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Bonelli et al recently reported reduced humoral responses to the BNT162b2 mRNA vaccine in five patients on rituximab therapy; in two patients with repopulated B cells, a low-level Spike protein antibody response occurred, but three patients with no detectable B-cells had no measurable antibody response to the vaccine.1 Of great interest, they reported that interferon-γ T-cell responses to SARS-CoV-2 Spike peptides were present in all five patients, irrespective of the antibody response to the vaccine.
It has been reported that patients on B-cell depleting therapy are at increased risk for hospitalisation and death from SARS-CoV-2 infection.2 In February 2021, the American College of Rheumatology (ACR) COVID-19 Taskforce published consensus guidelines regarding vaccine timing in immunosuppressed patients, despite the paucity of data available at that time on vaccine efficacy in patients on targeted B cell therapy.3 Moreover, the guidelines specifically recommended against antibody testing. There is also a public perception that vaccinated patients have minimal risk of infection and can resume a normal lifestyle. However, emerging data from patients on targeted B cell therapies suggest a more cautious approach.
Here, we report an additional 15 patients on targeted B-cell therapy from our institution who mounted no detectable anti-Spike IgG protein levels in response to vaccination (table 1). Several of these patients were on concomitant T-cell immunosuppression and/or methotrexate therapy. Anti-Spike antibodies were detected using the EUA Euroimmun assay (IgG binding SARS-CoV-2 spike protein S1 including the RBD domain) in a CLIA-certified laboratory. Results from this assay have been shown to correlate with viral neutralisation titers and have been used to quantify antibody levels following COVID-19 infection.4 Unlike the Bonelli et al study, this cohort depicts real-life clinical scenarios where patients pursued vaccination prior to or without knowledge of the ACR COVID-19 vaccine guidance recommendations. In the vast majority of cases, the decision to measure anti-Spike antibody levels was driven by the patient, who expressed concern regarding his/her level of protection during treatment with targeted B-cell suppression. It is worth noting that 2 of the 15 patients had CD19+ B cell levels measured at the time of anti-Spike IgG testing, and in both cases, CD19+ B cell levels were found to be nearly absent (case 1 with CD19+ absolute count 0.022×103/µL (2%) and case 8 with 0.000/µL (0%); normal range 0.160–0.390×103/µL).
These data raise concern for the safety of our patients on targeted B-cell therapy, particularly for those on additional immunosuppressive agents. Data regarding potential T-cell responses to the vaccine that might be important for protection remain unclear. However, knowing a patient’s serological antibody response to vaccination could be helpful in two respects: (1) for clinicians, knowledge of antibody titres may prioritise such individuals for booster doses and influence the decision to administer therapeutic monoclonal antibody in the event of SARS-CoV-2 infection and (2) for patients, knowledge of low antibody levels may provide value in self-regulation of high-risk activities. It is likely that evaluation of CD19+ B cell levels may help guide vaccination timing, as suggested by the Bonelli et al data. Until more information is available, we recommend that patients on targeted B-cell depleting or suppressive therapy follow local guidelines on COVID-19 prevention as if they were not vaccinated.
Contributors SHC, HR, MW and GCG contributed to the conception of manuscript. SHC, MW, AMB and GCG contributed to data collection and manuscript writing. CM, ABB, SLF, NSM, SC and AC provided critical feedback and helped shape the analysis and manuscript.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests None declared.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; internally peer reviewed.