MICA: Study of disease mechanisms in enteric fever to characterise innate & adaptive immunity in mucosa & blood in controlled human infection model

Lead Research Organisation: University of Oxford
Department Name: Experimental Medicine

Abstract

Typhoid fever (also known as enteric fever), an infection characterised by diarrhoea and rash, is most often caused by a type of bacteria called Salmonella enterica. After gaining entry to the body via contaminated food or drink, the Salmonellae travel first to the gut, and then the bloodstream, from where they can infect the lymph nodes, gallbladder, liver, spleen, and other parts of the body. Treatment of enteric fever is by rehydration either intravenously or by drinking uncontaminated water mixed with electrolytes. Antibiotics are used to kill the bacteria, but as there are increasing rates of antibiotic resistant S. enterica throughout the world, this means of treatment is becoming less effective.

Two Salmonella variants, known as serovars Typhi and Paratyphi, cause around 27 million cases of enteric fever and more than 200,000 deaths per year worldwide, mostly in the developing countries. Even though improved sanitation through economic development should eventually eliminate enteric fever, reduction of the disease burden in the medium term is achievable through effective immunisation, especially in the face of increasing antibiotic resistance.

Although effective vaccines are likely to be available for mass vaccination against typhoid in the near future, these vaccines will be effective only against those strains of S. Typhi and S. Paratyphi that bear the Vi polysaccaharide capsule proteins. Strains that do not have these capsule proteins, or that have no capsule (acapsulate) will be unaffected by vaccination and could fill the ecological space vacated by the capsulate strains. Indeed, enteric fever caused by S. Paratyphi A which does not carry the Vi protein and for which there is currently no vaccine, has risen during the past decade and accounts for more than half of all cases in some areas.

Thus it is important that effective vaccines are available to protect against infection by both capsulated and non-encapsulated Salmonella enterica. To develop such vaccines, we need a full understanding of the human immune response to the acapsulate Salmonella including the interactions between the inbuilt immune system and disease-specific immunity, contributions of immunity in the gut and the bloodstream, immune response to protein and to polysaccharide determinants, and the role of antibodies. How much cross-protection there is between capsulate and non-capsulate typhoidal Salmonellae after natural infection or vaccination is not known, but this is critically important to vaccine development.

With this project we aim to fill in the knowledge gaps highlighted above, by fully characterising the infection process and immune response in enteric fever.

Technical Summary

Vaccines for S. enterica currently under development are based on the S. Typhi and S. Paratyphi C Vi polysaccaharide capsule. However, enteric fever caused by S. Paratyphi A (which does not carry Vi) and for which there is currently no vaccine, has risen in the past decade and accounts for more than 50% of cases in some areas.
Design and evaluation of effective vaccines is limited by a gap in understanding the mechanisms of susceptibility to capsulate and non-capsulate typhoidal Salmonellae.
To fill this knowledge gap we will extend a controlled human infection model (developed by us in Oxford) with S. Typhi to infection with S. Paratyphi by challenging volunteers previously exposed to S. Typhi with either S. Typhi or S. Paratyphi. We will be able to relate responses in a controlled human infection model to natural protection, and use this for potential vaccine antigen discovery.

We aim to: A) identify the systemic and mucosal location of bacteria to determine potential for humoral and cellular protection; B) compare innate responses to S. Typhi and Paratyphi in peripheral blood and mucosa in individuals resistant and susceptible to infection; C) define the phenotype and antigen specificities of B cell and T cells responses against the two pathogens to identify correlates of protection against reinfection; D) identify CD1 restricted Salmonella derived lipid antigens that are conserved between different Salmonella strains and which may be used as T cell antigens for alternative vaccination strategies.

Our findings will be further validated in naturally exposed individuals in the Mucosal Research Unit within the Wellcome Trust Major Overseas Unit in Malawi.
This programme will give new insights into the innate and adaptive immune responses and the pathogenesis of human infection with the bacteria that cause enteric fever. It will provide important correlates of protection that will facilitate the design and optimisation of novel vaccination strategies.

Planned Impact

There are a large number of potential beneficaries of the proposed research since this is a wide-ranging multi-disciplinary pogramme including but not limited to:

1) Researchers in the field of enteric pathogens could use the approach we are planning to guide new investigation with enteric pathogens or replicate our model
2) Immunology researchers will gain new insight into the interaction between innate and acquired immune responses and bacteria which can be used to investigate other organisms
3) Vaccine developers in the commercial private sector who could use the data to guide development of improved vaccines or test their new products in the challenge model
4) The information produced in this project will be of interest to agencies that are currently considering implementation of vaccines for enteric fever including the World Health Organisation, Global Alliance for vaccines and immunisation (GAVI) and the Bill and Melinda Gates Foundation.
5) The project may also provide new insight into correlates of protection which would be of special interest to regulators
6) The project will generate considerable public interest and includes some important and compelling themes which can be readily conveyed to the public to enhance the understanding of science.
7) If the research were to support or lead to new or improved vaccines for enteric fever, there would be a major impact on the large numbers of individuals who are exposed to these pathogens and are at risk.
8) Reducing the burden of this disease has the potential to directly impact on the physical and economic health of affected populations.
9) The project provides a remarkable training opportunity for clinical trainees engaged in the trial and the endoscopy to learn about clinical research and for them to be introduced to the laboratory research that the clinical plan supports.

Publications

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Bedard M (2019) Sterile activation of invariant natural killer T cells by ER-stressed antigen-presenting cells. in Proceedings of the National Academy of Sciences of the United States of America

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Chen YL (2020) Re-evaluation of human BDCA-2+ DC during acute sterile skin inflammation. in The Journal of experimental medicine

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Gibani MM (2019) The Impact of Vaccination and Prior Exposure on Stool Shedding of Salmonella Typhi and Salmonella Paratyphi in 6 Controlled Human Infection Studies. in Clinical infectious diseases : an official publication of the Infectious Diseases Society of America

 
Description MRC Capital Prioritisation Equipment Bid
Amount £120,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 03/2017 
End 02/2018
 
Description Collaboration with Harvard University 
Organisation Harvard University
Department Harvard Medical School
Country United States 
Sector Academic/University 
PI Contribution Analysis of CD1 restricted Salmonella-specific T cell responses
Collaborator Contribution Collaborative project
Impact Publications of papers in peer-reviewed journals.
Start Year 2013
 
Description Collaboration with Professor Dick Strugnell 
Organisation University of Melbourne
Country Australia 
Sector Academic/University 
PI Contribution Use of libraries of Salmonella specific T cell clones generated from Salmonella infected volunteers to identify and characterize cross-reactive and serovar specific Salmonella T cell antigens
Collaborator Contribution Collaborative project
Impact No published outcome yet
Start Year 2016
 
Description Collaboration with Professor Dirk Bumann 
Organisation University of Basel
Department Biozentrum Basel
Country Switzerland 
Sector Academic/University 
PI Contribution Use of libraries of Salmonella specific T cell clones generated from Salmonella infected volunteers to identify and characterize cross-reactive and serovar specific Salmonella T cell antigens
Collaborator Contribution Collaborative project
Impact No published outcome yet
Start Year 2016
 
Description Collaboration with Professor Gordon Dougan 
Organisation The Wellcome Trust Sanger Institute
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Use of libraries of Salmonella specific T cell clones generated from Salmonella infected volunteers to identify and characterize cross-reactive and serovar specific Salmonella T cell antigens
Collaborator Contribution Collaborative project
Impact No published outcome yet
Start Year 2016
 
Description Collaboration with Professor Sarah Teichmann 
Organisation The Wellcome Trust Sanger Institute
Country United Kingdom 
Sector Charity/Non Profit 
PI Contribution Single cell RNAseq analysis of CD4 T cell responses to Salmonella Typhi and Paratyphi
Collaborator Contribution Collaborative project
Impact No published outcome yet
Start Year 2015
 
Description Collaboration with the Oxford Vaccine Group 
Organisation University of Oxford
Department Oxford Vaccine Group
Country United Kingdom 
Sector Academic/University 
PI Contribution In the context of the MRC Experimental Medicine Challenge Grant, my group has set up a close collaboration with the Oxford Vaccine Group directed by Professor Andrew Pollard.
Collaborator Contribution As a joint collaboration, we are investigating disease mechanisms in enteric fever to characterise innate and adaptive immunity in mucosa and blood in controlled human infection models
Impact Collaboration still ongoing
Start Year 2014
 
Description Article in WIMM Blog on invariant natural killer T cells 
Form Of Engagement Activity Engagement focused website, blog or social media channel
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Public/other audiences
Results and Impact An article entitled "Lights, Camera, Immuno-action!" on WIMM Blog presenting research on invariant natural killer T cells, and the role they may be able to play in the fight against cancer.
Year(s) Of Engagement Activity 2017
URL http://www.imm.ox.ac.uk/wimm-blog-2
 
Description Developing resources for teachers to use in classroom 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Working as part of team developing resources for teachers to help them enrich their curriculum with hands-on classroom activities, an existing activity that illustrates blood group compatibility to students was adapted and teaching materials for teachers were developed to conduct the experiment with students in classroom. This included the design of worksheets for the students and a detailed lesson plan for the teachers as well as introductory materials. A 3-minute animation explaining the immunological concepts underlying antibody-mediated immunity was written and produced.
Year(s) Of Engagement Activity 2017,2018
 
Description Flow Cytometry Talk for In2Science work experience programme 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact The aim was to introduce participants of the WIMM work experience programme to the basic concepts of flow cytometry; audience: high school age participants of the WIMM work experience programme
Year(s) Of Engagement Activity 2018
 
Description Hands on activities at the Oxford Museum of Natural History 
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 "The Blood Factory" - hands on activities about blood at the Museum of Natural History for secondary school students, adults etc.
Year(s) Of Engagement Activity 2017
 
Description Hands-on activities during Royal Society Summer Exhibition, London 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Hands-on activities, including virtual reality tour of DNA, during Royal Society Summer Science Exhibition, Royal Society London.
Year(s) Of Engagement Activity 2017
 
Description Hosting of an A-level student 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Last year we hosted Jasmine Godden, July 16-19 2018. She was a 6th former student at Cheney and was interested in Cancer Immunotherapy. She shadowed members of the Lab and discussed with them their research, then she wrote an essay on Cancer Immunotherapy in Melanoma.
She got an A* for this work, as part of her EPQ. She now intends to apply for medical school.
Year(s) Of Engagement Activity 2018
 
Description Hosting of severl A-level Work Experience students 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact The Group hosted five A-level students from local schools for a period of Work Experience. Two of the students subsequently decided to go on to study medicine.
Year(s) Of Engagement Activity 2019
 
Description MRC Festival of Medical Research 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact We set up and organised the "Cancer Immunotherpy Stand" in the context of the yearly MRC Festival of Medical Research
Year(s) Of Engagement Activity 2019
 
Description MRC Festival of Medical Research 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact Participation in a co-organised event set up in a series of regional supermarkets to raise awareness of the research and science carried out by the MRC
Year(s) Of Engagement Activity 2018
 
Description MRC Festival of Medical Research 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact To showcase and discuss the important work carried out in the Unit
Year(s) Of Engagement Activity 2016
 
Description MRC Festival of Science 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact The aim was to inform and engage with the public about gene editing techniques; audience: passers-by in the Newbury pedestrian zone
Year(s) Of Engagement Activity 2018
 
Description Oxford Hands-On Science school visit 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact The aim was to share enthusiasm for science with school pupils by taking hands-on science activities into classrooms; audience: local school children
Year(s) Of Engagement Activity 2018
 
Description Oxford Science and Ideas Festival 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Schools
Results and Impact Our group set up a Cancer Immunotherapy stand at the Oxford Science and Ideas festival
Year(s) Of Engagement Activity 2019
 
Description Oxfordshire Science Festival 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact To showcase our multi-disciplinary department through interactive demonstrations and hands-on activities.
Year(s) Of Engagement Activity 2016
 
Description Participation in Summer Roadshow - part of Oxford Hands-On Science (OXHOS) 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Schools
Results and Impact Participation in 2017 Summer Road Show by Oxford Hands-On Science - participating and help in organising activities in schools in and around Oxford in June and also a week of activities in various schools on the Isle of Wight in July.
Year(s) Of Engagement Activity 2017
URL http://oxhos.org/PDFs/OxHOS_Roadshow_Report_Summer_2017.pdf
 
Description Publication of glossy brochure for dissemination 
Form Of Engagement Activity A magazine, newsletter or online publication
Part Of Official Scheme? No
Geographic Reach National
Primary Audience Public/other audiences
Results and Impact Development and publication of a glossy brochure illustrating in lay terms the important work carried out in the unit and dissemination to the general public.
Year(s) Of Engagement Activity 2016
 
Description Science evening at Eynsham Primary School 
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 A hands-on interactive science evening at a local primary school
Year(s) Of Engagement Activity 2016
 
Description Secondary school student one day visit to the lab 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Secondary school student visited research lab for one day and shadowed a Post Doc observing lab work and experiments.
Year(s) Of Engagement Activity 2017
 
Description Secondary school student visited research lab for work experience and one day shadowing. 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact A secondary school student visited immunology research lab to get work experience and observe scientists in their daily work.
Year(s) Of Engagement Activity 2017
 
Description Teacher Training Evening 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact The aim was to equip teachers to use teaching resources on antibodies and microscopy developed by Eggeling and Cerundolo labs to enhance science curriculum with hands-on activities
Year(s) Of Engagement Activity 2018
 
Description Town and Gown Marathon 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Other audiences
Results and Impact Participation as the MRC Human Immunology team in the annual sponsored charity Town and Gown marathon
Year(s) Of Engagement Activity 2018
 
Description Visit by 50 students from the Utrecht Junior School, the Netherlands 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach International
Primary Audience Schools
Results and Impact A group of 50 students from Utrecht Junior College in the Netherlands took place in the WIMM and the MRC Human Immunology Unit. 100% of students who attended said that they both enjoyed the day and learnt something new about science.
Year(s) Of Engagement Activity 2015
 
Description Volunteering in Settlers Exhibition, Oxford Museum of Natural History 
Form Of Engagement Activity Participation in an activity, workshop or similar
Part Of Official Scheme? No
Geographic Reach Regional
Primary Audience Public/other audiences
Results and Impact An Exhibition to raise awareness into DNA and VR
Year(s) Of Engagement Activity 2018
 
Description Work Experience students in the MRC Human Immunology Unit 
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 The PIs in the MRC Human Immunology Unit hosted a total of 11 young students (16 and 17 year olds) on a work experience placement of one or two weeks, with the aim of fostering an interest in a scientific career and raising awareness in the type of work carried out in the Unit
Year(s) Of Engagement Activity 2015
 
Description Work experience visits by 5th & 6th year students 
Form Of Engagement Activity Participation in an open day or visit at my research institution
Part Of Official Scheme? No
Geographic Reach Local
Primary Audience Schools
Results and Impact Work experience visits to the MRC Human Immunology Unit by a total of 19 students in 2016.
Year(s) Of Engagement Activity 2016