A vaccine against the disease leishmaniasis could save tens of thousands of lives every year. Now, scientists report that they have used snippets of DNA to spur mice to fight back against the parasites responsible for the illness, an approach they hope to soon begin testing in people.
Leishmaniasis is caused by microscopic parasites of the genus Leishmania; some 20 different species can sicken humans. Leishmaniasis hits poor residents of tropical countries the hardest. The sandflies that spread the disease are silent and smaller than a mosquito. After a sandfly’s bite injects them into the body, Leishmania cells can attack the skin or mucous membranes, causing ulcers or disfiguring lesions. In an often lethal variety of the disease, they damage the liver, spleen, and bone marrow. Although the disease’s toll isn’t certain, estimates suggest there are about 1.3 million new cases and up to 40,000 deaths each year.
Leishmania parasites are tricky foes, and so far no vaccine has received approval for use in humans. One challenge is that the parasites lay low inside our cells, out of reach of the antibodies triggered by most other vaccines. The key to eradicating these sheltered invaders, researchers suspect, is stimulating the immune cells known as T cells. Although two experimental leishmaniasis vaccines that use this strategy have undergone preliminary safety and effectiveness tests in people, the best method for enlisting T cells isn’t clear.
Immunologist Peter Walden of Charité University Medicine Berlin and colleagues decided to try a DNA vaccine, a type of vaccine that is good at inciting T cells. Such vaccines contain DNA strands coding for proteins from a pathogen. Cells in the vaccine recipient's body absorb the DNA and start churning out the proteins—also called antigens—which alert the immune system and prime it to attack if a real infection occurs.
First, the researchers had to choose the right antigens. They settled on five different proteins that vary little across Leishmania samples from a range of species found around the world. To determine whether the antigens galvanize human T cells, the team obtained blood samples from people in India and Tunisia who had recovered from the disease or had been exposed to it without getting sick. They found that portions of all five proteins sparked a response by T cells from the blood samples.
The researchers’ final vaccine mixture, which they tested in mice, contained five kinds of DNA strands, each coding for all or part of one of the proteins. The vaccine stimulated the mice to produce defenses against leishmaniasis parasites, Walden and colleagues report online today in Science Translational Medicine. T cells from the vaccinated animals reacted vigorously to Leishmania antigens. To confirm that the vaccine helped the animals combat the invaders, the researchers injected the mice with cells of one Leishmania species. Three weeks later, mice that received the highest vaccine dose carried 94% fewer parasites in their liver than did mice that received a control shot. Although some parasites remained in the mice that received the largest dose, Walden says there weren’t enough of them to cause disease symptoms.
“We are ready for human trials,” he says. The vaccine should provide protection against different human Leishmania species, he adds, because the selected antigens are the same across species.
Immunologist Paul Kaye of the University of York in the United Kingdom agrees that the time for human trials has come. “There is every reason to believe that they should move forward as soon as possible,” says Kaye, who's excited that there are now three vaccines to try in humans. Kaye and colleagues’ own vaccine candidate, which stimulates T cells with a harmless virus that carries sections of two Leishmania genes, has already undergone a safety study in people, but the results have not yet been published.
“This is a significant advance,” says vector biologist Jesus Valenzuela of the National Institute of Allergy and Infectious Diseases in Rockville, Maryland. Walden’s group deserves credit for using human blood samples to identify the antigens, he says; other vaccine developers have used rodents.
Leishmaniasis is one of the neglected tropical diseases for which research cash is hard to obtain. Still, Walden is hopeful that he and his colleagues will find financing for safety trials.