A community divided: Post-transplant live vaccine practices among Society of Pediatric Liver Transplantation (SPLIT) centers

Abstract

Background:

Historically, the IDSA and the AST have recommended that live vaccines not be administered post-transplant due to concern for induction of vaccine-strain disease in immunocompromised hosts. However, recent prospective studies and revised AST guidelines published in April 2019 suggest that in the current era of immunosuppression minimization, live vaccines may be safely administered to select transplant recipients with resulting immunoprotection. The goal of this study was to assess current post-transplant live vaccine practices at individual pediatric liver transplant centers following the updated AST guidelines.

Methods:

A six-item email survey detailing center-specific post-transplant live vaccine practices followed by up to three response-specific questions were distributed between July 2019 and May 2020 to a representative from each center participating in the SPLIT consortium.

Results:

The overall survey response rate was 93% (41/44 centers). Only 29% (12/41) of centers offer live vaccines post-transplant; each of these 12 centers uses different eligibility criteria for live vaccines. There was no difference between large (ten or more transplants per year) and small (less than ten transplants per year) centers in likelihood to offer live vaccines post-transplant. The main reasons for a center not offering post-transplant live vaccines were safety concerns and inability to reach group consensus.

Conclusions:

The majority of pediatric liver transplant centers are reluctant to offer live vaccines post-transplant despite the updated AST guidelines. Prospective multicenter studies are needed to confirm safety and immunogenicity of live vaccines post-transplant.

1 |. INTRODUCTION

Historically, guidelines from the IDSA and the AST recommended against live vaccine administration after solid organ transplantation due to concerns of inducing vaccine-strain illness in immunocompromised hosts and inadequate immune response to vaccines while on immunosuppressive medications.^1,2 Over the past two decades, multiple case series report successful live vaccine administration in solid organ transplant recipients.^3–6 More recently, prospective studies have demonstrated that live vaccines can be both safe and immunogenic in transplant recipients on low levels of immunosuppression.^7–12 As such, an international multispecialty consortium of experts in pediatric transplantation, vaccinology, immunology, pharmacy, and infectious diseases assembled in 2018 to review the current evidence and to offer updated consensus recommendations.¹³ In their consensus report, they recommend consideration of live vaccine administration to liver transplant recipients susceptible to measles and/or varicella if doing well one-year post-transplantation and on “low-level immune suppression.”¹³ Additionally, in April of 2019, the AST ID COP revised their guidelines for immunization of immunocompromised solid organ transplant recipients to state that “MMR and varicella vaccination may be administered in carefully selected patients with appropriate education and close follow-up.”¹⁴

In light of these changing recommendations and the recent resurgence of measles infections across the globe increasing risk to susceptible transplant recipients,^15,16 we sought to understand current post-transplant live vaccine immunization practices among US and Canadian pediatric liver transplant centers. Specifically, we assessed whether programs (a) monitor immunity to measles and varicella post-transplantation, (b) offer MMR and varicella live attenuated vaccines to susceptible transplant recipients, and (c) have specific eligibility criteria for live vaccine use. In addition, for those centers offering live vaccines we sought to understand barriers faced when trying to implement a live vaccine policy. For those centers not offering live vaccines post-transplant, we sought to understand their remaining concerns about live vaccines and whether they anticipated making any policy changes in the next one to two years based on the newest AST guidelines and the consensus report.

2 |. METHODS

We conducted an email survey from July 2019 to May 2020 among 44 North American centers participating in the SPLIT registry, a consortium of pediatric liver transplant centers working together to assess long-term outcomes of children who undergo liver transplantation. The study was deemed exempt from patient consent by the Colorado Multiple Institutional Review Board prior to data collection. An introductory email was sent to all participants indicating that completion of the study implied informed consent.

2.1 |. Survey design and administration

The survey consisted of six single-choice, multiple-choice, or free-response questions that sought to understand a center’s post-transplant practices for assessing measles and varicella immunity and for providing live vaccinations to non-immune transplant recipients (see Data S1). The questions were designed with input from hepatologists, transplant infectious diseases specialists, liver transplant nurse coordinators, and survey design specialists at the Children’s Hospital Colorado and the University of Colorado and piloted among a sample of SPLIT hepatologists. The survey was electronically distributed through REDCap, a secure and HIPAA compliant web-based application designed for data collection for research studies, to the primary hepatology investigator at each of the 44 US and Canadian SPLIT centers. Up to three follow-up reminders were sent. If following the third reminder the survey was not completed, it was then sent to an alternative pediatric hepatologist identified at the same center. Three follow-up questions were emailed to respondents based on their initial survey responses.

2.2 |. Statistical analysis

All data were collected in REDCap. Descriptive statistics were used for most data and comparisons were made between groups using Fisher’s exact test. The number of transplants performed at each center was determined using Organ Procurement and Transplantation Network center data averaged between 2018 and 2019.¹⁷

3 |. RESULTS

The overall response rate was 93% (41/44 centers); 44% (18/41) of respondents were from centers that perform < ten transplants per year (small center) and 56% (23/41) were from centers that perform ≥ 10 transplants per year (large center). Centers from the United States made up 93% (38/41) of respondents; the remaining respondents (3/41) were from Canadian centers.

3.1 |. Use of antibody testing to assess for immunity against varicella and measles

Of all 41 centers in the study, 24% (10/41) routinely check measles, mumps, and varicella antibody titers in all liver transplant recipients to assess for immunity. Of the ten centers that check antibody titers post-transplant, one center checks titers in the first six months post-transplant, seven centers check titers at one-year post-transplant, and two centers check antibody titers at sporadic time points post-transplant.

3.2 |. Administration of live vaccines as part of standard post-transplant care

Of all 41 centers in the study, 29% (12/41) routinely offer live vaccines to liver transplant recipients; this has been the center’s practice in four for ≥ 10 years and in eight for < 5 years. There was no statistically significant difference in the likelihood of recommending live vaccines post-transplant between large centers and small centers; nine of 23 (39%) large centers and three of 18 (17%) small centers offer live vaccines post-transplant. Among the 12 centers routinely offering live vaccines post-transplant, criteria for determining patient eligibility for live vaccines varied (Figure 1). All 12 centers required the child to be on “low-dose” immunosuppression; however, there was no uniform designation of “low-dose” immunosuppression. The majority (9/12 centers) required single-agent immunosuppression. The required time interval post-transplant ranged from one to 5 years; the required time interval post-rejection ranged from 2 months to 4 years. Certain centers required negative titers (seven centers), an adequate lymphocyte count (four centers), having not received appropriate number of vaccine doses (two centers), no serious infections in the last 6 months (two centers), normal liver function tests (one center), a normal mitogen stimulation test (one center), a normal immunoglobulin G level (one center), an adequate neutrophil count (one center), no rituximab administered in the last six months (one center), a documented immune response to inactive vaccines (one center), and/or a compliant family who the center had confidence would call if an adverse event occurred following vaccination (one center).

FIGURE 1.

Criteria used to determine an eligible patient for post-transplant live vaccine administration (n = 12 centers)

Of the 12 centers that offer live vaccines, all stated that there was consensus among the providers at their centers to provide vaccines post-transplant. Initial barriers to implementation of a post-transplant live vaccine policy included not being able to offer vaccines in liver clinic (8/12), family concern or reluctance (2/12), and primary care physician concern or reluctance (2/12).

Of the 29 centers not offering live vaccines post-transplant; reasons for not offering live vaccines included concerns about safety (26 centers), inability to reach group consensus (ten centers), concerns about efficacy (eight centers), no capacity to give vaccines in liver transplant clinic (four centers), and prior adverse events with administration of live vaccines post-transplant (two centers). Twenty of these 29 centers anticipated definitely offering live vaccines in the next one to two years based on the updated AST guidelines. Of the nine remaining centers that did not anticipate offering live vaccines in the near future, reasons included needing more safety data (eight centers), needing more efficacy data (six centers), and needing clearer guidelines about appropriate candidates to receive post-transplant live vaccines (four centers).

3.3 |. Monitoring response to post-transplant live vaccination

Of the 12 centers administering live vaccines post-transplant, 67% (8/12) routinely assess antibody titers after administering live vaccines. Of these eight centers, three centers check antibody titers in the first two months after vaccination and five centers check antibody titers three months or greater after vaccination.

4 |. DISCUSSION

Recommendations regarding the use of live viral vaccines after pediatric solid organ transplantation are evolving.^13,14 Historically, the IDSA and the AST have recommended against administration of live vaccines post-transplant^1,2; however, updated guidelines in 2019 from the AST and an international group of experts suggested that live vaccines may be safe and immunogenic for select transplant recipients. We assessed current immunization practices among pediatric liver transplant centers in SPLIT following these updated recommendations and found wide variation still existed in monitoring of immunity and in consideration of live vaccine administration post-transplant.

Only 24% of all SPLIT centers routinely checked serologies to assess immunity against measles, mumps, and varicella post-transplant. Pediatric liver transplant recipients have a number of risk factors for inadequate protective immunity against measles, mumps, and varicella. Many pediatric liver recipients undergo transplant at a young age prior to completing their primary vaccinations. Despite recommendations from the IDSA that live vaccines can be accelerated and administered to children as young as six months of age,¹ in a recent survey of all pediatric liver transplants performed at SPLIT centers (excluding transplants for acute liver failure) less than 30% of liver transplant recipients ages six to eleven months of age have received accelerated live vaccines.¹⁸ Children with chronic liver disease often have suboptimal responses to vaccines.^19–21 In a study by Funoki et al of children undergoing liver transplant, the seropositivity rates after live vaccination pre–liver transplant were 47% for measles, 49% for mumps, and 68% for varicella.^22,23 Finally, even in those children who enter transplant with protective antibodies, immunosuppressive medications may result in waning immunity over time.^5,7,24–26 In a study of pediatric liver transplant recipients who entered liver transplant immune to measles and varicella, 22% lost immunity to measles and 63% lost immunity to varicella between two to seven years post-transplant.²⁷ With the national and international resurgence of measles, mumps, and varicella,^15,28 it is crucial to know a patient’s susceptibility to these viruses to help guide decisions about primary immunizations, booster immunizations, and post-exposure interventions.

The transplant community remains divided regarding best practice for vaccination post-transplant. Despite the updated AST 2019 guidelines, only one-third of SPLIT centers currently offer live vaccines as routine practice post-transplant. Taking into account center volume, approximately 34% percent of pediatric liver transplants at SPLIT centers in 2018 and 2019 were performed at centers that provide live vaccines post-transplant.¹⁷ Even among the 12 centers that provide post-transplant live vaccines, the definition of an eligible patient differs widely both regarding the appropriate timing of live vaccine administration as well as the definition of “low-dose” immunosuppression. This variation in center practice likely reflects the lack of data regarding eligibility criteria for live vaccination post-transplant.^7–12,29 In regard to timing post-transplant, the range in recent published studies and case series varies widely, ranging from six months to two years from the time of transplant.^7–12,29 Likewise, in regard to timing post-rejection, the recent literature varies from one month to six months post-rejection.^7–12,29 Criteria for defining “low-dose immunosuppression” also varies across studies with some studies allowing a recipient to still be on two immunosuppressive agents with tacrolimus troughs close to 10 ng/mL while other studies require a child to be on single-therapy immunosuppression with tacrolimus troughs < 5 ng/mL.^7–12,29

This survey study demonstrates that many pediatric hepatologists are still concerned about the safety and lack of efficacy data of live vaccines post-transplant and are waiting for more evidence before changing their practice. Large prospective, multicenter studies using defined parameters for live vaccine eligibility are needed to conclusively determine safety, immunogenicity, timing, eligibility, and effectiveness following live vaccination of pediatric liver transplant recipients. Longitudinal follow-up of children receiving live vaccines post-transplant will allow us to delineate best timing and schedules to provide long-term protection. An ideal study design would be structured to identify the optimal time for vaccination ensuring good immunologic response and inform optimal monitoring of immunity in immunosuppressed patients.

There are several limitations inherent to our study design. We only surveyed centers participating in SPLIT, so the findings of the survey may not be representative of the entire pediatric liver transplant community. However, SPLIT centers perform the majority of pediatric liver transplants done in the United States and Canada capturing ~ 85% of all transplants in a given year.^30,31 Additionally, only a single team member answered the survey for each center; therefore, responses may not represent uniform practice across an entire center. However, respondents stated that post-transplant live vaccine practice was uniform among their group. Finally, participants answered questions based on the best of their knowledge without reviewing individual patient charts to ensure accuracy of reported rates of antibody testing or immunization delivery.

Abbreviations:

AST

American Society of Transplantation

ID COP

Infectious Diseases Community of Practice

IDSA

Infectious Diseases Society of America

MMR

measles, mumps and rubella

SPLIT

Society of Pediatric Liver Transplantation