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

  1. Simeon Schietzel
  2. Manuel Anderegg
  3. Andreas Limacher
  4. Alexander Born
  5. Michael P Horn
  6. Britta Maurer
  7. Cedric Hirzel
  8. Daniel Sidler
  9. Matthias B Moor

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Abstract

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.

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  1. Version published to 10.1136/rmdopen-2021-002036
  2. ScreenIT

    SciScore for 10.1101/2021.09.30.21264335: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Ethicsnot detected.
    Sex as a biological variablenot detected.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.

    Table 2: Resources

    Antibodies
    SentencesResources
    We defined SARS-CoV-2 vaccine elicited humoral immune response as detection of anti-spike antibodies (anti-RBD or anti-S1 (spike protein) SARS-CoV2) above the cut-off reported by the manufacturer of the given assay.
    anti-spike
    suggested: None
    anti-RBD
    suggested: None
    anti-S1
    suggested: None
    Experimental Models: Organisms/Strains
    SentencesResources
    Three investigators (SS, AB and MBM) independently assigned a number of quality criteria (minimum 0, maximum 9) for each study.
    AB
    suggested: RRID:BDSC_203)
    Software and Algorithms
    SentencesResources
    Information sources and search strategy: PubMed (up to August 21, 2021), EMBASE (up to August 21, 2021), as well as pre-print servers medrxiv, SSRN and SSRN-Lancet (January 01, 2020 to August 21, 2021) were accessed online and searched within title/abstract without language restrictions.
    EMBASE
    suggested: (EMBASE, RRID:SCR_001650)
    Two authors (SS and MA) independently assessed all search results of PubMed database, and two authors (SS and MBM) independently assessed all search results of EMBASE database and preprint servers.
    PubMed
    suggested: (PubMed, RRID:SCR_004846)
    Synthesis methods: Synthesis was first obtained by tabulating the studies using Microsoft Excel and comparing against a list of exclusion criteria.
    Microsoft Excel
    suggested: (Microsoft Excel, RRID:SCR_016137)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    The evidence base included in this review contains some limitations. First, some participants may have been included who had asymptomatic COVID19 which was not detected by serological testing e.g. by anti-nucleocapsid immunoassays. Second, the seroconversion itself is a somewhat arbitrary outcome which is heterogeneous due to manufacturer cut-offs and no clear threshold for protective antibody levels exists to date. Further, the seroconversion may not ultimately translate to protection from severe COVID19 or symptomatic COVID19 directly in patients with a history of anti-CD20 therapies. Therefore, the scarce available data on cell-mediated immunity was included in the present analysis, which represents a second albeit assay-dependent measure of immunity against SARS-CoV2. Not enough data to allow disease subtype analysis of cellular immune responses. Published information was insufficient to allow analysis of different anti-CD20 therapies. Finally, for a closer discrimination of different autoimmune diseases, the current data were insufficient. The present review process was further limited by an arbitrary timing of the literature search (August 21, 2021) of a rapidly emerging knowledge database which renders the current evidence preliminary rather than definitive. Further, no external experts in the field were consulted, and no unpublished studies or clinical study registry data were queried. Some potential sources of heterogeneity in seroconversion rates in the study popula...

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    Results from scite Reference Check: We found no unreliable references.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  3. Version published to 10.1101/2021.09.30.21264335v1 on medRxiv