key: cord-0982203-ve8zr3yy authors: Kant, Sam; Kronbichler, Andreas; Salas, Antonio; Bruchfeld, Annette; Geetha, Duvuru title: Timing of COVID-19 Vaccine in the setting of anti-CD20 Therapy: A Primer for Nephrologists date: 2021-04-01 journal: Kidney Int Rep DOI: 10.1016/j.ekir.2021.03.876 sha: 1c52b9bfdbe9bfc0a791b9b3962689a6cb7dafd3 doc_id: 982203 cord_uid: ve8zr3yy nan rejection. Obinituzumab and Ofatumumab are humanized anti-CD20 agents, currently in phase 2 clinical trial in systemic lupus erythematosus. We would be remiss not to mention that vaccine "rollout" has been slow in this vulnerable population and should be prioritized. The purpose of this document is to review previous literature pertaining to established vaccine use in the setting of anti-CD20 treatment, along with providing recommendations for the timing of COVID-19 vaccine and measurement of response to administration. It is our hope that this review will serve as a primer for understanding the pathobiology of B cell depleting therapy and be helpful to practitioners and trainees in nephrology. B-lymphocytes or B-cells are a central component of adaptive immunity and are a requisite for the secretion of antibodies against "non-self" antigens. B cell depleting therapies do not eliminate B cell immunity completely. Anti-CD20 therapy results in depletion of circulating CD20 positive B cells in the periphery, but not hematopoietic stem cells in the bone marrow or antibody producing long-lived plasma cells that lack CD20. 4 Therefore, humoral immunity to childhood vaccines such as tetanus or meningitis is preserved during therapy with anti-CD20 therapy. 5 Nevertheless, immune responses to vaccination during rituximab administration may be dampened. In addition, anti-CD-20 therapy is also associated with substantial T cell depletion. 6 Moreover, CD 20 positive memory B cells are not completely abrogated during anti-CD20 therapy but can rapidly expand and differentiate into antibody producing cells when restimulated. Whilst it is known that anti-CD20 therapy impairs the humoral response to vaccination, the interaction between CD-20 depletion and immune response to vaccine is complex and remains poorly understood. Vaccination is known to reduce rates of hospital admissions due to infections, emergency room visits and the rate of invasive infectious diseases in patients with autoimmune disease. 7 However, it has been extensively demonstrated that anti-CD 20 therapy (both rituximab and ocrelizumab) is associated with impaired vaccine response. This was first demonstrated in patients with neuromyelitis optica on rituximab therapy, with reduction in protective antibody titer and seroconversion rate (37·5 versus 75·0% healthy controls) post H1N1 influenza A vaccination. 8 Similar blunting in immune response has been reported with respect to pneumococcus, hemophilus influenza B, hepatitis B and tetanus toxoid in the context of anti-CD20 therapy. 9-S3 Additionally, antibody responses can be impaired up to 6 months after anti-CD20 therapy, with reduction in cellular immunity in parallel with depleted B-cell pools. S4,S5 It has been proposed that vaccine response is blunted until B cells repopulate. S1 Repopulation kinetics varies among the anti-CD20 agents ranging from 24 weeks to 35 weeks for rituximab, 40 weeks for Ofatumumab and 72 weeks for Ocrelizumab. Table 1 elucidates studies assessing response to vaccines in various disease populations being treated with rituximab. The European League Against Rheumatism (EULAR) provided updated guidelines for vaccinations in the setting of anti-CD20 therapy in 2019. S6 In light of the increasingly documented reduction in response to vaccines in the setting of B-cell depleting therapy, EULAR recommends the following: 1. Vaccines should be ideally administered before the planned immunosuppression. 2. In case of non-immunized patients on B cell-depleting therapy, vaccination should be provided at the following time window: at least 6 months after the administration and 4 weeks before the next course of B cell-depleting therapy, based on the state of clinical practice. 3. In cases when this time window for immunization is not possible, vaccination may be considered under B-cell depleting therapy, taking into consideration a potential suboptimal response to vaccine A COVID-19 vaccine guidance clinical summary released by the American College of Rheumatology issued the following recommendations after a moderate consensus among the North American task force panel: 1. Initiate the vaccine series 4 weeks prior to next scheduled rituximab cycle. 2. After vaccination, the guidance states to delay rituximab 2 to 4 weeks after the second vaccine dose, if disease activity allows The generation of neutralizing antibodies are likely central to protection against coronaviruses, as has been shown previously with severe acute respiratory distress syndrome (SARS) and middle east respiratory syndrome (MERS). S7,S8 This humoral response is likely to be dampened as a consequence of anti-CD20 therapy, as has been demonstrated extensively by vaccine response studies discussed previously. Therefore, appropriate timing of vaccine in relation to anti-CD20 therapy is of paramount importance to gain maximum efficacy of vaccine and mitigate risk of infection along with associated complications. Based on available data on rituximab B-cell repopulation kinetics and previous vaccine studies, the following are recommendations for timing of COVID-19 vaccine: 1. Administer complete vaccine series 12 weeks prior to anti-CD20 therapy, since better responses are achieved when similar timeline was employed between previous types of J o u r n a l P r e -p r o o f vaccination and rituximab administration. S9,S10 This approach is particularly feasible in patients with membranous nephropathy who are at mild to moderate risk of progression and patients with ANCA associated vasculitis who receive rituximab for remission maintenance. 2. Individualized risk assessment with respect to co-morbidities and infection along with risk of disease relapse, must be undertaken in deciding delaying anti-CD20 therapy to aid in vaccine administration. 3. Delaying anti-CD20 therapy in a patient with active disease or high risk of relapse in favor of receiving vaccine is not advisable. Accentuated measures of physical distancing and use of personal protective equipment can be helpful in mitigating risk of COVID-19 in patients with autoimmune disease. 1 4. Delaying administration of the vaccine 6 months after anti-CD20 therapy has been deemed to be ideal to maximize efficacy of vaccines in general and likely to be applicable to COVID-19 vaccine. S2 5. Measurement of B-cell populations could be undertaken 3 months after rituximab treatment for guiding vaccine administration, since any evidence of repopulation may be a 'window' for vaccine administration and ensuing desired immune response (with need for assessing for concomitant risk for incipient disease relapse). It has been demonstrated that B-cell repopulation kinetics post anti-CD20 therapy can vary in individuals and disease processes. S11,S12 6. As vaccine response may be attenuated or occur at lower rates after anti-CD20 therapy, vaccine response can be quantified with titers also taking into consideration development of emerging virus variants This may guide the decision to revaccinate individuals after B cell reconstitution. 7. Centers of excellence should establish protocols to measure humoral response to vaccine and correlate this with demographics, treatment related factors and immune profile of these patients. There is a paucity of data to guide timing of vaccine in the patients receiving anti-CD20 therapy and current recommendations are being extrapolated from prior vaccine studies and knowledge of B-cell repopulation kinetics. Therefore, a pressing need exists for studies that can elucidate seroconversion to the COVID-19 vaccine in the setting of anti-CD20 therapy, along with defining parameters for assessing durable response. This is even more pertinent given well established risk of severe COVID-19 in patients on immunosuppression and ongoing vaccine shortage worldwide. Disclosures DG reports being consultant to ChemoCentryx and Aurinia. The other authors do not report any conflict of interest. No financial support/funding was required for this study. Supplementary Material "Supplementary references" in "PDF" "Supplementary information is available at KI Report's website" Anti-Hbs-anti hepatitis B surface antibody, NMOSD-neuromyelitis optica spectrum disorder, RA-rheumatoid arthiritis, NR-not reported, ITP-immune thrombocytopenic purpura The impact of COVID-19 pandemic on patients with ANCA associated vasculitis Impacts of immunosuppression and immunodeficiency on COVID-19: A systematic review and meta-analysis Vaccinations in adults with chronic inflammatory joint disease: Immunization schedule and recommendations for patients taking J o u r n a l P r e -p r o o f synthetic or biological disease-modifying antirheumatic drugs. 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