COVID-19 vaccines remain the main hope of stopping the ongoing pandemic, and for this strategy to achieve its full potential, estimates are that at least 70% of the population need to be vaccinated. As some countries continue to be ravaged by COVID-19, others have seen significant reductions in new cases due, at least in part, to widespread vaccination of their citizens. Over 2.3 billion doses have been administered worldwide, and more than 50% of eligible individuals have received at least one vaccine dose in more than a dozen different countries.
Patients who are immunocompromised are of particular concern. Not only are they at higher risk for negative outcomes if infected with COVID-19, but they also may be less likely to experience an adequate response to vaccination. Previous studies of other vaccines have been mixed. Adequate cellular and humoral responses to influenza or pneumococcal vaccines appear preserved for many patients receiving immunosuppressants. However, specific drugs like rituximab and methotrexate have been associated with decreased humoral or cellular responses to vaccination.
No unique COVID-19 vaccine-related adverse events have been identified in patients receiving immunosuppressants. Currently, general recommendations concerning the administration of inactivated vaccines to persons with altered immunocompetence state that inactivated vaccines can be safely administered but effectiveness may be suboptimal. Standard vaccine doses and schedules are recommended, but when possible, it is recommended to complete the COVID-19 vaccine series at least two weeks prior to starting an immunosuppressant.
General considerations
The humoral or cellular immune response to various COVID-19 vaccines have been evaluated in different populations who often require immunosuppressant medications. Of solid organ transplant recipients,10% to 54% of patients displayed antibody responses after two doses of an mRNA vaccine. In another study of transplant recipients, two/12 (17%) of vaccinated with an adenovirus-based COVID-19 vaccine had a detectable antibody response compared to 59% of those vaccinated with an mRNA vaccine. Antibody responses tend to be more favorable in patients with chronic inflammatory disease (CID) or rheumatic or musculoskeletal disease (RMD), with 65% to 100% of patients receiving an mRNA or inactivated virus vaccine series displaying a measurable antibody response, though antibody titers were lower among patients than controls. Similarly, fewer patients receiving cytotoxic chemotherapy for treatment of solid tumours had a neutralising antibody response to the mRNA vaccine series than did controls (80% versus 100%).
Specific immunosuppressant regimens appear to be at least one significant factor in the variable responses observed in these studies. Rituximab, mycophenolate, methotrexate, and corticosteroids are among the medications associated with poorer responses, while the tumour necrosis factor-α inhibitors do not appear to interfere with vaccine response. Based on the mechanisms by which these and some other medications work and available data regarding their impact on vaccine response, some organisations have issued recommendations regarding the timing of COVID-19 vaccination relative to the administration of certain immunosuppressants in patients with RMD. Specific medications addressed in these studies or published guidelines are discussed below.
Medication-specific considerations
Rituximab and other B-cell Depleting Medications
Rituximab is an anti-CD20 monoclonal antibody that is likely to decrease B-cell mediated immune response due to its depletion of CD20+ B-cells. In reports of patients without a serologic response to COVID-19 mRNA vaccination, 55% to 95% of non-responders received rituximab. In small studies of patients who received rituximab for rheumatologic disease, only 20% to 33% had an antibody response to the mRNA vaccine. Patients with a serologic response tended to have a greater time since last rituximab dose (median 704.5 days versus 98 days, respectively) and a greater degree of B-lymphocyte reconstitution.
Published recommendations encourage at least four weeks between initiation of the vaccine series and the next rituximab dose, when possible, as well as delaying rituximab for two to four weeks following the final vaccine dose if disease severity allows. For patients currently receiving rituximab, some recommendations encourage vaccinating at least 12 weeks to six months after rituximab treatment.
Whether other anti-CD20 medications (obinutuzumab, ocrelizumab, ofatumumab, ibritumomab tiuxetin), anti-CD52 medications (alemtuzumab), or other agents that can decrease circulating B-lymphocyte populations would have a similar effect as rituximab is unclear. Similarly, the optimal timing for COVID-19 vaccination relative to these agents is not known.
Mycophenolate, Azathioprine
Mycophenolate inhibits de novo guanosine nucleotide synthesis, on which T- and B-lymphocytes are dependent. Azathioprine also blocks purine synthesis, though not with the same specificity for lymphocytes. Antibody response after the mRNA vaccine series was particularly low in solid organ transplant recipients who were receiving a regimen containing mycophenolate or azathioprine (32% vs. 82% in patients not receiving these agents). Similarly, several small studies have shown poor antibody response or vaccine response in both solid organ transplant and RMD patients receiving mycophenolate and/or azathioprine, sometimes as low as 27%.
Rheumatology guidelines recommend holding mycophenolate for one week after each vaccine dose when possible. This is specific to use of mycophenolate for CID/RMD, as temporarily holding mycophenolate may not be recommended in transplant recipients. No specific recommendations have been issued for adjustments to azathioprine.
Methotrexate
At higher doses methotrexate inhibits the formation of reduced folates, leading to inhibition of purine synthesis and interference with DNA synthesis and repair. However, the mechanism by which methotrexate works at the lower doses typically used for rheumatoid arthritis and similar conditions is uncertain, but some impact on immune function is likely. In patients with CID/RMD, lower antibody response following the mRNA vaccine was observed in patients treated with methotrexate compared to other immunosuppresants (50% to 72% response with methotrexate vs. 91% to 92% with other immunosuppressants and 96% to 98% in healthy controls). In contrast, methotrexate use was not associated with poor vaccine response in several other studies.
Guidelines recommend holding methotrexate (specifically for RMD) for one to two 2 weeks after each vaccine dose when possible. One publication also recommends holding the methotrexate dose scheduled prior to the vaccine, but that recommendation is not included in other publications. No specific recommendations are available for higher, anti-cancer doses of methotrexate.
Janus Kinase Inhibitors
Janus kinase (JAK) inhibitors interfere with immune cell function by inhibiting the activation of signals responsible for upregulation of immune cell activity. There is limited data about the impact of JAK inhibitors on COVID-19 vaccine response. In one study of patients with RMD, two of the three patients receiving the JAK inhibitor tofacitinib had a measurable antibody response to a first COVID-19 mRNA vaccine dose.
Guidelines recommend holding JAK inhibitors (ie, baricitinib, tofacitinib, upadacitinib) for one week after each vaccine dose when possible.
Selective T-lymphocyte Costimulation Blockers
The selective T-lymphocyte costimulation blockers inhibit T-lymphocyte activation by interfering with the interaction between antigen presenting cells and T-lymphocytes. Studies have reported decreased response to the COVID-19 mRNA vaccine among post-transplant patients treated with belatacept. Between 5% and 6% of patients had an antibody response, and cellular immune response was observed in only 30% of patients one month after the second vaccine dose. Less data exists with abatacept, but in one study of patients with RMD, 3 of 6 (50%) patients receiving abatacept demonstrated an antibody response after the first mRNA vaccine dose.
No recommendations for adjustments to the timing of belatacept relative to COVID-19 vaccination have been published. Guidelines recommend holding subcutaneous (SQ) abatacept for both one week prior to and one week after the first vaccine dose, and to time intravenous (IV) abatacept so that the first vaccine dose is administered four weeks after the abatacept infusion and then to postpone the subsequent infusion for one week after the first vaccine dose. No interruption of abatacept administration is required around the second vaccine dose.
Cyclophosphamide
Cyclophosphamide is an alkylating agent that interferes with DNA synthesis and cell division, with substantial immunosuppressive actions. Specific data regarding concurrent use of the COVID-19 mRNA vaccine in patients treated with cyclophosphamide are not available. However, rheumatology guidelines recommend timing intravenous (IV) cyclophosphamide administration for at least one week after each vaccine dose when possible. For orally administered cyclophosphamide no modifications to the timing of cyclophosphamide or the vaccine are required. These recommendations are specific to use of cyclophosphamide for RMD and do not apply to cyclophosphamide used to treat cancer or for other indications.
Corticosteroids
Corticosteroids interfere with normal immune function in a variety of mechanisms. Systemic corticosteroids are subject to dose- and duration-dependency regarding their immunosuppressant effects. Corticosteroid doses equivalent to > 2 mg/kg or 20 mg/day of prednisone (for persons over 10kg) administered for ≥ 2 weeks are generally considered sufficiently immunosuppressive to warrant concern about coadministered vaccines. Corticosteroid use (particularly higher-dose) has been associated with impaired antibody response to COVID-19 vaccination in several studies of post-transplant patients as well as in patients with RMD. Most published guidelines for patients with CID/RMD do not include recommendations specific to corticosteroids, though one recommends vaccinating when the corticosteroid dose is <10 mg/day of prednisone (or equivalent) as possible.
Conclusions
Immune suppression does appear to decrease the antibody response to COVID-19 vaccines. This seems to be particularly significant among solid organ transplant recipients. Patients receiving rituximab, mycophenolate, and several other medications seem less likely to experience an antibody response. The extent to which antibody response findings relate to overall vaccine responsiveness and infection risk is unclear. Data with influenza vaccines have suggested that cellular immune response and recall responsiveness can remain at high levels despite the lack of an antibody response after vaccination.
The optimal management for patients requiring treatment with immunosuppressants is uncertain. Guidelines for adjusting the timing of selected immunosuppressants in patients with CID/RMD have been published, but these address only one specific population of at-risk patients. Decisions to delay immunosuppressive therapy for COVID-19 vaccination should consider a person’s risks relative to their underlying condition. It is not clear if patients vaccinated while receiving immunosuppressants should be revaccinated after immune competence has been restored or if such patients would benefit from receipt of an additional booster. In one case series of post-transplant patients with a low/no response to two doses of the mRNA vaccine, more than 50% continued to have a poor antibody response following receipt of a third vaccine dose. All patients should continue to adhere to current public health recommendations regarding minimising possible exposure to the virus, including ensuring that all eligible close contacts get vaccinated.
Dr Daniel S. Streetman is the manager of referential content in the Metabolism, Interactions, & Genomics group for Clinical Effectiveness at Wolters Kluwer, Health
