower humoral response rates than patients with haematological malignancies or autoimmune disease.

Interpretation: Patients on anti-CD20 therapies can develop humoral and cell-mediated immune responses after SARS-CoV-2 vaccination, but subgroups such as kidney transplant recipients or those with very recent therapy and depleted B cell are at high risk for non-seroconversion and should be individually assessed for personalised SARS-CoV-2 vaccination strategies. Potential limitations are small patient numbers and heterogeneity of studies included.

Funding: This study was funded by Bern University Hospital.

Keywords: antirheumatic agents; autoimmune diseases; rituximab; vaccination.

Figure 1

Flow chart describing the study search and selection process.

Figure 2

Humoral immune responses across all included studies. Prop., proportion.

Figure 3

Humoral immune responses according to prespecified subgroups of <6 or >6 months of time since the last dose of anti-CD20 therapy. Prop., proportion.

Figure 4

Humoral immune responses stratified by subgroups of patients with depleted versus replete B cell counts. Prop., proportion.

Figure 5

Humoral immune responses according to prespecified subgroups of indications for anti-CD20 therapy. Prop., proportion.

Figure 6

Cell-mediated immune responses across all included studies. Prop., proportion.

Figure 7

Funnel plot of all included studies.