Developing a vaccine to prevent death from melioidosis in people with type 2 diabetes mellitus in low- and middle-income countries

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.