key: cord-0727946-ifuc31qt
authors: Bemben, Nina M.; Berg, Melody L.
title: Efficacy of inactivated vaccines in patients treated with immunosuppressive drug therapy
date: 2022-02-18
journal: Pharmacotherapy
DOI: 10.1002/phar.2671
sha: cb90574fcaf8155152e9c0a0d891829fb3598fc3
doc_id: 727946
cord_uid: ifuc31qt

Inactivated vaccines are generally considered safe in immunocompromised patients but the ability of immunocompromised patients to generate an effective immune response to vaccines is uncertain. Although recent reviews have focused on the effects of vaccines in patients who are immunocompromised due to various disease states (primary immunodeficiency), the effects of immunosuppressive drug therapy (secondary immunodeficiency) has received relatively less attention. This review evaluates evidence regarding the efficacy of inactivated vaccines against influenza, COVID‐19, and other diseases in patients treated with immunosuppressive oncologic agents, immunosuppressants used for transplant recipients, and immunosuppressants used for autoimmune disorders. Although evidence is mixed for many immunosuppressive agents and vaccines, most studies have found an attenuated immune response to inactivated vaccines, with the majority of data indicate anti‐B‐cell antibodies have a more severe and prolonged negative effect on vaccine efficacy.

It is well known that immunosuppression impairs the ability of the immune system to effectively respond to vaccination. Although recent reviews have examined the response to vaccination in patients who are immunosuppressed due to a particular disease state, 1 The objective of this review was to evaluate the available evidence surrounding the efficacy of inactivated vaccines in patients who are immunocompromised due to drug therapy and consider the differential impacts of particular immunosuppressive therapies.

Although many individual drug therapies and classes are recognized as immunosuppressants, a consensus definition of what constitutes an immunosuppressive agent is lacking. For the purposes of this review, an agent was considered immunosuppressive if its labeling (i) contains a warning regarding the risk of serious infections or malignancies associated with its use, (ii) recommends testing for tuberculosis or hepatitis prior to initiating therapy due to the risk of viral reactivation, (iii) warns about a potential drug interaction with vaccines, or (iv) recommends dose adjustments for infectious complications, thrombocytopenia, neutropenia, or lymphopenia. In addition, systemic corticosteroids used for at least 2 weeks at immunosuppressive doses (≥2 mg/kg or 20 mg/day of prednisone [for persons

Several clinical studies have shown decreased antibody titer response to influenza vaccine in cancer patients being treated with chemotherapy when compared with healthy controls or patients with cancer who are in remission or not undergoing treatment. [5] [6] [7] A prospective study evaluated the response to trivalent inactivated influenza virus vaccine in 31 patients with ovarian cancer. Of the 31 patients included, 15 were treated with primary adjuvant chemotherapy or chemotherapy for recurrent disease consisting of cytotoxic chemotherapy (e.g., paclitaxel, carboplatin, liposomal doxorubicin), a VEGF inhibitor (e.g., bevacizumab, sorafenib), or a combination while 13 patients in remission received a dendritic cell vaccine with or without cyclophosphamide.

In addition, three patients in remission received no cancer treatment.

Fewer than 50% of patients achieved a 4-fold increase in hemagglutinin inhibition (HAI) titers for any of the three strains included in the influenza vaccine. 5 The frequency of patients achieving a 4-fold increase in HAI titers did not vary according to the number of chemotherapy cycles received or patient age. A second study evaluated influenza vaccination in 38 patients with breast cancer undergoing chemotherapy with fluorouracil, epirubicin, and cyclophosphamidecontaining chemotherapy regimens and found significantly lower vaccine response as measured by influenza virus-specific antibody titers among patients with breast cancer compared with healthy controls. 6 Vaccine efficacy was not significantly different between breast cancer patients who were vaccinated early (day 4) or late (day 16) during their chemotherapy cycle, although titers were numerically higher in the early vaccine group. Lastly, a study of 19 patients with chronic lymphocytic leukemia (CLL) treated with the irreversible Bruton tyrosine kinase inhibitor, ibrutinib, found that 26% of patients demonstrated seroconversion, as defined by an increase in HAI titers from <1:10 to ≥1:40 or a ≥4-fold increase in HAI titers, for at least one strain 3 months after influenza vaccination, and 37% of patients developed an influenza-like illness in the 6 months following vaccination. 7 The influenza-like illness was of grade 1 to 2 severity in all but one patient. 

Only one published study evaluated COVID-19 vaccination in patients treated with immunosuppressive oncologic agents. Among 195 patients with a hematologic malignancy or prior receipt of an allogeneic hematopoietic cell transplant (HCT) who received two doses of an mRNA COVID-19 vaccine, 47% developed IgG antibody levels consistent with an immune response to vaccination, compared with 87% in healthy controls. 10 The majority (67%) of these patients were treated with B-cell-targeted therapies, although a small number were treated other immunosuppressive oncologic agents such as cladribine, ibrutinib, and venetoclax. Despite the limited data available, patients with hematologic malignancies treated with immunosuppressive oncologic agents appear to have a diminished response to COVID mRNA vaccines.

This diminished immune response likely occurs with other COVID-19 vaccines as well. Current CDC guidelines recommend a three-dose primary series of COVID mRNA vaccines, followed by a booster dose at least 5 months later, for patients treated with immunosuppressants. 11

Although data surrounding influenza vaccination has generally shown decreased immune response to vaccination in patients receiving immunosuppressive oncologic agents, data with other inactivated vaccines is mixed. The response to the adjuvanted 23-valent pneumococcal polysaccharide vaccine, as measured by IgM levels 4 weeks after vaccination, was reduced among patients with chronic phase chronic myeloid leukemia treated with the tyrosine kinase inhibitors imatinib, dasatinib, or nilotinib when compared with that of healthy controls (40% vs 92% response rate in patients and controls, respectively). 12 Patients with breast cancer who received adjuvant chemotherapy with cyclophosphamide, methotrexate, and 5-fluorouracil and were vaccinated against tick-borne encephalitis (TBE) either during or 6 to 12 months after chemotherapy did not produce anti-TBE titers 2 to 4 weeks after the second of two vaccinations, although healthy controls did produce anti-TBE titers. 13 Patients who were vaccinated prior to initiating chemotherapy did develop significant anti-TBE titers, which persisted throughout chemotherapy.

In contrast, not all chemotherapeutic agents impair response to inactivated vaccines. Among 122 patients with multiple myeloma who underwent autologous HCT and were re-vaccinated against pneumococcus with the adjuvanted 13-valent pneumococcal conjugate vaccine 12 months after transplant, the response rate to pneumococcal vaccination (as measured by a 2-fold increase in titers for 70% of pneumococcal serotypes) was 58%, regardless of whether patients were receiving lenalidomide maintenance therapy or not. 14 In addition, the response rate to adjuvanted pertussis, diphtheria, tetanus, and Haemophilus influenzae (Hib) vaccinations administered beginning 1 year after transplant were 76%, 70%, 60%, and 71%, respectively. 14 Among 24 children receiving maintenance chemotherapy for acute lymphoblastic leukemia with cytotoxic chemotherapy (e.g., vincristine, daunorubicin, cytosine arabinoside, carmustine, mercaptopurine, doxorubicin, hydroxyurea, and/or cyclophosphamide), methotrexate, and/or prednisone who received booster doses of tetanus-diphtheria toxoids, followed by Hib 1 month later, patients had protective titers against tetanus, diphtheria, and Hib at rates of 100%, 92%, and 84%, respectively. 15 Vaccine response was defined as a pertussis toxin increase to >5 units/mL for pertussis, a 4-fold increase in protective antibody titers for diphtheria, >0.5 IU/ml for tetanus titers, and a non-protective to protective antibody level from <0.15 to ≥1 or 4-fold increase in antibodies for patients in the indeterminate range at baseline for Hib.

In summary, the available data suggest that patients undergoing treatment for cancer do not develop as robust immune response to inactivated vaccines as compared with healthy controls. However, patients who are vaccinated 1 year after HCT, and perhaps some pediatric oncology patients, do develop immune responses to inactivated vaccines. Adjuvanted vaccines, while generally associated with strong immune responses, do not ensure robust immune response in patients treated with immunosuppressive oncologic therapy. Importantly, how these immune responses correlate with protection from infection is not well defined.

A small study of seven patients with Non-Hodgkin's Lymphoma (NHL) treated with cyclophosphamide, doxorubicin, vincristine, prednisolone, and rituximab (R-CHOP) demonstrated that influenza vaccination produced a humoral response to recall antigens but not the primary antigen. 16 Other studies have found decreased rates of seroconversion after influenza vaccination among patients treated with rituximab compared with healthy controls or patients treated with other immunosuppressants, such tumor necrosis factor (TNF) inhibitors, or non-immunosuppressive therapies, such as disease-modifying antirheumatic drugs (DMARDs). [17] [18] [19] [20] Additionally, several studies found reduced immune response following influenza vaccine administration in rituximab-treated patients with rheumatoid arthritis (RA) [21] [22] [23] [24] [25] ; however, one study showed that the immune response to influenza vaccine seemed to return 6 to 10 months following rituximab administration. 24 Similar results were seen in rituximab-treated patients following influenza vaccination in other disease states including neuromyelitis optica spectrum disorder, other rheumatologic conditions, and NHL. [26] [27] [28] [29] Rituximab has been consistently shown to decrease the immune response to influenza vaccination across a wide range of disease states. This decreased immune response appears to persist for at least 6 months after rituximab treatment. Consistent with these findings, ACIP guidelines recommend vaccination with inactivated vaccines at least 14 days before initiating immunosuppressive therapy, and revaccination at least 6 months after rituximab discontinuation if vaccination occurs less than 14 days before or during rituximab therapy. 4 Clinical practice guidelines from the Infectious Disease Society of America (IDSA) do not recommend influenza vaccination for patients currently treated with rituximab, or those who received rituximab in the previous 6 months. 9 

The limited studies that have evaluated COVID-19 vaccination in patients treated with rituximab have consistently demonstrated decreased immune response to vaccination. One small prospective study evaluated five rituximab-treated patients and found only two patients had a detectable antibody response. 30 In a retrospective analysis of 89 patients with a rheumatologic disease who received at least one dose of the COVID-19 mRNA vaccine, 21 patients failed to achieve a serologic response and of those, 20 had received rituximab. 31 A total of 30 patients had been treated with rituximab in this analysis, and those who did respond to COVID-19 vaccination had significantly more time elapsed since their last rituximab exposure than those who did not respond to vaccination (704 vs. 98 days, respectively). Among patients receiving rituximab for oncologic diagnoses, a study of 195 patients with a hematologic malignancy or prior receipt of an allogeneic HCT, 67% of whom were treated with B-cell-targeted therapies such as rituximab, evaluated the efficacy of two doses of an mRNA COVID-19 vaccine, and found that 47% of patients developed IgG antibody levels consistent with an immune response to vaccination, compared with 87% in healthy controls. 10 Other studies have similarly found decreased response to the COVID-19 mRNA vaccine among patients treated with rituximab. 32, 33 Data evaluating the effect of rituximab on the adenovirus vector or inactivated COVID-19 vaccines are not currently available.

Although limited data are available, patients treated with immunosuppressive agents appear to have a diminished response to COVID mRNA vaccines. Current CDC guidelines recommend a three-dose primary series of COVID mRNA vaccines, followed by a booster dose at least 5 months later, for patients receiving immunosuppressants, such as rituximab. 11 

The immune response to other inactivated vaccines is also impaired among rituximab-treated patients. In a study of 24 patients with immune thrombocytopenia treated with rituximab who received a pneumococcal polysaccharide vaccination, only 21% achieved a 4-fold increase in anti-pneumococcal antibodies, compared to 67% of placebo-treated patients achieving a 4-fold increase in antipneumococcal antibodies after vaccination. 34 The same study found that only 29% of rituximab-treated patients achieved a 4-fold increase in antibodies after Hib vaccination, compared with 83% of placebo- 

Research has consistently shown that SOT patients have lower antibody titer response following influenza vaccination compared with healthy controls. [36] [37] [38] [39] [40] [41] [42] A study evaluating the incidence of influenza infection in renal transplant recipients found no difference in influenza infection rates between vaccinated versus unvaccinated renal transplant patients, suggesting vaccination did not provide protection against influenza in this patient population. 39 A study of liver transplant patients receiving a variety of immunosuppression regimens (e.g., cyclosporine with or without azathioprine and/or prednisone) showed that a second dose of influenza vaccine increased the proportion of patients having an antibody titer response of ≥40 from 68% to 80%. 38 Rates of seroconversion following influenza vaccination were lower in post-renal transplant patients receiving immunosuppression with tacrolimus or cyclosporine, mycophenolate mofetil, and methylprednisolone compared with dialysis patients (50% vs. 67%, respectively) but the rate did not seem to be impacted by dose of immunosuppressive therapy. 42 Some studies have shown the degree of response to influenza vaccine is impacted by type of immunosuppressive therapy. In studies of renal transplant recipients, immune response to influenza vaccination was better with azathioprine compared to cyclosporine-or mycophenolate-containing immunosuppressant regimens 43, 44 In contrast, antibody titer increase following influenza vaccination did not differ significantly between kidney transplant recipients receiving sirolimus-based immunosuppressive therapy versus calcineurin inhibitor-based regimens. 45 

Data available on efficacy and safety of COVID vaccine in the SOT population is limited to the mRNA COVID-19 vaccine. Thus far, use of the mRNA COVID-19 vaccine in the SOT population has not presented significant safety concerns but efficacy appears to depend on the number of vaccine doses and types of immunosuppressant used.

In one study, antibody response to first dose of mRNA COVID-19 vaccine was detected in only 15% of 658 SOT patients. 47 However, following the second dose, rates of antibody response ranged from 22 to 54%. [48] [49] [50] [51] [52] Type of immunosuppressive agent did not seem to impact response rate to COVID-19 vaccine in SOT recipients in one study, 49 whereas several studies showed that mycophenolate use reduced immune response to COVID-19 vaccination. [50] [51] [52] In a study of 609 transplant recipients, no patients receiving belatacept had a positive antibody response following first dose of mRNA COVID-19 vaccine compared to 14% of non-belatacept patients. 53 After the second dose of vaccine, 5% of belatacept patients had positive antibodies compared with 50% of the non-belatacept population. In a randomized trial, of 120 transplant recipients who had received 2 doses of mRNA COVID-19 vaccine antibody response occurred in 55% of transplant recipients receiving a third mRNA COVID-19 vaccine dose compared to 18% of patients receiving placebo. 54 Another study showed that the proportion of transplant patients with antibodies increased from 40% after the two-dose primary series of COVID-19 mRNA vaccine to 68% of patients 4 weeks after a 3rd supplemental dose. 55 Additionally, among the 59 patients who had been seronegative before the third dose, 44% were seropositive 4 weeks after the third dose.

Although limited data are available, SOT recipients seem to have a diminished response to COVID mRNA vaccines, the magnitude of which depends both on the type of immunosuppression used and the length of time elapsed since transplant. Current CDC guidelines recommend a three-dose primary series of COVID mRNA vaccines for patients receiving immunosuppressants, including solid organ or HCT recipients, followed by a booster dose at least 5 months later. 11 58 Longer time from transplant was associated with increased likelihood of vaccine response. Another study evaluating administration of two doses of PCV7 2 months apart followed by PPSV23 2 months later in 25 pediatric SOT patients showed that although antibody titers increased following the first PCV7 dose, it was a lower response than that seen in 23 age-matched healthy controls. 59 A significant antibody titer increase was not seen following the second PCV7 or PPSV23 doses in the SOT group. Immune response was worse among heart transplant recipients compared to liver transplant recipients.

The available data suggest that SOT patients treated with immunosuppressants have a diminished immune response to pneumococcal vaccination. Whether this diminished immune response is still sufficient to provide protection from pneumococcal infection is uncertain. The ideal pneumococcal vaccination schedule to maximize protection in SOT patients is also unknown.

The impact of immunosuppressant use for autoimmune diseases on immune response to vaccines can be more difficult to predict as the dose and frequency of immunosuppressant use may be more individualized depending on the condition treated, individual therapy goals, and flare frequency.

Data on efficacy of influenza vaccination in patients with autoimmune diseases has been conflicting. Studies have shown that patients with various autoimmune diseases, including RA, systemic lupus erythematosus (SLE), inflammatory bowel disease, and multiple sclerosis on different immunosuppressive regimens had a lower antibody titer response following influenza vaccination compared to healthy controls. [60] [61] [62] [63] [64] [65] [66] However, one study was not able to associate this reduced immune response to methotrexate-or prednisone-induced immunosuppression. 60 Another study in 24 patients with SLE found that those receiving azathioprine had a lower immune response to influenza vaccination, as measured by seroconversion and 4-fold increases in antibody titers, than patients receiving prednisone, hydroxychloroquine, or no treatment. 61 Similarly, reduced immune response to influenza vaccination as measured by increases in antibody titers was demonstrated in patients with psoriatic arthritis or ankylosing spondylitis treated with rituximab but not in those treated with methotrexate, anti-tumor necrosis factor (anti-TNF) therapy, or biologics. 67 A study in autoimmune patients on anti-TNF agents also confirmed no reduced immune response to influenza vaccination. 18 Several studies in patients with autoimmune diseases failed to show reduced immune response to influenza vaccination in patients on immunosuppressive therapy with corticosteroids and/ or DMARDs, TNF inhibitors, or IL-6 receptor antagonists compared with either healthy controls or patients not on immunotherapy. [68] [69] [70] For patients with autoimmune diseases on immunosuppressant therapy, the ability of influenza vaccination to induce an immune response depends on the type of drug therapy used for treatment.

Corticosteroids, DMARDs, TNF inhibitors, and perhaps azathioprine appear to present less risk of diminished immune response to influenza vaccine compared with other immunosuppressants.

The majority of data on the use of COVID vaccines in patients with autoimmune diseases are limited to the mRNA COVID-19 vaccine.

Most studies have shown safety and efficacy of the COVID-19 mRNA vaccine in this group but with the potential for reduced response depending on type of immunosuppressant therapy used. 32, 33, 72, 73 Two separate studies of patients with autoimmune diseases have shown that a higher proportion of patients not responding to the two-dose mRNA COVID-19 vaccine series were receiving mycophenolate. 33, 34 Another small case series in patients with RA and musculoskeletal diseases showed reduced immune response was associated with mycophenolate, corticosteroid, and rituximab use, whereas treatment with anti-TNF therapy was associated with a more favorable response. 71 In a study of patients with RA on various immunosuppressive therapy, administration of two doses of the mRNA COVID-19 vaccine with interruption of immunosuppressive therapy per American College of Rheumatology (ACR) guidelines (1 week for methotrexate and JAK inhibitors after each vaccine dose; 1 week before and after first vaccine dose only for abatacept) was found to be safe (no increase in disease activity) and effective (defined as humoral and t-cell specific response) in the majority of patients. 72 However, the degree of humoral and t-cell specific response was definitely influenced by type of immunosuppressive regimen with patients on IL-6 inhibitors or CLT4-inhibitors having a significantly lower titer response compared to a health care worker (HCW) control group.

A prospective cohort study examined the impact of the ACR recommendation for holding mycophenolate surrounding COVID-19 vaccination (either mRNA or adenovirus) and found a higher proportion of patients in the hold therapy group had a favorable immune response to vaccination compared to patients who did not hold mycophenolate therapy (92% vs 65%, respectively). 73 Two of 24 patients reported disease flare during the hold mycophenolate period requiring additional treatment with topical or oral corticosteroid therapy to control disease.

A small case series of 18 patients with autoimmune disease found that a booster dose of mRNA COVID-19 vaccine was associated with improved humoral response in almost all patients, with 80% of previous non-responders having a positive response. 74 Only two patients continued to fail to respond with one patient receiving mycophenolate and one receiving anti-CD20 therapy.

Finally, one observational study compared the response to adenovirus (n=45) versus mRNA (n=994) COVID-19 vaccines in patients with autoimmune disease and found that a higher proportion had a favorable immune response in the mRNA group versus the adenovirus group (92% and 80%, respectively). 75 Overall, although immunosuppressants used to treat autoimmune diseases appear to decrease the immune response to COVID-19 vaccination, the risk appears to be greatest with mycophenolate and inhibitors of IL-6 or CLT4. Guidance from the ACR recommends holding immunosuppressive therapies prior to COVID-19 vaccination; the duration of timing depends on the particular immunosuppressive agent used and level of disease activity. 76 As with other immunosuppressants, CDC guidelines recommend a threedose primary series of COVID mRNA vaccines for patients receiving immunosuppressants, followed by a booster dose at least 5 months later. 11

Several studies have suggested that patients with autoimmune diseases on immunosuppressant therapy have a lower antibody response to pneumococcal vaccination when compared with controls. 64, [77] [78] [79] [80] [81] [82] [83] However, antibody functionality, as measured by a multiplexed opsonophagocytic killing assay, was similar among healthy controls and patients with RA treated with abatacept or methotrexate, in one study. 78 Similarly, other studies found that among patients with RA, those treated with anti-TNF agents, 84 In a study of 73 patients with SLE on various immunosuppressive therapy regimens, administration of three inactivated vaccines, pneumococcal, tetanus toxoid (TT), and Haemophilus influenzae type B (HIib), was associated with a protective immune response in the majority of patients (90% and 88% for TT and HIB, respectively). 88 Protective immune response to pneumococcal vaccine was unable to be defined but 47% of patients had a 4-fold antibody titer response. Similarly, in a study of 43 autoimmune patients with inflammatory bowel disease who completed at least 24 weeks of therapy with azathioprine or 6-mercaptopurine, response to pneumococcal, TT, and HIB was similar to that of patients who were not treated with thiopurines. 89 Lastly, in a study of 68 patients with multiple sclerosis (MS), the proportion of patients responding to TT and PPSV23 vaccines was lower among those treated with ocrelizumab (23.9% and 71.6%, respectively) than those in the control group, who received interferon beta or non-diseasemodifying therapy (54.5% and 100%, respectively). 64 Overall, while some data suggest that patients with autoimmune disorders treated with immunosuppressant therapy may have a decreased immune response to inactivated vaccines compared with that of healthy controls, the majority of data indicate that the efficacy of inactivated vaccines, particularly adjuvanted non-influenza vaccines, is not compromised in patients with autoimmune disorders treated with these agents.

Although patients treated with immunosuppressant agents can safely receive inactivated vaccines, the efficacy of immunization is dependent on the specific immunosuppressant used. It is important to note that currently used measures of vaccine efficacy rely on the measurement of antibodies and, therefore, do not account for other measures of immune response (i.e., T-cell response) and

are not necessarily fully representative of the ability of vaccination to prevent infection or severe disease. The majority of data indicate that patients treated with oncologic agents, including rituximab, will have a reduced immune response to influenza vaccines. This is most likely due to the fact that influenza vaccines are not adjuvanted and, therefore, induce a less robust response than other adjuvanted inactivated vaccines. The response to other inactivated vaccines among patients treated with rituximab can similarly be expected to be diminished, although the data evaluating vaccine response in patients taking other oncologic agents is inconclusive. Solid organ transplant and patients with auto immune disorders treated with immunosuppressants can be expected to have a diminished immune response to inactivated vaccines, but the clinical relevance of this decrease in immune response is uncertain and likely depends on the specific agent used, as well as the time since transplant. In summary, although the antibodymediated immune response to inactivated vaccines is likely decreased in patients treated with immunosuppressant therapies, the impact of these therapies on other immune-mediated responses, as well as the ability of inactivated vaccines to provide protection against infection or serious disease remains to be fully investigated.

The authors would like to acknowledge Steve Stout, Daniel Streetman, Steve Sklar and Carrie Nemerovski for their support and assistance with the conceptualization of this project. 

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