A vaccine that offers protection from kala-azar, a deadly infection that affects large numbers of poor people in eastern India as well as neighbouring Nepal and Bangladesh, could be developed by crippling the disease-causing organism’s ability to access a vital iron-containing molecule, according to research from a team of Indian scientists.
Kala-azar — or visceral leishmaniasis — is the most severe form of disease produced by the single-celled parasite, Leishmania . Several internal organs, such as the spleen, liver and bone marrow, get affected and the infection can be fatal if left untreated. The parasite spreads when an infected female sandfly feeds on humans.
The World Health Organisation estimates that five lakh cases of kala-azar, with around 50,000 deaths, could be occurring each year in the Indian subcontinent, parts of Africa, southern Europe as well as central and south America. Among parasitic diseases, only malaria kills more people.
Nearly one lakh people become infected annually in India, Bangladesh and Nepal, according to the WHO figures. In India, the disease is endemic in Bihar, Jharkhand, Uttar Pradesh and West Bengal.
Drugs to treat the infection are toxic and expensive, and drug resistance has grown. No vaccine has yet been licensed to prevent infection.
In their quest for a vaccine, the Indian scientists have taken advantage of the Leishmania parasite’s inability to synthesise a crucial iron-containing molecule, haem, that it needs. It therefore relies on pulling in its human victim’s haemoglobin, the molecule that allows red blood cells to carry oxygen all over the body. The parasite then breaks up the haemoglobin and makes use of the haem.
Amitabha Mukhopadhyay of the National Institute of Immunology in Delhi and others showed 14 years back that the parasite used a protein on its outer surface to attach and drag in the haemoglobin. This protein is known as the haemoglobin receptor.
Dr. Mukhopadhyay and his colleagues have now found that a vaccine aimed at this receptor was able to protect mice and hamsters from the parasite. Their work has just been published in Science Translational Medicine .
The scientists made the vaccine by putting genetic information for the haemoglobin receptor into a strip of DNA. This DNA was then injected into the muscles of mice and hamsters. Muscle cells took up the DNA and produced the receptor protein. The protein generated a range of protective immune responses in the animals, including the production of antibodies that could block the haemoglobin receptor when the actual parasite turned up. The parasite was thus prevented from getting the haemoglobin it needed to survive.
When animals immunised in this fashion were subsequently injected with virulent strains of Leishmania donovani , they had far fewer parasites in the liver and spleen than those that had not been vaccinated. In the case of hamsters, all vaccinated animals remained healthy after being administered lethal doses of the parasite while unvaccinated ones died.
As the haemoglobin receptor was very similar across various Leishmania species, the vaccine might provide protection against all forms of leishmaniasis, said Dr. Mukhopadhyay in an email. But this needed experimental validation, he cautioned.
Creating a vaccine against the haemoglobin receptor appeared to be a “very promising” approach, commented Neeloo Singh, a scientist at the Central Drug Research Institute in Lucknow who studies Leishmania parasites.
However, a vaccine against kala-azar developed by the Infectious Disease Research Institute (IDRI) at Seattle in the U.S. was ready to start clinical trials in India, she noted.
Good immune response
The IDRI vaccine comprises a purified form of two parasite proteins fused together, given along with an additive to boost the immune response. The vaccine has already completed Phase 1 clinical trials in the U.S. to demonstrate safety and the ability to evoke a robust immune response.
The DNA vaccine demonstrated in animals had been a wholly indigenous effort, starting with identification of the haemoglobin receptor, pointed out Dr. Mukhopadhyay. Taking the work forward to deliver a proven vaccine would require a tie-up with industry and support from governmental funding agencies, he told this correspondent.
