Immunomodulation and Vaccines

Lead Research Organisation: London Sch of Hygiene and Trop Medicine

Abstract

Human beings evolved in the presence of exposure to many infectious diseases, including viruses, bacteria and worms. Our immune systems evolved to protect us from these agents. However, some of them have develop strategies to evade or regulate the human immune response in such a way that they can live in their human hosts for decades, or for life. These include some parasites (worms, malaria) the bacteria that live in our gut and on our skin, and some viruses. In populations where infectious diseases have become uncommon it is likely that our immune systems develop differently compared to populations where infections are still common. This may have both benefits and disadvantages. We are investigating the hypothesis that exposure to infections, and especially chronic parasitic infections, alters
1. Responses to vaccines – generally in an adverse way, reducing desired, protective vaccine responses
2. Responses to viruses which cause cancer – also reducing beneficial immune responses that control them
3. Susceptibility to asthma and allergy
4. Susceptibility to diabetes
We think that treating parasitic infections effectively may improve the response to vaccines and other infections, but increase the risk of allergy-related diseases and diabetes. Our studies are designed to find out whether this is so.

Technical Summary

Our goal is to understand the impact of infection exposure on human immunological programming and health. Our overarching hypothesis is that chronic and cumulative infection exposure influences immunological mechanisms through active processes (during current infection), lasting epigenetic modifications, and genetic selection; that (therefore) some effects do not immediately respond to treatment; and that effects critically impact upon major health outcomes including vaccine responses and susceptibility to pathogens, allergy-related disease and metabolic conditions (Figure 8.8).
The main focus of our work is on vaccine responses, addressing the role of infectious exposures in striking population differences in vaccine immunogenicity. We also support studies on the role of chronic infection in allergy-related and metabolic disease susceptibility. Building on recent findings, exploiting unique platforms that we have established, we aim to determine the effects of infectious exposures (prenatal, cumulative life-time and current, active exposures) on health outcomes comprising:
1. Vaccine immunogenicity
2. Infectious disease susceptibility – focussing on oncogenic viruses
3. Asthma phenotypes and allergy-related effector mechanisms
4. Infection, inflammation and cardio-metabolic risk
To obtain deeper insights into mechanisms by which infections have their effects, we plan complementary studies (for which funding is available, or being sought elsewhere) on the mediating role of the microbiome and on the mediating role of epigenetic modifications
In addition, the programme supports related studies on tuberculosis and schistosomiasis, and genetic studies.

Publications

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Friedman JF (2018) Praziquantel for the treatment of schistosomiasis during human pregnancy. in Bulletin of the World Health Organization

 
Description Advisory Board member, AAS Open Research
Geographic Reach Africa 
Policy Influence Type Participation in a advisory committee
Impact This is an Open Research publishing platforms targeting leading African researchers
URL https://aasopenresearch.org/
 
Description Joint Ethical/Regulatory Review Meeting on Controlled Human Infection studies for schistosomiasis
Geographic Reach National 
Policy Influence Type Participation in a national consultation
Impact Part of a series of engagement on controlled human infection studies informing the development of regulatory procedures and approaches in Uganda. This was also the first step in the process for achieving approval of our proposed work on controlled human infection with schistosomiasis in Uganda
 
Description Wellcome Genome Campus Advanced Courses - Overseas Expert Panel member
Geographic Reach Multiple continents/international 
Policy Influence Type Participation in a advisory committee
Impact Advising on international courses on genetics and bioinformatics run by the Wellcome Trust Sanger Institute, impacting on education for African scientists.
URL https://coursesandconferences.wellcomegenomecampus.org/event-type/overseas-courses/
 
Description HIC-VAC pump priming grant with Meta Roestenberg "Preparing for Schistosoma mansoni controlled human infection studies in Uganda"
Amount £89,563 (GBP)
Organisation Imperial College London 
Sector Academic/University
Country United Kingdom
Start  
 
Description Human infection studies for Schistosoma mansoni vaccine testing in Uganda
Amount £30,000 (GBP)
Funding ID 215993 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 05/2019 
End 11/2019
 
Description Masters Training Fellowship for Agnes Mutua: "Investigating the influence of vitamin D status on cognitive and motor development in young African children" (role, sponsor)
Amount £119,212 (GBP)
Funding ID 209640 
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start  
 
Description Population differences in vaccine response: the role, reversibility and mediators of immunomodulation by chronic parasitic infections in the tropics
Amount £2,319,188 (GBP)
Funding ID MR/R02118X/1 
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 05/2018 
End 04/2022
 
Title Educational materials on CHI-S 
Description (Please note, our tool does not exactly fit the categories above!). We developed and tested educational materials for potential participants in CHI-S studies. A publication is in preparation. 
Type Of Material Model of mechanisms or symptoms - human 
Year Produced 2019 
Provided To Others? No  
Impact Will be used in future studies 
 
Description Afzal Siddiqui, Texas Tech University Health Sciences Center 
Organisation Texas Tech University Health Sciences Center
Country United States 
Sector Academic/University 
PI Contribution We have developed a funding proposal to be supported by the Wellcome Trust for establishment of a Controlled Human Infection model for Schistosomiasis (CHI-S) in Uganda. Together with Meta Roestenberg and colleagues, we held a meeting in Leiden to discuss the proposed work.
Collaborator Contribution Dr Siddiqui and colleagues have developed a candidate vaccine which we plan to test using the CHI-S model
Impact The grant application was recommended for funding by the Wellcome Trust panel; details of the award are in the final stages of negotiation
Start Year 2019
 
Description Arbovirology, UVRI 
Organisation Uganda Virus Research Institute
Department Department of Arbovirology, Emerging and Re-emerging Infections
Country Uganda 
Sector Public 
PI Contribution We are conducting the POPVAC research programme, samples from which will be processed by the department of arbovirology at UVRI
Collaborator Contribution They will undertake yellow fever plaque reduction neutralisation tests.
Impact Not yet
Start Year 2020
 
Description Co-supervision with colleagues from Witwatersrand 
Organisation University of the Witwatersrand
Department School of Public Health
Country South Africa 
Sector Academic/University 
PI Contribution We are jointly supervising PhD student Lawrence Lubyayi who is using data form this project for his PhD
Collaborator Contribution We are jointly supervising PhD student Lawrence Lubyayi who is using data form this project for his PhD
Impact Draft paper
Start Year 2017
 
Description Edridah Tukahebwa, Narcis Kabatereine 
Organisation Ministry of Health, Uganda
Department Vector Control Division
Country Uganda 
Sector Public 
PI Contribution These collaborators have expertise in the epidemiology, diagnosis and control of helminth infections. They also understand policy implications and applications. We have worked with them on implementation of all our helminth related work in Uganda.
Collaborator Contribution These collaborators have expertise in the epidemiology, diagnosis and control of helminth infections. They also understand policy implications and applications.
Impact Numerous papers and presentations Stakeholders' meetings Grants
 
Description Helen McShane, Adrian Hill, Alex Mentzer 
Organisation University of Oxford
Department Jenner Institute
Country United Kingdom 
Sector Academic/University 
PI Contribution Collaboration on (1) genetic studies on the response to infant vaccines (on-going) (2) a trial investigating the impact of schistosomiasis on the response to candidate TB vaccine MVA85A (completed) (3) a trial of ChAdOx1 85A and MVA85A as a new regimen for boosting TB immunity in adolescents. We are conducting the trial in Uganda (about to start)
Collaborator Contribution For (1) the partners provide expertise in genetics For (2) and (3) the partners are providing the vaccine, as well as contributing expertise in TB vaccine trials
Impact Publications and conference presentations DPhil for Alex Mentzer (completed) Contributions to PhDs for Swaib Lule (completed), Anne Wajja (on-going) and Beatrice Nassanga (about to commence)
Start Year 2017
 
Description Maria Yazdanbakhsh; Meta Roestenberg 
Organisation Leiden University Medical Center
Country Netherlands 
Sector Academic/University 
PI Contribution We are undertaking collaborations with LUMC department of parasitology on immuno-epidemiological effects of helminths, and on schistosomiasis vaccine development including controlled human infection models for schistosomiasis (CHI-S) In 2019 we developed a proposal for establishing the CHI-S in Uganda which the Wellcome Trust panel supported for funding. We are awaiting the award letter.
Collaborator Contribution The partners provide technical expertise, particularly in parasite immunology and
Impact PhD: co-supervision to completion of two fellows, Gyaviira Nkurunungi and Moses Egesa (both completed successfully in 2019). Publications and conference presentations. New grants for preparatory work on Sm-CHI
Start Year 2011
 
Description MoH UNEPI programme 
Organisation Uganda National Expanded Programme on Immunisation
Country Uganda 
Sector Public 
PI Contribution We are running the POPVAC trials which will provide EPI with information on the effects of parasitic infections on the response to widely used vaccines.
Collaborator Contribution The EPI programme is providing HPV vaccine for individuals in the POPVAC trials. As well, they are supporting us with training and advice.
Impact None as yet
Start Year 2018
 
Description Richard Grencis 
Organisation University of Manchester
Country United Kingdom 
Sector Academic/University 
PI Contribution Together with Prof Grencis, we won a Royal Society Collaborative Award to support further work on the metabolic impacts of helminth infection. We contribute studies in humans populations
Collaborator Contribution Prof Grencis and colleagues support work in the mouse model, as well as training for Ugandan scientists.
Impact A Masters degree in Bioinformatics form the University of Manchester for Bridgious Walusimbi
Start Year 2016
 
Description Sarah Atkinson 
Organisation Wellcome Trust
Department KEMRI-Wellcome Trust Research Programme
Country Kenya 
Sector Academic/University 
PI Contribution We have provided samples and data from the Entebbe Mother and Baby Study for work on the relationship between iron deficiency and malaria.
Collaborator Contribution Our partners have assembled an international collaboration with data from four major cohorts and have conducted analyses on iron status and genetics.
Impact Publications and conference presentations. PhD in progress for John Muriuki Two Masters degrees in progress.
Start Year 2016
 
Description Engagement with CHI-S target communities 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Other audiences
Results and Impact We undertook a project engaging target communities for Controlled human infection studies to understand knowledge of schistosomiasis, attitudes to controlled infection studies and issues that might arise for participants from endemic communities during such studies; we tested information to be provided, and the consenting process.
Year(s) Of Engagement Activity 2019,2020
 
Description Legal status of controlled human infection studies in Uganda 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Professional Practitioners
Results and Impact We met with lawyers in Uganda and obtained a legal opinion to the effect that there is no legal barrier to controlled human infection with schistosomes in Uganda.
Year(s) Of Engagement Activity 2019
 
Description Meeting with Koome island community leaders 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Study participants or study members
Results and Impact Two meetings were held (April and July) with community leaders from island communities who will take part in the study
Year(s) Of Engagement Activity 2018
 
Description Meeting with UNEPI 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact A meeting was held with colleagues from the Uganda National Expanded Programme on Immunisation to discuss project plans
Year(s) Of Engagement Activity 2018
 
Description Meeting with policy makers 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Policymakers/politicians
Results and Impact Meeting with the manager of the Uganda Tuberculosis Control Programme to share results.
Year(s) Of Engagement Activity 2018
 
Description Meetings at Koome schools 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Study participants or study members
Results and Impact A series of meetings were held with teachers, parents and community members to inform them about the study
Year(s) Of Engagement Activity 2018
 
Description Mukono District meeting 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Policymakers/politicians
Results and Impact Discussions were held with Mukono district leaders about the project plans
Year(s) Of Engagement Activity 2018
 
Description Open Day for Secondary Schools 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact We led an Open Day at the Uganda Virus Research Institute, in collaboration with Makerere University. About 900 senior secondary students attended with their teachers. The guest of honour was the Minister of State for Education and Sports (Higher Education).
Year(s) Of Engagement Activity 2018
URL http://www.muii.org.ug/
 
Description Outbreaks stakeholders workshop 
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 This was a stakeholders' workshop for researchers and outbreak control implementers from East Africa, to share activities and discuss needs in terms of research and implementation capacity for the control of outbreak diseases
Year(s) Of Engagement Activity 2019
 
Description SYMPOSIUM. "Research in Context: contributing to the SDGs" 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Postgraduate students
Results and Impact We held a symposium to discuss how research, particularly laboratory based health research, in Uganda could contribute to the Sustainable Development Goals. We had excellent keynote addresses from the WHO representative to Uganda, and from Dr Annettee Nakimuli, an obstetrician and rising research star on maternal and neonatal health. We also had a dynamic panel discussion on translating laboratory work into implementable tools and products. As well as short presentations from research students and fellows. There was interaction with the media.
Year(s) Of Engagement Activity 2019
URL http://www.muii.org.ug/
 
Description Symposium: Science for Africa: looking to the 2020s 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Postgraduate students
Results and Impact A symposium held as part of the Annual General Meeting of our DELTAS-funded capacity building programme, MUII-plus
Year(s) Of Engagement Activity 2020
URL https://www.muii.org.ug/
 
Description UNEPI EPI Technical working committee membership 
Form Of Engagement Activity A formal working group, expert panel or dialogue
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Policymakers/politicians
Results and Impact The POPVAC project leader has been able to participate in the Uganda National Expanded Programme on Immunisation Technical working committee in order to share our research and keep abreast of national policy developments.
Year(s) Of Engagement Activity 2020