Researchers at Ohio State University offered an insight into their work against leishmaniasis in August 2023. Phase I human trial planning is underway after positive progress in animal studies, but research in iScience shows how they prompt “molecular-level changes” in host cells, with specific roles in supporting the generation of an immune response. Although the two vaccines were developed with the same CRISPR gene-editing technique, each is based on a different species of Leishmania parasite to “very different effects”.
Leishmaniasis is a parasitic disease caused by strains of the blood-borne protozoan species Leishmania, transmitted to humans through bites from infected sandflies. One of the studies reports that an approximate one billion people are at risk of infection, “mainly in tropical and subtropical countries”. It is found it over 90 countries worldwide.
The most common form is cutaneous leishmaniasis (CL), which is seen in skin lesions that can ulcerate or cause disfiguring scars. It can also affect organs and is “fatal if left untreated”. However, no licensed vaccines exist, and treatment options “remain limited”. Drug treatment requires weeks of daily injections and is associated with “unpleasant side effects”.
Old meets new
To develop the live attenuated vaccines, Professor Abhay Satoskar and team combined old approaches with new technology. The practice of leishmanisation involves introducing the live parasite to the skin to provoke a small infection. Once this heals, the patient benefits from life-long immunity to the disease.
Previous research demonstrated that CRISPR can delete centrin, the gene for a protein that supports the parasite’s physical structure, from the genomes of both Leishmania major and Leishmania mexicana. Experiments in mice revealed that the vaccinated creatures “remained clear of skin lesions” and were able to limit parasites at the infection site.
Two different approaches
The vaccines were produced with the same technique but have different effects. One enables the immune response by “inhibiting a host metabolite that suppresses immune activity”. The other “drives up activation of a chemical pathway” to “prime immune cells” against pathogens. Ohio State reports that “the primary vaccine” was developed by editing the genome of Leishmania major, prevalent in tropical and subtropical regions of the Eastern Hemisphere. A “backup vaccine” uses Leishmania mexicana, a “more virulent species” that is found in the Americas.
In the latest studies, mouse ears were inoculated with a normal parasite, a mutated parasite vaccine, or a placebo. Through mass spectrometry at the inoculation site the researchers identified the most prominent metabolites. The results indicate that the L. major vaccine “promoted a pro-inflammatory metabolic response” by using the amino acid tryptophan to block signals from an immune-suppressing molecule. By contrast, the L. mexicana vaccine “enriched” a series of metabolic reactions that activated the “necessary pro-inflammatory work” of “front-line immune cells”.
Professor Satoskar thinks it’s “important” to see that, while both vaccines are protective, “at a molecular level the mechanisms can be totally distinct”.
“This is not only conceptually important, but if you can find how these things are modulating the immune response in the right direction, and identify the pathways, then perhaps those pathways could be used for developing new interventions.”
Through an “unbiased approach”, the team were able to better understand the role immune cell metabolism plays in “modulating immune function”.
“We also learned that by removing the centrin gene, we got rid of the parasites’ ability to manipulate metabolic pathways in a way that would impair development of protective immunity and, in fact, promoted vaccine-induced immunity.”
For Professor Satoskar, this is “important” for a live attenuated vaccine. Furthermore, as there are “only four existing drugs” for the disease, understanding the mechanism of vaccines can support future interventions: “what you learn from immunomodulation can be used for developing other therapeutic agents”.
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