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http://www.mpg.de/en...0324/index.html

Germany Starts Clinical Development of a New Tuberculosis Vaccine

Federal-financed German research initiative organizes clinical testing of a highly promising vaccine candidate which has been developed in the Max Planck Institute for Infection Biology

With some 2.5 million deaths and 9 million new cases annually, tuberculosis (TB), along with HIV/AIDS, is responsible for the greatest number of infectious disease victims worldwide. Of particular concern is the fact that an ever-increasing number of pathogens are becoming resistant to conventional medications. Figures from the World Health Organisation indicate that some 50 million people around the globe are infected with these multi-resistant strains. An effective tuberculosis vaccine, therefore, is more urgently needed than ever.

Image: MPI for Infection Biology/Volker Brinkmann

To mark World Tuberculosis Day on March 24th, a consortium of business and research centres have launched a programme to develop just such a vaccine. Scientists at the Max Planck Institute for Infection Biology (MPIIB) in Berlin, under the direction of Prof. Stefan H. E. Kaufmann, have developed a highly promising vaccine candidate. And now, Vakzine Projekt Management GmbH (VPM) has acquired a worldwide licence for several patents from Max Planck Society. VPM was founded by Germany's Federal Ministry for Education and Research (BMBF) as part of a national vaccine initiative. In collaboration with MPIIB and the German Rearch Centre for Biotechnology (GBF) VPM will manage the pre-clinical and clinical study program.

"For our new tuberculosis vaccine candidates we are relying on genetically modified variants of the live BCG vaccine that has been in use since 1921," says MPI director, Prof. Dr. Stefan Kaufmann. "The vaccine consists of an attenuated bacteria that is very closely related to the TB pathogen, Mycobacterium tuberculosis. BCG has a proven safety record for many decades, but unfortunately it lacks effectiveness," notes Kaufmann, adding that children can be protected against certain forms of TB only. There is no protection at all against pneumotuberculosis, by far the most common form of the disease.

The protection provided by the presently existing BCG vaccine is assumed to be limited because the BCG bacteria are hidden in the body cells inside so-called phagosomes. The group of Professor Kaufmann, therefore, has inserted a gene coding for the protein listeriolysin. "This protein causes perforation of the phagosomes thus making BCG cells available to the immune system to build up immune protection," says Dr. Leander Grode, now project manager at VPM and co-inventor of the new strain. "Preclinical experiments have already indicated an increased immune response," he notes.

Estimates suggest that one third of the world's population is infected with TB bacteria. Initially, the pathogens are dormant. The disease later erupts in about 10 percent of those infected, who develop open, contagious tuberculosis. With more than 7,500 cases annually in Germany the disease is nowhere near eradication. "Medical need is high and on the rise with the spread of multi-resistant strains," emphasises VPM Managing Director, Dr. Albrecht Läufer, "therefore, a successful TB vaccine has considerable economic potential." VPM's goal is development up to Phase II, followed by licencing out to an industrial partner. Joint early stage development with partners is also under consideration.

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http://www.scienceda...40324070420.htm
Source: World Health Organization
Date: 2004-03-25

WHO Sees Surge In Progress Against Tuberculosis On Eve Of Global Summit

The number of tuberculosis patients diagnosed and treated under DOTS*, the internationally recommended strategy for TB control, is now rising much faster than at any time since DOTS expansion began in 1995, according to a new report by the World Health Organization (WHO). Indeed, the past two years have witnessed accelerated growth in the implementation of DOTS programmes worldwide.

The 2004 Global Tuberculosis Control report confirms that DOTS programmes are now treating three million TB patients every year, an increase of more than one million patients compared to just two years ago. That increase is nearly double the average annual increment of 270,000 patients during the previous six-year period, and the trajectory is still heading upward. India is leading the surge with more than a quarter of all additional DOTS cases being treated, followed by smaller but significant increases in five other key countries with high rates of TB: South Africa, Indonesia, Pakistan, Bangladesh and the Philippines.

The findings of the report will be presented Wednesday by LEE Jong-wook, WHO Director-General, at the opening session of the 2nd Stop TB Partners' Forum in New Delhi, a two-yearly summit of donors, technical agencies, NGOs and ministers from the 22 high-TB burden countries under the umbrella of the global Stop TB Partnership.

"DOTS expansion is one of the major public health success stories of the past decade, one that is saving thousands more lives every day," Dr Lee said. "But to reach the 2005 targets for detection and treatment, the challenge now is to add another one million TB patients to DOTS programmes each year. Many of these new cases will be recruited from the hospitals and private health sector in Asia, especially China, and from beyond the present limits of health systems in Africa."

The global 2005 targets for TB control are to detect 70% of all infectious TB cases and cure 85% of those cases detected. According to the WHO report, the case detection rate has risen to 37% and cure rates to 82%. Meeting the 2005 targets will put the world's TB control programmes on the path to achieving the Millennium Development Goal (MDG) of halving the global TB burden by 2015.

Expanding and strengthening DOTS is key to halting the spread of TB because it is cost-effective, ensures treatment compliance, and prevents the development of drug-resistant strains of TB. Of the 210 countries that reported TB case notifications and/or treatment outcomes to WHO in 2002, 180 are today implementing the DOTS strategy and providing access to services for nearly 70% of the world's population.

The World Bank, a key member of the Stop TB Partnership and a leading financier of TB-related programmes in developing countries, welcomed the WHO report as evidence that donor funding for expanding DOTS treatment had proven effective in improving the health and welfare of communities afflicted by the disease. "This new evidence is important. Speeding up TB case detection is the critical first step in curing more patients and driving down disease," said James Wolfensohn, President of the World Bank. "This gives us solid ground to push for the greater support needed to reach our goals faster. Strengthening overall health systems to reach the poor will be another critical route towards controlling TB."

There are an estimated 8.8 million new cases of TB each year of which 3.9 million are infectious. The number of new cases is increasing rapidly in Eastern Europe, mainly countries of the former Soviet Union which only recently started to implement DOTS. A special surveillance report issued last week by WHO found that TB patients in parts of Eastern Europe and Central Asia are 10 times more likely to have multidrug-resistant TB than in the rest of the world. TB incidence rates also continue to rise at an alarming rate in African countries with high HIV prevalence.

"HIV/AIDS is driving the TB epidemic in southern and eastern Africa and will worsen the situation in Eastern Europe, India and China in the years ahead," said Dr Jack Chow, the WHO Assistant Director-General for HIV/AIDS, Tuberculosis and Malaria. "We cannot control one without controlling the other, and must begin rapidly scaling up TB/HIV collaborative activities to provide a synergy of prevention, treatment and care for co-infected patients."

Another key document to be presented at the Delhi summit will be a progress report on the Global Plan to Stop TB, the strategic roadmap which guides the development and work of the Stop TB Partnership. The report assesses progress in 8 key areas: DOTS expansion; DOTS-Plus for Multidrug-Resistant (MDR) TB; TB/HIV, research and development for new TB drugs, diagnostics and vaccines; the Global TB Drug Facility; and resource mobilization. "The Global Plan covers the five-year period from 2001-2005, and this progress report will tell us how well we are doing in meeting the process targets of the Plan at the midway point," said Ernest Lowensohn, chairman of the Stop TB Coordinating Board.

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http://www.scienceda...40510012438.htm

Wisconsin Chemists Find A New Chink In TB's Armor

MADISON - The family of bacteria that causes tuberculosis (TB) and leprosy are notoriously sturdy. And although the diseases they cause have been held in check for the past 50 years by antibiotics, some strains are becoming increasingly resistant to existing therapy.

Now, however, a new chink has been found in the cellular armor that makes these infectious diseases difficult to treat. The discovery, reported today (May 9) in the online editions of the journal Nature Structural & Molecular Biology by a team of chemists and biochemists from the University of Wisconsin-Madison, opens the door to the development of a new family of antibiotics to treat diseases that still claim as many as 3 million lives annually worldwide.

"Most of the treatments we have for these diseases date from the 1950s," says Laura L. Kiessling, a UW-Madison professor of chemistry and the leader of the team reporting the new discovery. "Many traditional antibiotics don't work against tuberculosis."

The bacteria that cause tuberculosis are literally tough as nails. With unique multilayered cell walls, the microbes resist easy treatment.

Current drug regimens typically last up to six months and require a mix of as many as six different drugs. Because the drugs cause unpleasant side effects, and because patients often feel better after a month or two, many people do not complete treatments, a phenomenon contributing to a worldwide epidemic of multidrug-resistant TB. Adding to the problem, in less developed countries where TB is most common, health care is spotty and drug supplies are frequently inadequate.

Kiessling and her colleagues, working with the support of the National Science Foundation, have detailed the workings of a key enzyme that the bacterium requires to maintain the integrity of its cell walls. Enzymes are proteins that initiate chemical reactions within plant and animal cells.

"We've figured out how this enzyme works. If you knock it out, the bacteria aren't viable," Kiessling explains. "It's an essential enzyme."

The TB microbe's success and resistance to traditional drugs is attributed in large measure to its multilayered cell wall, composed of chicken wire-shaped molecules wrapped around an inner membrane. Atop that structure, are three more layers that further insulate the microbe from attack by traditional antibiotics.

The enzyme is required for the TB bacterium to build its cell wall. The enzyme, in turn, depends on a derivative of vitamin B2 to make a cell wall building block. The work published today by Kiessling's group shows that the enzyme uses the vitamin in a new way, which also gives it a new biological role.

Detailing the interplay between vitamin B2 and the enzyme provides a blueprint for inhibitors of the enzymes that keep the bacterium's cell walls intact. As a result, Kiessling's group has effectively identified a target for drug manufactures interested in developing new antibiotics to combat TB and other diseases such as leprosy, which are caused by similar types of bacteria.

"Because we understand the mechanism better, we can design inhibitors of this enzyme," Kiessling says.

However, she notes that under the best circumstances, it takes years and many millions of dollars for new drugs to be developed. What's more, she says, many major drug manufacturers are not actively pursuing the development of new antibiotics, despite growing resistance by microbes to antibiotics currently in use.

Tuberculosis, once commonly referred to as consumption, has a long history. Evidence of tubercular decay has been found in the bones of Egyptian mummies. It was identified by Hippocrates, the ancient Greek physician, as the most widespread and fatal disease of the ancient world. It has claimed many notable victims throughout history, including the poet John Keats, composer Frederick Chopin, playwright Anton Chekhov and writers Robert Louis Stevenson, Emily Bronte, D.H. Lawrence and George Orwell.