Leishmaniasis is a global disease which can scar people’s skin, erode their face and even kill them if it is not treated. In some parts of the world, drugs may not be available; in others, drug resistance may limit their effectiveness. The ultimate solution may lie in vaccine development. Scientists at the Liverpool School of Tropical Medicine are uniquely well equipped to test candidate vaccines.
Imagine over 10 per cent of a country’s population dying from a single disease within a couple of years. It sounds like a futuristic horror film, but it actually happened in the Sudan in the early 1990s. The disease concerned was Leishmaniasis.
You can catch it – and so can your dog – in France, Italy, Greece, Spain, Portugal and several other European countries, if you are bitten by an infected sandfly. In fact, Leishmaniasis is endemic in 88 nations on four continents, putting ~350M people at risk of contracting it; at any given time, twelve million people around the world are infected.
Cause and effect
SandflyThe disease is caused by a parasite – protozoa of the genus Leishmania; there are ~20 different species and sub-species. It is transmitted by sandflies, and at least 70 different species are known to carry the disease.
Skin ulcer
Sudan, India, Bangladesh and Brazil suffer the most serious form; in humans, this causes the liver and spleen to swell; victims also experience fever, weight loss and anaemia, and without treatment they will die. The mildest form is found in Europe, the Middle East and parts of Latin America; in humans, it presents as painless skin lesions or ulcers – though in one form the disease can migrate to the soft palate, where it invades the cartilage, gradually eroding the face.
Dogs are less fortunate: the canine form of the disease affects every organ. They become emaciated and shabby, and develop strikingly long nails. Treatment can prolong life, but eventually the disease will kill them.
Prevention versus treatment
The sheer number of ‘vectors’ makes it impossible to decode the precise pattern of infection in particular cases or locations: you may know what type of insect bit you – but you won’t know where it got its previous blood meal. It could have been an infected human, a dog, a sand rat, a gerbil or a tree rat; rodents are the most common natural ‘reservoirs’ for the parasite, as are domestic dogs.
Attempts have been made to control this reservoir by eliminating the rodents’ burrows – but they just move to a new location; dog culling is expensive, controversial and difficult to implement on a major scale. Vector control – eg barring or eradicating sandflies – is not practicable either, due to the high cost of insecticides and logistics difficulties in developing countries. In any case, scientists know very little about the epidemiology of vectors in remote or difficult terrain like the Sudan or the jungles of Latin America.
Leishmaniasis can be treated by antimony-based drugs which have been available since the 1940s, but one form of the disease does not respond well and there is growing evidence of drug resistance developing. New drugs are essential – but there’s currently no sign of a single drug which could treat the whole complex of Leishmaniasis diseases.
A vaccine may be achievable – which is why the WHO and the Bill & Melinda Gates Foundation are funding research in this area. It’s unclear who would commercialise a human vaccine, however; although the market is huge, developing countries would be hard-pressed to pay for it, let alone distribute and administer it.
Dog infected by LeishmaniasisFrom a commercial perspective, a vaccine for dogs is much more attractive; it could unlock the wallets of North America’s and mainland Europe’s comparatively wealthy pet-owners. With widening take-up of the Pet Passport scheme, it could also attract customers in the UK where Leishmaniasis is not endemic.
Transmission mechanisms
Any candidate vaccine – human or canine – needs to be tested in the lab before embarking on any field trials, and that presents pharmaceutical companies with a problem. “They don’t have a sufficiently in-depth understanding of the transmission mechanisms involved in Leishmaniasis”, says Dr Paul Bates of the Liverpool School of Tropical Medicine (LSTM).
Paul leads the Leishmaniasis Research Group at the LSTM – part of the School’s Molecular & Biochemical Parasitology Research Group. He has spent over ten years investigating the biology of the parasite in the vector, and the mechanism of its transmission to the host, with support from the World Health Organisation and the Welcome Trust. There are very few scientists with expertise in this specialised area, which is an essential prerequisite to the development of successful vaccines.
“We’ve been studying a species of the parasite which causes generalised, systemic Leishmaniasis in dogs and the most serious form of the disease in children”, says Paul. “We’ve made some key advances over the past few years. “For instance, we now know that the secretory products which the parasite deposits in the insect’s gut are key to what happens next. The point in the life cycle of the parasite at which the insect takes a blood meal is also of paramount importance. The shape and length of the insect’s proboscis plays a critical role, too.
“These discoveries have enabled us to develop a much more accurate model of natural transmission in animals – one which is much more predictive than earlier models. This is an important development, because using poor models of infection and disease can easily lead to ineffective vaccines or might even make matters worse.”
Vaccine testing
One of the rodent reservoirs for the Leishmaniasis parasiteThis development, together with the colonies of uninfected sandflies which he maintains, has placed Paul in an ideal position to test any candidate vaccines which might emerge. “Essentially, this would involve infecting sandflies with a mix of blood and parasites – whichever species or strain of parasite was required, and then exposing them to mice immunised with the candidate vaccine”, he explains.
There are very sound reasons for this approach. “The shape and length of the sandfly proboscis and the depth of its bite play a key role in the transmission of the parasite”, says Paul. “It’s not possible to simulate a sandfly bite with complete accuracy using a syringe.
“We can never predict with certainty how a vaccine will fare in the real world, but by studying, understanding and using our knowledge of the complex biology of these parasites, we can minimise the risk that it won’t do what it sets out to do.”
Paul is already collaborating with one company which is trying to develop a canine vaccine.
There have been 4 cases of this disease in polis two in peyia and one in armou in the last 30 days.