Vaccine protects against 'tough cookie' parasite found in the Americas
Date:
March 15, 2022
Source:
Ohio State University
Summary:
The parasites that cause a disfiguring skin disease affecting
about 12 million people globally may have met their match in
vaccines developed using CRISPR gene-editing technology, new
research suggests.
FULL STORY ==========================================================================
The parasites that cause a disfiguring skin disease affecting about 12
million people globally may have met their match in vaccines developed
using CRISPR gene-editing technology, new research suggests.
========================================================================== Phase 1 human trials are set to start later this year with a vaccine
designed to prevent infection by Leishmania major, the parasite species
that causes cutaneous leishmaniasis in tropical and subtropical regions
of the Eastern Hemisphere.
The same research team, co-led by Abhay Satoskar, professor of pathology
in The Ohio State University College of Medicine, has used CRISPR
technology to develop a vaccine targeting Leishmania mexicana, the
species of the parasite that is found in South, Central and North America.
In mice, the vaccine -- created with a mutated live parasite -- posed
no threat of causing skin lesions and provided long-term infection
prevention.
This "New World" species causes a more chronic infection that, unlike skin lesions generated by L. major infection, will not self-heal. Researchers
expect the L. major mutant parasite vaccine to be effective against
the L. mexicana species, but have developed the second vaccine as a
backup -- and to find out whether their technique could tame the more
virulent organism.
"The main thing we wanted to see was if this approach, removing a specific gene, could break this tough cookie, which has always been a problem. It's
not an easy parasite," said 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 -- deliberately introducing the live parasite to the skin to create a small infection
that, once healed, leads to life-long immunity against further disease.
"One question we had was, is leishmanization even possible with
L. mexicana, which normally doesn't self-resolve? We're talking about
two leishmania species and they cause the same disease, but the clinical outcome and response to treatments differ," Satoskar said. "And even
CRISPR might not have worked, because this species has different
molecules, proteases and enzymes." Using the precision technology to
edit the genome of L. mexicana, researchers deleted centrin, the gene
that codes for a protein that supports cell division, and inactivated an antibiotic resistance marker gene that is introduced into the parasite
as part of the process of knocking out centrin.
Under normal conditions, these parasites cause infection by hijacking
immune cells, and use host cells to replicate indefinitely. Experiments
in immune cell cultures showed that the mutant parasite could enter
cells and make limited copies of itself, but not enough to cause symptoms.
The study showed in mice that the vaccine is safe, causing no skin
lesions in animals that are susceptible to the disease. In further
experiments, researchers vaccinated mice and exposed them six weeks
later to the L. mexicana parasite with a needle challenge to the ear
-- a technique used to mimic a sand fly bite. In humans and animals,
leishmania is transmitted through the bite of infected sand flies.
========================================================================== Unlike the unvaccinated control group, vaccinated mice remained clear
of skin lesions and the number of parasites at the infection site was
held at bay - - and the protection was sustained over 10 weeks.
The immune response produced by vaccination with the New World species
differs substantially from the type of response generated by the
previous vaccine, the researchers found. With L. major vaccination, pro-inflammatory proteins are increased to provide protection. The
L. mexicana vaccine had little effect on pro-inflammatory proteins,
but suppressed anti-inflammatory proteins instead.
"The parasites are different, and the mechanism by which they confer
protection is totally different," Satoskar said. "It's a balance. They
both work." Researchers are pursuing vaccines to provide an affordable
way to prevent a disease that can lead to disfigurement, disability,
social stigma and poverty.
The team estimates 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.
Visceral leishmaniasis affects organs and is fatal if left
untreated. While the L. major vaccine may also prevent this more severe
form of the disease, the team has used the CRISPR technique to work on
a vaccine with the Leishmania donovani parasite that causes visceral leishmaniasis.
This work was funded by the Global Health Innovative Technology Fund
and the National Institutes of Health.
The study was co-led by Greg Matlashewski of McGill University and Hira
Nakhasi of the FDA Division of Emerging and Transfusion Transmitted
Diseases.
Additional Ohio State co-authors include Greta Volpedo, Thalia Pacheco- Fernandez, Erin Holcomb, Blake Cox, Rebecca Fultz, Chelsea Mishan,
Chaitenya Verma, Ryan Huston, Abigail Wharton and Steve Oghumu.
========================================================================== Story Source: Materials provided by Ohio_State_University. Original
written by Emily Caldwell. Note: Content may be edited for style and
length.
========================================================================== Journal Reference:
1. Greta Volpedo, Thalia Pacheco-Fernandez, Erin A. Holcomb, Wen-Wei
Zhang,
Patrick Lypaczewski, Blake Cox, Rebecca Fultz, Chelsea
Mishan, Chaitenya Verma, Ryan H. Huston, Abigail R. Wharton,
Ranadhir Dey, Subir Karmakar, Steve Oghumu, Shinjiro Hamano,
Sreenivas Gannavaram, Hira L. Nakhasi, Greg Matlashewski, Abhay
R. Satoskar. Centrin-deficient Leishmania mexicana confers
protection against New World cutaneous leishmaniasis.
npj Vaccines, 2022; 7 (1) DOI: 10.1038/s41541-022-00449-1 ==========================================================================
Link to news story:
https://www.sciencedaily.com/releases/2022/03/220315113010.htm
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