Discussion
MR, mumps
MUMPS, RUBELLA, MEASLES
In this study, we assessed seroconversion rates against measles, mumps, rubella, and YF antigens following co-administration or individual administration of MMR and YF vaccines and documented non-inferiority with co-administration for all antigens compared with individual administration in our ITT population. However, co-administration resulted in significantly lower antibody levels for rubella and YF compared with the values seen with individual administration.Our results are in agreement with a randomized controlled trial that reported the immune response following individual and co-administration of YF and MR vaccines in children living in The Gambia [The immunologic findings from The Gambia, France, and our study are different from a randomized controlled trial performed in Brazil where children aged 12–23 months were administered one of two YF vaccines (17DD and 17D-213 sub-strains) at the same time or 28 days following MMR vaccination [In our study, the decreases in antibody levels for rubella and YF seen when the vaccines were co-administered were not large enough to result in an inferior seroconversion rate in the ITT population—regardless of MMR or YF vaccines being given first or second in the series. However, non-inferiority in YF seroconversion was not demonstrated in the PP analysis, with the lower bound of the 90% CI just crossing the − 5% non-inferiority margin. However, the CI also included zero; therefore, it is also possible that there is no difference among the groups. Overall, this discrepancy is difficult to interpret because the PP analysis was insufficiently powered after the loss of ~ 16% of the ITT participants due to follow-up visits outside of the 28–35 days post-vaccination window.Interestingly, higher seroconversion rates were seen for measles and rubella when MMR and YF vaccines were co-administered compared to when MMR was administered second in the sequential series. On a related note, seroconversion rates for measles, rubella, and mumps following MMR administration as the second vaccine did not demonstrate non-inferiority when compared to seroconversion rates following MMR administration as the first vaccine. These findings suggest that YF vaccination and its associated immune response notably impact the immune response to MMR vaccine when administered 28–35 days after YF vaccine. These findings could impact considerations for travel vaccinations or vaccination campaigns that target children outside of routine immunization schedules. However, they have limited implications for routine childhood programs if these vaccinations are co-administered or spaced at intervals of two to six months as observed in many routine programs.While antibody levels were lower for rubella and YF following co-administration compared with individual administration, the geometric mean titers/concentrations achieved for both the co-administration and individual groups were far above the cut-off points used for seropositivity. It is unknown whether the observed magnitude of decrease in antibody levels could affect long-term immunity. Follow-up studies could provide information on whether the co-administration of MMR and YF vaccines has an influence on the long-term dynamics of the respective vaccine-induced IgG antibodies, especially for YF, where only one dose is administered compared to MMR where two doses are administered [The co-administration of vaccines often enables receipt of the vaccines at the earliest recommended age—a strategy that minimizes missed opportunities for vaccination [One of this study’s strengths was that it was embedded within the national immunization program of Argentina. The results of the ITT analysis demonstrate the vaccinees’ immune response under standard clinic conditions. In addition, with baseline samples on all participants, we were able to exclude the few children that were already seropositive to an antigen before vaccination. However, the study also had several limitations. We encountered challenges completing follow-up visits within the narrow, pre-specified window of 28–35 days post-vaccination; hence our PP population was under-powered for the planned analyses. In addition, we may not have observed peak antibody titers that often occur later after vaccination as seroconversion and antibody titers were measured 4–5 weeks post vaccination. This could impact the magnitude of the differences seen in the antibody concentrations. We did not calibrate the YF antibody titers using an international reference preparation, which makes it difficult to compare our titers to those obtained in Brazil [