MALARIA: World Malaria Day : National Institute of Allergy and Infectious Diseases

April 25, 2011
 B.F. (Lee) Hall, M.D., Ph.D., and Anthony S. Fauci, M.D., National Institutes of Health
In commemorating World Malaria Day and reflecting on this year’s theme, “Achieving Progress and Impact,” we celebrate the important strides made in many regions of the world to control malaria, while acknowledging the enormous challenges that remain.
In 2000, an estimated 350 million to 500 million clinical cases of malaria occurred worldwide and more than 1 million people died from the disease, according to the World Health Organization (WHO). By 2009, there were about 225 million cases of clinical malaria and 781,000 deaths. Decreases in cases of malaria occurred in all affected regions, with the greatest decline in the number of malaria deaths occurring in Africa. Furthermore, in 2010, WHO certified that two countries, Morocco and Turkmenistan, had eliminated malaria—that is, reduced the incidence of infections in their countries to zero. Although these numbers reflect significant improvements, the global burden of malaria remains far too high and will require sustained and coordinated efforts from the international community to reduce it further.
Today we enter the third year of the Global Malaria Action Plan (GMAP), developed by the Roll Back Malaria (RBM) Partnership. The GMAP, an international framework for coordinated action against malaria, sets ambitious goals to control, eliminate and eradicate malaria. The National Institutes of Health is committed to supporting the GMAP. To make continued progress and achieve long-term GMAP goals, we must build a sustainable pipeline of new products, novel interventions and innovative strategies to diagnose, treat and prevent malaria as well as interrupt its transmission. Below we describe examples of significant advances made in these areas during the past year.
The emergence and spread of parasites resistant to conventional anti-malarial drugs threatens treatment efforts. Recently, NIH grantees identified a novel compound that rids mice of malaria-causing parasites with a single oral dose. This compound acts on a novel target in the parasite that may allow it to kill parasites that have developed resistance to other antimalarial drugs. Further studies will determine whether this compound can become a new therapy. Similarly, insecticide resistance can undercut mosquito-control strategies for containing malaria. Although research on insecticides with novel mechanisms of action continues, such compounds, like current insecticides, run the risk of selecting for the emergence and spread of mosquitoes resistant to the new insecticide. Therefore, novel approaches must be pursued.
NIH-funded researchers recently identified a genetically modified fungus that blocks development of malaria parasites in the mosquito and thereby interrupts malaria transmission. Because the fungi do not kill the mosquitoes, they would be unlikely to develop resistance. Such fungi could become an important malaria intervention if future studies demonstrate that they are safe and effective.
Within the next few months, we expect to learn the results of a large-scale clinical trial in Africa of a candidate malaria vaccine known as RTS,S. We all hope that an effective vaccine that confers protection against the most deadly type of disease, Plasmodium falciparum malaria, soon will be available. Meanwhile, efforts to develop new and improved malaria vaccines continue globally, with 16 candidates currently in preclinical development and another 23 in clinical trials.
Early this year, we joined with others in announcing a renewed interest in the possible eradication of malaria, as described in the Malaria Eradication Research Agenda (MalERA), the result of a global consultation effort among multiple stakeholders and disciplines. A key message of MalERA is that the tools to eradicate malaria do not exist and must be developed. A major challenge will be to continually assess the changing epidemiology of malaria as control and elimination efforts prove successful to ensure that appropriate tools and interventions are developed and effectively deployed.
To bridge clinical and field research with new laboratory-based methods in immunology, molecular biology and genomics, we at the NIH National Institute of Allergy and Infectious Diseases recently launched a network of International Centers of Excellence for Malaria Research. This network, which supports teams of scientists conducting research in more than 20 malaria-endemic countries, will provide new insights from research conducted in the context of rapidly changing malaria epidemiology.
A strong foundation of scientific insight, technological innovation and effective implementation has enabled us to achieve progress and advance several fronts in the fight against malaria. We must sustain this critical foundation as we continue to work together toward our shared goals of global malaria control, elimination and eradication.

For more information on malaria, visit NIAID’s Malaria Web portal.
Lee Hall, M.D., Ph.D., is Chief of the Parasitology and International Programs Branch in the NIAID Division of Microbiology and Infectious Diseases. Anthony S. Fauci, M.D., is Director of the National Institute of Allergy and Infectious Diseases at the National Institutes of Health in Bethesda, Maryland.
http://www.niaid.nih.gov/news/newsreleases/2011/Pages/2011WorldMalariaDay.aspx

BIOTERRORISM: Overcoming Challenges to Develop Countermeasures Against Aerosolized Bioterrorism Agents

The highest priority of the National Institute of Allergy and Infectious Diseases (NIAID) is the development of countermeasures against bioterrorism agents that are highly infectious when dispersed in aerosol form. However, the development of drugs to prevent or treat illnesses caused by bioterrorism agents requires that their effectiveness be tested in animals because human clinical trials would be unethical. At the request of NIAID, the National Research Council conducted a study of appropriate testing in animals. The report provides recommendations to researchers on selecting animal models, aerosol generators, and doses of bioterrorism agents to closely mimic disease processes in humans. It also urges researchers to fully document experimental parameters in the literature so that studies can be reproduced and compared. The report recommends that all unclassified data on studies of bioterrorism agents--including unclassified, unpublished data from the U.S. Army Medical Research Institute of Infectious Diseases (USAMRIID)--be published in the open literature. The report also calls on the Food and Drug Administration to improve the process by which bioterrorism countermeasures are approved based on the results of animal studies.
http://www.nae.edu/19582/Reports/25541.aspx?layoutChange=Normal

TUBERCULOSIS: A new molecular test for tuberculosis made by Cepheid

By Kate Kelland
Sep 1, 2010 5:02pm EDT
A new molecular test for tuberculosis made by Cepheid can diagnose TB and detect a drug-resistant form of it far more easily and rapidly than other tests currently available, scientists said on Wednesday.
In a study in the New England Journal of Medicine (NEJM), researchers said that when used on 1,730 patients with suspected TB and suspected drug-resistant TB, the Xpert MTB/RIF test successfully identified 98 percent of all cases.
It also identified 98 percent of patients with a form of TB resistant to rifampin, or rifampicin -- one of the most powerful TB drugs -- and achieved these results in less than two hours.
Anthony Fauci, director of the U.S. National Institute of Allergy and Infectious Diseases described the test findings as "impressive" in terms of speed, accuracy and sensitivity.
"Within two hours, you can not only have a diagnosis, but you can also have a good idea of the range of drugs you can use," he told Reuters, adding that such capabilities were "unheard of" with current testing methods.
Doctors say current diagnostic testing for TB -- which involves microscopy in labs with trained experts and can take weeks -- has barely been improved in the last 125 years.
Tests for drug-resistant TB can take months and are notoriously insensitive, so new, more accurate tools to rapidly diagnose TB and its drug-resistant forms are urgently needed.
"We're very pleased with the outcome," said Mark Perkins, chief scientific officer at the Geneva-based non-profit organization the Foundation for Innovative New Diagnostics (FIND), which worked on the study.
TB afflicts mostly the poor in developing regions such as sub-Saharan Africa, India and China, but also occurs in poor regions of developed nations and is common in patients with the HIV virus that causes AIDS. It is among the world's top 10 leading causes of death and killed 1.8 million people worldwide in 2008, or one person every 20 seconds.
COSTS
Perkins said his team had since followed up on this initial study and carried out further "demonstration trials" in six countries to see how the test works in real-life settings.
He said initial signs from these trials, which involved nearly 7,000 patients but have yet to be published or peer-reviewed, suggest the test is just as effective at detecting TB in real patients on the ground.
In a commentary about the NEJM study, Peter Small, who runs the TB program at the Bill & Melinda Gates Foundation global aid group, said he was encouraged by the results but concerned that the potential high cost of such a sophisticated test might limit its use around the world.
"Critical to a rapid scale-up of the test will be...whether its use improves outcomes for patients in a cost-effective manner," he wrote.
Perkins said FIND had already negotiated concessionary prices with Cepheid which would apply in developing countries which decide they want to use the test.
The machine and computer to analyze the tests cost around $17,500, and the negotiated price of the test kits for poorer countries will be based on the cost of manufacture plus a small margin, he said. He was not able to give a precise figure.
"Our goal is to make...tests as inexpensive as possible, This one happens to be quite sophisticated and quite difficult to make inexpensive. But it is like any other public good -- it will obviously have a big impact, and it obviously costs money."
http://www.reuters.com/article/idUSTRE68071A20100901

TUBERCULOSIS: Molecular profiling

Thanks to molecular profiling, scientists now have a better idea about how a mass killer selects its victims. And the new analysis suggests that the killer, TB, may use a different murder weapon than researchers previously believed.
Mycobacterium tuberculosis infects one-third of people worldwide. But only about 10 percent of people infected will actually get sick with a debilitating lung disease. Until now, scientists had no way to predict who would become ill.
Now, an international consortium of researchers has compiled profiles of genetic activity in the blood of people with dormant TB infections, people with active infections, and healthy people. Those profiles show how the immune system deals with tuberculosis and point to some surprising culprits responsible for awakening a slumbering infection. Such profiles may help predict who will succumb to TB, the researchers report in the Aug. 19 Nature.
“This is literally the way to tell who is going to get sick,” says Clifton Barry, chief of the tuberculosis research section at the U.S. National Institute of Allergy and Infectious Diseases in Bethesda, Md. This study could revolutionize TB diagnosis in the same way that breast cancer treatments were forever changed by the discovery that some tumor cells make molecules that respond to estrogen, and that those molecules can serve as targets for chemotherapy, Barry says.
In the new study, researchers drew blood from TB patients and from healthy people in London and analyzed gene activity in the blood cells. People who had active infections had 393 genes with activity different from that seen in healthy people. The team could classify people into groups—no infection, latent infection or active illness—just by looking at the gene activity profiles in their blood. The findings were replicated in a separate group of patients from Cape Town, South Africa. The TB signature disappeared as people were treated with antibiotics.
About 10 to 25 percent of people with latent infections had signatures similar to those of people with active infections, indicating that people with the active profile may go on to develop the disease even if their infection is currently dormant, says study coauthor Matthew Berry of the MRC National Institute for Medical Research in London. The researchers are planning to follow people with latent infections to see if those with the signature really are the same ones who develop active infections later. If the results hold up, the blood profiles could be the first means of predicting who is likely to get sick from TB.
That could spare people from developing a lung-damaging infection, but may also mean that people who aren’t likely to get sick won’t need to take anti-TB drugs that can damage the liver.
Blood cells called neutrophils also appeared in the new study to be important for spreading the disease. Previously, researchers didn’t think that short-lived neutrophils could play any role in such a long-term infection as tuberculosis. The dogma in the field was that the bacterium infected only immune cells called macrophages, says study leader Anne O’Garra, also of the MRC National Institute for Medical Research. The new study indicates that genes turned on by a protein known as type 1 interferon become active in the neutrophils of people with full-blown TB. Interferon helps to fight off viral infections but may actually make bacterial infections such as TB even worse, O’Garra says.
These findings fit well with recent data from mouse studies implicating both neutrophils and interferon in serious disease caused by tuberculosis, says Andrea Cooper, an infectious disease immunologist at the Trudeau Institute in Saranac Lake, N.Y.
“We’re at a watershed here in changing what we think the disease is about,” she says.
TB’s molecular signature was distinct from the profiles of blood taken from people with autoimmune diseases, such as lupus, and from those with other infectious diseases like Streptococcus or Staphylococcus infections, the researchers found. The discovery was unexpected, as most researchers thought that different types of bacteria might change the activity of specific genes at the site of the infection but that those differences would not show up in the blood, Cooper says. The variety of signatures indicates that the immune system has developed multiple ways of dealing with infectious organisms.
“It highlights the beauty of the immune response and its finesse in dealing with different pathogens,” Cooper says.
http://www.usnews.com/science/articles/2010/08/19/gene-profiles-may-predict-tb-prognosis.html

MALARIA: Malaria Parasites Use Unique Metabolic Pathway

NIH Grantees Discover Malaria Parasites Use Unique Metabolic Pathway, Uncovering Potential New Drug Targets
A newly described metabolic pathway used by malaria-causing parasites may help them survive inside human blood cells. The finding, by researchers supported by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, clarifies the picture of parasite metabolism and provides clues to potential weak points in the pathway that might be attacked with drugs. In most living things, several major chemical processes involved in converting food to energy are linked through a cyclic hub called the tricarboxylic acid cycle, also known as the Krebs cycle. NIAID grantee Manuel Llinás, Ph.D., of Princeton University, and his colleagues discovered that Plasmodium falciparum, the deadliest malaria parasite, uses a double-branched metabolic pathway instead of the classical loop. According to Dr. Llinás, this specific branched pathway has not been detected previously in any other organism.
The malaria parasite appears to use one branch primarily to generate the molecule acetyl-CoA, which it needs to thrive within a host organism. This branch may represent particularly vulnerable spots to target with anti-malarial drugs, says Dr. Llinás. The detailed description of the chemical steps involved in the metabolic pathway of the malaria parasite also could aid future malaria drug development efforts because the pathway sits at the heart of several other biological processes currently being investigated as drug targets. So far, it is clear that the newly discovered pathway operates while the parasites are growing inside human blood cells. Next, the scientists will explore whether the parasite uses the same pathway during other stages of its lifecycle in humans and in mosquitoes, and how exactly it is involved in the metabolic control of the cell.
Nature. DOI: 10.1038/nature09301 (2010).
http://www.niaid.nih.gov/news/newsreleases/2010/Pages/malariaMetabolism.aspx

BIOTERRORISM: smallpox vaccine

Two U.S. universities are studying whether one strong injection of a new smallpox vaccine would offer greater protection than two doses of a weaker treatment provided over a period of four weeks, St. Louis University in Missouri announced this week (see GSN, May 18).
"Because of continuing concern about biowarfare and bioterrorism throughout the world, the United States government is working to improve its ability to protect its citizens in the event of a possible bioterrorist attack with the smallpox virus," chief researcher Sharon Frey, an infectious diseases professor at the Saint Louis University School of Medicine, said in a press release.
"If there is a smallpox outbreak, getting people vaccinated as quickly as possible will be a matter of urgency. Giving a single injection of a much stronger vaccine could allow us to protect people much more quickly, when time is of the essence," she added. "We're comparing two doses of the same vaccine to see if a single injection of the high-dose vaccine stimulates the body's defense system against smallpox as well as giving two injections of the lower dose."
The study is funded by the National Institute of Allergy and Infectious Diseases and would involve 90 volunteers at St. Louis University and the University of Iowa. It would use Imvamune, a developmental vaccine produced by Danish biotechnology firm Bavarian Nordic (St. Louis University release, June 30).
http://www.globalsecuritynewswire.org/gsn/nw_20100702_9539.php

TUBERCULOSIS: new form of early test

Thursday, May 27, 2010
By Juan Diasgranados - Doctors hope a new test for tuberculosis will be available soon because it can confirm the presence of the disease in 45 minutes rather than the six weeks required by the current test.
Doctors said they are close to being able to use a new test that will allow them to diagnose cases of drug-resistant tuberculosis in 90 minutes, down from six weeks. Cepheid geneXpert, a new TB test jointly developed by Cepheid and the University of Medicine and Dentistry of New Jersey, allows specimens to be tested with high-tech equipment in health settings and to produce results while patients are still in their doctors' offices.The test, which doctors hope will be approved soon, would lead to earlier diagnosis and earlier treatment for patients. A spokeswoman for the Food and Drug Administration said the test is under review but had no information about when a decision will be made.The current test, sputum microscopy, was developed in 1882 and is outdated. It takes six weeks to obtain results, and in that time, doctors lose track of some patients and others die.The Center for Global Health Policy held a briefing last week to discuss its new publication, "Confronting the Global HIV and Tuberculosis Epidemics." The center is a project of the Infectious Diseases Society of America and the HIV Medicine Association through a grant from the Bill and Melinda Gates Foundation.The new publication highlights projects doctors and researchers have been working on that will soon allow them to test tuberculosis patients and shrink the time it takes to diagnose drug-resistant tuberculosis from six weeks to 90 minutes. New tuberculosis drugs will offer a safer and faster cure for standard and drug-resistant tuberculosis.According to the center's website, HIV and tuberculosis are the world's top two most deadly infectious diseases. In 2008, 2 million people died from HIV/AIDS. Tuberculosis claimed the lives of 1.8 million people.Doctors and professionals at the briefing spoke about the deadly epidemics and new discoveries in science that can dramatically change the routes of these diseases."A lot has been accomplished," said Dr. Anthony Fauci, director of National Institute of Allergy and Infectious Diseases. "But tuberculosis is still a threat, and there's still a lot that needs to be done."Fauci said there is only one vaccine for tuberculosis."The current vaccine right now is not very good ... but I'm staying optimistic that one day soon down the line we will have a more effective vaccine for TB," he said.According to the Center for Global Health Policy, the Bacille Calmette Guerin vaccine is the only vaccine for tuberculosis. The vaccine is effective at preventing the disease in children but not for adults.At the briefing, doctors said patients who are infected with both HIV and tuberculosis usually have a high risk of death. The two diseases work synergistically, speeding up the progression of illness. In 2007, one in four deaths from tuberculosis was HIV related.Speakers echoed the need for new policies and the need to push U.S. officials to make "key decisions" in the next few weeks when the debate over global health spending arises. The center is hoping for more funding to provide more research and diagnostic testing along with opportunities to open treatment centers overseas.Dr. Kenneth Mayer, director of the Brown University AIDS program, emphasized the importance of making people around the world award of these issues."We need to push our government and really think strategically how we use our resources to help this crisis," Mayer said.Mayer ended the briefing by saying, "progress has been made, but more can be done. Tuberculosis is still growing."
http://www.infozine.com/news/stories/op/storiesView/sid/41351/