Live Vaccines in Pediatric Liver Transplant Recipients: “To Give or Not to Give”

Content available: Audio Recording Historically, live attenuated vaccines (LAVs; measles, mumps, rubella, and varicella) have not been recommended for transplant recipients because of concern of inciting vaccine-strain illness in an immunocompromised patient. However, recent studies have demonstrated safety and immunogenicity of live vaccines in select transplant recipients. In addition, the number of measles cases is increasing nationally and internationally, placing nonimmune transplant recipients at risk for community acquisition. As a result, recommendations about live vaccine use in transplant recipients have recently changed and will be discussed in detail in this review. Since the start of solid organ transplantation (SOT) in the second half of the 20th century, the American Society of Transplantation (AST) and Infectious Diseases Society of America have recommended against administration of LAVs after LT.1, 2 The rationale for this recommendation included the following concerns: (1) that LAVs could produce overwhelming vaccine-strain illness in an immunocompromised transplant recipient, (2) a dysregulated immunological response to LAVs while on immunosuppressive agents could result in allograft rejection, and (3) an immunocompromised host may not be able to mount a protective response to LAVs.3 The dogma that LAVs could never be given after LT was first challenged during the late 1980s and early 1990s when individual providers, concerned about the risk of community measles acquisition in their nonimmune patients, began administering LAVs to certain transplant recipients. Small case series, initially in bone marrow transplant recipients and then in LT recipients, showed safety of measles, mumps, and rubella (MMR) and measles-only vaccines, respectively.4, 5 These small studies laid the foundation for larger retrospective reviews and prospective cohort studies of LAV in SOT recipients.5-15 In addition, better understanding of how to use immunosuppressive agents in pediatric LT recipients resulted in a trend toward immunosuppression minimization, thus reducing the theoretical risk for LAVs in the LT population.16-21 Over the past three decades, there have been several retrospective, cohort, and prospective studies looking at safety and immunogenicity of LAVs after pediatric SOT.5-15 In these studies, seroconversion rates after vaccination ranged from 44% to 63% for measles, 73% to 100% for mumps, 100% for rubella, and 32% to 97% for varicella (Table 1).7-11 Mild adverse events were observed (including fever, local reaction, and disseminated rash); however, there were no cases of disseminated infection. There was one case of allograft rejection 3 weeks after measles vaccination; however, there were no clinical features to suggest measles, and it was impossible to determine whether the vaccine triggered the rejection.5 Other reported cases of rejection after vaccination occurred a minimum of 6 months after and were considered unrelated to the vaccination itself.7, 10 In a recent Japanese retrospective analysis of 209 pediatric LT recipients who received 422 LAVs between 2010 and 2019, no serious adverse events were reported.22 Although there are no studies to support prolonged immunogenicity and clinical protection after administration of LAVs to pediatric LT recipients, Verolet et al.23 found that with appropriate boosters, 96% of pediatric LT recipients maintained protective antibody concentrations at a median of 5.5 years after vaccination. In 2000, measles was declared to be eliminated from the United States, and the risk for community acquisition for non-immune LT recipients was minimal. However, because of vaccine hesitancy and resistance among the general population, herd immunity has fallen, and there has been a resurgence in vaccine-preventable infections. In 2019, there were 1,282 measles cases in the United States, the highest number of cases since 1992 (Fig. 1).24 Likewise, in 2019, there were more than 800,000 confirmed cases of measles globally, up 300% from the year prior.25 The severe acute respiratory syndrome-associated coronavirus 2 epidemic has led to significant decreases in childhood immunizations nationally and internationally.26 Even before the pandemic started, twenty-nine states reported kindergarten measles vaccination rates at less than the 95% level necessary to ensure herd immunity against measles, with two of the states (Idaho and Colorado) at less than 90% (Fig. 2).27 It is likely that many additional states are now below the herd immunity threshold. COVID-19 has left the entire global community at risk for a resurgence in vaccine-preventable infections, and immunocompromised pediatric LT recipients are at significant risk for community acquisition. Based on the increasing risk for community acquisition of measles, along with multiple studies showing safety and immunogenicity, a group of international experts convened in 2018 to provide updated guidance on this topic. After reviewing the literature, they recommended that LAVs are likely to be safe in pediatric SOT (liver and kidney) recipients who are clinically well, more than 1 year after LT, more than 2 months after any acute rejection episode, and meet specific immune criteria on low levels of immunosuppression.28 In addition, in 2019, the AST Infectious Disease Community of Practice also revised their guidelines for immunization of SOT recipients stating that MMR and VZV vaccination may be administered in carefully selected patients with appropriate education and close follow-up.29 Despite the growing body of literature supporting the safety and immunogenicity of LAVs in LT recipients, as well as these updated consensus and community of practice guidelines, significant variability remains in vaccine practices among pediatric LT providers. A recent survey of Society of Pediatric Liver Transplantation (SPLIT) centers demonstrated that only 29% of pediatric LT centers currently recommend live vaccines posttransplant.30 Reasons for not recommending LAVs posttransplant included concerns about vaccine safety (90% of centers), concerns about vaccine efficacy (28% of centers), inability to reach consensus among transplant providers at their center (34% of centers), no capacity to give live vaccines in transplant clinic (14% of centers), and/or prior history of adverse events with administration of live vaccines posttransplant (7% of centers).30 Likewise, in a recent survey of members of the International Pediatric Transplantation Association, only 57% of respondents believe that LAVs should be administered posttransplant, and only 21% have actually administered LAVs to one of their transplant recipients.31 Both of these studies occurred after the Suresh and AST consensus papers28, 29 were published, suggesting that not only is education required to update transplant providers on new recommendations but also that further studies are needed to obtain additional data to ensure full support from the entire transplant community. Large multicenter prospective studies are clearly needed to confirm safety and immunogenicity of LAVs after transplant and to better define which transplant recipients are appropriate candidates for LAVs. Currently, there is a prospective observational study being jointly conducted by SPLIT and the Pediatric Infectious Diseases Society to collect these needed data. More than 25 pediatric and liver kidney centers are contributing clinical, laboratory, and immunological data on transplant recipients who receive LAVs. The goal of this study is to collect larger amounts of pragmatic data on safety, immunological response, and clinical protection after LAVs in children posttransplant. In addition, novel health information technology tools such as mobile apps could be used to provide education to families and providers about changing recommendations; enhance communication between families, primary care physicians, and transplant providers about vaccines; and provide automated reminders when vaccines are due.32-35 One of the authors (A.G.F.) has worked with the CANImmunize laboratory in Canada to develop a transplant-specific immunization app and will be evaluating the app as a vaccine implementation strategy in the future.36-38 Although the available data suggest that LAVs are safe and immunogenic in pediatric LT recipients, there are important nuances to consider when discussing live vaccines for pediatric transplant recipients. The following points are not meant to preclude LAVs in all LT recipients. Rather, the below counterpoints are intended to aid in the informed consent process with patients, to ensure shared decision making with families, and to guide future research. First, although vaccine-strain measles and varicella infections are rare, there have been case reports in highly immunocompromised hosts.39-41 The studies that have been done to date are not powered to detect these rare serious adverse events. Second, although antiviral therapy is available for varicella infection, there is no effective therapy for measles beyond supportive management should a transplant recipient acquire measles from the vaccine. Infection with measles virus in an immunocompromised individual carries a 40% to 70% mortality rate.42 This concerning statistic argues for vaccination in immunocompromised posttransplant patients; however, it also emphasizes the importance of selecting transplant patients at the lowest risk for acquiring vaccine-strain infection. These patients, as outlined in the 2018 consensus guidelines, include those who are at least a year out from transplant, not currently being treated for graft rejection, on low-dose immunosuppression, and with normal immune function.28 Given local and international measles epidemics over the last several years and decreasing population herd immunity secondary to vaccine hesitancy and refusal, it is time for the transplant community to reassess whether LAVs should be contraindicated posttransplant. The small theoretical risk of acquiring infection from a LAV may now be outweighed by the very real risk of community exposure for pediatric LT recipients. Studies suggest that for select clinically well LT recipients on low-dose immunosuppression, LAVs may not only be safe but also efficacious and clinically protective. Multicenter prospective studies are needed to confirm safety and define the appropriate timing posttransplant to receive live vaccines.

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