Immune response to co-administration of measles, mumps, and rubella (MMR), and yellow fever vaccines: a randomized non-inferiority trial among one-year-old children in Argentina

Background: In yellow fever (YF) endemic areas, measles, mumps, and rubella (MMR), and YF vaccines are often co-administered in childhood vaccination schedules. Because these are live vaccines, we assessed potential immune interference that could result from co-administration.

Methods: We conducted an open-label, randomized non-inferiority trial among healthy 1-year-olds in Misiones Province, Argentina. Children were randomized to one of three groups (1:1:1): Co-administration of MMR and YF vaccines (MMR₁YF₁), MMR followed by YF vaccine four weeks later (MMR₁YF₂), or YF followed by MMR vaccine four weeks later (YF₁MMR₂). Blood samples obtained pre-vaccination and 28 days post-vaccination were tested for immunoglobulin G antibodies against measles, mumps, and rubella, and for YF virus-specific neutralizing antibodies. Non-inferiority in seroconversion was assessed using a -5% non-inferiority margin. Antibody concentrations were compared with Kruskal-Wallis tests.

Results: Of 851 randomized children, 738 were correctly vaccinated, had ≥ 1 follow-up sample, and were included in the intention-to-treat population. Non-inferior seroconversion was observed for all antigens (measles seroconversion: 97.9% in the MMR₁YF₁ group versus 96.3% in the MMR₁YF₂ group, a difference of 1.6% [90% CI -1.5, 4.7]; rubella: 97.9% MMR₁YF₁ versus 94.7% MMR₁YF₂, a difference of 3.3% [-0.1, 6.7]; mumps: 96.7% MMR₁YF₁ versus 97.9% MMR₁YF₂, a difference of -1.3% [-4.1, 1.5]; and YF: 96.3% MMR₁YF₁ versus 97.5% YF₁MMR₂, a difference of -1.2% [-4.2, 1.7]). Rubella antibody concentrations and YF titers were significantly lower following co-administration; measles and mumps concentrations were not impacted.

Conclusion: Effective seroconversion was achieved and was not impacted by the co-administration, although antibody levels for two antigens were lower. The impact of lower antibody levels needs to be weighed against missed opportunities for vaccination to determine optimal timing for MMR and YF vaccine administration.

Trial registration: The study was retrospectively registered in ClinicalTrials.gov (NCT03368495) on 11/12/2017.