Leishmania are protozoan parasites that are transmitted between mammalian hosts by biting Phlebotomine sand flies. Approx. 15 species of Leishmania infect humans and cause a spectrum of clinical diseases that affect the skin and mucosa (tegumentary leishmaniasis) or systemic tissues (visceral leishmaniasis). Although the type of leishmaniasis is often closely associated with parasite species, this is not always the case, and varying clinical presentations may occur e.g. due to malnutrition or host genetic diversity.
Found in 98 countries worldwide, leishmaniasis affects over 150m people, with approx. 20,000 deaths annually due to visceral leishmaniasis (VL). Most forms of leishmaniasis are zoonotic diseases, infecting a range of hosts including rodents and canids, but in some cases transmission may be restricted to humans (anthroponotic VL). Canine VL is an important veterinary disease and an important target for controlling disease in humans.
Latest estimates of the worldwide prevalence of the different forms of leishmaniasis can be found in (1). Importantly, many people exposed to these parasites do not develop clinical leishmaniasis, indicating the ability of the human immune system to control infection in most cases. However, suppression of the immune system by co-infection with human immunodeficiency virus (HIV) or by elective therapy (e.g. for autoimmune disease) may lead to clinical leishmaniasis (2). Drug resistance is of increasing concern in leishmaniasis. Diagnosis of the disease is by looking for the parasites in biopsies, by antibody-based tests or by clinical exam. Developing drugs for leishmaniasis is complicated as these are eukaryotic parasites and share much of their biochemistry with human cells. Most anti-leishmanials, therefore, have narrow therapeutic windows; one contains a heavy metal (antimony), whilst another is teratogenic. The most effective drug, liposomal Amphotericin B (AmbiSome) has revolutionised treatment for VL in South Asia, but is much less effective in other parts of the world. Drugs for CL have changed little in >50 years. Many treatment courses are protracted, painful and have significant side effects. An effective vaccine could revolutionise leishmaniasis control (3, 4).
The challenges of developing a leishmaniasis vaccine
Developing an effective vaccine for leishmaniasis is not easy, but epidemiological, clinical and experimental data suggests it should be possible (3, 4). It is known that deliberate infection with live Leishmania can prevent against re-infection (this practice of “leishmanisation” was once widespread in the Middle East) and vaccines have been developed for use in dogs. Vaccines for leishmaniasis could be used to prevent disease (prophylactic vaccines) or to treat patients by stimulating their immune system (therapeutic vaccines).
Some of the scientific challenges in leishmaniasis vaccine development are highlighted below:
Lack of immune correlates
For some vaccines, we know exactly the level of a particular kind of immune response that is needed for the vaccine to work – i.e. to stop someone getting disease. For leishmaniasis, we do not know what kind of immune response is needed, or what level of response is required. This means we can only test if a vaccine works in humans by doing large, expensive and time consuming human efficacy trials. This limits the number of vaccines that can be tested in humans.
Uncertain predictive value of animal models
It is not possible to test a vaccine in humans without testing it first in animals. However we do not know which if any of the animal models best predicts efficacy in humans. Again, this means we can only determine if a vaccine will work in humans by testing it in large, expensive, human efficacy trials.
Importance of the vector
Unlike some diseases, such as TB, where transmission occurs directly between people, leishmaniasis is a vector-borne disease. It is now known that during the taking of a blood meal, sand flies introduce a variety of proteins into the mammalian host that affect local immune function. The effects of these proteins have to be taken into account in developing a vaccine for leishmaniasis. Indeed, some have been proposed as candidates to include in a vaccine (5)!
Difficulty of working with leishmania
Some forms of leishmaniasis (VL, mucocutaneous leishmaniasis) are particularly serious once contracted and difficult to treat, and so in some countries (including the UK) they can only be studied in laboratories using special containment measures (called Category or BSL 3). To study natural transmission of disease, sand flies also need to be reared in captivity and once experimentally infected, these sand flies must be kept under BSL 3 containment to prevent their escape. This limits the number of laboratories that can work on the most serious forms of leishmaniasis.
How VALIDATE will help
By bringing together researchers working on different (but similar) pathogens, discoveries in one field can be more quickly taken advantage of in research against another pathogen. Bringing together researchers from different disciplines and institutes in new collaborations means knowledge can be exchanged and new research ideas for the field can be generated and investigated. Bringing new researchers into this field, and progressing the careers of early career researchers, will aid with new ideas and the continuation of the field into the future.
1. Alvar J, Velez ID, Bern C, Herrero M, Desjeux P, Cano J, et al. Leishmaniasis worldwide and global estimates of its incidence. PloS one. 2012;7(5):e35671.
2. Fletcher K, Issa R, Lockwood DN. Visceral leishmaniasis and immunocompromise as a risk factor for the development of visceral leishmaniasis: a changing pattern at the hospital for tropical diseases, london. PloS one. 2015;10(4):e0121418.
3. Alvar J, Croft SL, Kaye P, Khamesipour A, Sundar S, Reed SG. Case study for a vaccine against leishmaniasis. Vaccine. 2013;31 Suppl 2:B244-9.
4. Gillespie PM, Beaumier CM, Strych U, Hayward T, Hotez PJ, Bottazzi ME. Status of vaccine research and development of vaccines for leishmaniasis. Vaccine. 2016;34(26):2992-5.
5. Reed SG, Coler RN, Mondal D, Kamhawi S, Valenzuela JG. Leishmania vaccine development: exploiting the host-vector-parasite interface. Expert review of vaccines. 2016;15(1):81-90.