A randomised controlled trial to evaluate the effect of maternal or neonatal pneumococcal conjugate vaccination on pneumococcal carriage in early life

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The last decade has witnessed significant reductions in the number of children dying before they reach their fifth birthday (under-five mortality) across the world. Despite this, we fall far short of Millennium Development Goal 4 which called for a two-third reduction in under-five mortality between 1990 and 2015. Overall, 70 percent of under-five mortality (5.4 million deaths, 2010) occurs in those under the age of one and forty percent occurs in the first month of life. Nearly half of all deaths occur in sub-Saharan Africa, with countries in West Africa, including The Gambia, having the highest mortality rates anywhere in the world. Consequently, new interventions to reduce mortality in early infancy in this setting have tremendous potential for life-saving impact. Streptococcus pneumoniae (or pneumococcus) is a leading cause of childhood mortality worldwide. Recent estimates suggest the bacteria are responsible for around 11 percent of deaths in children under five, with over half of these deaths occurring in Africa. Infants in this setting become rapidly 'colonised' with bacteria in the back of the nose. For example, in The Gambia, over 80 percent of infants will be carrying the bacteria by two months of age. Carriage is an immediate and necessary precursor to disease. Reflecting these high carriage rates, a recent systematic review confirmed that pneumococcus is the leading cause of life-threatening infections, both sepsis and meningitis, in infants up to three months of age in sub-Saharan Africa. The burden of pneumonia related mortality is similarly extremely high in the same group.The currently available pneumococcal-conjugate vaccines (PCV) are recommended by the WHO according to a three dose six, 10 and 14 week schedule. As a result, infants are not protected against pneumococcus until 16 to 18 weeks of age, or later if the vaccines are delayed, by which point a significant burden of pneumococcal related mortality has already occurred. Therefore, the objective of this trial is to explore alternative schedules for PCV administration to prevent pneumococcal disease in this critical window of susceptibility. Two intervention arms will be compared to a control arm in which infants will receive PCV according to a standard three dose schedule. In the maternal intervention arm, expectant mothers will be given a dose of PCV in the third trimester of pregnancy. This aims to boost the mother's pneumococcal antibody levels with the expectation that these will be transferred to the infant across the placenta and in breast milk, thus protecting the infant from birth. In the neonatal intervention arm, a dose of the vaccine will be administered to newborns on the first day of life with the aim of generating a protective immune response in the newborn as early as possible. The rate at which the infants acquire pneumococcal carriage in the back of the nose will be compared between the two intervention arms and the control arm. Given the link between carriage and disease, the rate of carriage acquisition is becoming an established 'surrogate' for disease in pneumococcal vaccine trials, substantially reducing the size and complexity of the trials required. Antibody levels and other measures of pneumococcal immunity will also be measured and important safety data will be collected throughout. Given the sensitivity of vaccination in both expectant mothers and newborns the trial will also examine the acceptability of these interventions with the aim of identifying any barriers to implementation. The WHO already recommends PCV vaccination and the vaccines are provided to eligible countries through funding provided by the GAVI Alliance. Consequently, a policy change influenced by the results of this trial could be rapidly implemented without major barriers. Given the burden of disease in infancy, if proven, the impact of the trial in terms of lives saved in early life could be rapidly significant.