This is a hospital-based, cohort study of 35,000 mothers and their infants >90 days of age at Mulago Hospital, Kampala and active surveillance for neonatal and infant disease in all infants presenting to the Mulago health care units during this time frame.

Globally, neonatal mortality remains unacceptably high, with little change in the death rate in the first 28 days of life since 1990, despite reductions in under-5 mortality of up to 50% over the same period. In 2014, neonatal deaths accounted for 44% of all deaths in children under 5 with neonatal infection accounting for over a third of all deaths. Group B Streptococcus (GBS) is a major cause of septicemia and meningitis in infants globally, and a cause of severe adverse neurodevelopmental outcomes in up to 50% of meningitis survivors. It can also lead to sepsis in pregnant women. GBS acquisition occurs through vertical transmission in 15%-50% of infants born to a vaginally/rectally colonized mother. Maternal colonization is a prerequisite for early onset (EO) and a risk factor for late onset (LO) disease.

A maternal vaccine would be effective in preventing EO- and LO-GBS disease via placental anti-GBS antibody transfer, as well as protecting the mother against puerperal GBS sepsis. There are several capsular polysaccharide (CPS) conjugate vaccine candidates for maternal vaccination in development to prevent both EOand LO-GBS disease. However, several obstacles exist in moving the most advanced vaccine into phase III clinical trials. The first is that, given the relative rarity of GBS disease in Europe and the USA, large numbers of infants would need to be recruited to determine vaccine efficacy (at an incidence rate of 1/1000 live births it is estimated that 60,000 infants would be required to show vaccine efficacy). Secondly, outside of the USA, Europe and South Africa we have little data from surveillance programs which define the serotypes causing disease and colonisation. This poses additional uncertainty in designing vaccine efficacy studies in those areas of the world where the burden of neonatal infection is highest. Finally, obstacles exist in determining what concentration of antibody is required to protect the infant from disease and/or colonisation for the duration of the at-risk period (first three months of life), as there are currently no internationally recognised standards from which to interpret individual immunogenicity study results.

Our proposal will provide these critical data in Uganda (a country with high neonatal disease burden) by conducting a study with two defined objectives:

Firstly, we will determine the burden of GBS disease in a cohort of mother/infant pairs and establish an active surveillance platform for monitoring of early and late onset neonatal infection in term and preterm infants in Uganda and compare this to the burden known for other African countries. This provides essential data on GBS disease outcomes from a high-HIV burden African cohort reflecting the usual standard of care in a low income, highly deprived urban environment. Secondly, we will determine the level of antibody against GBS in cord blood from pregnancies where women are GBS colonized and non-colonized but whose infants do not develop GBS disease in the first three months of life and compare this to the level in the blood of infants who develop GBS disease. We will compare these results with those from other African countries such as South Africa to enable a robust estimate of potential sero-correlates of protection from natural infection against the most common GBS-disease-causing serotypes

November 2018 – April 2021