Multimodal Safety Assessment of Measles-Mumps-Rubella Vaccination After Pediatric Liver Transplantation

Laure F. Pittet; Charlotte M. Verolet; Valérie A. McLin; Barbara E. Wildhaber; Maria Rodriguez; Pascal Cherpillod; Laurent Kaiser; Claire-Anne Siegrist; Klara M. Posfay-Barbe

Disclosures

American Journal of Transplantation. 2019;19(3):844-854. 

In This Article

Discussion

In this cohort of 44 pediatric LT recipients that fulfilled our vaccination criteria, we did not observe any serious adverse events related to MMR vaccination and we demonstrated that the vaccine is immunogenic reaching a high seroprotection rate (98%), similar to previous studies in both healthy individuals and transplant recipients.[6,11,22] One dose was sufficient to elicit seroprotection in 89% of our patients. While 38% lost this protection within 1 year, all responded to booster dose(s), which emphasizes the importance of annual serological monitoring to evaluate the need for subsequent booster dose(s) in immunocompromised patients.

Although exposure is more frequent in countries with low MMR-immunization coverage, measles may be imported and outbreaks can occur if the overall measles immunity of the population is less than 95%.[23,24] Recent large outbreaks have been observed in Europe and elsewhere. In Switzerland, vaccination coverage is only 86%, leading to sporadic outbreaks.[25] In 2016, measles incidence was 0.81 cases per 100,000 inhabitants.[26] For many children, the MMR vaccine cannot be given before transplantation due to their young age or unstable medical condition.[8,9,16] While postexposure management with nonspecific intravenous immunoglobulins may be effective to prevent death,[27] it is a costly intervention requiring hospitalization and not readily available in routine care. As measles is highly contagious, contact is not always recognized and diagnosis can be further complicated by atypical presentations in these immunocompromised patients. Thus, revising recommendations for measles immunization after transplantation may be warranted.

A unique multimodal approach was used to closely monitor MMR safety in LT patients after each immunization. The overall safety of MMR could not be fully assessed given the limited size of our study population and the low frequency of severe adverse events. However, this study adds much-needed data on the safe use of live vaccines in carefully selected SOT recipients.[12,14–19,28–33] By contrast with previous reports, measles RNA shedding was not detected after MMR vaccination in LT recipients, despite sensitive molecular assays.[34–36]

Measles vaccination should be encouraged before SOT. In our cohort, 70% of patients immunized before transplantation were seroprotected at inclusion and did not require further vaccination despite immunosuppression. Not surprisingly, patients immunized and transplanted at an older age had a higher chance of being seroprotected against measles at inclusion than those transplanted at a younger age. However, we identified five seroprotected patients who had been immunized before 9 months of age. This should encourage practitioners to administer MMR before transplantation by using an accelerated schedule if needed.[8] Nevertheless, one-third of our patients immunized before LT were not seroprotected at inclusion, a much higher rate of antibody loss than in healthy subjects. Similar observations have been made in HIV-infected patients,[37,38] indicating the impact of immune deficiency/immunosuppression on the persistence of measles antibodies. Remarkably, all patients responded to re-immunization, retaining high seroprotection rates during follow-up. Thus, regular serological monitoring after LT should be used to identify the need for booster doses.

While this study is somewhat limited by the small number of immunized patients, it is the largest cohort reported to date with the longest follow-up period that also presents detailed, individualized, multimodal safety monitoring. Measles-specific antibody concentrations were assessed using an ELISA (instead of the gold standard plaque reduction neutralization assay), not only because its correlation with protection was established in our laboratory conditions as elsewhere, but also because ELISA is used in routine practice and enables generalizability to clinical settings.[39] In healthy subjects, T cell-mediated immunity is considered a key factor in controlling measles virus replication and disease severity.[4,40] However, as its assessment is not standardized and the role of T cells in immunosuppressed patients is undefined, we consider serology as a more appropriate measure of immunogenicity in this population at present. We only monitored measles shedding, whereas the systemic adverse events observed after vaccination could possibly be partly due to rubella or mumps vaccine virus replication. Finally, while our study was limited to selected pediatric LT recipients, its results could be cautiously extrapolated to the adult LT population and perhaps also to other SOT recipients with similar immunosuppressive regimens.[41]

In summary, we demonstrated that the live attenuated MMR vaccine can be administered after LT, being well tolerated and inducing measles seroprotection in most children after a single dose. Yearly monitoring of measles serology identified patients requiring subsequent boosters, which also were immunogenic and safe.

processing....