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

Results

Patient Characteristics

Of 98 pediatric LT recipients, 90 were included in the study (Figure 1; participation rate, 92%; 43 females, 48%). Patients were transplanted at a median age of 1.4 years of age (IQR, 0.8-4.1), most frequently (57%, 51/90) for biliary atresia (Table S2). Median age at study inclusion was 10.3 years (IQR, 5.7-13.6), approximately 5 years (IQR, 1.8-9.9) after their last transplant and 5.7 years (IQR, 1.9-9.9) after the last rejection episode (among the 45 patients [50%] with a previous history of acute cellular rejection). Most patients (94%) were receiving tacrolimus and 24% were receiving two different antirejection drugs.

Figure 1.

Flowchart of study participants. *Some patients received MMR vaccine both before and after transplantation (before study inclusion). **One patient received a MMR dose when it was not indicated (see Appendix S1). MMR, measles-mumps-rubella; FO, follow-up; LT, liver transplantation; n, number of patients [Color figure can be viewed at wileyonlinelibrary.com]

Measles Seroprotection at Inclusion

Fifty-one percent (46/90) of children were not seroprotected against measles at inclusion, although 39% of these unprotected patients (18/46) had previously been immunized. Overall, six patients were immunized on an off-label basis after LT (median, 3.9 years; range, 0.8–13.7) before inclusion (Table S3). None had a history of overt measles disease before inclusion. Most of the patients who were not immunized before inclusion (22/28; 79%) were transplanted before the age of 12 months (43% before 9 months). Among children immunized before LT, 40 of 57 (70%; 95% CI, 57–82%) were seroprotected at inclusion (Figure 1, Table S3 and Figure S1 in Appendix S1). The 44 children seroprotected against measles at inclusion had been transplanted at an older age (median age, 4.0 years; IQR, 1.7–10.5) and immunized at a median age of 1.1 years (IQR, 1.0–1.4). Univariate factors associated with seroprotection after LT are shown in Table 1. Patients immunized and transplanted at an older age had a higher chance of being seroprotected against measles at inclusion than younger transplanted children. Multivariate analyses showed that all variables were highly dependent on each other, thus preventing the identification of independent factors.

Seroresponse to Measles-mumps-rubella Immunization

MMR vaccine was given at baseline to 40 of 46 nonseroprotected patients (Figure 1 and Table 2). Thirty-seven of the 40 patients (93%; 95% CI, 80–98%) reached seroprotection 4 weeks after the first dose; 2 of 40 were protected only after the second dose (Figures 1 and 2; Figure S2 in Appendix S1). The seroresponse to a two-dose schedule thus reached 98% (39/40; 95% CI, 87–100%) as is expected in nonimmunocompromised patients.[6,21] Among the 28 LT patients who had never received a measles containing vaccine before inclusion, 24 were vaccinated (Figure 3). Primary response rates reached 88% (21/24; 95% CI, 68–97%) and 96% (23/24; 95% CI, 79–100%) after one and two doses, respectively. MMR vaccine was also administered during follow-up to 3 of 44 previously immunized patients who lost seroprotection during follow-up. All responded to one or two doses of MMR (Figure 1). One patient received the MMR vaccine at inclusion while it was not indicated as he was retrospectively identified as seroprotected before vaccination (see Appendix S1). Vaccine responses to the rubella and mumps components followed similar trends (see Appendix S1).

Figure 2.

Reverse cumulative distribution curves of measles IgG concentration following MMR immunization after transplantation. MMR, measles-mumps-rubella; IU/L, international unit per liter; IgG, immunoglobulin G [Color figure can be viewed at wileyonlinelibrary.com]

Figure 3.

Evolution of seroprotection against measles throughout the study and seroresponse to MMR vaccine in patients with or without prior MMR immunization. MMR, measles-mumps-rubella vaccine; IU/L, international unit per liter; IgG, immunoglobulin G

Maintenance of Seroprotection Against Measles at 1-year Follow-up

At 1-year follow-up, seroprotection was maintained in 62% (95% CI, 45–78%) of patients that had previously responded to immunization (MMR-naïve: 81%; 95% CI 58–95%; nonnaïve: 44%; 95% CI, 20–70%). Fourteen patients had measles serology below the seroprotection-associated threshold (Figure 2). Factors associated with the maintenance of seroprotection at 1-year follow-up are shown in Table S4. Briefly, patients that were MMR-naïve at inclusion were more likely to maintain seroprotection 1 year later (Figure 3; OR, 6.8; 95% CI, 1.7–27.5). Similarly, a stronger response 4 weeks after the first dose of MMR (concentration >400 IU/L) significantly increased the chance of remaining seroprotected (OR, 4.1; 95% CI, 1.0–16.0). Among patients who lost seroprotection 1 year after vaccination, 12 received booster doses and 10 (83%; 95% CI, 52–98%) reached seroprotection after one supplementary dose, while two patients required two supplementary doses. Therefore, the seroprotection rate was 100% (one-sided 97.5% CI, 74–100%) after boosting.

Maintenance of Seroprotection Against Measles at 2- and 3-year Follow-up

Among the 35 immunized patients for whom a 2-year follow-up serology was available, 30 remained seroprotected (86% maintenance of protection; 95% CI, 70–95%; MMR-naïve: 90%; 95% CI 70–99%; nonnaïve: 79%; 95% CI, 49–95%). Four required a third dose (Figure 2) and the remaining patient had already received three doses. All five patients who lost seroprotection had successfully responded to the first dose, but required a 1-year follow-up booster dose. All four were seroprotected after this supplementary dose. At 3-year follow-up, 16 of 18 were still seroprotected (89% maintenance of protection; 95% CI, 65–99%; MMR-naïve: 100%; 97.5% CI 72–100%; nonnaïve: 75%; 95% CI, 35–97%); the two patients who lost seroprotection responded well to a third dose. The evolution of seroprotection against rubella and mumps is detailed in the Appendix S1.

Vaccine Safety Monitoring

All patients were closely monitored during 8 weeks after each immunization. Among the 70 total doses of MMR administered, the standardized diary card was only answered for 49 injections (70%; Table S5). However, each patient was contacted by telephone at least three times after each dose, thus enabling individualized safety monitoring (Table S6). There was an 18% rate of self-reported overall injection site reaction during the first week following vaccination, mostly local redness/induration (6%) and pain (8%). Almost half of the patients (41%) experienced a systemic side effect during the first 2 weeks. There were some differences in adverse event rates in the MMR-naïve group compared to the nonnaïve group, but none was statistically significant (Table S5). Particular attention was paid around day 10 after MMR administration as it represents the peak of measles replication (Table S7). Four patients reported fever, three patients increased tiredness, and two headache around day 10. One patient had fever at day 20 including headache, irritability, myalgia, arthralgia, and gastrointestinal symptoms. Another patient reported afebrile coryza and conjunctivitis at day 21 and 4 patients experienced a localized rash starting between days 11 and 21. All these events are possibly attributable to viral replication. However, measles RNA was not identified in urine at days 7 to 10, 20, or 30, nor in the biological samples of two patients with fever around day 10 (Appendix S1). All patients with side effects received supportive care and amoxicillin was prescribed to two patients with acute otitis media starting at days 3 and 8, respectively. All cases improved clinically within a few days. No serious adverse event attributable to vaccination was detected during the 4 weeks following any dose of MMR.

Severe adverse events included one alloimmune hepatitis 4.5 months after vaccination in a patient with slightly abnormal liver function tests before immunization. He was successfully treated with steroids. Three other patients had a rejection episode at 6 months, 9 months, and 3 years after vaccination. Each patient was successfully treated by transiently increasing immunosuppression. Posttransplant lymphoproliferative disorder was diagnosed at 4 and 18 months after immunization in two patients. One patient was hospitalized 7 weeks after his second dose of MMR because of intestinal obstruction (Table S8). Causality assessment indicated these severe adverse events as unlikely to be related to MMR immunization. Among the enrolled, but nonimmunized patients, there were nine serious adverse events, including one posttransplant lymphoproliferative disorder and eight cases of graft dysfunction (abnormal liver tests). One patient required retransplantation and another, unfortunately, died. As safety is a major concern when considering MMR immunization of immunosuppressed patients, all relevant side effects reported are presented individually as narratives in the Appendix S1.

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