Component Of Fly Saliva Makes Promising Leishmaniasis Vaccine

Leishmaniasis, a major health problem in many tropical and desert climates, has resisted efforts to develop an effective vaccine. "Today's report describes a novel vaccine," says NIAID Director Anthony S. Fauci, M.D. "Rather than targeting the parasite, as is typical, our researchers produced a vaccine to the saliva of the insect that transmits the parasite. This approach could potentially be used to develop vaccines for other insect- or tick-borne diseases."

Leishmaniasis refers to a group of related diseases. Different species of the single-celled parasite Leishmania can cause flesh-eating nose, throat and mouth infections (mucosal leishmaniasis); painful skin lesions (cutaneous leishmaniasis); or fatal infestations of the internal organs (visceral leishmaniasis). An estimated 12 million people currently are affected by one or more of these diseases, most of whom live in South or Central America, Africa and the Middle East.

NIAID's José Ribeiro, M.D., Ph.D., an expert on the biochemistry of blood-feeding bugs, has spent more than 30 years studying how components of saliva not only help insects and ticks obtain their blood meals but also modulate the immune response. He and others have previously shown that laboratory animals immunized with sand fly saliva often resist infection when later bitten by a Leishmania-carrying insect, or challenged with parasites in the presence of sand fly saliva. In the new study reported August 6 in the Journal of Experimental Medicine, Dr. Ribeiro directed a research team that sought to use this information to produce a novel vaccine against the disease. Jesus Valenzuela, Ph.D., Dr. Ribeiro and colleagues examined saliva from the sand fly carrier of Leishmania major, a parasite species that causes cutaneous leishmaniasis. The researchers separated the proteins of the saliva and identified one, dubbed SP15, which appeared to be the target of natural immune responses in mice. They then worked backwards, using the protein to help them find its underlying gene.

Once they identified the SP15 gene, Dr. Ribeiro's team used it to construct a DNA vaccine, which they used to immunize mice. When the immunized mice were later injected with L. major parasites mixed with fly saliva, the infection was markedly milder compared to infection in mice that had not been vaccinated. The immunized mice had much smaller skin lesions, and their infections cleared within six weeks. Unvaccinated mice developed large skin ulcers and did not eliminate the parasite.

Because sand fly bites produce both antibodies and T-cell responses, the researchers analyzed the mice to see which type of immune response was keeping the parasites in check. When the NIAID team vaccinated "knockout" mice, genetically engineered not to produce antibodies, the mice were still protected by the vaccine, suggesting T cells were protecting the animals from disease.

The results demonstrate a vaccine containing a component of sand fly saliva can protect mice from the severe symptoms associated with cutaneous leishmaniasis, perhaps by mimicking natural immunity to the infection. "People get bitten by infected sand flies all the time without developing leishmaniasis," says Dr. Ribeiro. "It could be that those who develop disease are merely unlucky; they are bitten by a Leishmania-carrying fly before uninfected flies have had time to naturally immunize them."

Dr. Ribeiro next plans to test his vaccine in dogs-natural reservoirs of the parasite-and monkeys. His team also will look at other Leishmania species and the sand fly species that transmit them, hoping to develop vaccines for other forms of leishmaniasis. In addition, he has begun to study people who are naturally exposed to Leishmania to see which components of fly saliva might protect them from disease. "Different sand fly species, each with its unique collection of salivary proteins, transmit different Leishmania species," he explains. "If anti-saliva vaccines are to work in people, they will have to be specifically engineered for the problem insects of each region."

NIAID is a component of the National Institutes of Health (NIH). NIAID supports basic and applied research to prevent, diagnose, and treat infectious and immune-mediated illnesses, including HIV/AIDS and other sexually transmitted diseases, tuberculosis, malaria, autoimmune disorders, asthma and allergies.