Development of a serocorrelate of protection against invasive Group B Streptococcus disease (iGBS)

Group B Streptococcus (GBS) is a bacterium (a bug) that causes serious infections (iGBS) 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 invasive GBS disease (iGBS), resulting in 90 000 deaths and at least 10 000 children with long term disabilities. Around 20% of all pregnant women carry GBS in their bowel and vagina and babies mostly acquire the GBS bacteria from their mothers around the time of birth. The global burden of iGBS 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 normally 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 iGBS disease in their babies, the precise level (the serocorrelate) is not currently known - we aim to establish this in a case-control study.

In order to do this we will collect a small sample of cord blood from new-born babies at delivery and store these samples in the freezer. With the cooperation of paediatricians and microbiologists we will be alerted if any of the babies develop iGBS disease over the next 3 months (they are the cases). For those who do develop iGBS, we can then compare the antibody levels in their cord blood samples with the antibody levels in the cord blood samples of other babies who were also exposed to GBS at delivery, but did not develop iGBS disease (the controls) - we are in the process of recruiting the controls in a separate 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 180 000 babies in order to find at least 170 babies with iGBS disease (of which 100 will have disease with the most common type, STIII) which is around the number we need to establish the serocorrelates of protection. However, it may also be possible to obtain blood at the time of disease in iGBS cases, and from this, work out what their antibody level would have been in their cord blood. If so, we can reduce significantly (by half) the number of cord blood samples we need to collect. We will test this possibility in the first part of the study. To maximise the efficiency of the study, and minimise the costs, we will embed our study in a large, already funded study which is looking at different ways of screening for GBS (the GBS3 Trial).

Group B Streptococcus (GBS) is the leading cause of early onset (EO) infections and neonatal meningitis in the UK and the burden of disease is increasing. A potential solution is to vaccinate women in pregnancy in order to provide antibody protection against the major disease-causing serotypes (ST). It is generally agreed that a serocorrelate of protection (CoP) against iGBS disease is required. We plan to determine this CoP in a UK population by embedding collection of cord blood into an existing GBS trial (GBS3, NIHR HTA). In principle, it is necessary to identify the CoP in cord blood, thus we would collect cord blood from around 180 000 women in order to capture the estimated 100 cases of STIII disease that will occur over the first 3 months of life in the babies born to these women. However, based on knowledge of antibody decay over the first 3 months of life it may be possible to estimate the cord blood antibody concentrations by measuring the antibody concentrations at the time of disease. This would reduce the number of cord blood samples needed and represent a significant cost saving. Phase one of our study will therefore collect cord blood from around 85 000 women and follow their infants up until three months of life. Blood will be taken from any infant with iGBS disease and the antibody concentration will be compared to the antibody concentration in their cord blood. If this is a robust means of estimating cord blood antibody concentrations then phase II of our study will recruit the remaining cases of iGBS disease required but not require collection of cord blood. In a separate study we are recruiting the controls - babies born to colonised women who do not go on to develop iGBS disease. Ultimately, we will derive a CoP against invasive GBS disease in infants. Such a correlate will then be used to facilitate the licensure of suitable GBS vaccines.

GBS is present in all regions of the world, in both HIC and LMICs. In 2015 it was estimated that worldwide there were at least 319 000 infants <3 months of age with iGBS resulting in 90 000 infant deaths and at least 10 000 children with disability related to GBS meningitis. Additionally, 33 000 maternal cases and 57 000 stillbirths were attributed to GBS disease.

In the UK there has been an increasing burden of iGBS over the last 15 years and the incidence is now almost double the global incidence (0.94 vs. 0.49 per 1000 live births); the 2nd highest incidence of any developed country. Over a 13-month period in 2014-5, 856 cases of iGBS were identified in infants < 3 months of age. GBS is now the most common cause of bacterial meningitis in children less than 5 years of age in the UK.

The UK population has widely accepted the concept of maternal vaccination, with high coverage of maternal pertussis vaccination (>70%) and the first (ever) demonstration of its effectiveness. The UK is therefore in an excellent position to pursue the development, licensure and implementation of a maternal vaccine against GBS.

Recent estimates suggest that an effective GBS maternal vaccine (>80% efficacy) with high (90%) global coverage could prevent 231 000 infant and maternal GBS cases, 41 000 stillbirths and 66 000 infant deaths annually. A recent cost-effectiveness analysis of maternal immunisation in the UK estimated that an effective programme could substantially reduce the burden of iGBS disease and would be cost-effective, even at a relatively high vaccine price.

Licensure and policy decisions for a candidate GBS vaccine would be significantly accelerated if an immune marker was established as a correlate of protection (CoP). Regulatory bodies have made it clear that they would now consider this approach to licensure if robust evidence can be developed. Additionally, the UK JCVI has indicated it would consider a recommendation for routine implementation of a vaccine licensed on the basis of a CoP - as it has for other recent vaccines (meningococcal B and C).

The critical gaps that have to be filled are: (i) the development of a standardised immunoassay to measure antibody levels that act as the correlates of natural immunity, and (ii) to establish the correlate using these standardised assays on a large biobank of sera. The first of these gaps is being addressed by a consortium from academia, public health, and industry (lead by co-applicant KLD), and the second is the basis of this study.

The outcomes of this research will be of direct interest to industrial partners (Pfizer, GSK, Minervax) who are developing GBS vaccines. All data will be made available as soon as possible in a freely available and widely accessible format as per MRC policies to enable data analysis across platforms and to compare results from different studies.

The close collaboration with WHO through membership of co-applicants (PH, KLD, AK) on its GBS vaccine scientific advisory panel will ensure that international policy-makers are kept fully informed of the study. The data will be of direct benefit to the UK government in understanding the potential benefit of a GBS vaccine.

Most importantly, the results of this programme of research will directly benefit pregnant women and their infants, by providing the most comprehensive information available on the potential for vaccines against GBS to protect infants and by hastening the implementation of such vaccines.

The most advanced vaccine candidate is currently in Phase II trials and it is anticipated that vaccine licensure could be as early as 2025, if based on a serocorrelate of protection. Our study will complete in three years and be ready for any potential regulatory submission for licensure of such a vaccine.