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


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

In This Article

Materials and Methods

Study Design and Patients

This interventional, prospective, national cohort study was conducted at Geneva University Hospitals (Geneva, Switzerland), the Swiss national center for pediatric LT. All LT recipients were approached at least 1 year posttransplantation. A total of 90 patients less than 18 years of age were enrolled between April 2013 and December 2016. Written informed consent was obtained from parents/legal guardians. Further details are provided in the Appendix S1.

The study was performed in accordance with the principles of the Declaration of Helsinki and the study protocol was approved by the regional ethics committee (approval number CE12-226) and by the Swiss Agency for Therapeutic Products (Swissmedic, approval number 2013DR4003). All authors vouch for the accuracy and completeness of the data presented.

Antigen-specific Antibody Titer

Measles specific IgG antibodies were assessed using automated enzyme-linked immunosorbent assays (ELISA) at baseline, 4 weeks after each MMR dose, and annually. Seroprotection was set at a concentration of >150 IU/L, a threshold previously determined experimentally as correlating with the presence of neutralizing antibodies. Seroconversion was defined as a rise in measles-specific IgG concentration above the seropositivity threshold in a previously nonseroprotected patient (see Appendix S1 for further details, as well as mumps and rubella serology).

Measles-mumps-rubella Vaccine Administration

Patients without measles seroprotection who fulfilled all safety criteria, including low immunosuppression (steroids <2 mg−1 kg d−1, tacrolimus <0.3 mg−1 kg d−1, and tacrolimus level <8 ng/mL for >1 month) and a sufficient lymphocyte count (≥0.75 G/L) were eligible for MMR immunization. Participants received a standard dose (0.5 mL) of Priorix (GlaxoSmithKline, Switzerland) including at least 103 50% tissue culture infective dose (TCID50) of measles (Schwarz strain), 103.7 TCID50 of mumps (RIT 4385 strain), and 103.0 TCID50 of rubella (Wistar RA 27/3 strain). A second dose was administered at least 4 weeks after the first one to patients who did not seroconvert after the first dose, if the safety criteria were fulfilled. According to the authorization of Swissmedic, a maximum of two additional MMR doses was administered to these nonresponders or if antibodies waned below seroprotection levels during follow-up, irrespective of the number of doses received before study inclusion.

Vaccine Safety and Breakthrough Disease Monitoring

Patients were closely monitored for 8 weeks after each immunization, using at least three standardized telephone interviews (7 to 10 days, 20 days, and 1 month after each immunization) and diary cards. Urinary vaccine virus shedding was screened using an in-house polymerase chain reaction targeting the measles nucleoprotein gene as previously described.[20] Parents were requested to consult immediately if a skin rash appeared. In this case, biological swabs were collected to distinguish measles wild strain from vaccine strain or other viruses by polymerase chain reaction. A history of breakthrough disease or serious adverse events was sought at annual visits.

Statistical Analysis

The sociodemographic and clinical characteristics of patients were described using standard descriptive statistics, ie, frequencies, median, and interquartile range (IQR) if the variable was not normally distributed. Patients with no previous history of MMR vaccination (before and/or after transplantation) were considered as "MMR-naïve," and were described separately from the "nonnaïve" patients. Rates of local and systemic adverse events were expressed after each dose according to the number of patients returning symptom diaries. The occurrence of each adverse event in the MMR-naïve group was compared to the nonnaïve group using Chi-squared or Fischer's exact tests depending on the sample size. The seroprotection rate was calculated by dividing the number of seroprotected patients by the total number of patients receiving the vaccine with exact binomial 95% CI. Factors associated with measles seroprotection at inclusion and at 1-year follow-up were identified using univariate logistic regression adjusted for age at first LT (see Appendix S1). All tests were two-tailed and a P-value <.05 was considered statistically significant. Nonparametric tests were used when variables were not normally distributed. All tests were performed with Stata software, version 13 (StataCorp, College Station, TX).