Impact of maternally derived antibodies and infant microbiota on the immunogenicity of rotavirus vaccines in African, Indian and European infants.

Lead Research Organisation: University of Liverpool
Department Name: Institute of Infection and Global Health

Abstract

Rotavirus is the commonest cause of severe childhood diarrhoea, leading to almost half a million infant deaths worldwide each year. Rotavirus vaccination is recommended by the World Health Organisation for all infants, especially in countries with the highest mortality due to diarrhoeal disease which are in sub-Saharan Africa and in southern Asia, but current vaccines are least effective in the countries where most deaths from diarrhoea occur. The reasons for the inferior vaccine performance are not well understood, but are likely to be complex.
Rotavirus vaccines rely on the oral administration of weakened rotaviruses which multiply in the gut of the baby to stimulate the immune system to produce antibodies and protect the child from developing rotavirus diarrhoea. Factors that affect how well rotavirus vaccines perform may include a) maternal antibodies passed to the baby in the womb or via breast milk (passively-acquired immunity); b) the baby's gut bacteria (microbiota), which is important for maintaining a healthy gut and promoting effective immune responses following natural infection or vaccination and c) giving two oral vaccines together where one virus may interfere with the other. Children living in poor countries are also exposed to many gut infections, which lead to gut inflammation and which may contribute to the inability to respond well to oral vaccines, development of malnutrition and physical and cognitive growth delays.
The key goals of this project are to determine the roles of passively-acquired immunity, the composition of the baby's gut bacteria and the effect of giving two oral vaccines together on immune responses to rotavirus vaccine. The study will follow babies before and after rotavirus vaccination in three countries (Malawi, India and the UK), from birth to 14 to 16 weeks of age. Studies have shown that babies in Malawi and India have poor responses to rotavirus vaccination, whereas children in the UK will have stronger responses leading to protection from rotavirus diarrhoea, as in other high-income countries. We will compare the levels of antibodies transferred from the mothers to the babies during pregnancy and after birth, by measuring the antibodies in the mothers' blood and in their breast-milk. We will study the composition of the gut microbiota from birth to the time of rotavirus vaccination in each of the three groups. We will relate the microbiota composition in the gut of child to that of the mother's gut and breast-milk, and analyse the data taking into account factors such as nutrition and early gut infections, which differ by location, in order to assess how they impact the infant's ability to respond to rotavirus vaccination, and measure the levels of rotavirus antibody generated by the babies after vaccination. We will also carry out a study in India that compares the response to rotavirus vaccine in babies who are given polio vaccines at the same time as the oral rotavirus vaccine by two different routes, orally or by injection. This study is important because there is a global plan to introduce the injectable polio vaccine as part of the plan to eradicate poliovirus. This will help provide a comparison between India and Malawi which uses the oral polio vaccine, and India and the UK which uses the injectable vaccine. We can also compare the effect of giving two oral vaccines together compared with the oral rotavirus vaccine given with the injectable polio vaccine in the same population. These studies will develop the tools for new assays and protocols to ensure that the cross-country comparisons are not affected by differences in the way the studies and the analyses were conducted. The results of these studies will directly inform the design of alternative or complementary strategies to improve the performance of these and other anti-diarrhoea vaccines, with an aim to reduce infant deaths by improving resistance to diarrhoea in infants living in developing countries.

Technical Summary

Live, attenuated, orally administered rotavirus (RV) vaccines have the potential to greatly reduce diarrhoea deaths but they work less well in countries where they are needed most. In Sub-Saharan Africa and South Asia, vaccine efficacy is 43-66% compared to >90% in high-income countries. The reasons are not understood, but likely to be complex.
Serum IgA responses are lowest where RV vaccine efficacy is poor, and are used as an imperfect correlate for protection. Vaccine virus shedding in stool indicates "vaccine take", but its predictive value as a correlate of protection has not been explored in low income settings. We will address the following questions:
1. What is the role of maternally derived antibodies on RV vaccine take and serum IgA response in infants?
2. Is dysbiosis at the time of vaccination associated with poor RV vaccine take and serum IgA response in infants?
3. What is the effect of co-administered oral poliovirus vaccine (OPV) on the immunogenicity of RV vaccine in infants in low-income settings?
The study will enrol birth cohorts in three countries: Malawi and India, with infant populations in whom RV vaccine efficacy is poor, and the United Kingdom, where vaccine efficacy is high. In India, two cohorts will be recruited to allow comparison of the effect of OPV and inactivated polio vaccine on RV vaccine immunogenicity in the same population. Infants will be followed from birth up to 16 weeks of age. Blood and breast milk samples will be collected to investigate the impact of maternal antibody transfer on seroconversion. Serial stools will examine gut microbiota development, early exposure to natural RV infection and RV vaccine virus shedding post immunisation. Gut and systemic inflammation at the time of vaccination will be assessed. An improved understanding of RV vaccine performance will inform strategies for delivery and design of rotavirus and other enteric vaccines in low-income settings with high burden of enteric infection.

Planned Impact

This study will primarily benefit infants living in low income countries by identifying reasons for poor efficacy of live attenuated rotavirus vaccines, which can then be addressed through specific interventions. Improved performance of rotavirus vaccines will directly impact on infant mortality and improve health and quality of life of children living in the poorest countries. Increasing rotavirus vaccine efficacy will also result in improved cost benefit analyses in countries that are or will be investing significant proportions of their limited resources on the introduction of rotavirus vaccination.
In the short term, studying different populations and accounting for their different risk factors will inform the design of appropriate interventions and future clinical trials aimed at improving RV vaccine efficacy among infants living in sub-Saharan Africa and South East Asia. Such interventions, may involve: (a) Changes to vaccine dosing to overcome inhibition of vaccine take by maternally derived immunity; (b) Maternal or new-born vaccination to prevent disease in the neonatal period up to the age of current vaccination; (c) Bringing forward the switch to inactivated poliovirus vaccine to avoid competition between two oral vaccines given concomitantly (oral polio and rotavirus vaccines are currently being currently co-administered in Africa and potentially in south East Asia); (d) Interventions aimed at promoting a "healthy" microbiota in the infant gut leading to improved vaccine efficacy and resistance to enteric disease. These would impact on vaccine manufacturers, and on vaccination policies driven by national departments of health and WHO.
This study will provide novel data on the maternal microbiota imprinting of the infant gut microbiota in different populations, which will inform the most effective approach for targeting interventions for improved gut health and prevention of disease though enhanced immune responses. In the longer term the results and findings derived from this study are likely to be applicable to other enteric infections and vaccines. Enhanced enteric vaccine efficacy in children in resource poor settings will have significant impact beyond reducing infant mortality and morbidity associated with vaccine preventable enteric pathogens. Treating/ preventing dysbiosis which leads to inflammation and impaired immune responses is likely to promote resistance to infection or reduce disease severity associated with enteric pathogens. The resolution of dysbiosis and the reduction of enteric infectious disease will also directly impact on other important morbidities including malnutrition, leading to far reaching health improvements, such as reduction of infant morbidity and mortality, increase health and quality of life resulting in longer term advancements in productivity and the economies of low income countries.
In addition this project will serve as a platform for multilateral capacity building, providing training for Malawian and Indian clinical and laboratory scientists by mentoring and cross-institutional training, including formal workshops lead by Indian and UK investigators in Vellore and Malawi
 
Description ACMSF
Geographic Reach Europe 
Policy Influence Type Participation in a advisory committee
Impact Advise on microbiological safety of food, provide expertise on risks posed by viruses
 
Description A Phase 3 double-blind, randomized, active comparator-controlled, group-sequential, multinational trial to assess the safety, immunogenicity and efficacy of a trivalent rotavirus P2-VP8 subunit vaccine in prevention of severe rotavirus gastroenteritis in
Amount $15,000,000 (USD)
Organisation PATH 
Sector Charity/Non Profit
Country Global
Start 05/2019 
End 09/2023
 
Description GLOBAL CHALLENGES RESEARCH FUND: IMPACT ACCELERATION ACCOUNT
Amount £10,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 01/2017 
End 03/2017
 
Description NIHR Health Protection Research Unit in Gastrointestinal Infetions
Amount £3,999,954 (GBP)
Organisation National Institute for Health Research 
Sector Public
Country United Kingdom
Start 04/2020 
End 03/2025
 
Description The human gut microbiome as the key link between childhood malnutrition and risk of metabolic disorders in later life in south India. Preparatory grant
Amount £50,621 (GBP)
Funding ID MR/T008512/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 01/2019 
End 05/2020
 
Description Collaborative project proposal on mechanism of malnutrition 
Organisation Christian Medical College, Vellore
Country India 
Sector Academic/University 
PI Contribution We have set up a group to prepare a research programe acmes at understanding the impact of the microbiome from birth on malnutrition and its influence on risk for NCDs
Collaborator Contribution CMC: expertise in paediatric malnutrition, in endocrinology, community health, NCDs UOL: Malnutrition, food systems and microbiome Leeds: development and assessment of interventions for tacking NCDs in LMICs and policy
Impact preparing submission to MRC
Start Year 2019
 
Description Collaborative project proposal on mechanism of malnutrition 
Organisation University of Leeds
Country United Kingdom 
Sector Academic/University 
PI Contribution We have set up a group to prepare a research programe acmes at understanding the impact of the microbiome from birth on malnutrition and its influence on risk for NCDs
Collaborator Contribution CMC: expertise in paediatric malnutrition, in endocrinology, community health, NCDs UOL: Malnutrition, food systems and microbiome Leeds: development and assessment of interventions for tacking NCDs in LMICs and policy
Impact preparing submission to MRC
Start Year 2019
 
Description Computational Biology 
Organisation University of Liverpool
Department Computational Biology Facility
Country United Kingdom 
Sector Academic/University 
PI Contribution Exploration of systems biology analytical pipeline for RoVI study data integration
Collaborator Contribution system biology expertise
Impact received in kind contribution from the computational Biology centre in the form of 3 months worth of data analysis after a competitive application and selection process (DATARAMA)
Start Year 2018
 
Description Glycome 
Organisation University of Liverpool
Department NMR Centre for Structural Biology
Country United Kingdom 
Sector Academic/University 
PI Contribution Glycome characterisaiton from breast milk samples. Method optimisation
Collaborator Contribution Glycome and metabolome expertise
Impact Applied for Fellowship (Dr Christina Bronowski) to characterise the glycan composition of breast mild samples collected from the RoVI study in India and thein the UK and study the relationship with the infant breast milk and infant microbiome and vaccine take.
Start Year 2018
 
Description HPRU extenssion 
Organisation University of Liverpool
Department Institute of Psychology, Health and Society
Country United Kingdom 
Sector Academic/University 
PI Contribution Through the collaboratiions within the RoVI study and the developemtn of new analystical proposals, a collaboration was set up with Prof Sarah O'Brien and Prof Christiane Hertz-Fowler to further develop "metaomics" approaches for diagnosing and identifying infectionus intestinal disease.
Collaborator Contribution Leveraging samples frome the "Integrate" study, access to metabolomics expertise and facilities, proposal submitted to NIHR for a new project to be conducted as part of the HPRU in gastrointestinal infections
Impact funding applied for a new project leveraging expertise and samples from various ongoing studies between the partners
Start Year 2018
 
Description Microbiome development in the C-GULL cohort 
Organisation University of Glasgow
Country United Kingdom 
Sector Academic/University 
PI Contribution We are developing a joint proposal to investigate the development ion the microbiome in an infant cohort in Liverpool, with the main aim to study the role of the microbiome on the development of atopy, obesity and metabolic disorders in a community with a large proportion of children living in poverty or disadvantaged circumstances
Collaborator Contribution expertise in microbiome and complex data integration, expertise in nutrition
Impact Proposal has undergone 1st round review by Wellcome and we are preparing now for full application (Wellcome collaborative Award)
Start Year 2019
 
Description Microbiome development in the C-GULL cohort 
Organisation University of Warwick
Country United Kingdom 
Sector Academic/University 
PI Contribution We are developing a joint proposal to investigate the development ion the microbiome in an infant cohort in Liverpool, with the main aim to study the role of the microbiome on the development of atopy, obesity and metabolic disorders in a community with a large proportion of children living in poverty or disadvantaged circumstances
Collaborator Contribution expertise in microbiome and complex data integration, expertise in nutrition
Impact Proposal has undergone 1st round review by Wellcome and we are preparing now for full application (Wellcome collaborative Award)
Start Year 2019
 
Description Rotavirus:new measures for protection 
Organisation Medical Research Council (MRC)
Department MRC Laboratory of Molecular Biology (LMB)
Country United Kingdom 
Sector Academic/University 
PI Contribution Started a collaboration with Dr Sarah Caddy, recently awarded a Wellcome Clin postdoctoral training fellowship to assed the role of maternal antibodies on vaccination. She has develop a new neutralisation assay that need validation with samples from clinical trials or studies in humans. We have been collaborating on assay optimisation and validation using samples obtain in this and other relevant studies. Analysed result and provided advice on future steps
Collaborator Contribution shared novel assay and performed testing using sample collections provided
Impact presentation at research seminars at Cambridge university and university of Liverpool
Start Year 2018
 
Description Virome study 
Organisation Imperial College London
Country United Kingdom 
Sector Academic/University 
PI Contribution We have developed a collaboration to study the "Virome" as a key important of the microbiome in between Dr Edward Parker, Imperial college, Dr Ira Praharaj, CMC Vellore, Dr Christina Bronowski and myself at UoL, with the aim to analyse the sampel collection from the RoVI study and the expertise between the three teams on sample preparation and laboratory processes and data analysis (supported by Baylor college of Medicine, Houston USA).
Collaborator Contribution Pilot data generated from samples from a previous study in Vellore, to optimise sample preparation and data analysis pipelines (all three partners).
Impact laboratory and data analysis pipelines optimised. Funds fro testing identified, and sample processing and data anlysis expected 1st Q of 2019.
Start Year 2017
 
Description application for NIHR Global Health Research Centre 
Organisation Kenyan Institute for Medical Research (KEMRI)
Country Kenya 
Sector Public 
PI Contribution Expertise and intellectual input, research proposal development particularly on enteric infectious diseases
Collaborator Contribution Expertise and intellectual input, research proposal development particularly on enteric infectious diseases, but also identifying appropriate partners for input on other areas of the research proposal
Impact An application lead by the Institute of Infection and Global Health (Prof T Solomon) wass been submitted to the NIHR GHRC bid was sumbmitted in partnership with Scientist in CMC Vellore, College of Medicine Malawi, MLW and KEMRI, Kenya focused on enteric respiratory and neurological infections. Varios of the partners in already working together in the Newton award funded project have leadership roles in this new collaborative initiative, but the collaboration had been extended involving additional institutions and infectious disease areas. this was unsuccessful. Subsequently the application was revised and a revised version focusing on neurological infections was submitted to NIHR Global Health Grant which was successful. Collaboratinos initiated in the initial application were maintained and developed further for the revised submission.
Start Year 2016
 
Description 13th international rotavirus symposium, Minsk Belarus 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact preliminary results of the study were presented at this meeting by Dr Sudhir Babji, and myself in two separate presentations.
Year(s) Of Engagement Activity 2018
 
Description Inaugural talk 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Gave an inaugural lecture at the university of Liverpool to mark my appointment as a chair in virology. Presented much of my work on enteric viruses and vaccines, with a focus on the ongoing work funded by the Newton Grant. as well as colleagues, members of the public and family attend the events, providing an excellent opportunity to raise awareness of our work. there were various informal discussions following the lecture.
Year(s) Of Engagement Activity 2016
 
Description Official opening of the Centre for Global Vaccine Research at the University of Liverpool 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact Talk on enteric infections and vaccines to a mostly scientific audience. Engagement with industry.
Year(s) Of Engagement Activity 2016
 
Description PPI meeting held at the Centre for Women's Health research and the Harris-Wellbeing Preterm Birth Research Centre 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Patients, carers and/or patient groups
Results and Impact The RovI study aims and protocl was discussed. Particular attention was provided to participant information packs and sample collection instructions. The feedback obtained from the group was extremely vvaluable and was incorporated to the final study protocol prior to submission for ethical review.
Year(s) Of Engagement Activity 2015
 
Description Public poster presentation at the MRC Festival of Medical Science Victoria Gallery and Museum from 4:30 to 8:00 on Wednesday 22nd Jun 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Public/other audiences
Results and Impact Approximately 50 memebrs of the public attended this event, at which posters were presented during an informal reception. MEmebrs of the public asked questions about the study and the general topic of my and my institute's research
Year(s) Of Engagement Activity 2016
 
Description RoVI study kick off meeting 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact The study protocol and in particular the practicalities of participant recruitment and follow up, sample collection, laboratory testing in each of the thee locations, Liverpool, UK, Blantyre, Malawi and Vellore, India were discussed in detail. In addition to the study principal investigators and co-investigators, midwifes, research nurses, paediatricians, and laboratory scientists and epidemiologists contributed tot he meeting which resutled in a robust study protocol, and a clear set of actions.
Year(s) Of Engagement Activity 2015,2016
 
Description School visit , Liverpool 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Talk and workshop for children in years 5 and 6 at Childwall Valley Park school on "Tummy bugs and the importance of clean hands" on the 29th of April 2017
Year(s) Of Engagement Activity 2017
 
Description UK veterinary vaccines network meeting. 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact Invited talk on the role of the micro biome on oral vaccine take and immunogenicity. The talk was well received and sparked numerous questions and discussion, with new research contacts being made and further discussions on areas of mutual interest and cross over between animal and human vaccinology
Year(s) Of Engagement Activity 2017
 
Description science in the pub 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Gave a talk on the impact of viral gastroenteritis and vaccines for enteric disease to the general public at Liverpool's Everyman Bistro Bar. This is an event organised by scientist at the University of Liverpool aimed at communicating our work to the public. There are a total of 6 talks in an evening event.
Year(s) Of Engagement Activity 2017
 
Description seminar at Nottingham QMC immunology group 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Professional Practitioners
Results and Impact presented current research on enteric virus infections to a group of clinicians and scientist. This was followed by a discussion and planning of joint working on a small exploratory project for the treatment of chronic diarrhoea in immunodeficient patients.
Year(s) Of Engagement Activity 2017
 
Description training workshop in Vellore 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Professional Practitioners
Results and Impact A Rotavirus serology and standardisation of assays for clinical trial was conducted in Vellore in August 2018 involving participants from Malawi, UK and South Africa
Year(s) Of Engagement Activity 2018