Gene-modifying vaccine protects against parasite found in America

(ORDO NEWS) — The parasites that cause the disfiguring skin disease that affects about 12 million people worldwide may have met their mate in vaccines developed using CRISPR gene-editing technology, new research suggests.

Later this year, the first phase of human trials of a vaccine designed to prevent infection with Leishmania major, the parasite that causes cutaneous leishmaniasis, will begin in tropical and subtropical regions of the Eastern Hemisphere.

The same research team, led by Abhay Satoskar, a professor of pathology at the Ohio State University College of Medicine, used CRISPR technology to develop a vaccine against Leishmania mexicana, a species of parasite found in South, Central and North America.

In mice, the vaccine, based on a mutated live parasite, did not cause skin lesions and provided long-term prevention of infection.

This “New World” species causes a more chronic infection which, unlike the skin lesions that occur with L. major infection, does not self-heal.

The researchers expect a vaccine against the L. major mutant parasite to be effective against the L. mexicana species, but have developed a second vaccine as a fallback — and to see if their method can tame a more virulent organism.

“The main thing we wanted to see was whether this gene-deleting approach could break down this tough Pecheneg, which has always been a problem. It’s not an easy parasite,” says Satoskar, also a professor of microbiology at Ohio State. “Based on our experimental data, we should be able to use the L. major vaccine in the New World. But if it doesn’t work, we have a plan B.”

The study is published in the journal NPJ Vaccines.

In both vaccines, the team applied gene-editing technology to the century-old Middle Eastern practice of leishmanization the deliberate introduction of a live parasite into the skin to create a small infection that, when cured, leads to lifelong immunity against further disease.

“We had a question: is it possible for leishmania to occur in L. mexicana, which usually does not resolve itself? We are talking about two types of leishmania and they cause the same disease, but the clinical outcome and response to treatment are different,” Satoskar said. . “And even CRISPR might not work, because this species has different molecules, proteases and enzymes.”

Using precision technology to edit the L. mexicana genome, the researchers removed centrin, a gene encoding a protein that supports cell division, and inactivated an antibiotic resistance marker gene that is introduced into the parasite as part of the centrin removal process.

Under normal conditions, these parasites cause infection by taking over immune cells and using host cells to replicate endlessly. Experiments in immune cell cultures have shown that the mutant parasite can enter cells and create limited copies of itself, but not enough to cause symptoms.

A study in mice showed that the vaccine was safe, causing no skin lesions in animals susceptible to the disease. In further experiments, the researchers vaccinated mice and subjected them six weeks later to infection with the parasite L. mexicana by needle pricking into the ear, a technique used to simulate a sand fly bite. Leishmania is transmitted to humans and animals through the bite of infected sand flies.

Unlike the unvaccinated control group, the vaccinated mice had no skin lesions, and the number of parasites at the site of infection was contained – and protection was maintained for 10 weeks.

The immune response elicited by vaccination with this New World species is significantly different from that elicited by the previous vaccine, the researchers found. Vaccination of L. major increases the amount of pro-inflammatory proteins to provide protection. The L. mexicana vaccine had almost no effect on pro-inflammatory proteins, but rather suppressed anti-inflammatory proteins.

“Parasites are different, and the mechanism by which they provide protection is completely different,” Satoskar said. “It’s a balance. They both work.”

Researchers are aiming to create a vaccine to provide an affordable way to prevent a disease that can lead to disfigurement, disability, social stigma and poverty.

The team estimates the vaccine is likely to cost less than $5, compared to $100-$200 for treatment in the hardest-hit countries – a treatment that requires several weeks of daily injections of drugs with unpleasant side effects, resulting in poor adherence. the patient’s treatment regimen and allows the parasites to develop drug resistance.

Visceral leishmaniasis affects organs and, if left untreated, is fatal. Although a vaccine against L. major could also prevent this more severe form of the disease, the team used CRISPR to work on a vaccine against the parasite Leishmania donovani, which causes visceral leishmaniasis.

This work was funded by the Global Health Technology Innovation Fund and the National Institutes of Health.

The study was led by Greg Matlaszewski of McGill University and Hira Nahasi of the FDA’s Division of Emerging and Transfusion Transmitted Diseases. Other Ohio State contributors include Greta Volpedo, Thalia Pacheco-Fernandez, Erin Holcomb, Blake Cox, Rebecca Fultz, Chelsea Mishan, Chaitena Verma, Ryan Huston, Abigail Wharton, and Steve Oghumu.

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