Phase 1 clinical trial set to begin on first leishmaniasis vaccine

“A phase 1 clinical trial testing the safety of a leishmaniasis vaccine is set to begin in the coming months – the first vaccine created to protect against the disfiguring skin disease common in tropical regions of the world and gaining ground in the United States. The researcher who led development of the vaccine is the senior author of a New England Journal of Medicine review article published last week describing the difficulties of treating most forms of the disease and reporting that the live vaccine, found to be safe in animals, is expected to be tested in humans later this year. Up to 1 million new cases of cutaneous leishmaniasis (CL), caused by many species of Leishmania and transmitted through the bite of infected sand flies, are diagnosed worldwide each year. At any given time, approximately 6 million people are infected – yet up to 1 billion people in 99 territories and countries where leishmaniasis is endemic, including the U.S., are at risk of contracting the disease, the authors wrote . Lead researcher Abhay Satoskar , professor of pathology at The Ohio State University College of Medicine , has been working on development of a leishmaniasis vaccine for over 20 years. In 2020, he and colleagues reported strong results in mice with a vaccine developed using CRISPR gene-editing technology to mutate the parasite that causes the skin disease. Late last year, the vaccine cleared a key U.S. Food and Drug Administration hurdle: approval of an investigational new drug (IND). “This means the FDA has seen the product and our preclinical data and has deemed that this product can be tested in people now,” Satoskar said. “It’s a big milestone in terms of product development, especially when the product was conceived in academia. “This helps everywhere in the world because once the U.S. FDA gives its approval, it means other regulators know that it has gone through a very thorough review.” To develop the vaccine, the researchers used CRISPR technology to edit the genome of Leishmania major by deleting centrin, the gene for a protein that supports the parasite’s physical structure. The team applied the new technology to the century-old Middle Eastern practice of leishmanization – deliberately introducing the live parasite to the skin to create a small infection that, once healed, leads to life-long immunity against further disease. These parasites cause infection by hijacking immune cells and using those host cells to replicate indefinitely. Studies of the vaccine in mice showed that the mutant parasite lacking centrin could still find its way into cells and make copies of itself, but for only a limited amount of time and not at a pace that leads to clinical disease. Immunization with the mutated parasites induced immunity against vector-transmitted infections. “Live vaccines like that are the best vaccines, but there’s a potential risk of causing serious disease in some people,” said Satoskar, also a professor of microbiology at Ohio State. “We refined the concept using modern technology, making a parasite that does not cause clinical disease but allows for induction of immunity.” Satoskar and his collaborators will be responsible for conducting the initial trials in Kenya and Brazil, two countries in which leishmaniasis is endemic and among the countries targeted for eventual vaccine deployment. A site in Cincinnati, Ohio, may also be added to the trial. Between about 75 and 100 people will participate. This initial trial is focused on testing the safety of the vaccine in healthy people, but the team will also collect blood samples to investigate whether the vaccine provokes an immune response. Testing in endemic regions is an important step in gauging whether people who may have already been exposed to the parasite, and therefore have antibodies in their blood, experience an allergic reaction or other adverse effect. In a parallel project, the team is developing a leishmaniasis skin test similar to a tuberculosis skin test . “Testing positive with the skin test means that a person has been exposed to the disease and is now immune to the disease,” Satoskar said. “It is a test for immunosurveillance but also for immunogenicity of our vaccine. Without this kind of test, you cannot do surveillance. You cannot know the level of immunity in the community.” After interim analysis of the Phase 1 results, the team is aiming to conduct a Phase 2 trial in at least 3,000 people with the purpose of understanding the effectiveness of the vaccine and any side effects. “An effective prophylactic vaccine is indispensable for elimination or eradication of leishmaniasis,” Satoskar said. “This is true for almost all infectious diseases.” A vaccine would also provide an affordable way to prevent a disease that can lead to disfigurement, disability, social stigma and poverty, he said. Researchers estimate that a vaccine would likely cost less than $5, compared to the $100 to $200 cost for treatment in the hardest-hit countries – treatment that requires weeks of daily drug injections with unpleasant side effects, leading to poor patient compliance that allows parasites to develop resistance to the drugs. A much more severe form of the disease, visceral leishmaniasis, affects organs and is fatal if left untreated. While the L. major vaccine may also protect against the visceral form, Satoskar and colleagues have used the CRISPR technique to work on a vaccine with the Leishmania donovani parasite that causes visceral leishmaniasis. The Phase 1 trial and leishmaniasis skin test production is supported by $10 million in grants from the Japan-based Global Health Innovative Technology Fund, which also supported the vaccine’s development along with the Wellcome Trust UK. Additional partners on the trial include Nagasaki University in Japan; Gennova Biopharmaceuticals Ltd., which manufactures the vaccine; Universidade Federal de Minas Gerais in Brazil; HJF Medical Research International in Kenya; the FDA; the National Institute of Allergy and Infectious Diseases; and Johns Hopkins University. Co-authors of the review article were Naomi Aronson of the Uniformed Services University of the Health Sciences in Maryland and Ahmed Musa of the University of Khartoum in Sudan.

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