RxPG News : Leishmaniasis

Vaccine developed to fight black fever

Tue, 25 Apr 2006 20:37:37 PST

( from http://www.rxpgnews.com ) Swiss scientists have developed a vaccine that could protect animals and humans from Leishmaniasis, or black fever, a parasitic disease that kills about 60,000 people a year.

Leishmaniasis, spread by the bite of the sandfly, attacks the spleen, bone marrow and liver and destroys the immune system. Untreated, it is nearly always fatal.

No vaccine yet exists for the disease that affects 500,000 people worldwide each year - mostly in India, Bangladesh, Nepal, Sudan and Brazil.

The vaccine, designed by researchers at the Laboratory for Organic Chemistry at the Swiss Federal Institute of Technology (ETH), Zurich, uses synthetic forms of carbohydrates taken from the parasite or bacteria responsible for the disease.

Laboratory studies have shown that the possible vaccine designed by the team produces a protective action against Leishmaniasis, stimulating the patient's own immune system, reported the online edition of BBC News.

The Swiss team is now moving on towards testing the vaccine on animals.

However, they say the vaccine development is in an early stage. Animal tests will take two years and pre-clinical trials another two to three years. A final vaccine is at least five years off, one researcher said.

Among common symptoms of the disease are lesions on the skin, persistent fever, night sweats, fatigue, weakness, appetite loss, vomiting and diarrhoea in children and cough.

There are about half a million new cases of visceral Leishmaniasis occurring each year.

The disease currently does not have any effective treatment. The most common drugs used to treat the disease have serious side effects and are expensive.

Potential vaccine developed for deadly leishmaniasis disease

Sat, 22 Apr 2006 19:36:37 PST

( from http://www.rxpgnews.com ) Development of a fundamentally new "candidate," or potential, vaccine for visceral leishmaniasis (LEASH-ma-NIGH-a-sis), a parasitic disease that kills about 60,000 people annually, is reported in the current issue of ACS Chemical Biology. Spread by the bite of infected female sand flies, visceral leishmaniasis infects about 500,000 people annually, with the majority of cases occurring in India, Bangladesh, Nepal, Sudan and Brazil.

Despite a major research thrust by the World Health Organization (WHO), no effective vaccine exists for the visceral, or internal, form of leishmaniasis. A milder form of leishmaniasis, which infects the skin, was reported among American military personnel during Operation Desert Storm and other conflicts in the region.

Peter H. Seeberger, Ph.D., of the Laboratory for Organic Chemistry at the Swiss Federal Institute of Technology (ETH) in Zurich headed the research group. It also included researchers from the Swiss Tropical Institute in Basel and Pevion Inc., a biotech company focusing on virosomal delivery systems. The group reported their findings in ACS Chemical Biology, one of 34 peer-reviewed journals published by the American Chemical Society, the worlds largest scientific society.

Several leishmaniasis candidate vaccines are in various stages of development. Seebergers group, however, reported development of a unique two-part preparation. It is among a new genre of carbohydrate-based vaccines stirring excitement in medical circles. Carbohydrates are chemical compounds that include sugar and are made from units linked together like beads on a chain.

"This is the first and only carbohydrate vaccine candidate against this disease," Seeberger stated. "This candidate vaccine brings something new to the table and may be of use not only in humans but also for pet vaccines. Dogs get leishmaniasis, particularly in Southern Europe and a vaccine is urgently needed there, as well."

Carbohydrate vaccines already are used in everyday medicine, including vaccines to immunize against meningitis and other bacterial infections, mainly in small children in the United States. Those vaccines use carbohydrates isolated from the actual bacteria responsible for the diseases. The carbohydrates act as antigens, which stimulate the immune system to deploy a protective shield against disease.

"Right now there is a major push to utilize synthetic carbohydrates as antigens in order to control the purity and composition and avoid possible contamination," Seeberger explained. His own group, together with a biotech company Ancora Pharmaceuticals in Medford, Mass. is working on one such malaria vaccine that is in late-stage preclinical trials. Other candidate vaccines against anthrax and tuberculosis are at an earlier stage of development.

One major drawback with carbohydrate vaccines is the difficulty in getting them to produce a strong immune response. Vaccine manufacturers achieve this by adding a booster substance an adjuvant. The standard existing adjuvant, alum, has limitations. Potential alternative adjuvants are toxic, expensive or have other problems.

Seebergers candidate vaccine combines the delivery vehicle, immune-stimulating antigen and adjuvant into one package.

The delivery vehicle is an influenza virosome the empty envelope of the influenza virus. These flu virus shells contain none of the infectious genetic material in full-fledges flu viruses. The virosome also acts as an "adjuvant," boosting the immune response of the candidate vaccine. The antigen is a synthetic carbohydrate similar to substances on the surface of the leishmaniasis bacteria.

With laboratory studies showing that the candidate vaccine produces a strong protective action against leishmaniasis, Seebergers group is moving on to the next step toward a leishmaniasis vaccine tests in animals.

"To date, carbohydrates have not been used on this delivery platform," Seeberger said. "Therefore, this is a proof-of-principle study that will be applicable to many carbohydrate antigens of importance in other diseases as well," he said. Seeberger cited both infectious and parasitic diseases and vaccines against cancer.

WHO assigned a high priority to development of a leishmaniasis vaccine because of the huge human toll and the lack of any effective treatment. The most common drugs used to treat leishmaniasis have serious side effects and are expensive.

Symptoms of visceral leishmaniasis include fever, weight loss, and abnormalities of the liver and spleen.

Drug-Resistant Leishmania tropica Parasites Detected in Iranian Cutaneous Leishmaniasis

Fri, 21 Apr 2006 00:40:37 PST

( from http://www.rxpgnews.com ) Leishmaniases are parasitic diseases that are endemic (constantly present) in many tropical and temperate countries. Every year, 2 million people become infected with one of 20 pathogenic species of Leishmania through the bites of infected female sand flies. These pick up parasites by biting an infected animal (zoonotic transmission) or an infected person (anthroponotic transmission). In their human host, Leishmania parasites reproduce inside macrophageswhite blood cells that usually kill microorganisms, clear up cellular debris, and activate other immune cells. When the macrophages are full of parasites, they burstthis destruction causes the symptoms associated with leishmaniasesand the released parasites infect further macrophages.

In cutaneous leishmaniasisthe most common form of the diseasepatients develop skin ulcers a few weeks after being bitten by infected sand flies. These usually heal spontaneously but leave ugly, sometimes disabling, scars. Cutaneous Leishmania infections can spread to the nose or mouth to cause mucocutaneous leishmaniasis, which destroys the sensitive linings of these organs. Cutaneous and mucocutaneous leishmaniases are not life-threatening in themselves, but patients can develop fatal secondary infections. Visceral leishmaniasis, which affects the spleen and other internal organs, is often fatal if untreated.

Leishmaniases are usually treated with pentavalent antimony-containing drugs, such as meglumine antimoniate (Glucantime), but patients are becoming increasingly unresponsive to these drugs. In India, for example, more than 60% of cases of visceral leishmaniasis do not respond to treatment. Unresponsiveness can be caused by the parasite developing drug resistance, by changes in the host's immunological status, or by suboptimal treatment regimens. Ramtin Hadighi, Mehdi Mohebali, Marc Ouellette, and colleagues have been investigating whether the increased incidence of Glucantime-unresponsive cutaneous leishmaniasis in Iran correlates with parasite resistance to the drug. They now report that treatment failure for cutaneous leishmaniasis in Iran, like the treatment failure seen for visceral leishmaniasis in India, is due to Glucantime-resistant parasites.

The researchers isolated Leishmania parasites from 185 skin lesions from untreated patients living in Mashhad, a region of Iran where anthroponotic cutaneous leishmania is endemic. Of these patients, 20 did not respond to Glucantimetheir skin ulcers failed to heal. To find out if this was due to drug-resistant parasites, the researchers infected mouse macrophages with all 185 isolates and then treated the infected cells with Glucantime. Several days later, the parasites surviving inside the cells were stained with a dye and then counted using a microscope. The researchers report that although initial infection rates were similar, parasites from the unresponsive patients were resistant to intermediate or high levels of Glucantime. On average, parasites from unresponsive patients were 4-fold less susceptible to Glucantime than parasites from responsive patients.

Next, the researchers partly characterized the 20 drug-resistant parasite isolates and 11 drug-susceptible isolates. By sequencing the gene for the metabolic enzyme pteridine reductase 1, the researchers discovered that 28 of the isolates were L. tropica; the remaining three were L. major. Only one unresponsive isolate was L. major; the rest were L. tropica. The researchers also used pulsed-field gel electrophoresis to separate and study Leishmania chromosomes. Because these evolve quickly, the chromosome composition (karyotype) of different isolates indicates their genetic relatedness. The L. major isolates formed one group using this technique but the L. tropica isolates fell into three distinct groups, each of which included drug-susceptible isolates and isolates with intermediate and high Glucantime resistance. In other words, susceptible and resistant isolates were often closely related. Finally, the researchers confirmed the drug sensitivity of several closely related strains by testing their ability to grow in a human monocyte cell line in the presence of Glucantime, and also showed that drug resistance was stable over time in resistant isolates but could be reversed by treatment with an inhibitor of glutathione biosynthesis. This last result indicates that thiols (molecules containing a sulphur atom bonded to a hydrogen atom) may be important for the resistant phenotype, and may suggest a way to reverse drug resistance.

Overall, these results provide the first evidence that Leishmania parasites can acquire drug resistance that contributes to treatment failure in cutaneous leishmaniasis. They also indicate that Glucantime-resistant L. tropica isolates are now frequent in Iran. Additional work is needed to understand the nature of the resistance mechanisms, with the goal to improve diagnosis and treatment of resistant leishmaniasis.