Measles Vaccination in the Presence of Maternal Measles Antibody Reduces All-Cause Child Mortality - A Planned Cohort Study Nested in a Randomised Trial

Background:  Several smaller studies suggested that measles vaccination (MV) in the presence of maternal measles antibody (MatAb) reduces all-cause mortality. We tested the hypothesis that children receiving early MV at 4 months in the presence of MatAb would have 35% lower mortality than children receiving MV at 4 months with no detectable MatAb. We further hypothesised that among children, who did not receive early MV, there would be no difference in mortality between those with and without MatAb. Methods:  The study was an observational study nested within a randomised controlled trial (RCT) of early MV, carried out in Guinea-Bissau from 2011-2019. The RCT compared the mortality between 4 and 60 months of age for children randomised 2:1 to two doses of MV at 4 and 9 months of age or to only one dose of MV at 9 months of age. At enrolment in the RCT, a blood sample was collected from all children. A multiplex immunoassay was used to determine the measles MatAb level; as control exposures, levels of varicella, mumps and rubella antibody were assessed. We assessed overall mortality as a function of randomisation group and presence of MatAb in Cox proportional hazards models. Results:  6,598 children were enrolled in the RCT, 6,239 (95%) had a valid enrolment blood sample. In children receiving early MV at enrolment, mortality was 50% (95% CI: 20-68%) lower for those vaccinated in the presence of MatAb (n=3132; 51 died) compared with those vaccinated in the presence of no MatAb (n=1028, 31 died). There was no beneficial effect of having MatAb in children who did not receive early MV (test of interaction, p=0.045). The result was specific for measles antibody; no effect was found for varicella, mumps or rubella antibodies. In a meta-analysis of five available studies, MV in the presence of MatAb was consistently associated with lower mortality compared with MV in the absence of MatAb, the combined meta-estimate indicating 55% (35-68%) lower mortality. Interpretation:  The results support the previous findings that MV in the presence of maternal antibody enhances the beneficial effects of MV on child survival. Earlier measles vaccination should be considered. Further research is needed to examine whether it is beneficial to vaccinate women of fertile age to transfer higher level of maternal antibodies to their children. Trial Registration (for the RCT): NCT01486355 Funding:   The RCT was funded by an ERC Starting Grant to Christine S Benn (ERC-2009-StG-243149) and by a “Center of Excellence” grant from the Danish National Research Foundation (DNRF108). The work on non-specific effects of vaccines has been supported by the Danish Council for Development Research, Ministry of Foreign Affairs, Denmark [grant number 104.Dan.8.f.], Novo Nordisk Foundation and European Union FP7 support for OPTIMUNISE (grant: Health-F3-2011-261375). The funding agencies had no role in the study design, data collection, data analysis, data interpretation, or the writing of the report. Declaration of Interests: Authors declare no competing interests. Ethics Approval Statement: The protocol was approved by the National Ethical Committee in Guinea-Bissau and given consultative approval by the Danish Central Ethical Committee