Invasive Group B Streptococcus disease in young infants: understanding host and pathogen immunity ito inform maternal GBS vaccination development

Lead Research Organisation: St George's, University of London
Department Name: Institute of Infection & Immunity

Abstract

Infections during the first month of life are the leading cause of death in Africa and Group B Streptococcus (GBS) is emerging as a major culprit. GBS is a bacterium living in the back passage and vagina of women. GBS can cause lethal infection in pregnant women, stillbirths and premature births. It can be passed from mother to baby at birth or in breastmilk. Once passed on, GBS either remains harmless or causes severe pneumonia, sepsis and meningitis in new born babies. One way a mother protects her baby is by passing antibody against GBS through the placenta and in breastmilk after birth. However, we do not yet know how much antibody needs to be passed in this way to protect babies from disease. It is also unclear what changes GBS undergoes to become a potentially fatal bacteria.

At present, babies in the Africa are still dying or being born too early and too small because of infections like GBS. Our research group is dedicated to finding out why GBS passes from mother to child, what the "protective" antibody levels need to be passed through the placenta to stop babies from getting sick in the first place and how to prevent GBS disease through new treatments such as maternal vaccination. We use a variety of different ways to find out the answers - through doing fieldwork (where mother and their babies are followed up over three months from birth to see what effect GBS has on their health) or by developing laboratory tests to see how antibody works to protect against GBS.

We will use these answers to change how we look after pregnant women and monitor their babies for signs of infection. We do this so that we can improve the health of women and their babies. We bring together a number of different ways of working with the single aim of preventing GBS infections in babies (and their mothers). Our planned work includes the following:
1. Following mothers and babies in Uganda and collecting blood samples to work out how much antibody a mother needs to pass to her infant to protect against GBS infection;
2. Collecting bacteria and blood samples from babies who get GBS disease (via public health agencies we work with already) in the UK, Netherlands and France to compare if the type of bacteria found in different populations affects the amount of antibody needed to protect babies against GBS disease.
3. Helping hospitals in Uganda to investigate infections in babies by strengthening diagnostic laboratory capacity and working with clinicians to investigate and treat infections early.
4. Engaging with women in the African sites to understand whether a vaccine given to pregnant women to prevent GBS-as is currently being developed- is likely to be taken up sufficiently to be effective.

Planned Impact

Over 3 million infants and 300,000 women died in the period between birth and during the first month postpartum each year. It is estimated that 40% of these deaths are due to infectious diseases and most of these deaths occur in countries in sub-Saharan Africa such as Uganda. It is therefore unsurprising that infection during the peripartum and postnatal period is a critical area of development highlighted in the United Nations Sustainable Development Goal 3. The success of the maternal tetanus vaccination programmes has seen deaths from neonatal tetanus decline by 80% over the last 20 years and highlights the potential benefits to mother and infant of vaccination against key infectious diseases during pregnancy.
Group B Streptococcus (GBS) is the leading cause of invasive infant disease during the first three months of life in many countries and is emerging as a leading cause of stillbirth and maternal infection. Maternal vaccines against the major disease-causing serotypes of GBS are under development, yet major gaps in knowledge of serotype prevalence and disease in countries with the highest mortality and morbidity from infant infections prevent a comprehensive assessment of potential vaccine efficacy in populations such as Uganda.
It is widely accepted that efficacy trials of a potential GBS vaccine will be difficult outside of high burden settings such as South Africa and there is much interest in alternative pathways to licensure such as serocorrelates of protection.
This research programme aims to plug these gaps by providing epidemiological data from a high HIV-burden setting of serotype-specific GBS antibody to predict serocorrelates of protection against invasive disease in HIV-infected and uninfected Ugandan cohorts and compare these to European cohorts using standardised assays developed by the consortium that Dr Le Doare currently leads.
The outcomes of this research will be of direct interest to industrial partners, Pfizer, GSK, Minervax, Biovac and PATH, all of whom are developing GBS vaccines for high and low resource settings. All data will be made available as soon as possible in a freely available and widely accessible format as per UKRI policies to enable data analysis across platforms and to compare results from different studies. In this way, it is anticipated that the impact may be achieved through intellectual property protection (e.g. patenting) and subsequent commercialisation through licensing out the novel assay to an external commercial partner, thereby making the assay available to the market to benefit society and economy. I am in close contact with SGUL JRES Enterprise and Innovation which will provide expert knowledge, support and additional resources to achieve this impact. It is anticipated that the first data will be available within the first 4 years of this fellowship.
The close collaboration with WHO and NIHR through my membership on advisory panels will ensure that national and international policy-makers are kept fully informed of the serocorrelates work as it progresses. We anticipate annual stakeholder meetings to present our findings. Additionally, the data generated from Uganda will be of direct benefit to the Ugandan government in deciding whether a GBS vaccine can be adopted onto the extended programme on immunisation country schedule. The results of this work will also be available to Global Alliance for Vaccines Initiative to inform vaccine cost-effectiveness analyses as vaccine development progresses.
Most importantly, though, the results of this programme of research will directly benefit pregnant women and their infants in Uganda, by providing the most comprehensive information on infection in pregnancy and infancy to date. The platform that this research will create will initially be used for GBS vaccine trials but can be extended to other vaccine-preventable disease because of the comprehensive data that will be generated.

Publications

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Carreras-Abad C (2020) A Vaccine Against Group B Streptococcus: Recent Advances. in Infection and drug resistance

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Collin SM (2021) Uncovering Infant Group B Streptococcal (GBS) Disease Clusters in the United Kingdom and Ireland Through Genomic Analysis: A Population-based Epidemiological Study. in Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

 
Description We have been further involved in developing guidelines for COVID19 in maternity units in Uganda. We have developed a series of films about neonatal infection with the Ugandan department of health that are shown in Antenatal clinics in Uganda. We have been invited to present at the Gates Serocorrelates meeting on 23rd Feb. 2021
First Year Of Impact 2020
Sector Communities and Social Services/Policy,Healthcare,Government, Democracy and Justice
Impact Types Cultural,Societal,Policy & public services

 
Description WHO GBS Vaccine Scientific Advisor
Geographic Reach Multiple continents/international 
Policy Influence Type Citation in other policy documents
 
Description WHO Group B Streptococcal Vaccine Full Value Proposition
Geographic Reach Multiple continents/international 
Policy Influence Type Membership of a guideline committee
Impact Vaccine equity and accessibility for GAVI consideration
URL https://www.who.int/publications/i/item/9789240037526
 
Description Development of a serocorrelate of protection against invasive Group B Streptococcus disease (iGBS)
Amount £970,232 (GBP)
Funding ID MR/T030925/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 07/2020 
End 01/2022
 
Description Development of a serocorrelate of protection against invasive Group B Streptococcus disease in infants (iGBS),
Amount £950,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 04/2020 
End 04/2022
 
Description Development of serocorrelates of protection and testing of maternal GBS vaccines in Uganda
Amount € 10,400,000 (EUR)
Organisation European Commission 
Sector Public
Country European Union (EU)
Start 05/2019 
End 05/2024
 
Description Standardising assays for the assessment of serocorrelates of protection of antibodies against key GBS proteins to facilitate vaccine licensure
Amount £49,947 (GBP)
Organisation BactiVac Network 
Sector Academic/University
Country United Kingdom
Start 11/2019 
End 11/2021
 
Description Understanding the determinants of transmission of SARSCoV-2 from pregnant women to their babies
Amount £199,996 (GBP)
Organisation Action Medical Research 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2020 
End 01/2022
 
Title Dried blood spots 
Description We have developed a protocol for the optimum collection, storage and elution of dried blood spots to assess antibodies against disease. This is being published as a Newborn Screening/ Public Health England document and is under final review at BMC Immunology. 
Type Of Material Biological samples 
Year Produced 2021 
Provided To Others? Yes  
Impact We have submitted our report the the England Newborn Screening Committee who are reviewing criteria for storage of dried blood spots. 
 
Title Ugandan Biobank 
Description We have created a biobank of sera, breastmilk and bacterial isolates from newborn and maternal infections, housed at MRC Uganda. 
Type Of Material Biological samples 
Year Produced 2020 
Provided To Others? Yes  
Impact We have attended the Gates Foundation convening for Klebsiella and presented our findings. 
 
Title Group B Streptococcal Antibody in Mothers and Infants (GAMI): Study protocol to describe the strain-specific prevalence of Group B Streptococcus carriage in women and their infants in Gambia 
Description Group-B streptococci: developing a correlate of protection for future vaccine trials with the help of pregnant Gambian women and their infants. Study protocol.Objectives: To determine risk factors for GBS colonisation in Gambian mothers and in their infants from birth to day 60-89 of age. Methods: Swabs and breastmilk from mothers/infant pairs were collected and cultured on selective agar. Negative samples were analysed for GBS DNA via real-time PCR. Positive isolates were serotyped using multiplex PCR and gel-agarose electrophoresis. Results: Seven hundred and fifty women/infant pairs were recruited. 253 women (33.7%) were GBS-colonised at delivery. The predominant serotypes were: V (55%), II (16%), III (10%), Ia (8%) and Ib (8%). 186 infants were colonised (24.8%) at birth, 181 (24.1%) at 6 days and 96 at day 60-89 (14%). Infants born before 34 weeks of gestation and to women with rectovaginal and breastmilk colonisation at delivery had increased odds of GBS colonisation at birth. Season of birth was associated with increased odds of persistent infant GBS colonisation (dry season vs. wet season AOR 2.9; 95% CI 1.6-5.2). Conclusion: GBS colonisation is common in Gambian women at delivery and in their infants to day 60-89 and is dominated by serotype V. In addition to maternal colonisation, breastmilk and season of birth are important risk factors for infant GBS colonisation. 
Type Of Material Database/Collection of data 
Year Produced 2020 
Provided To Others? Yes  
Impact Data presented at ESPID 2020 
URL https://sgul.figshare.com/articles/online_resource/Group_B_Streptococcal_Antibody_in_Mothers_and_Inf...
 
Title Protocol for serocorrelates studies 
Description We have published our protocol for serocorrelate study of GBS in Uganda 
Type Of Material Data handling & control 
Year Produced 2020 
Provided To Others? Yes  
Impact The protocol will enable data to be translatable and is being discussed as a model at the Gates convening on 23rd Feb 2021 
 
Description Collaboration with Centrer for Diseases Control 
Organisation Center for Disease Control Foundation
Country United States 
Sector Charity/Non Profit 
PI Contribution We have developed an assay that can be used to assess antibodies against GBS from newborn blood spots which we are anticipating transferring to the CDC.
Collaborator Contribution The CDC have technology to make large quantities of standards on blood cards which we have visited to learn.
Impact A standard operating procedure is still in process which will be submitted to Wellcome open source.
Start Year 2019
 
Description Collaboration with PRECISE network 
Organisation King's College London
Country United Kingdom 
Sector Academic/University 
PI Contribution We are now collaborating with the PRECISE network to understand seroepidemiology in 7 African Countires
Collaborator Contribution the partners are providing data and samples from Gambia, Mozambique and Kenya
Impact Development together with the WHO for a generic protocol
Start Year 2020
 
Description World Health Organisation GBS Vaccine Scientific Advisory Group 
Organisation World Health Organization (WHO)
Country Global 
Sector Public 
PI Contribution I am a member of the WHO GBS Scientific Advisory Group and the results from our study will contribute to: 1. GBS vaccine value proposition - economic analysis 2. GBS disease burden - long term neurodevelopmental outcomes 3. GBS seroepidemiology 4. GBS vaccine preferred product characteristics
Collaborator Contribution Involved in developing the above documents
Impact None yet
Start Year 2019
 
Description A film about vaccination in pregnancy in Lugandan 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact We have developed a short film in Luganda about vaccinations in pregnancy working together with our community champions and Comunity advisory board who developed the film script and key themes. The film is played in antenatal care across Uganda.
Year(s) Of Engagement Activity 2020
 
Description Recognition of neonatal sepsis signs - Lugandan 
Form Of Engagement Activity A broadcast e.g. TV/radio/film/podcast (other than news/press)
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact We developed a short 10 minute video on signs of infection which was endorsed by the Ugandan Department of Health. The video is now shown in a loop in three hospitals in Kampala emergency department and antenatal clinic with the aim of releasing nationwide. Current reach is 25,000 pregnant women.
Year(s) Of Engagement Activity 2019