WP1

An RCT of an additional measles vaccine (MV) at 4 months of age to reduce child mortality and to explore the role of maternal measles antibodies (MatAb) in the beneficial non-specific effects (NSEs) of MV

Hypotheses

  1. MV at both 4 and 9 months of age compared with the standard MV at 9 months of age will reduce mortality by 30% between 4 months and 5 years of age
  2. Children receiving early MV in the presence of MatAb will have 35% lower mortality than children receiving MV with no detectable MatAb

Background

 Current WHO policy is based on the premise that the efficacy of MV against measles infection is higher when it is given after MatAb have waned by age 9 months45. Nonetheless, all studies indicate that survival is much better when MV is given earlier28,46-50. In a recent RCT, MV at both 4 and 9 months of age reduced overall mortality between 4 and 36 months of age by 50% (95%CI 22-68%) compared with the current policy of one dose at 9 months in the majority of children, who had not received vitamin A supplementation (VAS) at birth3. The beneficial NSEs continued after 3 years of age. Among 450 children who had MatAb tested, those vaccinated early in the presence of MatAb had 77% (18-96%) lower mortality than children vaccinated in presence of no MatAb26. We aim to provide further evidence for the beneficial NSEs of early MV in the context of no VAS at birth, and to explore the interaction between MV and MatAb.

Study design

 The study is conducted by the Bandim Health Project (BHP) in Bissau, the capital of Guinea-Bissau. Children aged 4-7 months who have received the 3rd dose of Pentavalent (Diphtheria-tetanus-pertussis (DTP)-Hib-Hep B) vaccine at least 4 weeks earlier are eligible. No children have received VAS at birth according to current policy. Following parental consent, children are randomized to early MV (2/3) or no vaccine (1/3). All children will have MatAb measured and DNA and serum preserved for the determination of genetic and pathogen determinants of NSEs. All children will receive standard MV at age 9 months.

Outcomes and sample size

 The main outcome is overall mortality from 4 months to 5 years of age. Hypothesis A: With an expected 5.6% mortality and 8% loss to follow-up, we need to enroll 6,269 children to detect a 30% reduction in mortality. Hypothesis B: With 4,400 in the group receiving early MV, we can detect a 35% difference in mortality between those with MatAb (60%) and those without (40%). Secondary outcomes are hospital admissions, consultations, specific morbidity, growth and immunological markers (WP8).

Deliverables

An estimate of the effect on overall mortality of providing:

  1. Early MV at 4 months of age
  2. MV in the presence or absence of MatAb

Implications

 If we confirm a beneficial effect of early MV, this should persuade the WHO to recommend MV at 4 and 9 months. If MV in presence of MatAb is beneficial, new research questions will be raised: MatAb levels are declining because vaccinated mothers transfer fewer antibodies transplacentally than naturally infected mothers. Should MatAb be boosted by vaccination of young women and can children be vaccinated even earlier? Which immune mechanisms underlie the beneficial effects?

Ethics 

 The trial will result in increased MV coverage. The protocol has been approved by the Guinean Ethical Committee (GEC) and the Danish National Committee on Biomedical Research Ethics (DNCBRE).

Status

 The trial was initiated in August 2011 with funding from an ERC Starting Grant to Christine Stabell Benn. This grant provides funding for Christine Stabell Benn’s salary to the end of 2014. It furthermore provides some of the expenses in relation to local staff to the end of 2014.