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The Global Public Health Concern of Leishmaniasis: FDA Scientists Play a Major Role in Development of a Candidate Vaccine to Protect Populations and Blood Supplies
The parasitic disease leishmaniasis poses a potential global threat as it spreads out of tropical and subtropical countries in the absence of a vaccine that could protect vulnerable populations, according to a review article by Food and Drug Administration (FDA) scientists and their colleagues.
A review of the growing threat of leishmaniasis and initial efforts of FDA scientists to develop a vaccine against it appears in the Journal of Tropical Medicine (doi:10.1155/2012/631460)( http://www.hindawi.com/journals/jtm/2012/631460/ ).
Leishmania is caused by a Protozoan parasite that hijacks the immune system for its own purposes. (Protozoa are single-celled microorganisms nearly as complex as a cell in our bodies). The primary targets of the parasite are immune system cells called neutrophils. Parasites spread from neutrophils to immune cells called macrophages, which consume the infected neutrophils. This enables the parasite to disrupt the ability of immune system cells to communicate with each other and launch an effective counterattack against the infection.
Leishmaniasis causes skin sores and liver and spleen damage; the most serious form of the disease, called visceral leishmaniasis, is potentially fatal if left untreated. There are about 12 million individuals in tropical and subtropical regions with the disease, which causes about 50,000 deaths each year. Two other, less serious forms of the disease are cutaneous and mucocutaneous leishmaniasis. The parasite spreads among humans through the bite of the sand fly. Leishmaniasis also can be transmitted through blood and blood products, though such transmission is a relatively rare cause of infection.
More than 90% of visceral leishmaniasis cases occur in Bangladesh, Brazil, India, and Sudan, mostly among children under 15 years of age who already are chronically undernourished and have other illnesses. There are also occasional cases of infection in the southwest United States. Moreover recent studies have suggested with the climate changes there is an increase risk of spreading of the pathogen by the sand fly vector in the northern part of USA hence risk to human population.
There are no effective vaccines available against any kind of Leishmaniasis. Chemotherapy treatment, which is long-term and highly toxic, is often hindered by the parasite’s resistance, especially to antimony, the drug usually used for initial therapy. Resistance reportedly is also growing to a newer drug, miltefosine. ( These drugs are not currently approved in the United States; however, they are available in other countries.).
FDA scientists and colleagues from the Institute of Molecular Medicine and their co-authors from the Indian Council of Medical Research ( New Delhi, India) note that animal model studies show that the parasite survives blood banking storage conditions and retains its ability to infect humans. This suggests that leishmaniasis has the potential to spread from infected individuals who show no symptoms to others, through transfusion of donated blood. In fact, an outbreak among U.S. troops returning from Iraq in the 1990s temporarily led to deferral of those individuals as blood donors.
According to the FDA authors and their colleagues, vaccines made from selected constituents of the parasite (subunit vaccines) have so far failed to provide adequate protections from infection by the parasite that causes visceral leishmaniasis. However, humans who recover from infection with this protozoan develop life-long protection. Therefore, in order for vaccination to be effective, it might need to mimic a true infection by using a live but attenuated (weakened) parasite, the FDA scientists suggest.
The key to developing a safe, live, attenuated vaccine is to eliminate certain genes from the protozoan so the leishmaniasis parasite either 1) lasts for a long time in the body, continually stimulating the immune system; or 2) persists in the body for only a short time before the immune system eliminates it, but long enough to induce effective immunity without causing disease.
The FDA researchers and others have developed several genetically modified versions (mutants) of the leishmaniasis parasite Leshmania donovani and studied them in “test tube” experiments and in laboratory animals. The idea is that administering these modified versions in a vaccine could confer immunity on the recipient without also causing disease symptoms. The first mutant, which lacked a gene that regulates growth, was safe in animals and effective in preventing infections. The vaccine also protected mice against leishmaniasis parasites that cause two other forms of the disease, cutaneous and mucocutaneous leishmaniasis. The second mutant, which lacked an important component of an enzyme system needed to extract energy from nutrients, is currently being evaluated in mice for its potential as a vaccine.
The challenge to using genetically altered parasites as vaccines is the possibility that they might regain their ability to cause disease as they reproduce after being administered in a vaccine. Therefore, the scientists are trying to find a way to reliably identify parasites that remain unable to cause disease. To date the researchers have identified two genes whose activities indicate that the parasite is too weak to cause disease. However, further research is needed to make sure that there are no other genes that alter their function to compensate for such genetic abnormalities.
In addition, the scientists identified a culture medium that would support growth of the parasites for use as vaccines. They also found that if sand flies feed on vaccinated individuals and ingest the weakened parasite vaccine, the parasite might not be able to survive in the sand fly gut. This is important because it suggests that such ingested parasites would not be able to survive in the sand fly long enough to produce offspring that had reacquired the genes enabling them to cause disease.
The authors note that improved experimental models of the disease—infected immune cells and infected animals—are needed to study how the disease progresses after infection and to design and test leishmaniasis vaccines and therapies.
The FDA scientists are now focusing on developing realistic animal models of the disease—animals that were infected by the bites of sand flies and underwent the same immune system changes that occur in humans. Such a model would be extremely useful for evaluating the efficacy of genetically altered live-attenuated Leishmania parasites as vaccines.
The same strategy used for developing a vaccine against visceral leishmaniasis could also be used to developed live-attenuated vaccine candidates for other pathogens that infect blood cells, such as malaria and some bacterial pathogens.
“Immunity to Visceral Leishmaniasis Using Genetically Defined Live-Attenuated Parasites”
Journal of Tropical Medicine
2012; 2012: 631460. Published online 2011 September 6. doi: 10.1155/2012/631460
Angamuthu Selvapandiyan1, Ranadhir Dey,2 Sreenivas Gannavaram,2 Ines Lakhal-Naouar,2 Robert Duncan,2 Poonam Salotra,3 and Hira L. Nakhasi2
1Institute of Molecular Medicine, New Delhi, India
2Division of Emerging and Transfusion Transmitted Diseases, Office of Blood Research and
Review, Center for Biologics Evaluation and Research, Food and Drug Administration,
3Institute of Pathology, Safdarjung Hospital, New Delhi