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Correspondence on “SARS-CoV-2 vaccination in rituximab-treated patients: evidence for impaired humoral but inducible cellular immune response” by Bonelli et al
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  1. Caoilfhionn Marie Connolly1,
  2. Darya Koenig2,
  3. Srekar N Ravi3,
  4. Antoine Azar2,
  5. Sam Kant4,
  6. Monika Dalal1,
  7. Jessica Duchen5,
  8. Philip Seo1,
  9. Brendan Antiochos1,
  10. Julie J Paik1,
  11. Duvuru Geetha1,4
  1. 1 Division of Rheumatology, Department of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
  2. 2 Division of Allergy and Immunology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  3. 3 Department of Medicine, Florida Atlantic University—Treasure Coast Campus, Boca Raton, Florida, USA
  4. 4 Division of Nephrology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  5. 5 Biostatistics, Epidemiology and Data Management, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA
  1. Correspondence to Dr Duvuru Geetha, MEDICINE, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA; gduvura{at}jhmi.edu

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SARS-CoV-2 vaccination elicited high levels of immunogenicity in immunocompetent people in the original vaccine trials1 2 though recent studies have shown blunted immunogenicity in patients with rheumatic diseases treated with lymphocyte depleting agents.3 4 B-lymphocytes have been implicated in the pathogenesis of anti-neutrophil cytoplasmic antibidy (ANCA)-associated vasculitis (AAV) and B-cell-targeted therapy with rituximab is recognised as an established induction and maintenance strategy in management.5 6 SARS-CoV-2 infection in patients with AAV has been associated with severe outcomes,7 while rituximab has been associated with worse outcomes among patients infected with SARS-CoV-2.8 9 A recent study by Bonelli et al found evidence of an ameliorated humoral response but possible inducible cellular response in five patients treated with rituximab.10

We studied the tolerability and humoral response to the SARS-CoV-2 vaccine series in 48 patients with a diagnosis of AAV. Patients underwent SARS-CoV-2 antispike antibody testing to assess humoral response. Antibody testing was performed using antispike IgG enzyme immunoassay (Roche Elecsys via Quest, DiaSorin Liaison assay via LabCorp or Euroimmun via Hopkins lab). Demographics, clinical information including immunosuppressive therapy were extracted from medical records. Time from last rituximab administration to receipt of the first dose of the vaccine was recorded. We recorded serum creatinine, white blood cell count, serum immunoglobulins, Cluster of CD19 and ANCA status. CD19 reconstitution was defined as CD19-positive B cells greater than 0/mm3. Hypo-IgG and hypo-IgM were defined as less than the lower limit of normal for the lab. Patients were asked solicited questions about local and systemic adverse events after each vaccine dose (D1, D2) to assess tolerability. Descriptive statistics and bivariate comparisons were performed using χ2 and Fischer’s exact tests for categorical variables and t-tests and Wilcoxon rank-sum tests for continuous variables. All analyses were conducted in SAS V.9.4 (SAS Institute).

We studied 48 patients with AAV (table 1). Most patients (98%) had renal involvement, while 77% had extrarenal involvement. Immunosuppressant regimens included rituximab (44 patients; 92%), prednisone (14 patients; 30%) and mycophenolate mofetil (6 patients; 12%). The median (IQR) daily dose of prednisone was 4 mg (2–8 mg). The indications for rituximab included induction (1 patient) and remission maintenance (43 patients). The median (IQR) interval from the time of last rituximab administration to receipt of vaccine was 200 days (124–425 days).

Table 1

Patient demographics stratified by presence or absence of SARS-CoV-2 antispike antibody

Only 18 (37%) developed detectable humoral response. No recipient of Johnson & Johnson vaccine (0/4) had evidence of humoral response. Among those treated with rituximab (online supplemental table 1), absence of serologic response was associated with vaccine type (p=0.024), lack of CD19 reconstitution (p<0.0001), hypo-IgM (p=0.03) and shorter interval from last rituximab infusion (p=0.002) (online supplemental figure 1). Nineteen (43%) of those treated with rituximab had evidence of B-cell reconstitution, of whom fifteen had detectable humoral response (p<0.0001). Of the four patients who did not have a humoral response despite B-cell reconstitution, one was undergoing treatment for lung cancer with Navelbine, one was on concurrent mycophenolate mofetil and two were on subcutaneous immunoglobulin.

Thirteen patients (27%) reported adverse events after D1, while 17 (39%) patients reported adverse events after D2. Fatigue (n=9) and headache (n=9) were the most reported events. There was no association of either local or systemic adverse events with humoral response. No AAV relapses were reported. Two patients without humoral response developed severe SARS-CoV-2 infection. The first patient required mechanical ventilation and died on day 10 of hospitalisation. The second patient required hospitalisation for 1 week.

In this study, only 37% of participants had detectable humoral response to SARS-CoV-2 vaccination. The majority (92%) of patients were on rituximab maintenance therapy. Longer duration from rituximab exposure, as well as B-cell reconstitution, was associated with a greater likelihood of response. In this study, no patient who received Johnson-Johnson vaccine mounted a detectable humoral response, though our analysis is limited by the small sample size. While this single dose vaccine has induced immunogenicity in healthy individuals, patients on immunosuppression were not well represented in the trials11 12 and this warrants additional study.

Vaccine-associated side effects were similar to those reported in the clinical trials.1 2 There were no reports of disease relapse following vaccination. Two patients developed severe SARS-CoV-2 infection following vaccination; one of these patients died.

Similar to other reports,3 13 we demonstrated a limited humoral response to SARS-CoV-2 vaccination in patients treated with rituximab. No safety concerns were identified. Patients treated with rituximab are more likely to experience poor outcomes if they are infected with COVID-19,14 and should be aware of the potential for limited vaccine response. It is critical that providers continue to recommend risk-minimisation strategies and ongoing vigilance in preventative measures. These high-risk patients may benefit from alternative vaccination strategies such as additional booster doses or combination of vaccine types to enhance immunogenicity, although more studies are needed to define an optimal strategy in this vulnerable population.

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Footnotes

  • Twitter @CaoilfhionnMD

  • Contributors All authors contributed equally to this manuscript.

  • Funding This work was supported by grant number K23AR073927 (Paik) from National Institute of Arthritis and Musculoskeletal and Skin Diseases. The analyses described here are the responsibility of the authors alone and do not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products or organizations imply endorsement by the US Government.

  • Competing interests DG has the following disclosures: consultant to ChemoCentryx and Aurinia.

  • Provenance and peer review Not commissioned; internally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

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