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

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.

The objective of the trial is to establish whether the administration of a dose of a 13-valent pneumococcal-conjugate vaccine (PCV13) antenatally to an expectant mother or neonatally to her infant results in a lower rate of pneumococcal carriage acquisition in early infancy when compared to a routine eight, 12 and 16 week schedule.
A randomized, controlled trial will compare two intervention arms (1. Maternal = PCV13 administered to mothers in the third trimester of pregnancy; 2. Neonatal = PCV13 administered to infants within 48 hours of birth) to the control arm (Control = PCV13 administered according to the eight, 12 and 16 week routine infant schedule in The Gambia).
Laboratory staff examining the primary and secondary bacteriological and serological endpoints will be blinded to study arms. Parent and field staff will not be blinded.
Expectant mothers, recruited in the third trimester of pregnancy, will be randomised in equal number into one of three groups of 157 participants per group (calculated to include 10% non-evaluable subjects).

Primary outcome measures:
Rate of acquisition vaccine-serotype specific pneumococcal carriage by infants between birth and 20 weeks of age
Serious adverse events in mothers and infants throughout the trial

Secondary outcome measures:
Vaccine-serotype specific antibody titres and seroprotection rates in mothers and infants
Total and vaccine serotype specific pneumococcal carriage rates up to nine months of age in infants
Selected vaccine serotype-specific opsonophagocytic activity, memory B-cells and breast milk IgA
Local and systemic reactogenicity and adverse events in mothers and infants from birth until five months of age including pneumococcal infections

Measures of acceptability and perceptions surrounding maternal vaccination
To determine the acceptability of maternal and neonatal vaccination to mothers and families
To identify barriers to the introduction of a maternal or a neonatal dose of PCV13

The WHO highlights the need for 'A research strategy...to evaluate pneumococcal maternal immunisation' and also calls for further research in the area in a statement endorsed by the SAGE committee that advises the WHO on vaccine policy globally. The results of this study will directly address this research need and will provide the WHO with an evidence base to inform future pneumococcal-conjugate vaccine scheduling.
The burden of pneumococcal disease in infants is highest in sub-Saharan Africa, where our work is based, and pneumococcal-conjugate vaccines are being rolled out widely as part of the GAVI alliance. In this setting, the bacterium is the commonest cause of meningitis and septicaemia over the first three months of life. Mortality related to pneumonia, caused by the same bacteria, is similarly extremely high over the same time period.
As such, if the interventions are shown to be effective, the potential impact of the study at an international policy level and hence on pneumococcal disease in early life is clear. In addition to the WHO, the data will be available for use by governmental agencies to direct immunization scheduling at a national level. Thus the impact of such a policy change may be rapidly ascertained in certain countries where the pneumococcal disease burden is highest in early life, even prior to a change in international policy
More broadly, maternal or neonatal immunisation is an attractive option to reduce morbidity and mortality in early infancy if it can be shown to be safe, efficacious and acceptable. The principals could be applied to other vaccines, such as those being developed against Group B streptococcus, where the burden of disease in early infancy is high. Therefore, the findings of the trial are likely to guide all those exploring these approaches in the academic and commercial sector as well as at the level of national and international policy. The place of antenatal tetanus toxoid immunisation in the schedule is already established. However, expanding experience in this area, including the provision of data on safety, transplacental antibody transfer and newborn immunogenicity, and disease related endpoints (in this case carriage) can only serve to drive forward this field more broadly. The qualitative research component, which will examine the acceptability of maternal and neonatal immunisation in West Africa, is also critical if rollout was to be considered on a large-scale. Consequently, the finding of the trial are expected in impact directly on policy decision regarding the scheduling of pneumococcal conjugate vaccines but also in both the academic and commercial sectors where several vaccines aimed at maternal or neonatal immunisation are under development.