Title: Feasibility study for the development of a sero-correlate of protection against invasive Group B Streptococcus disease (iGBS)
Funder: Department of Health and Social Care

Abstract: Group B Streptococcus (GBS) is a bacterium (a bug) that causes infection in young infants in all regions of the world. Worldwide in 2015 it was estimated that there were at least 319,000 infants under 3 months of age with GBS disease, resulting in 90,000 deaths and at least 10,000 children with long term disabilities. Babies mostly acquire the GBS bacteria from their mothers around the time of birth and around 20% of all pregnant women carry GBS in their bowel and vagina. The global burden of GBS is therefore high and the options for prevention are currently limited. An effective vaccine that could be given to pregnant women has the greatest potential to benefit mothers and babies worldwide and such vaccines are now being tested in clinical trials, including in pregnant women. To license a new vaccine so that it can be recommended for routine use usually requires evidence that the vaccine is safe and effective in preventing the disease. This usually means undertaking a large trial in which the new vaccine is given to half of the subjects, who are then compared to the other half who did not receive the new vaccine. Such trials are expensive and time-consuming to perform. Another way of licensing a new vaccine is to show that when it is given to relevant groups of people it is able to produce levels of immunity (usually measured as antibody) in their blood that are known to result in protection. Such levels are called serocorrelates (because they “correlate” with protection). Although there is considerable evidence that high levels of antibody against GBS in pregnant women do correlate with protection against GBS disease in their babies, the precise level(the serocorrelate) is not currently known - we aim to establish this in a case-control study. Although GBS is the most common cause of serious early infections in UK babies it is still relatively rare overall, so we will need to follow around 150,000 babies in order to find at least 150 babies with GBS disease, which is around the number we need to establish the serocorrelates of protection. In order to assess our recruitment and test our methods we will therefore start by doing a smaller(feasibility) study of around 4000 women (this application). If we show that our feasibility study works well we hope to proceed to the larger study that will address the main study question. We will collect a small sample of blood from pregnant women and/or from the cord of their newborn babies at delivery and store these samples in the laboratory. With the cooperation of paediatricians and microbiologists we will be alerted if any of the babies develop GBS disease over the next 3 months (cases). For those who do, we can then compare the level in their blood samples at birth with that of other babies (controls) who did not develop GBS disease. Because many babies acquire the GBS from their mothers at birth we will also do a study in which a smaller number of mothers will have a swab taken to see if they are carrying GBS around the time of birth. The babies of mothers identified as carrying GBS will be the control babies as we know for certain that they were exposed to GBS at birth but didn’t develop GBS disease.

Lay abstract: Scientific Summary Research question What are the Group B Streptococcus (GBS) capsular polysaccharide serotype-specific IgG immunecorrelates of protection against the most prevalent serotypes of GBS causing invasive infant disease (iGBS)? Background GBS is present in all regions of the world with an estimated 21.7 million pregnant women colonised in the gastrointestinal or genitourinary tract. In 2015 it was estimated that worldwide there were 319,000 infants <3 months of age with iGBS resulting in 90,000 infant deaths and at least 10,000 children with disability. The burden of GBS is high and the rationale for an effective maternal vaccine is clear. Licensure of a GBS vaccine would be significantly accelerated if an immune marker, measured in analytically and clinically validated assays, was established as an immune correlate of protection against invasive disease. Aims and objectives Given the anticipated study size of this study and its logistic complexities, the aim of this initial feasibility study is to test key operational aspects of the study design of such a study. The feasibility study aims to collect data on maternal GBS colonizing serotype prevalence, anti-capsular IgG concentrations, kinetics of antibody transfer and IgG decay in the first three months of life and enable sample size and power assumptions for the main study to be assessed. Methods We will establish maternal delivery / infant cord serum collection from 5 maternity units (around 4000 women) and test the feasibility of our strategies. In a sub-study we will additionally collect maternal vaginal-rectal swabs from 1000 women and blood samples from 50 babies. We will assess the following parameters: - enrollment rate (the rate (proportion) of eligible women who are willing to participate in the blood collection study) - maternal and / or cord blood collection rate - the impact of different timings related to blood sample processing and storage - key clinical data collection rate - rectovaginal swab / delivery blood sample study enrollment rate - rectovaginal swab and delivery blood sample collection rate - infant blood sample study consent rate - infant surveillance consent rate The collection of blood samples in colonised women will allow us to derive estimates of GBS anticapsular IgG concentrations using a standardised assay. Output: Results from this feasibility study will inform the sample size required to establish the control group for the MAIN STUDY. The GBS anti-capsular IgG concentrations in maternal, cord and infant sera will ultimately be used to establish serotype-specific IgG levels that correlate with a reduced risk of iGBS disease in infants up to three months of age. Timelines for delivery The duration of the feasibility study will be 6 months to include 1 month set up, 4 months recruitment, 90 day follow up for infants identified in the first month of enrolment and 1 month for analysis and report. Anticipated impact and dissemination The feasibility study will allow an objective assessment of proposed recruitment and collection methods to be made as well as assumptions around sample size calculations for THE MAIN STUDY. Ultimately the feasibility study data will be pooled with THE MAIN STUDY analysis set.

Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES
Health categories: INFECTION