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

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.

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.

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.