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

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.

The leishmaniases are global diseases impacting millions. No vaccine against human leishmaniasis has yet been developed. What is needed is a rapid, cost effective means for early evaluation of the efficacy of candidate vaccines. Our solution to this roadblock is a human challenge model (HCM) of sand fly initiated Leishmania major infection.

In stage 1, we will hold focus group discussions to assess acceptability and attitudes towards the study and preferred approaches for conducting it. We will validate/modify a NIH protocol for sand fly bite on healthy volunteers, evaluating sand fly number/feeding time and identifying adverse events. We will develop a clinical parasite bank to the required standards, screening fresh isolates of L. major (through clinical/immune profiling of donors, parasite genome sequencing, drug sensitivity, sand fly infectivity, transmissibility) and selecting one for full scale development. By Milestone 1, we will have assembled the components necessary to initiate human challenge studies. By Milestone 2, we will have received a favourable ethical opinion to proceed with human challenge.

In stage 2, we will conduct human challenge infection in healthy adult volunteers, with safety as a primary endpoint. We will minimise risk by careful escalation of infected sand fly number, assessment of take rate and by drug terminating infections at a suitable clinical endpoint. Blood analysis will provide additional safety data, as well as novel information on the host response to infection. Milestone 3 reflects the primary outcome, namely the development of an effective (i.e. high take rate) L. major HCM with 100% lesion clearance after treatment. Secondary outcomes include immune response parameters and analysis of lesion development.

Collectively, the project will provide a new tool to assess vaccine efficacy and to allow for evidence-based decisions to be made on down selection/progression of candidate vaccines for leishmaniasis.

The project will create impact in the following ways:
1. Patients with leishmaniasis, their families and communities: The main aim of the research is ultimately to improve patient health, by developing vaccines to prevent leishmaniasis in populations at risk. Leishmaniasis may be fatal or have lifelong impact on life chances (through stigmatization associated with scaring or persistent skin disease). Drugs for leishmaniasis can have serious side affects, may be painful on administration and / or may require long treatment courses. Furthermore, the direct and indirect costs of treatment have considerable impact on populations with low household incomes. Thus, research on vaccines that prevent disease will have significant health and economic impact for people in endemic regions.

2. Women and children: The impact of tegumentary leishmaniasis may be most profound on young girls and women, particularly in regions where clothing limits sand fly exposure to the face. This may affect interpersonal relationships, marriage prospects, social activities and capacity for work. This may lead to isolation, late presentation for treatment and consequently less favourable outcomes. Development of a vaccine for tegumentary leishmaniasis would improve life chances for many.

3. Countries with high disease burden: Leishmaniasis ranks highly amongst NTDs for DALYs, suggesting there would be an overall economic gain from reducing disease burden and increasing productivity. Health systems will be less strained by the development of an effective vaccine, reducing hospital admission times or out-patient clinic loads. Hence, there will be societal gain.

4. LMIC Researchers and non-clinical trainees: Although not directly impacted during the current project, the development of a new platform for the assessment of vaccines will ultimately provide new training opportunities in clinical research for LMIC investigators.

5. UK workforce: The project serves to develop the UK as a centre of excellence for human infectious challenge models. There is potential for advanced training opportunities for scientists, clinicians, and pathologists.

6. Industrial partners and economic growth: Within this project we will develop and optimize a platform for evaluating efficacy of human leishmaniasis vaccines. This may be of benefit to industrial partners and spur their interest in co-funding or co-developing future generations of vaccines, given that it considerably de-risks later stages of development.

7. Leishmaniasis vaccine R&D community: Given the paucity of resource available for leishmaniasis vaccine development, a centralized platform for comparative testing of vaccine candidates, using cluster or adaptive clinical trial designs will be important in bringing the community together and driving rapid iterative progress in this field.

8. Research funders: Funders from LMICs as well as international donors will gain added value from their investment in pre-clinical research knowing that there is a defined route for clinical evaluation. Perceived added value may indirectly encourage additional funding into NTD research.