Development of a human challenge model of Leishmania major infection as a tool for assessing vaccines against leishmaniasis

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Leishmaniasis is a serious disease caused by infection with a small parasite called Leishmania. The disease is transmitted from person to person by biting sand flies and can also be found in a variety of other animals such as rodents or dogs. Leishmaniasis is one of the most important of the neglected diseases of poverty, and is found in 98 countries worldwide. In many cases, the disease presents as chronic ulcers on the skin, often affecting the face. Although these may heal over several months, patients with severe cutaneous leishmaniasis are left with a scar that can significantly affect quality of life, particularly for women and children. In other forms of the disease, parasites enter the internal organs and cause organ failure and suppress the immune system, often leading to death. About 20,000 people die each year from this type of disease, called visceral leishmaniasis. Although we have drugs that can work against leishmaniasis, some have serious side effects and their effectiveness varies in different countries. As with other microbes, the Leishmania parasite is also beginning to find ways to resist the action of the drugs we have available. The need to develop a vaccine to stop people becoming infected in the first place is therefore imperative. Recently, there has been good progress in developing experimental vaccines for leishmaniasis that have been tested with greater or lesser effect in animal models. However, animal models cannot fully predict how a vaccine will work, if at all, in humans. Hence, we need to be able to conduct vaccination trials in humans. The first stage in this process is to conduct a safety study with a vaccine made to the highest quality standards (so called GMP). This is called a Phase I clinical trial and usually involves only a few volunteers. If safe, the next stage is to extend the safety tests to more volunteers and also try to gain an idea of how people respond to the vaccine. This often means trying to use blood tests that we think are predictors of a protective immune response. However, these predictors or correlates of protection are not always clear, so again the results of these trials do not necessarily mean the vaccine will work. Currently, this can only be tested by doing large scale trials (called Phase III trials) in countries where there is natural exposure of the population to the parasite. These studies often require thousands of participants and may take several years. The cost and time involved is substantial and limits investment in vaccine development, given that most vaccines (and drugs) fail at this late stage. What is required to stimulate vaccine development and make more informed evidence-based decisions about which vaccine to take to Phase III trial is a safe, cost effective and rapid way to evaluate efficacy soon after a Phase I trial has been completed.In this project, we propose to develop a "human challenge model" for leishmaniasis that will serve this purpose. A human challenge model involves volunteers being experimentally infected with a microbe and then following the development of disease until a suitable end point. These models are being used to test vaccines for malaria, dengue fever and other diseases. To establish a human challenge model of leishmaniasis, we will first conduct focus group discussions with members of the public to ascertain attitudes to this type of research and inform how we design the studies. As leishmaniasis is transmitted by sand flies, we will then evaluate the best way to allow sand flies to bite humans in a controlled manner. Similar studies are often performed with mosquitoes. We will also develop a well-characterised stock of parasites for use now and in the future. Finally, we will conduct the first human challenge study in volunteers, thereby establishing the parameters by which this approach could be implemented in future clinical trials of leishmaniasis candidate vaccines.