Immunogenicity and safety of a measles and rubella-containing vaccine at age 6 and 9 months in Bangladesh: an open-label, randomised trial.

BACKGROUND

The first dose of measles-rubella (MR) vaccine is routinely administered to infants aged 9 months as part of a standard two-dose schedule. However, during large measles outbreaks and in other settings of increased circulation or increased risk, WHO recommends administering a supplementary dose at age 6 months to protect young infants. We aimed to assess the immunogenicity and safety of a first dose of MR vaccine administered to infants aged 6 months and its effect on the immune response to the routine MR vaccine at age 9 months.

METHODS

This open-label, randomised trial enrolled healthy infants aged 6 months in Matlab, Bangladesh, who had never received an MR vaccine dose and had no history of measles or rubella. Using a computer-generated block randomisation scheme, infants were randomly assigned (1:1) to receive either two doses of the MR vaccine, one at age 6 months and the second at age 9 months (two-dose group), or one dose at age 9 months (one-dose group). Baseline characteristics were recorded for all enrolled participants at age 6 months. Blood samples were drawn for antibody assays before each vaccination and at final follow up when infants were aged 11 months. The primary outcome was immunogenicity of a first MR vaccine in infants aged 6 months or 9 months and the immunogenicity of a second MR vaccine in infants aged 9 months who received their first MR vaccine at 6 months. Immunogenicity was measured as the proportion of infants who seroconverted in the 12 weeks after vaccination at age 6 months or the 8 weeks after vaccination at age 9 months. Seroconversion was defined as a 4-times increase in IgG concentrations relative to the pre-vaccination concentrations or achieving seroprotective antibody concentrations between study timepoints. The modified intention-to-treat analysis included all infants who received MR vaccines per group assignment and had antibody results at baseline, 9 months, and 11 months. All enrolled infants were included in the safety analysis of the immediate reactions (observed by study staff at the fixed-site clinic in the first 30 min after vaccination), adverse events within 48 h of vaccination among infants in the two-dose group receiving their first MR vaccine at age 6 months, and adverse events observed by study staff or parents at any time during the study. The trial is registered on ClinicalTrials.gov, NCT03071575, and is closed to enrolment.

FINDINGS

Between March 9, 2017, and March 18, 2018, 620 infants were enrolled and randomly assigned to the two study groups (312 in the two-dose group and 308 in the one-dose group). Of the 301 infants vaccinated at 6 months, 282 seroconverted for measles (94%, 95% CI 90-96), and 283 seroconverted for rubella (94%, 91-96). By 11 months, after receiving a second dose at age 9 months, 297 (cumulative 99%, 95% CI 97-100) infants seroconverted for measles and 297 infants seroconverted for rubella (cumulative 99%, 96-100). Of the 292 infants vaccinated at 9 months only, 291 seroconverted for both antigens by age 11 months (100%, 95% CI 98-100). 123 adverse events were observed; 72 in the two-dose group and 51 in the one-dose group, with no differences in severity (p=0·78) or outcomes (p=0·71) by study group. 12 (17%) events in the two-dose group and seven (14%) in the one-dose group were severe; most events were mild, resolved without sequelae, and were unrelated to the MR vaccine. One death occurred in the one-dose group before the infant received the 9-month dose of the vaccine, and therefore was deemed to be unrelated to the MR vaccine.

INTERPRETATION

The data presented support use of MR vaccine at 6 months to protect young infants during measles outbreaks and in settings with increased risk or high transmission. We recommend additional studies to evaluate longer-term immunity based on age at vaccination.

FUNDING

US Centers for Disease Control and Prevention.

TRANSLATIONS

For the French and Spanish translations of the abstract see Supplementary Materials section.