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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 17  |  Issue : 1  |  Page : 30-33

Humoral responses to SARS-CoV-2 vaccination in rituximab-treated patients depend on peripheral B cell re-population rather than the timings of the dosing


1 Center For Arthritis and Rheumatism Excellence, Ernakulam, Kerala, India
2 Department of Transfusion Medicine, Amritha Institute of Medical Research, Kochi, Kerala, India
3 Department of Rheumatology and Clinical Immunology, Kalinga Institute of Medical Research, Bhubaneswar, Odisha, India

Date of Submission20-Sep-2021
Date of Acceptance15-Dec-2021
Date of Web Publication02-Feb-2022

Correspondence Address:
Dr. Padmanabha Shenoy
Centre for Arthritis and Rheumatism Excellence, Nettoor, Kochi - 682 040, Kerala
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/injr.injr_215_21

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  Abstract 


Introduction: Previous exposure to Rituximab affects the immunogenicity of vaccination including that against coronavirus disease (COVID-19). However, dynamics of the effect of rituximab on vaccination are not well understood. This study aims to assess the role of timing of vaccine dosing and B-cell repopulation on vaccine seroconversion.
Methods: Autoimmune rheumatic disease (AIRD) patients treated with rituximab who had completed two doses of COVID-19 vaccination were enrolled. Peripheral B-cell counts were estimated along with the titer of immunoglobulin G antibody-directed against the receptor-binding domain of spike1 protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Antibody titers of participants were compared against B-cell re-population.
Results: Out of the 33 participants with available prevaccination B-cell counts, 11 did not have any detectable peripheral B cells before vaccination, and out of these patients, only 1 developed antibodies postvaccination, whereas, of the remaining 22, 18 (81.8%) had a positive seroconversion. Although all patients who had received the last dose of Rituximab at least 1 year before vaccination had antibodies, there was no direct correlation between time from the last dose and antibody positivity. B-cell re-population was strongly associated with seroconversion (P = 0.0001).
Conclusion: In rituximab-treated patients, humoral responses to SARS-CoV-2 vaccination depend on peripheral B-cell re-population rather than the timing of the vaccination postrituximab infusion.

Keywords: Autoimmune inflammatory disorders, B-cells, COVID-19, rheumatic diseases, rituximab, vaccine


How to cite this article:
Umesh R, Paul A, Shenoy V, Ahmed S, Cherian S, Prasad A, Shenoy P. Humoral responses to SARS-CoV-2 vaccination in rituximab-treated patients depend on peripheral B cell re-population rather than the timings of the dosing. Indian J Rheumatol 2022;17:30-3

How to cite this URL:
Umesh R, Paul A, Shenoy V, Ahmed S, Cherian S, Prasad A, Shenoy P. Humoral responses to SARS-CoV-2 vaccination in rituximab-treated patients depend on peripheral B cell re-population rather than the timings of the dosing. Indian J Rheumatol [serial online] 2022 [cited 2022 Oct 4];17:30-3. Available from: https://www.indianjrheumatol.com/text.asp?2022/17/1/30/337184




  Introduction Top


Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) which started as an outbreak of pneumonia like illness in China in December 2019,[1] has now affected more than 200 million people in the world.[2] Vaccination is currently the strongest weapon to fight against the COVID-19 pandemic. India is vaccinating its population with the Adenovirus vector-based ChAdOx1 ncov-19 vaccine (COVISHIELD) and the Indian indigenous whole-virion β-propiolactone-inactivated SARS-CoV-2 vaccineBBV152 vaccine (COVAXIN).[3]

Patients with auto-immune rheumatic diseases (AIRD) have increased susceptibility to infections due to the effect of disease and the immunosuppressive medications they are exposed to.[4] Due to associated comorbidities, they are at higher risk of complications.[5] The persistence of virus in immunosuppressed patients may lead on to the development of transmissible and immune evasive mutants.[6] Immunogenicity of vaccines in immunosuppressed patients is a major concern.[7] It has been shown that drugs such as Rituximab, Methotrexate, Mycophenolate mofetil, and others impact the immunogenicity of the vaccines.[8] Rituximab, a chimeric anti CD 20 monoclonal antibody, acts by depleting the circulating B-cells. It is used as targeted therapy for the treatment of many AIRD such as rheumatoid arthritis ANCA associated vasculitis.[9],[10],[11] Patients on rituximab therapy have been found to have worse outcome when they are affected with COVID-19.[12] It has been also shown that Rituximab affects the immunogenicity of SARS CoV2 vaccine.[13] It is recommended to space the vaccination in such a way that the vaccine is given 1 month prior to rituximab infusion or time it after 6 months of last infusion of rituximab.[13] However, it remains unclear whether and to what extent, repopulation of peripheral B-cells is needed for antibody development in rituximab treated patients.[14] In our cohort of AIRD patients who have been treated with rituximab, we assessed the immunogenicity of the vaccines and the factors affecting seroconversion.


  Methods Top


This is a cross-sectional study done on a cohort of AIRD patients in regular follow-up at Center of Arthritis and Rheumatism Excellence (CARE), Kochi, Kerala. AIRD patients who have been treated with rituximab in the past and had estimated B cell counts 2 months prior to the first dose vaccination were included in the study. Those patients who had a history of prior COVID 19 or whose prevaccination B cell counts were not available were excluded. Serum samples were obtained from the patients 1 month after the second dose of vaccination. Peripheral blood B-cell counts were estimated using a DxFLEX flow cytometer by Beckman Coulter using Anti-CD19 conjugated with fluorochrome PE (phycoerythrin, Beckman Coulter) with acquiring a minimum of 20000 events. If the percentage of B-cell was >0.01% of the total lymphocytes its was considered that B cells have repopulated.[15] Immunoglobulin G antibody titers directed against the receptor-binding domain (RBD) of Spike1 protein of SARS-CoV-2 was estimated using the elecsys chemiluminescent assay (Roche, Switzerland) as per the manufacturer's instructions. If the value is >0.84, it was considered as positive.

Statistical analysis

Normality of data was checked by the Shapiro–Wilk tests. The continuous variables were assessed using the t-test, whereas categorical variables were compared using the Chi-square test. Antibody titers were compared by the Student's t-test after log conversion.


  Results Top


We identified 38 patients with AIRD who have been treated with Rituximab and had received both doses of COVID-19 vaccine. Five patients were excluded from the analysis as their prevaccination B-cell counts were not available. Of the 33 patients, 27 had received ChAdOx1 and 6 other had received BBV152. The mean age was 56 years (52–65.5) in CD19 repopulated group and 58 years (51–65.5) in CD 19 nonrepopulated group (P = 0.80) with majority being females. Other variables such as the type of vaccine, duration, and number of rituximab doses were similar between the groups (P < 0.01) [Table 1]. The most common rheumatic disease was rheumatoid arthritis.
Table 1: Characteristics of autoimmune rheumatic diseases patients who had previously received rituximab divided into two groups: One with and the other without B-cell repopulation

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Out of the 33 patients, 22 patients with B-cell repopulation, 18 (81.8%) seroconverted, whereas among 11 who did not have any detectable peripheral B-cells before vaccination, only 1 (9.09%) developed antibodies postvaccine. The median (interquartile range) anti spike antibodies developed in patients who did not have any detectable peripheral B cells before vaccination was 0.4 (0.4–0.4), whereas it was 239.25 (42.47–1974.5) in patients with detectable peripheral B cells before vaccination. [Table 1] shows the characteristics of groups with and without peripheral B-cells repopulation. Although all patients who had received the last dose of RTX at least 1 year before the vaccination had B-cell repopulation and developed antibodies, there was no direct correlation between time interval from the last dose and antibody positivity (P > 0.05). B-cell re-population was strongly associated with seroconversion [Figure 1]; exact test: P = 0.0001]. Although B cell repopulated in all the patients who had received rituximab a year before vaccination and in some patients who had taken last dose of RTX within 1 year, the B cell repopulation was variable.
Figure 1: Seroconversion status and B cell population assessed after 1 month of vaccine showing strong association. Although all patients who had received the last dose of RTX (rituximab) at least 1 year before the vaccination had B cell repopulation and developed antibodies, there was no direct correlation between time interval from the last dose and antibody positivity (P > 0.05)

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  Discussion Top


The recommendation for timing for COVID-19 vaccination in persons who had received rituximab was based on expert opinion only. The current study shows that the key factor determining sero-conversion is B cell repopulation. Rituximab depletes naive B cells in the blood, lymphoid tissue and to some extent in bone marrow and can also disrupt germinal center formation in secondary lymphoid tissues.[16],[17]

B-cells play an important role in the development of humoral immune responses.[18] Recent studies have shown that Rituximab affects antibody response to COVID-19 vaccination.[19],[20] Mrak et al. had showed that humoral responses can be mounted once peripheral B cells are present and the number of peripheral B cells correlate with the levels of antibody.[14] The availability of B-cell counts before vaccination and the wide variation in the timing between the last RTX dose and SARS-CoV-2 vaccination enabled us to show that B-cell repopulation is a better biomarker for COVID-19 vaccination than the time since the last Rituximab dose. Similar data have also been reported in ANCA-associated vasculitis.[21] Limitations of the study were data regarding cell-mediated immunity was not available for the cohort. However, recent studies have shown that antibody titers against the RBD domain of the viral spike protein correlate with real-world immunity against COVID-19 infection.[22] Another limitation is that the diseases and immunosuppression, which may act as confounders could not be matched between the groups. A study done in CARE previously had shown that antibody production occurs in patients on RTX even postnatural infection.[23]

The current recommendation for COVID-19 vaccination to be delayed till just before the next anticipated RTX dose is based mostly on expert opinion and a study on influenza vaccination.[13],[24] It stems from the belief that the effects of RTX lasts for 6 months and immune responses will be blunted until then. Although there is still some controversy on spacing RTX based on B-cell counts,[25],[26] it can be utilized for predicting the optimal time for vaccination. Hence, seroconversion to SARS-CoV-2 vaccination in rituximab-treated patients depends on peripheral B-cell repopulation rather than the timing of the vaccine. Thus, it may be a better strategy to assess B cell counts before vaccination and plan vaccination accordingly.

Financial support and sponsorship

This study was funded by Indian Rheumatology Association.

Conflicts of interest

Sakir Ahmed has received honorarium as speaker from Pfizer, DrReddy's, Cipla and Novartis (outside of the current work). The other authors declare no conflicts of interest.



 
  References Top

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Furer V, Rondaan C, Heijstek M, van Assen S, Bijl M, Agmon-Levin N, et al. Incidence and prevalence of vaccine preventable infections in adult patients with autoimmune inflammatory rheumatic diseases (AIIRD): A systemic literature review informing the 2019 update of the EULAR recommendations for vaccination in adult patients with AIIRD. RMD Open 2019;5:e001041.  Back to cited text no. 4
    
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Mrak D, Tobudic S, Koblischke M, Graninger M, Radner H, Sieghart D, et al. SARS-CoV-2 vaccination in rituximab-treated patients: B cells promote humoral immune responses in the presence of T-cell-mediated immunity. Ann Rheum Dis 2021;80:1345-50.  Back to cited text no. 14
    
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Bavaliya M, Shenoy PAB0470 Efficacy of Very low Dose (100MG) Rituximab in Active Rheumatoid Arthritis Despite Combinations Dmards Annals of the Rheumatic Diseases 2015;74:1054.  Back to cited text no. 15
    
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Cioc AM, Vanderwerf SM, Peterson BA, Robu VG, Forster CL, Pambuccian SE. Rituximab-induced changes in hematolymphoid tissues found at autopsy. Am J Clin Pathol 2008;130:604-12.  Back to cited text no. 16
    
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Ramwadhdoebe TH, van Baarsen LG, Boumans MJ, Bruijnen ST, Safy M, Berger FH, et al. Effect of rituximab treatment on T and B cell subsets in lymph node biopsies of patients with rheumatoid arthritis. Rheumatology (Oxford) 2019;58:1075-85.  Back to cited text no. 17
    
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Deepak P, Kim W, Paley MA, Yang M, Carvidi AB, El-Qunni AA, et al. Glucocorticoids and B cell depleting agents substantially impair immunogenicity of mRNA vaccines to SARS-CoV-2. medRxiv 2021;2021:21254656.  Back to cited text no. 19
    
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Connolly CM, Koenig D, Ravi SN, Azar A, Kant S, Dalal M, et al. Correspondence on “SARS-CoV-2 vaccination in rituximab-treated patients: Evidence for impaired humoral but inducible cellular immune response” by Bonelli et al. Ann Rheum Dis 2021;80:e164.  Back to cited text no. 21
    
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Bergwerk M, Gonen T, Lustig Y, Amit S, Lipsitch M, Cohen C, et al. Covid-19 breakthrough infections in vaccinated health care workers. N Engl J Med 2021;385:1474-84.  Back to cited text no. 22
    
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Shenoy P, Ahmed S, Shanoj KC, Shenoy V, Damodaran D, Menon AR, et al. Antibody responses after documented COVID-19 disease in patients with autoimmune rheumatic disease. Clin Rheumatol 2021;40:4665-70.  Back to cited text no. 23
    
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Van Assen S, Holvast A, Benne CA, Posthumus MD, van Leeuwen MA, Voskuyl AE, et al. Humoral responses after influenza vaccination are severely reduced in patients with rheumatoid arthritis treated with rituximab. Arthritis Rheum 2010;62:75-81.  Back to cited text no. 24
    
25.
Charles P, Terrier B, Perrodeau É, Cohen P, Faguer S, Huart A, et al. Comparison of individually tailored versus fixed-schedule rituximab regimen to maintain ANCA-associated vasculitis remission: Results of a multicentre, randomised controlled, phase III trial (MAINRITSAN2). Ann Rheum Dis 2018;77:1143-9.  Back to cited text no. 25
    
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