Title: Developing a vaccine to prevent death from melioidosis in people with type 2 diabetes mellitus in low- and middle-income countries
Funder: Department of Health and Social Care

Abstract: Most people with diabetes (77%) live in a low- or middle-income country (LMIC), where they are at increased risk of global infections including tuberculosis, dengue and the neglected tropical disease melioidosis. Melioidosis is caused by the soil-dwelling Gram-negative bacterium Burkholderia pseudomallei, is hard to diagnosis, resistant to first-line antibiotics, and has an in-hospital case fatality rate of up to 50% in resource-limited settings. There are an estimated 89,000 deaths per annum, and people with diabetes have a 12-fold increased risk of melioidosis. A vaccine to prevent disease or death, targeted at people with diabetes is predicted to be a cost-effective public health intervention. I am leading a Phase 1 clinical trial of the leading vaccine candidate CPS-CRM197/Hcp1 in 36 healthy human subjects, funded to take place in Oxford in 2020. This is first-in-human for any vaccine for melioidosis. The subunit vaccine has been developed at University of Nevada, Reno (UNR) and combines the bacterial capsule polysaccharide (CPS) conjugated to the immunogenic diphtheria toxin mutant CRM197, with recombinant B. pseudomallei Hcp1 protein in an Alhydrogel-CpG adjuvant. In a mouse model, the combined vaccine generated high levels of opsonising anti-CPS antibodies, alongside high T-cell responses to Hcp1, and protected 100% of mice against a robust lethal inhalational B. pseudomallei challenge. In this proposal I plan to develop the vaccine as a public health vaccine for people with diabetes in LMICs. Firstly, I will evaluate the safety and immunogenicity of the vaccine in 12 subjects aged 40-60 years with Type 2 diabetes in Oxford, and compare immunogenicity with healthy non-diabetic subjects. Secondly, I will extend the clinical trial to test the vaccine in the target population (Phase Ib), immunising adults aged 40-60 years in Ubon Ratchathani (Ubon), Thailand, where I have eight years' experience undertaking clinical studies of the immune response to B. pseudomallei in Thai melioidosis patients, and have established productive collaborations with local and international researchers. Thirdly, my team seeks to define the key immune correlates of protection for monitoring vaccine efficacy in subsequent field trials, using functional growth inhibition assays and transcriptomics in the vaccinated population, existing melioidosis patient cohort studies, and animal models in collaboration with UNR. Finally, a community consultation project will be undertaken in Ubon, to explore perceptions and sensitivities for efficacy trials of a melioidosis vaccine amongst people living with diabetes and healthcare workers in Ubon. This work will prepare for large-scale evaluation of a vaccine for melioidosis in Ubon using the clinical trial infrastructure established at the Mahidol-Oxford Tropical Medicine Research Unit in Thailand. A Thai doctor will be recruited and trained to develop expertise in vaccine trials, including spending an initial year in Oxford during the Phase 1 clinical trial, and laboratory expertise in Thailand will be strengthened. Ultimately this proposal seeks to accelerate production of a vaccine for the 280 million people with diabetes and the many with other risk factors for melioidosis including older age, chronic renal disease and immunosuppression who live in melioidosis-endemic regions in 83 countries across the globe.

Lay abstract: Melioidosis is a grossly under-recognised tropical disease, caused by a bacterium in the soil. Each year, 165,000 people in tropical regions across the world are estimated to become ill from melioidosis, with 89,000 deaths. Most people with melioidosis are the rural poor, typically working in rice farming. Melioidosis does not feature on the World Health Organisation's 'official' neglected tropical disease list, in spite of its annual death toll being higher than every single one of the list's 21 diseases, which includes dengue, leishmaniasis and snakebite. A perceived lack of solutions such as mass drug administration or a vaccine to tackle melioidosis has been cited as a reason for its lack of inclusion. Over half of people with melioidosis have type 2 diabetes mellitus, and 280 million people with diabetes live in regions at risk of melioidosis. Nearly 4/5 people with diabetes now live in low and middle income countries (LMIC) and more knowledge is needed about why people with this non-communicable disease are at increased risk of global infections like melioidosis, and how to tailor vaccines for this group of people. I am conducting the world's first clinical trial of a vaccine for melioidosis, in healthy people in Oxford. I will test the most promising vaccine candidate, which has been developed by scientists at the University of Nevada in Reno (UNR). This vaccine contains the bacteria's protective shell that is known to be needed to cause disease ('capsular polysaccharide') and a key part of the mechanism that the bacterium uses to spread from cell to cell ('Hcp1'). This clinical trial will be funded by the MRC's Development Pathway Funding Scheme. After testing the vaccine in healthy volunteers in Oxford, I will next test the vaccine in adults with Type 2 diabetes in Oxford, to see if the vaccine is also safe and builds the immune system to fight the bacteria and prevent illness. Since 2011 I have worked with Thai colleagues to develop capacity for clinical immunology studies in Ubon Ratchathani, Northeast Thailand, and in this proposal I will build on this foundation to test the vaccine in the target population for a public health vaccine for melioidosis - people with diabetes living in an endemic area. A Thai doctor will undergo initial training in Oxford learning how to conduct a vaccine trial, and we will then undertake a pilot vaccine trial in 24 people with diabetes in Thailand. We will identify the biomarkers to be used to monitor how the vaccine works in Thailand, and also work with people in the community with diabetes to explore their understanding and sensitivities about testing vaccines for melioidosis. We will explain the results of our research to this community and publicise it internationally through scientific articles, conferences talks and public events. By the end of 5 years we will have built the experience in Thailand to vaccinate large numbers of people with diabetes in the region and see how it works at preventing illness and death. This work will demonstrate a pipeline for rapidly transferring vaccine candidates from the research laboratory to low- and middle-income countries. In addition, I will build knowledge about the differences between people with and without diabetes in how the body's immune system responds to infection and vaccination. A successful vaccine that prevents illness and death from melioidosis in people with diabetes can then be extended to people with other risk factors for melioidosis such as older age, chronic kidney disease, and immunosuppression. The ultimate goal is implementation of vaccination in low-income countries across the world where melioidosis is endemic, including Laos, Cambodia, Bangladesh and sub-Saharan Africa.

Research activity codes: 3.4 VACCINES
Health categories: INFECTION;METABOLIC AND ENDOCRINE