Bioengineered Antibiotic Could Lead to Improved Malaria Therapy

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A natural antibiotic long known for its power to fight bacteria, viruses and tumors has recently shown strength against malaria, but its extreme toxicity has impeded its use in medicine.

However, a bioengineering breakthrough has opened a new avenue in the global battle against malaria.

Scientists at Oregon State University have engineered several new versions of the antibiotic pactamycin that are up to 30 times less toxic than the parent compound. The new compounds, whose genetic structures were modified in the lab, retain their potency against malaria-causing parasites yet pose fewer risks to patients.

“The results could lead to a new direction in the discovery and development of drugs against malaria and other life-threatening infections caused by protozoa,” said OSU researcher Taifo Mahmud, an author of the study reported in the journal Chemistry & Biology.

The natural form of pactamycin occurs in soil bacteria. It attacks not only protozoa such as the mosquito-borne P. falciparum, which causes malaria, but also bacteria, viruses and tumors. Unfortunately, it attacks healthy cells in mammals, as well. In an effort to capture pactamycin’s benefits while eliminating or minimizing its detriments, OSU researchers modified the genetic structure of the microbe that produces the antibiotic by inactivating or “knocking out” certain genes. They tested the new versions – called “analogues” – on human colorectal cancer cells.

“The results revealed that the new analogues are significantly less toxic than pactamycin,” said Mahmud, a medicinal chemist in the OSU College of Pharmacy.

Mahmud said the OSU study is a promising development in the struggle against malaria, which annually infects 250 million people and kills nearly 1 million worldwide, according to the World Health Organization.

“Although pactamycin was first reported in the 1960s and its various biological activities have been extensively investigated, further development of this compound was hampered by its wide-ranging cytotoxicity,” Mahmud said.

“The study resulted in a number of pactamycin analogues that showed potent antimalarial activity but, in contrast to pactamycin, have reduced cytotoxicity against mammalian cells.”

Source: Oregon State University

New Biomarkers Study Could Lead to Improved Malaria Vaccines

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In the first study of its type in the malaria field, Seattle BioMed has been awarded an $8.9 million grant from the Bill & Melinda Gates Foundation to identify biomarkers that will allow malaria vaccine design based on robust predictors of protective immunity.

According to Ruobing Wang, M.D., Ph.D., the goal of the study is to identify and validate biomarkers that correlate with vaccine-induced protective immunity against malaria infection.

“In order to bring the burden of malaria under control – with the ultimate goal of eradicating the pathogens that cause disease – we know we need a highly efficacious anti-infection vaccine,” she explained. “But, without reliable biomarkers of anti-infection immunity, the development and testing of malaria vaccines is a slow and expensive process.” Biomarkers will be used for prediction and monitoring the vaccine efficacy in clinical trials and to select optimal vaccine candidates for development.

To conduct this research, the company will call upon its areas of expertise and knowledge – vaccine and immunology studies in animal models of malaria, the ability to grow human malaria parasites in mosquitoes for research and clinical studies, and its ability to develop genetically attenuated parasite strains for human trials. It will also begin full-scale trials in its Malaria Clinical Trials Center, and employ its newfound expertise in the area of systems biology.

Seattle BioMed scientists have developed genetically attenuated whole parasite vaccine strains that have proven successful in rodent malaria models and have moved into human studies. “In this new study, we will use genetically attenuated parasite strains as probes to determine whether host correlates of immunity can be identified during vaccination in mice,” explained Seattle BioMed’s Stefan Kappe, Ph.D. “These model vaccines provide an opportunity to discriminate biomarkers associated with complete, long-lasting protection from those associated with partial, short-lived or lack of protection.”

Researchers at Seattle BioMed will then apply the knowledge gained in mouse models to human studies. “Through studies conducted at Seattle BioMed’s Malaria Clinical Trials Center, we’ll evaluate whether biomarkers of protection identified in the rodent models will predict protective immunity in humans,” explained Wang.

Seattle BioMed researchers will employ network analysis of transcriptional responses to predict protection in both mice and humans to determine if they can find universal markers that will allow them to optimize vaccine candidates. According to Alan Aderem, Ph.D., the power of systems biology lies in its capacity to predict the behavior of a biological system.  “If we have the ability to predict whether a vaccine candidate for malaria will work before it goes into large scale clinical trials, we could move away from today’s typical ‘trial and error’ method toward a more powerful predictive approach to vaccine discovery and development,” he said.

Through these integrated studies, Seattle BioMed researchers will deliver a set of candidate immune biomarkers associated with protection against malaria infection that can be used for monitoring vaccine efficacy. “This will facilitate future malaria vaccine trials with the ultimate goal of accelerating the development of a highly effective malaria vaccine that has the potential to save millions of lives,” said Wang.

Wang is leading the study – Seattle BioMed’s first to include the integration of its recently announced systems biology approach to infectious disease research – with a team that includes Seattle BioMed’s Stefan Kappe, Ph.D., and Alan Aderem, Ph.D., along with Patrick Duffy, M.D., of the National Institutes of Health, Jonathan Derry, Ph.D., of Sage Bionetworks, and Xiaowu Liang, Ph.D., of Antigen Discovery Inc. (ADi).

Source: PR Newswire

Fighting Malaria with Mobile Phone Technology in Haiti

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Mobile phone technology is being used to bring life saving information to millions of Haitians.The Red Cross has embarked on a nationwide malaria prevention campaign, sending over 3.5 million SMS messages which include information on how malaria is transmitted, how to recognize the symptoms, treatment options, and simple steps for prevention.“There are nearly four million mobile phone subscribers in Haiti” said Sharon Reader, IFRC Beneficiary Communications delegate. “Mobile technology is a fast, easy and cost-effective way to put life-saving information directly in the hands of the population.”

Read more, via IFRC.

Peace Corps Volunteers Join Malaria Fight with Education and Bed Net Distribution Program

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Peace Corps volunteers are collaborating with host country government agencies, nongovernmental organizations (NGOs), the President’s Malaria Initiative (PMI), and local community members to raise awareness of malaria prevention techniques and help control the disease.

Malaria is an infectious disease caused by a parasite (plasmodium) transmitted from human to human by the bite of infected female Anopheles mosquitoes. Young children, pregnant women, and people living with HIV/AIDS have the highest risk for malaria morbidity and mortality. The World Health Organization states that, in 2008, there were 247 million cases of malaria and nearly one million deaths, mostly among children living in Africa.

Peace Corps volunteers are working to mitigate malaria’s devastating impact. Volunteers play a key role in grassroots education and activities that improve community-based knowledge about malaria transmission and promote behavior changes to reduce the spread of the disease.

In addition to their primary service assignments, all Peace Corps volunteers in Benin and Senegal are encouraged to work in malaria-prevention efforts. This year, volunteers have partnered with host-country agencies and NGOs to distribute over 110,000 mosquito nets.

In Senegal, Peace Corps is delivering bed nets to remote villages and conducting malaria lessons with community members before distribution. Volunteers aim to provide a mosquito net for every bed in areas with high malaria rates and are conducting post-distribution evaluations with local health workers to verify that the nets are being properly used.

Peace Corps volunteers in Benin are working closely with PMI cooperating agencies to facilitate the wholesale purchase of mosquito nets from the private sector to sell at a subsidized price to community health centers and individual families. These nets are often distributed during pre-natal consultations and vaccination campaigns.

African nations are not the only ones that have to deal with malaria. In Ecuador, Peace Corps volunteer Kristen Mallory of Cincinnati, Ohio, has taken a hands-on approach with the Ecuadorian Ministry of Public Health to combat malaria and Dengue Fever. Mallory distributed chemicals that kill mosquito larva in water tanks to rural communities and educated locals about malaria prevention and how to destroy mosquito breeding grounds.

April 25th was World Malaria Day, a unified commemoration of the global effort to provide effective control of malaria around the world.

As Peace Corps approaches its 50th anniversary, its service legacy continues to promote peace and friendship around the world with 7,671 volunteers serving in 76 host countries. Historically, nearly 200,000 Americans have served with the Peace Corps to promote a better understanding between Americans and the people of 139 host countries. Peace Corps Volunteers must be U.S. citizens and at least 18 years of age. Peace Corps service is a 27-month commitment.

Read Peace Corps Response volunteer Kris White’s full account.

Mosquitos Make Proteins to Handle Heat Spike of Hot Blood Meals

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Mosquitoes make proteins to help them handle the stressful spike in body temperature that’s prompted by their hot blood meals, a new study has found.

The mosquito’s eating pattern is inherently risky: Taking a blood meal involves finding warm-blooded hosts, avoiding detection, penetrating tough skin and evading any host immune response, not to mention the slap of a human hand.

Until now, the stress of the hot blood meal itself has been overlooked, researchers say.

Scientists have determined in female mosquitoes that the insects protect themselves from the stress of the change in body temperature during and after a meal by producing heat shock proteins. These proteins protect the integrity of other proteins and enzymes, in turn helping the mosquitoes digest the blood meal and maintain their ability to produce eggs.

Tests in two other types of mosquitoes and in bed bugs showed that these insects undergo a similar response after a blood meal.

“These heat shock proteins are really important in a lot of stress responses. Our own bodies make these proteins when we have a fever,” said David Denlinger, professor of evolution, ecology and organismal biology at Ohio State University and senior author of the study. “It’s one of those things that, in retrospect, seems obvious – that blood meals might cause a stress like that. But it hadn’t been pursued before.”

The research appears this week in the online early edition of the Proceedings of the National Academy of Sciences.

Denlinger and colleagues conducted experiments in the Aedes aegypti mosquito, which is a carrier of yellow fever.

The researchers placed sensors on female mosquitoes and observed that upon taking in a blood meal on a chicken, the insects’ body temperatures increased from 22 to 32 degrees Celsius (71.6 to 89.6 Fahrenheit) within one minute – among the most rapid body temperature increases ever recorded in a cold-blooded animal. After the feeding, their body temperatures decreased to room temperature within a few minutes.

In response to that blood feeding, the mosquitoes’ level of Hsp70 – heat shock protein 70 – increased nearly eightfold within one hour and remained at least twice as high as usual for 12 hours. The increase in these proteins was most pronounced in the midgut area.

Denlinger and colleagues tested potential triggers for this protein increase by injecting the mosquitoes with a saline solution at two temperatures: 37 degrees Celsius (98.6 degrees Fahrenheit) and room temperature. Only the warmer saline generated an increase in Hsp70, suggesting that the elevation in temperature associated with the meal, rather than the subsequent increase in body volume, is what causes the generation of those proteins.

Sometimes, mosquitoes feed on cold-blooded amphibians, which should not cause the same amount of stress. To test that theory, the researchers also gave mosquitoes a feeding opportunity on cooler blood, which failed to generate an increase in heat shock proteins.

And what happens if this protein is not produced? The researchers manipulated the mosquitoes’ RNA to figure that out.

When the scientists knocked down expression of the gene that encodes the heat shock protein, the amount of Hsp70 production was reduced by 75 percent. Under those circumstances, mosquitoes still ate a normal blood meal. But blood protein levels remained elevated for a longer period of time, suggesting that digestion of those proteins was impaired. In addition, egg production decreased by 25 percent when the heat shock protein was suppressed.

Heat shock proteins help maintain the three-dimensional integrity of enzymes and proteins when temperatures rise suddenly, and can target damaged proteins and enzymes for elimination, Denlinger said. “We think that in this case, they are important to maintaining the integrity of some critical enzymes and proteins involved in digestive processes. When we knock out those proteins, it impairs digestion a bit and as a result the mosquitoes don’t lay as many eggs,” he said.

The researchers observed similar body temperature increases and elevations in Hsp70 levels in three other insects: Culex pipiens and Anopheles gambiae, mosquitoes that are carriers of West Nile virus and malaria, respectively, and Cimex lectularius, the bed bug. Though new knowledge about the genetics of these insects, especially the mosquitoes, might someday inform attempts to kill them as a method of disease control, Denlinger said the primary contribution of this research is better understanding of how mosquitoes protect themselves in this novel way.

This work was supported by grants from the National Institutes of Health/National Institute of Allergy and Infectious Diseases and the National Science Foundation.

Co-authors include Joshua Benoit, a former Ohio State graduate student who is now a postdoctoral researcher at Yale University, and Giancarlo Lopez-Martinez, Kevin Patrick, Zachary Phillips and Tyler Krause of Ohio State’s Departments of Entomology and Evolution, Ecology and Organismal Biology. Lopez-Martinez is now at the University of Florida.

Source: Proceedings of the National Academy of Sciences, Ohio State University

NetGuarantee: Financing Speeds Delivery of Mosquito Nets

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NetGuarantee, a new innovative finance facility, announces its first transaction with Zurich in North America, part of the Zurich Financial Services Group, to celebrate World Malaria Day today, April 25. This collaboration will help accelerate access to and advance the delivery of vital malaria prevention tools in Africa by six to 10 months, and shows how core business competencies and best practices can improve efficiencies in global health and save lives.

[Read more…]

Genetically Modified Mosquito “Selfish Gene” Could Helps Stop Spread of Malaria

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Many scientists have played with the idea of creating a genetically modified mosquito that won’t transmit malaria, which kills about 850,000 people a year, and releasing it into the wild. But in the face of the millions of mosquitoes out there that do ferry malaria around, how would the trait spread fast enough to make a difference?

Now, scientists have developed a way to cause a “selfish” gene to spread to more than half of a mosquito population over just a few generations, suggesting a method to quickly and broadly disrupt genes required for carrying malaria.

Read more, via Discover Magazine.

World Malaria Day: April 25, 2011

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National Institutes of Health (NIH) statement on World Malaria Day, by B.F. (Lee) Hall, M.D., Ph.D., and Anthony S. Fauci, M.D., National Institute of Allergy and Infectious Diseases, 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) http://www.rbm.who.int/gmap/gmap.pdf, developed by the Roll Back Malaria (RBM) Partnership, http://www.rollbackmalaria.org/. 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.

Source: NIH

Chemotherapy Drugs Show Promise in Fighting Malaria

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Ahead of World Malaria Day (25 April), EU-funded researchers have discovered that drugs originally designed to inhibit the growth of cancer cells can also kill the parasite that causes malaria. They believe this discovery could open up a new strategy for combating this deadly disease, which, according to World Health Organization statistics, infected around 225 million and killed nearly 800 000 people worldwide in 2009.

Efforts to find a treatment have so far been hampered by the parasite’s ability to quickly develop drug resistance. The research involved four projects funded by the EU (ANTIMAL, BIOMALPAR, MALSIG and EVIMALAR) and was led by laboratories in the UK, France and Switzerland with partners from Belgium, Germany, Denmark, Greece, Spain, Italy, Netherlands, Portugal, and Sweden, along with many developing nations severely affected by malaria.

“This discovery could lead to an effective anti-malaria treatment that would save millions of lives and transform countless others. This demonstrates yet again the added value both of EU-funded research and innovation in general and of collaboration with researchers in developing countries in particular. The ultimate goal is the complete eradication of the global scourge of malaria and collaborative work across many borders is the only way of confronting such global challenges effectively,” said Research, Innovation and Science Commissioner Máire Geoghegan-Quinn.

Cancer drugs to kill malaria parasite

Malaria is caused by a parasite called Plasmodium, which is transmitted via the bites of infected mosquitoes. In the human body, the parasites reproduce in the liver, and then infect and multiply in red blood cells. Joint research led by EU-funded laboratories at the Inserm-EPFL Joint Laboratory, Lausanne, (Switzerland/France), Wellcome Trust Centre for Molecular parasitology, University of Glasgow (Scotland), and Bern University (Switzerland) showed that, in order to proliferate, the malaria parasite depends upon a signalling pathway present in the host’s liver cells and in red blood cells. They demonstrated that the parasite hijacks the kinases (enzymes) that are active in human cells, to serve its own purposes. When the research team used cancer chemotherapy drugs called kinase inhibitors to treat red blood cells infected with malaria , the parasite was stopped in its tracks.

Until now the malaria parasite has managed to avoid control by rapidly developing drug resistance through mutations and hiding from the immune system inside liver and red blood cells in the body of the host, where it proliferates. The discovery that the parasite needs to hijack some enzymes from the cell it lives in opens up a whole new strategy for fighting the disease. Instead of targeting the parasite itself, the idea is to make the host cell environment useless to it, by blocking the kinases in the cell. This strategy deprives the parasite of a major modus operandi for development of drug resistance.

Several kinase-inhibiting chemotherapy drugs are already used clinically in cancer therapy, and many more have already passed phase-I and phase II clinical trials. Even though these drugs have toxic side-effects, they are still being used over extended periods for cancer treatment. In the case of malaria, which would require a shorter treatment period, the problem of toxicity would be less acute. Researchers are proposing therefore that these drugs should be evaluated immediately for anti-malarial properties, drastically reducing the time and cost required to put this new malaria-fighting strategy into practice.

The next steps will include mobilising public and industrial partners to verify the efficacy of kinase inhibitors in malaria patients and to adjust the dose through clinical trials, before the new treatments can be authorised and made available to malaria patients worldwide.

Background

Since 2002, the EU has invested nearly EUR 180 million in malaria research through the EU’s Framework Programmes for Research (FP6, 2002-2006, and FP7, 2007-2013).

The EU also contributes to the European and Developing Countries Clinical Trials Partnership (EDCTP) which aims to accelerate the development of new or improved drugs, vaccines and microbicides against HIV/AIDS, malaria and tuberculosis. Established in 2003, this successful ongoing European and African collaboration focuses on clinical trials as well as capacity building in sub-Saharan Africa. To date, 10 clinical trials on malaria costing EUR 69 million have been financed under EDCTP with EUR 35 million support from the EU.

Source: Europa.eu

Médecins Sans Frontières Calls for Switch from Quinine to Artesunate

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After the revision of World Health Organization (WHO) guidelines yesterday,  international medical humanitarian organization Médecins Sans Frontières (Doctors Without Borders) calls for a drug proven to reduce deaths in children suffering from severe malaria to be immediately rolled out in African countries.

In its new report, entitled “Making the Switch,” Médecins Sans Frontières (MSF) calls on African governments to follow new World Health Organization (WHO) guidelines, and switch from the far less effective quinine to artesunate, which could avert nearly 200,000 deaths each year. MSF also calls on WHO and donors to support governments so this urgent treatment change can happen quickly.

“When children arrive at the clinic with severe malaria, they often are having convulsions, vomiting or at risk of going into shock, and you just want to be able to give them effective treatment quickly,” said Veronique De Clerck, Medical Coordinator for MSF in Uganda. “For decades, quinine has been used in severe malaria, but it can be both difficult to use and dangerous, so it’s time to bid it farewell.  With artesunate, we now have a drug that saves more lives from severe malaria, and is safer, easier and more effective than quinine.”

Quinine has to be given three times a day in a slow intravenous drip that takes four hours, a treatment that is burdensome for both patients and health staff. Artesunate, in contrast, can be given in just four minutes, by giving a patient an intravenous or intramuscular injection.

A landmark clinical trial in late 2010 concluded that the use of artesunate to treat children with severe malaria reduces the risk of death by nearly a quarter.  The study, carried out in nine African countries, found that for every 41 children given artesunate over quinine, one extra life was saved.  Because of the complexities of administering quinine, children in the trial who were assigned to receive quinine were almost four times more likely to die before even receiving treatment.

MSF participated in the trial through its research affiliate Epicentre, with a research site in Uganda. MSF has since changed its own treatment protocols and now plans to work with national health authorities to roll out artesunate in its projects over the coming months.

The evidence is overwhelming, but MSF’s report stresses that change will not happen on its own. While WHO has now issued new guidelines recommending artesunate for treating severe malaria in children in Africa, it needs to also develop a plan to help countries make this switch.  African governments must urgently change their treatment protocols and donors must send a clear signal to countries that they will support the additional cost where needed.  Artesunate is three times more expensive, but the difference in cost of US$31 million each year for a global switch is very little for the nearly 200,000 lives that researchers say could be saved.

“We’ve been here before—when WHO changed its treatment recommendations for simple malaria in 2001 it took years for countries to actually make the switch, and shockingly, in some countries the far inferior drugs are still being used ten years on,” said Dr. Martin De Smet, who coordinates MSF’s malaria work.  “With severe malaria, WHO needs to make sure that the change is much less sluggish, so lives can be saved immediately.  There’s simply no excuse not to make the switch now.”

MSF provided malaria treatment to around one million people in 2010.  Severe malaria kills over 600,000 African children under the age of five annually.  Each year, around eight million simple malaria cases progress to severe malaria, where patients show clinical signs of organ damage, which may involve the brain, lungs, kidneys or blood vessels.

More information: Full MSF Report (PDF)

Source: MSF