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 death. Group B Streptococcus (GBS) is a major cause of septicaemia and meningitis in infants globally, and a cause of severe adverse neurodevelopmental outcomes in 50% of meningitis survivor. 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 EO- and 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.

An alternative/additional approach that could facilitate the development, licensure and introduction of a GBS vaccine would be to reliably identify biomarkers that represent a correlate of protection against infant disease. Such correlates have facilitated the licensure of other life-saving vaccines in the past, e.g. meningitis A, B, C and are used for licensure of new generations of already established vaccines, e.g. pneumococcal vaccines.

It has already been shown that higher titres of naturally occurring, serotype-specific maternal antibody to the CPS of GBS correlate to a reduced risk of infant disease, but an accepted serological correlate of protection has yet to be defined. The majority of assays used to measure anti-GBS antibody have been developed to establish quantity but without an assessment of function. However, functional antibody matters, as it is the sustained protection against low levels of bacteraemia in the infant that will prevent disseminated infection from occurring. Antibodymediated opsonophagocytic killing has been used to determine antibody activity. Thus, both immunogenicity (ELISA or binding assay) and assessment of functional antibody (opsonophagocytosis) are relevant parameters when measured together in order to obtain the most reliable estimate of protection from disease.

Our proposal will provide these critical data by conducting a study with three defined objectives.

Firstly, it will seek to develop standardized capsular polysaccharides (Ia, Ib, II, III & V) for use in immunogenicity and standard GBS strains for use in functional assays. In parallel, our consortium will develop serological positive standards for use in all assays. The availability of such reagents is of paramount importance as interpretation of immune responses to vaccines will depend on the reproducibility of data across sites and this can only occur if results can be compared through these standard reagents. Secondly, this proposal will seek to establish what assays are currently in use by industry and by academic partners globally. This is a vital step towards assay standardization as there may be key steps that vary between groups. Once protocols have been shared, a technical advisory group- already part of the consortium- will identify one or two assays that are most likely to progress to the final stages of the project. Finally, we will conduct an assay performance and refinement study between suitable accredited laboratories to test the performance of the current quantitative and functional assays identified in the landscaping analysis using the standard reagents. The ultimate goal will be to prepare for a third phase that will use available serum banks to determine a correlate of protection against GBS disease using a standardized approach to antibody measurement with standardized reagents.

August 2016 – August 2024