Studies to understand the response of the infant’s immune system to infectious diseases and vaccines

Lead Research Organisation: MRC Unit, The Gambia

Abstract

Despite progress overall in reducing the number of children dying before they reach the age of five, deaths in the first year of life and even more strikingly in the first month of life have not fallen in the same way. At this age many babies die as the result of infections.
The research being carried out in the infant immunology group aims to reduce deaths from infection in this most vulnerable group though better understanding the way the immune (or defence) system works.
We want to understand the best possible ways to give some of the vaccine we already have available. This might include giving vaccine to mums so that the immunity they generate (the antibodies) can protect a baby as soon as the baby is born (before the baby can be vaccinated themselves). We also want to know how the baby’s immune system responds when it comes across an infection. If understood this better we might be able to improve these response, for example with new vaccines, so the baby would not become unwell. Finally we carry out research which gives us a better understanding of how vaccines themselves working in babies. This research includes new vaccines against malaria, HIV and TB as well as established vaccines like the pneumococcal vaccine. Understanding better the vaccines we have should allow the next generation of vaccines to be designed even more effectively so that less newborns and infants die needlessly.

Technical Summary

Millennium Development Goal 4 sets out to reduce mortality in children under five-years of age. Despite progress with this overall, including in many countries across sub-Saharan Africa, mortality in infancy and in particular in newborns has so far been comparatively resistant to intervention. Although the reasons for this are multi-factorial, many deaths in this period occur as a result of infections. Consequently, understanding the distinct way in which infants respond to infections and vaccines, facilitating the rational development of novel interventions to protect newborns is a top global health priority. These areas are the focus of current research within infant immunology.
Objectives:
To characterise the key elements of the immune response to given pathogens (e.g. pneumococcus, staphylococcus) which may be associated with the development of natural immunity to these agents in order to facilitate the develop novel protective strategies
To describe, at both a cellular and a humoral level, the immunity generated by currently licensed (e.g. rotavirus) as well as experimental (e.g. malaria, HIV, TB) vaccines in order to guide future rational vaccine development
To establish the optimum regimens for the use of current vaccines (e.g. inactivated poliovirus vaccine, pneumococcal conjugate vaccines) which will maximise the protection of infants while also ensuring the logistical challenges of vaccine delivery on a large scale (e.g. through using fractional doses, novel delivery methods, maternal immunisation, multi-dose vials) are met
Methodology:
These critical objectives are being addressed across a series of maternal and infant cohorts.
A combination of interventional studies, including GCP-clinical vaccine trials, as well as longitudinal observational studies, is used according to the questions being addressed. We have the established capacity to recruit mothers antenatally allowing newborns to be followed right from delivery. We also recruit infants over the first year of life as they are presented for their routine immunisations
A range of laboratory approaches are used including large-scale serological studies monitoring correlates of vaccine induced protection, as well detailed immunological investigations. Such studies, which are often nested within larger scale trials, use techniques including multi-parameter flow-cytometry, ELISpot assays, evaluation of cytokines and antibodies using Luminex-based multi-analyte technology.
Impact
The findings of certain key studies (e.g. inactivated poliovirus vaccine trial) are expected to directly influence WHO policy over the coming year. Other work is focussed on studying pathogens (e.g. pneumococcus, malaria, rotavirus) which remain at the top of the research agenda internationally and address question recognised to be high priority.

Publications

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Basu Roy R (2012) Current understanding of the immune response to tuberculosis in children. in Current opinion in infectious diseases

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Battersby AJ (2012) Vitamin D in early childhood and the effect on immunity to Mycobacterium tuberculosis. in Clinical & developmental immunology

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Bibby J (2017) The Immunogenicity of Fractional Intradermal Doses of the Inactivated Poliovirus Vaccine Is Associated With the Size of the Intradermal Fluid Bleb. in Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

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Clarke E (2016) Maternal and neonatal pneumococcal vaccination - where are we now? in Expert review of vaccines

 
Description Maternal Immunization Pharmacovigilance - Landscape Review - A Roadmap for Program Development in Low and Middle Income Countries
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in a advisory committee
Impact The document resulting from this advisory committee consultation is expected to be used to focus future work to measure health impacts in expectant mothers receiving vaccines in low and middle income countries as well as to direct the development of the otherwise fledgling regulatory framework globally
 
Description Member - Bill & Melinda Gates Foundation Expert Advisory Group on Single Dose HPV vaccine scheduling
Geographic Reach Africa 
Policy Influence Type Membership of a guideline committee
Impact The expert committee has been set up to drive the research and implementation agenda for single dose HPV vaccine schedules in Low and Middle Income Countries
 
Description Novartis maternal immunisation strategy board
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in advisory committee
Impact the advice from the group of which I was an scientific member led to critical appraisal within industry which vaccines to push forward for maternal immunisation.
 
Description Pfizer GAVI advisory board
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in advisory committee
Impact possible impact, as Nigeria haas now introduced the PcV vaccine which was advised by the board
 
Description Press panel RCPCH
Geographic Reach National 
Policy Influence Type Participation in a national consultation
 
Description WHO Polio Research Committee Meeting attendance and data presentation
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in a advisory committee
Impact Based on funded research undertaken at the Unit we presented data to the WHO polio research committee on delivery of fraction doses of IPV in outbreak campaigns. Such data has the potential to directly impact WHO policy recommendations regarding polio outbreak control.
 
Description WHO advisory board
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in advisory committee
Impact improvements in delivery of clinical services to children exposed to TB by advocating contact tracing for vulnerable groups in the WHO guideline document to which I contributed
 
Description introduction of new vaccine in The Gambia EPI
Geographic Reach Local/Municipal/Regional 
Policy Influence Type Implementation circular/rapid advice/letter to e.g. Ministry of Health
Impact In August 2013 the Government of The Gambia introduced the Rotavirus vaccine into the EPI schedule. This was amongst other things prompted by data from the MRC Unit showing that rotavirus made a significant contribution to morbidity and mortality in children in The Gambia. The lab work was led by Vaccinology (Dr Antonio)
 
Description Al Thrasher Award
Amount $350,000 (USD)
Organisation Thrasher Research Fund 
Sector Charity/Non Profit
Country United States
Start 11/2014 
End 11/2017
 
Description Assessment of case definitions for reporting the outcomes of maternal vaccination trials
Amount $25,000 (USD)
Organisation Bill and Melinda Gates Foundation 
Sector Charity/Non Profit
Country United States
Start 10/2017 
End 12/2018
 
Description Clinical Trial scheme MRC/DFID/WT
Amount £1,300,000 (GBP)
Organisation Government of the UK 
Department Department for International Development (DfID)
Sector Public
Country United Kingdom
Start 01/2015 
End 01/2018
 
Description Global Health Wellcome Trust fellowship Dr LeDoare
Amount £55,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2013 
End 09/2014
 
Description Investigator initiated proposal
Amount $350,000 (USD)
Organisation Pfizer Ltd 
Sector Private
Country United Kingdom
Start 03/2012 
End 03/2014
 
Description Maternal Men A vaccination
Amount £195,000 (GBP)
Organisation Meningitis Research Foundation 
Sector Charity/Non Profit
Country United Kingdom
Start 01/2016 
End 01/2018
 
Description N/A
Amount $4,700,000 (USD)
Organisation PATH Vaccine Solutions 
Sector Charity/Non Profit
Country United States
Start 12/2016 
End 09/2018
 
Description PCV10 Clinical Vaccine Trial Scheme
Amount $1,900,000 (USD)
Organisation PATH 
Sector Private
Country Global
Start 09/2013 
End 07/2016
 
Description PhD studentship Dr Battersby
Amount £370,000 (GBP)
Funding ID 098980/Z/12/Z 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 03/2013 
End 02/2016
 
Description Project grant Polio trial BMGF
Amount $2,000,000 (USD)
Organisation Bill and Melinda Gates Foundation 
Sector Charity/Non Profit
Country United States
Start 01/2013 
End 07/2016
 
Description Pump-priming grant - IMPRINT Network
Amount £25,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Academic/University
Country United Kingdom
Start 09/2017 
End 09/2018
 
Description Stanford University - The effects of the infant microbiome on the immune responses to vaccination
Amount $160,000 (USD)
Organisation Stanford University 
Sector Academic/University
Country United States
Start 04/2018 
End 04/2020
 
Description Wellcome Trust Training Fellowship
Amount £247,000 (GBP)
Organisation Wellcome Trust 
Department Wellcome Trust Research Training Fellowship
Sector Charity/Non Profit
Country United Kingdom
Start 09/2014 
End 09/2017
 
Title The development of a research platform within which to undertake maternal vaccination safety and immunogenicity trials in The Gambia 
Description Maternal vaccination trials in low income countries require the development of significant research infrastructure. IN particular we have established an antenatal ultrasound facility within which to undertake gestational ultrasound assessments (not otherwise available in the country) and a framework for the capture and reporting of safety outcomes 
Type Of Material Improvements to research infrastructure 
Provided To Others? No  
Impact The platform will be used for future research in this field in The Gambia and is also likely (based on a planned publication related to the development of the platform) to guide researchers elsewhere 
 
Description Harvard Levy lab 
Organisation Boston Children's Hospital
Country United States 
Sector Hospitals 
PI Contribution exchange of staff and technology
Collaborator Contribution contributed research samples
Impact publication by Burl et al
Start Year 2010
 
Description Harvard Levy lab 
Organisation University College London
Department Institute of Child Health
Country United Kingdom 
Sector Academic/University 
PI Contribution exchange of staff and technology
Collaborator Contribution contributed research samples
Impact publication by Burl et al
Start Year 2010
 
Description ICH London Goldblatt lab 
Organisation University College London
Department Institute of Child Health
Country United Kingdom 
Sector Academic/University 
PI Contribution scientific exchange re pneumococcal immunisation policies, practice and research, sharing of reagents and assay development
Collaborator Contribution scientific exchange re pneumococcal immunisation policies, practice and research, sharing of reagents and assay development
Impact 1 shared PhD studentship, scientific workshop at MRC The Gambia input into senior appointments
Start Year 2012
 
Description Merck Vaccines 
Organisation Merck
Country Germany 
Sector Private 
PI Contribution As part of a clinical trial of HPV vaccines we will provide serum samples to Merck to analyse on their multiplex based serology platform which has been used in past efficacy trial of the vaccine. The results will be provided to us (MRC Unit The Gambia) for analysis.
Collaborator Contribution As part of a clinical trial of HPV vaccines we will provide serum samples to Merck to analyse on their multiplex based serology platform which has been used in past efficacy trial of the vaccine. The results will be provided to us (MRC Unit The Gambia) for analysis.
Impact Nil as yet - trial underway
Start Year 2016
 
Description Novartis Vaccine development 
Organisation Novartis Institutes for BioMedical Research (NIBR)
Department Novartis Vaccines Institute for Global Health (NVGH)
Country United States 
Sector Private 
PI Contribution generated data for pertussis seroprevalence
Collaborator Contribution funding for consumables
Impact manuscript in progress
Start Year 2011
 
Description Public Health Engalnd 
Organisation Public Health England
Country United Kingdom 
Sector Public 
PI Contribution Provision of clinical trial serum samples
Collaborator Contribution Processing of clinical trial serum samples for serological analysis
Impact Presentation of clinical trial results and World Health Organisation Meeting
Start Year 2012
 
Description RIVM Holland 
Organisation National Institute for Public Health and Environment (RIVM)
Department Centre for Infectious Diseases, Epidemiology and Surveillance
Country Netherlands 
Sector Public 
PI Contribution analysis of samples at MRC using RIVM technology, following successful tec transfer from RIVM results on pertussis of interest to RIVM epidemiologists
Collaborator Contribution facilitating Tec Transfer to MRC by hosting 2 technicians
Impact 1 manuscript submitted, 1 in preparation
Start Year 2011
 
Description Viral illnesses in infants and mothers in the PROPEL trial 
Organisation University of Cincinnati
Country United States 
Sector Academic/University 
PI Contribution Provision of samples
Collaborator Contribution Provision of laboratory supplies and expertise
Impact Awaited
Start Year 2015
 
Title 10 valent pneumococcal conjugate vaccine manufactured by the Serum Institute of India (generic for GAVI purchase) 
Description We have recently completed a phase 1/2 trial and a phase 3 licensure trial is now planned 
Type Therapeutic Intervention - Vaccines
Current Stage Of Development Early clinical assessment
Year Development Stage Completed 2017
Development Status Under active development/distribution
Clinical Trial? Yes
Impact The phase 1/2 trial completed and the phase 3 trial planned aim to result in the licensure of the first generic pneumococcal conjugate vaccine specifically targeting those pneumococcal serotypes prevalent in low and middle income countries 
URL https://clinicaltrials.gov/ct2/show/NCT02308540?term=VAC017&rank=1
 
Title Prevenar13 (licensed vaccine) for use in expectant mothers (unlicensed indication) 
Description Prevenar13 is licensed in infants, children and adults but is not licensed in pregnancy. This trial is testing the safety and efficacy against pneumococcal nasopharyngeal carriage of the vaccine in pregnant women and newborns 
Type Therapeutic Intervention - Vaccines
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2017
Development Status Under active development/distribution
Clinical Trial? Yes
Impact The trial is currently underway and data has yet to be analysed. 
URL https://clinicaltrials.gov/ct2/show/NCT02628886
 
Title polio needleless devices 
Description 2 needleless devices to administer vaccines are currently under evaluation within Vaccinology/Inf Immunology. funding: BMGF/PATH 
Type Therapeutic Intervention - Medical Devices
Current Stage Of Development Late clinical evaluation
Year Development Stage Completed 2013
Development Status Under active development/distribution
Clinical Trial? Yes
Impact trial ongoing 
URL http://clinicaltrials.gov/show/NCT01847872
 
Title polio vaccine 
Description currently conducting new application of polio vaccine to be given i.m at 9 months with other EPI vaccines funding: BMGF 
Type Therapeutic Intervention - Vaccines
Current Stage Of Development Refinement. Clinical
Year Development Stage Completed 2013
Development Status Under active development/distribution
Clinical Trial? Yes
Impact trial in progress 
URL http://clinicaltrials.gov/show/NCT01847872
 
Description Community sensitisation events 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Participants in your research and patient groups
Results and Impact The community sensitisation events are regularly conducted to inform past, present and future participants in our research on the results of previous studies and upcoming new research studies and clinical trials. They serve as a link to the community decision makers and are well supported by community members and MRC researchers.

Increased participation in clincial trials and ongoign research
Year(s) Of Engagement Activity 2010,2011,2012,2013,2014
 
Description Inaugural lecture 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Type Of Presentation Keynote/Invited Speaker
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact Travel with T cells, now on YouTube

inerest in academic medicine by GCSE-level students, several University students requesting mentorship
Year(s) Of Engagement Activity 2012