Scientists Describe Breakthrough in Anti-Malarial Precurser

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Scientists from Amyris published in the journal Nature the details of a major breakthrough in the field of synthetic biology that allows for the production of a key precursor to Artemisinin, the key ingredient in the world’s most effective and preferred drug in combating malaria. Earlier today, pharmaceutical company Sanofi announced the launch of large-scale industrial production of Artemisinin utilizing Amyris designed strains.

“Yesterday, a group of scientists led by Amyris detailed how we engineered simple baker’s yeast strains to produce unprecedented concentrations of the precursor to the anti-malarial drug ingredient. Today, Amyris scientists celebrate Sanofi’s successful launch of the industrial production of the world’s first semi-synthetic Artemisinin utilizing Amyris designed strains,” said John Melo, President & Chief Executive Officer of Amyris.

“Sanofi’s commercial launch of this key precursor to life-saving drugs produced with our technology underscores not only the success of Amyris’s synthetic biology platform at scale but also the positive impact this technology can have on our planet,” Melo concluded.

Malaria is a preventable disease that affects over a quarter of a billion people and claims the lives of 650,000 people annually, mostly children under the age of five in Africa. Artemisinin, sourced from the wormwood plant, Artemisia annua, has been used for centuries in treating malaria but its availability, cost and quality have been highly volatile.

Working with a number of partners, and with generous support from the Bill & Melinda Gates Foundation via OneWorld Health (now PATH’s Drug Development Program), Amyris developed technology to convert plant-sugars into Artemisinic Acid, a late stage precursor to the anti-malarial drug ingredient, Artemisinin. The details of this breakthrough process, as well as an alternative process for converting Artemisinic Acid into Artemisinin, can be found in the online publication of the scientific journal Nature.

In 2008, as part of this non-profit project, Amyris made available its Artemisinic Acid-producing yeast strains to Sanofi, via OneWorld Health, on a royalty-free basis. As separately announced by Sanofi earlier today, this technology is now being used at large-scale to produce Artemisinin, which will be combined in pill form with another anti-malarial in what is called Artemisinin-based Combination Therapy (ACT). Sanofi has indicated it plans to produce enough semi-synthetic Artemisinin for up to 150 million ACT treatments by 2014 and will ensure its distribution under the “no profit, no loss” principle.

“Amyris technology will alleviate drug manufacturers’ dependency on erratic supply of plant-derived Artemisinin and reduce costs to malaria patients. This non-profit project is at the core of Amyris’s values and culture, born from a passion to make a positive impact in the world through science,” said Jack Newman, Amyris co-founder and Chief Scientific Officer.

Source: Amyris

Cancer Drugs May Help in Preventing Malaria

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In the fight against malaria, cancer drugs are far from being considered a useful tool. But new research reveals that liver cells, which are first infected by Plasmodium parasites after their transmission by mosquito bite, actually behave in similar ways to cancer cells. The work also shows that with the help of cancer drugs, the liver can become a hostile environment for the malaria parasite. This exciting new development is published in this month’s issue of the journal Cell Reports.

Humans get malaria by bites from mosquitoes that carry Plasmodium parasites, the most deadly of which is P. falciparum. In malaria research, mouse malaria parasites are frequently used because, like human parasites, they have a “liver phase,” in which the parasite first multiplies in the liver and then breaks out into the blood stream to cause disease.

“We knew the malaria parasite goes to the liver, infects liver cells and replicates within them, but we didn’t know how it forces the liver cell into submission on a molecular level,” says Alexis Kaushansky, lead author and postdoctoral scientist at Seattle BioMed, describing this key stage to the parasite’s infectious abilities as a black box.

Kaushansky’s background is in cancer biology, so she decided to draw on her strengths to better understand how liver cells were responding to the malaria parasites when she joined the laboratory of Stefan Kappe, professor and director of the malaria program at Seattle BioMed.

One of the challenges to studying the liver phase of malaria is the sheer paucity of infected cells. The liver is a large organ, and the parasites only infect a few cells – so isolating these cells to study them is extremely difficult, even in mice. As a graduate student, Kaushansky had used systems biology tools to study cancer signaling, and with collaborators Albert Ye and Gavin MacBeath at Harvard Medical School, worked to develop a protein array technology that enabled her to get a large number of read-outs from the few cells she could isolate. Though the technology had been developed in a cancer lab, she eagerly applied it to her work on malaria.

The study yielded a surprising result: many of the molecular changes that malaria parasites cause in infected liver cells are strikingly similar to changes that happen when normal cells transform into cancer cells. But since a liver cell infected with malaria dies when the parasite leaves, there is no characteristic tumor like in liver cancer.

In particular, the malaria parasite dramatically lowers the activity of p53, a classic “tumor-suppressor” in infected cells. This was exciting, since p53 is thoroughly studied in the cancer field, and many cancer drugs are specifically targeted to increase its activity.

Kaushansky and Kappe administered the small molecule Nutlin-3, originally developed as an anti-cancer compound, to mice infected with liver-stage malaria. The cancer drug dramatically reduced malaria infection in the liver, killing 80-90% of the parasite-infected cells.

Using cancer drugs to prevent malaria potentially addresses a key economic challenge in drug creation. Since a vast majority of people who are afflicted with malaria live on less than two dollars a day, developing new drugs, each of which can cost upwards of a billion dollars, can be daunting to pharmaceutical companies who are trying to satisfy shareholders. However, if a drug that has been developed to treat cancer can also be used to prevent malaria, much of the development cost need only to be paid a single time.

Another enticing aspect of using cancer drugs to prevent malaria is that it could avoid the development of drug resistant parasites. All antimalarial drugs currently available for clinical use target the malaria parasite directly, and do so at the peril of a few parasites escaping treatment and rapidly evolving resistance that renders the drugs ineffective. Malaria parasites are even beginning to show signs of resistance to artemisinin, one of the most powerful and affordable malaria drugs currently used in combination therapy. Since the cancer drugs target the non-dividing liver cell rather than the rapidly dividing malaria parasite, there is less opportunity for mutation – and mutation is what causes drug resistance. For this reason, Kaushansky and Kappe hope their work will provide new opportunities to prevent malaria infection without the occurrence of resistance.

“This is the beginning of a new, exciting research area and much work is needed to bring this to application, including finding liver cell-targeted drug combinations that completely prevent malaria infection,” Kappe says. “However, it demonstrates already that new ideas to fight malaria can come from surprising directions, and we must think and work beyond the confines of our study area to come upon the next great discovery.”

Source: Seattle BioMed

Mobile Technology Used to Fight Malaria Drug Counterfeiting

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African Social Enterprise mPedigree Networks has been running a program in Nigeria and Ghana that allows consumers to verify the authenticity of anti-malaria drugs by using mobile phone SMS technology. With the new service, patients taking a range of medication and send a free text message to get an instant response as to whether the medications are genuine.

Counterfeit medicines often contain the wrong quantity of active pharmaceutical ingredients, which can result in illness or death. The system assigns a code that is revealed by scratching off a coating on the drugs’ packaging. This code can be text messaged by the consumer or medical professional to a free SMS (short message service) number to verify the authenticity of the drug.

If the drug packaging contains a counterfeit code, the consumer will receive a message alerting them that the pack may be a fake, as well as a phone number to report the incident. Pharmaceutical safety regulators in Ghana and Nigeria are working to ensure that the concerns of users are promptly addressed.

“Counterfeit pharmaceuticals are a big problem for developing nations, particularly in Africa. It is important that we developed an African solution to an African problem, using the resources and technologies that are widely available and easy to implement,” said Bright Simons, founder, mPedigree Network. “It’s absolutely imperative that people can trust the authenticity of the drugs they are consuming, and this system will give them an easy and effective way of doing so.”

“Over the years, we have invested a huge amount of time and money in developing drugs which will protect the health of people around the world,” said Dr. Joseph Ikemefuna Odumodu, chief executive, May & Baker Nigeria, and president, West African Pharmaceutical Manufacturers Association. “It’s in both our and our customers’ interest that they receive the full benefit of that investment. This system will safeguard both of us now and in the future.”

HP is providing the hosting infrastructure for the service, as well as the security and integrity systems, through its data centers in Frankfurt, Germany. mPedigree Network is providing the business process interfaces that allow pharmaceutical companies to code their products for the system and to monitor use of genuine and counterfeit drugs.

The service, which was endorsed by the West African Health Organization, is expected to be available for other medications and in more countries in the near future. All GSM mobile network operators in Ghana and Nigeria are signatories to the scheme.

“Technology plays a critical role in solving many serious health problems around the world,” said Gabriele Zedlmayer, vice president, Office of Global Social Innovation, HP. “While Nigeria and Ghana are the starting points for this program, we are working to create a scalable infrastructure to be used by other regions where counterfeit medicine is a growing issue.”

In November 2010, mPedigree won the start-up category of the Global Security Challenge in London, becoming the first organisation in the Southern Hemisphere to win the award according to the organizers, and in February 2011, mPedigree won the 2011 Netexplorateur Grand Prix at UNESCO in Paris, for combating fake medicine in Africa through texting.

Sources: HP Press Release (12-10-10); Wikipedia (http://en.wikipedia.org/wiki/Mpedigree)
More information: mPedigree; BBC

Cholesterol Drug Lovastatin Might Help Treat Serious Malaria Cases

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Each year, an estimated 500,000 children in sub-Saharan Africa develop the most serious form of malaria, so-called cerebral malaria. Experts say many of those who do not die from this parasitic infection go on, years later, to develop memory problems and learning difficulties.

Now, researchers say, a study on mice may indicate that  these malaria-induced cognitive impairments could be averted with a commonly used cholesterol-lowering drug lovastatin (Mevacor).

In a mouse model, an international research team has discovered that a lovastatin prevents the late cognitive problems seen in approximately 120,000 children throughout sub-Saharan Africa who survive cerebral malaria, which causes inflammation of brain and spinal tissue. In the study, researchers from the U.S. and Brazil treated a group of mice infected with the disease, using the standard anti-malarial drug, chloroquine. Half of the animals also received lovastatin, according to study leader Guy Zimmerman, a researcher at the University of Utah School of Medicine in Salt Lake City.

“The mice that got the anti-malarial drug and the lovastatin had a dramatically, significantly reduced incidence of the late brain dysfunction,” Zimmerman said.

Lovastatin is part of a family of drugs that reduces the body’s inflammatory response to infection. Generated by the immune system, inflammation is a normal response to disease. But occasionally, the body mounts an aggressive inflammatory response that attacks the body’s own tissue. Zimmerman says cognitive problems can mean a lifetime of challenges for children who’ve survived cerebral malaria.

“Trying to learn, if indeed they do have access to schools. Trying to do that while they are still mired in poverty while they are still at risk for AIDS. And if you begin to think about what that could do to their long-term intellectual capacity and their ability to function in their local societies, it’s staggering,” Zimmerman said.

He recommends lovastatin be added to treatments for malaria as well as for sepsis, a systemic blood infection commonly known as blood poisoning that sickens and threatens the lives of more people worldwide than cerebral malaria. Zimmerman has asked government drug regulators to speed their review process, but says he’s not optimistic that the prerequisite human trials will be easy to conduct in far-flung regions of Africa, where malaria is prevalent.

Source: VOA News

Malaria Programs at Risk Due to Funding Cuts

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Funding for programs to control malaria and provide universal treatment for the mosquito-borne disease is falling short of international goals, according to the World Health Organization. In its annual report, the WHO also warns that the latest drugs could soon become ineffective against some deadly malarial parasites.

Ami Diabate, has brought her three children to a rural clinic to get the latest anti-malarial drugs.

The aid agency Médecins Sans Frontières – or Doctors Without Borders – is rolling out the pilot program across Mali. Results are encouraging – a 65-percent drop in infections a week after distribution.

Diabate said she has noticed an immediate difference.

“My children used to have fevers regularly, she said, but since they started taking this medicine, they haven’t run a temperature.”

Malaria kills an estimated 660,000 people every year. Over the past decade, advances in prevention and treatment have cut the death rate by 30 percent.

The World Health Organization warns, however, that funding increases over the past two years have slowed significantly – putting such progress at risk.

Simon Wright is head of child survival at the aid agency, Save the Children.

“The financial crisis means that a lot of governments – not all by any means – but a lot of governments are tailing off in their aid budgets. And so where we were seeing growth we’re not seeing growth any more. But also there’s a factor of maybe donors changing their interests,” said Wright.

In 2011, international donors made $2.3 billion available to fight malaria – less than half the $5.1 billion that the WHO says is needed annually.

The money goes toward some simple tools, said Professor Sir Brian Greenwood of the London School of Hygiene and Tropical Medicine.

“One of those is the humble bed-net, which people have been using for hundreds of years. But the relatively new advance has been in treating the nets with insecticide. Now, the insecticide is actually incorporated into the material,” he said.

The number of insecticide-impregnated nets delivered to sub-Saharan Africa fell from 145 million in 2010 to 66 million in 2012. Indoor spraying programs also have leveled off.

Greenwood said the greatest concern is the growing resistance of the malarial parasite to the latest medicines known as artemisinins.

“We do have now quite clear evidence that there is resistance to the artemisinins, particularly in Cambodia, but probably in the neighboring countries. Fortunately not yet in Africa, but it would be a disaster if those parasites got loose in Africa, and our main treatment was failing again, like it did with chloroquin,” he said.

Until an effective malaria vaccine is developed and made available globally, researchers say it is vital that donors continue to fund prevention and treatment programs that have made such progress until now.

By Henry Ridgwell
Source: VOA News

Whole-plant Artemisia May Curtail Malaria Drug Resistance

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Artemisia Malaria Red Blood Cells

Artemisia superimposed on a slide of malaria infected red blood cells. A University of Massachusetts research team reports a promising new, low-cost combined therapy for treating the most deadly form of malaria that offers a much higher chance of outwitting the parasite than current modes. (Image courtesy of University of Massachusetts Amherst.)

Malaria affects millions of people in the developing world each year, and fighting the disease can be difficult, because the  mosquito-borne parasite Plasmodium falciparum, which causes the deadliest form of malaria, has developed resistance to every anti-malaria drug.

Molecular parasitologist Stephen Rich at the University of Massachusetts Amherst is leading a research team that has found a promising new low-cost combined therapy with a much higher chance of outwitting P. falciparum than current modes. He and plant biochemist Pamela Weathers at the Worcester Polytechnic Institute (WPI), with research physician Doug Golenbock at the UMass Medical School, also in Worcester, have designed an approach for treating malaria based on a new use of Artemisia annua, a plant employed for thousands of years in Asia to treat fever.

“The emergence of resistant parasites has repeatedly curtailed the lifespan of each drug that is developed and deployed,” says UMass Amherst graduate student and lead author Mostafa Elfawal. Rich, an expert in the malaria parasite and how it evolves, adds, “We no sooner get the upper hand than the parasite mutates to become drug resistant again. This cycle of resistance to anti-malarial drugs is one of the great health problems facing the world today. We’re hoping that our approach may provide an inexpensive, locally grown and processed option for fighting malaria in the developing world.”

Currently the most effective malaria treatment uses purified extracts from the Artemisia plant as part of an Artemisinin Combined Therapy (ACT) regime with other drugs such as doxycycline and/or chloroquine, a prescription far too costly for wide use in the developing world. Also, because Artemisia yields low levels of pure artemisinin, there is a persistent worldwide shortage, they add.

The teams’s thesis, first proposed by Weathers of WPI, is that locally grown and dried leaves of the whole plant, rich in hundreds of phytochemicals not contained in the purified drug, might be effective against disease at the same time limiting post-production steps, perhaps substantially reducing treatment cost. She says, “Whole-plant Artemisia has hundreds of compounds, some of them not even known yet. These may outsmart the parasites by delivering a more complex drug than the purified form.”

Rich adds, “The plant may be its own complex combination therapy. Because of the combination of parasite-killing substances normally present in the plant (artemisinin and flavonoids), a synergism among these constituent compounds might render whole plant consumption as a form of artemisinin-based combination therapy, or what we’re calling a ‘pACT,’ for plant Artemisinin Combination Therapy.”

Rich’s group conducted experiments in rodents to explore whether feeding them the whole plant was effective. They found that animals treated with low-dose whole-plant Artemisia showed significantly lower parasite loads than those treated with much higher doses of the purified artemisinin drug or placebo.

Further, in their most recent experiments in a rodent malaria model, Elfawal and colleagues confirmed Weathers’ earlier results showing that animals fed dry, whole-plant Artemisia had about 40 times more of the effective compound in their bloodstream than mice fed a corresponding amount of the purified drug. This is eight times the minimum concentration required to kill P. falciparum. In dose-response experiments, treatment with whole-plant Artemisia was just as effective at reducing parasitemia as the purified form for the first 72 hours, and faster reduction of symptoms thereafter compared to other groups.

These results, if they translate to humans with further research, could solve two problems with the current drug strategy, Rich says. First, parasites may be less able to evolve resistance to the whole plant because the makeup is far more complex. Second, it could drastically reduce the high cost associated with malaria treatment by allowing for low cost, locally sustainable production of whole plant therapy.

“It’s a local agriculture solution to a global health problem,” says Rich. Preliminary findings from dose-response experiments suggest that whole plant therapy would require a far smaller dose of dried plant than the corresponding amount of purified artemisinin, perhaps as much as a five-fold increased potency for the whole plant.

This work was funded by UMass Medical School’s Center for Clinical and Translational Science. Findings appear in the current issue of the journal PLOS ONE.

Source: University of Massachusetts Amherst

WHO Report – Funding and Support for Anti-Malaria Programs Slows

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During the past decade, a concerted effort by endemic countries, donors and global malaria partners led to strengthened malaria control around the world. The scale-up of malaria prevention and control interventions had the greatest impact in countries with high malaria transmission; 58% of the 1.1 million lives saved during this period were in the ten highest burden countries.

However, after a rapid expansion between 2004 and 2009, global funding for malaria prevention and control leveled off between 2010 and 2012, and progress in the delivery of some life-saving commodities has slowed. According to the World malaria report 2012, these developments are signs of a slowdown that could threaten to reverse the remarkable recent gains in the fight against one of the world’s leading infectious killers.

For example, the number of long-lasting insecticidal nets (LLINs) delivered to endemic countries in sub-Saharan Africa dropped from a peak of 145 million in 2010 to an estimated 66 million in 2012. This means that many households will be unable to replace existing bed nets when required, exposing more people to the potentially deadly disease.

The expansion of indoor residual spraying programmes also levelled off, with coverage levels in the WHO African Region staying at 11% of the population at risk (77 million people) between 2010 and 2011.

“During the past eight years, scaled-up malaria control helped us avert over a million deaths. We must maintain this momentum and do our utmost to prevent resurgences,” says Ellen Johnson Sirleaf, President of Liberia and Chair of the African Leaders Malaria Alliance, who held an official launch event for the report in Monrovia, Liberia.

Tracking progress towards 2015 targets

According to the report, 50 countries around the world are on track to reduce their malaria case incidence rates by 75% by 2015 – in line with World Health Assembly and Roll Back Malaria targets. However, these 50 countries only represent 3%, or 7 million, of the malaria cases that were estimated to have occurred in 2000, the benchmark against which progress is measured.

“Global targets for reducing the malaria burden will not be reached unless progress is accelerated in the highest burden countries,” says Dr Robert Newman, Director of the WHO Global Malaria Programme in Geneva. “These countries are in a precarious situation and most of them need urgent financial assistance to procure and distribute life-saving commodities.”

The malaria burden is concentrated in 14 endemic countries, which account for an estimated 80% of malaria deaths. The Democratic Republic of the Congo and Nigeria are the most affected countries in sub-Saharan Africa, while India is the most affected country in South-East Asia.

“The multi-pronged strategy to fight malaria, outlined in the Global Malaria Action Plan, is working. However, in order to prevent a resurgence of malaria in some countries, we urgently need fresh ideas on new financing mechanisms that will reap greater resources for malaria,” says Dr Fatoumata Nafo-Traoré, Executive Director of the Roll Back Malaria Partnership. “We are exploring many options – financial transaction taxes, airline ticket taxes together with UNITAID, and a “malaria bond”, among others.”

Major funding gap

The World malaria report 2012 indicates that international funding for malaria appears to have reached a plateau well below the level required to reach the health-related Millennium Development Goals and other internationally-agreed global malaria targets.

An estimated US$ 5.1 billion is needed every year between 2011 and 2020 to achieve universal access to malaria interventions in the 99 countries with on-going malaria transmission. While many countries have increased domestic financing for malaria control, the total available global funding remained at 2.3 billion in 2011 – less than half of what is needed.

This means that millions of people living in highly endemic areas continue to lack access to effective malaria prevention, diagnostic testing, and treatment. Efforts to prevent the emergence and spread of parasite resistance to antimalarial medicines and mosquito resistance to insecticides are also constrained by inadequate funding.

While the plateauing of funding is affecting the scale-up of some interventions, the report documents a major increase in the sales of rapid diagnostics tests (RDTs), from 88 million in 2010 to 155 million in 2011, as well as a substantial improvement in the quality of tests over recent years. Deliveries to countries of artemisinin-based combination therapies, or ACTs, the treatment recommended by the WHO for the treatment of falciparum malaria, also increased substantially, from 181 million in 2010 to 278 million in 2011, largely as a result of increased sales of subsidized ACTs in the private sector.

Weak surveillance systems

Tracking progress is a major challenge in malaria control. At present, malaria surveillance systems detect only one-tenth of the estimated global number of cases. In as many as 41 countries around the world, it is not possible to make a reliable assessment of malaria trends due to incompleteness or inconsistency of reporting over time.

Stronger malaria surveillance systems are urgently needed to enable a timely and effective malaria response in endemic regions, to prevent outbreaks and resurgences and to ensure that interventions are delivered to areas where they are most needed. In April 2012, WHO launched new malaria surveillance manuals, as part of its T3: Test. Treat. Track. initiative.

Source: World Health Organization

New Diagnostic Test for Malaria

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REEAD Malaria Diagnostics

The high sensitivity is achieved by performing the REEAD technology within droplets surrounded by oil. The malaria parasites are distributed in the pico-litre droplet, where they react effectively with the other components of the REEAD technology (Source: Sissel Juul and Birgitta Knudsen).

A new diagnostic test could revolutionize the treatment of malaria, one of the world’s most persistent and deadly diseases, making it possible to diagnose the illness from a single drop of blood or saliva.

The test, developed by researchers at Aarhus University in Denmark, detects very low levels of an enzyme produced by the Plasmodium parasite, the organism that causes malaria. This could allow intervention before an outbreak develops, researchers say. [Read more…]

Phase III Trial of RTS,S Malaria Candidate Vaccine Reduces Malaria by One Third

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Results from a pivotal, large-scale Phase III trial, published online today in the New England Journal of Medicine, show that the RTS,S malaria vaccine candidate can help protect African infants against malaria. When compared to immunization with a control vaccine, infants (aged 6-12 weeks at first vaccination) vaccinated with RTS,S had one-third fewer episodes of both clinical and severe malaria and had similar reactions to the injection. In this trial, RTS,S demonstrated an acceptable safety and tolerability profile.

Eleven African research centres in seven African countries1 are conducting this trial, together with GlaxoSmithKline (GSK) and the PATH Malaria Vaccine Initiative (MVI), with grant funding from the Bill & Melinda Gates Foundation to MVI.

Dr. Salim Abdulla, a principal investigator for the trial from the Ifakara Health Institute, Tanzania, said: “We’ve made significant progress in recent years in our battle against malaria, but the disease still kills 655,000 people a year—mainly children under five in sub-Saharan Africa. An effective malaria vaccine would be a welcome addition to our tool kit, and we’ve been working toward this goal with this RTS,S trial. This study indicates that RTS,S can help to protect young babies against malaria. Importantly, we observed that it provided this protection in addition to the widespread use of bed nets by the trial participants.”

Efficacy
When administered along with standard childhood vaccines,2 the efficacy of RTS,S in infants aged 6 to 12 weeks (at first vaccination) against clinical and severe malaria was 31% and 37%,3 respectively, over 12 months of follow-up after the third vaccine dose.4 Insecticide-treated bed nets were used by 86% of the trial participants, which demonstrated that RTS,S provided protection beyond existing malaria control interventions. The efficacy observed with RTS,S last year in children aged 5-17 months of age against clinical and severe malaria was 56% and 47%, respectively. Follow-up in this Phase III trial will continue and is expected to provide more data for analyses to better understand the different findings between the age categories.

Dr. Abdulla added: “The efficacy is lower than what we saw last year with the older 5-17 month age category, which surprised some of us scientists at the African trial sites. It makes us even more eager to gather and analyze more data from the trial to determine what factors might influence efficacy against malaria and to better understand the potential of RTS,S in our battle against this devastating disease. We were also glad to see that the study indicated that RTS,S could be administered to young infants along with standard childhood vaccines and that side effects were similar to what we would see with those vaccines.”

Safety
There was no increase in overall reporting of serious adverse events5 (SAEs) between the infants vaccinated with the RTS,S malaria vaccine candidate and infants in the control group, which received a comparator vaccine. Side effects primarily included local injection site reactions, which were less frequent following RTS,S vaccinations compared to the DTP-HepB/Hib vaccine. Fever was reported more frequently following RTS,S vaccinations than the control vaccine group (30.6% versus 21.1% of vaccine doses, respectively).

Two new cases of meningitis were reported in the 6-12 week-old infant age category in addition to the 9 reported last year; one in the RTS,S group and one in the control vaccine group. Further analysis revealed a bacterial cause of the meningitis in 7 of the 11 cases.

Sir Andrew Witty, CEO, GSK said: “While the efficacy seen is lower than last year, we believe these results confirm that RTS,S can help provide African babies and young children with meaningful protection against malaria. They take us another important step forward on the journey towards having a new intervention available against this disease, which is a huge burden on the health and economic growth of Africa. We remain convinced that RTS,S has a role to play in tackling malaria and we will continue to work with our partners and other stakeholders to better understand the data and to define how the vaccine could best be used to provide public health benefit to children in malaria endemic areas in Africa.”

David Kaslow, Director of the PATH Malaria Vaccine Initiative, said: “Determining the role of RTS,S in Africa will depend on analyses of additional data. We are now an important step closer to that day. Success in developing malaria vaccines depends on many factors: at the top of the list are partnerships and robust evidence, coupled with an understanding that different combinations of tools to fight malaria will be appropriate in different settings in malaria-endemic countries. My congratulations go out to the team at GSK and to the African research centres for their exemplary conduct of this trial.”

“This is an important scientific milestone and needs more study,” said Bill Gates, co-founder of the Bill & Melinda Gates Foundation. “The efficacy came back lower than we had hoped, but developing a vaccine against a parasite is a very hard thing to do. The trial is continuing and we look forward to getting more data to help determine whether and how to deploy this vaccine.”

The vaccine is being developed in partnership by GSK and MVI, together with prominent African research centres1*. The collaborators are represented on the Clinical Trials Partnership Committee, which oversees the conduct of the trial. An extended team of organisations work on RTS,S, including scientists from across Africa, Europe, and North America. Major funding for clinical development of RTS,S comes from a grant by the Bill & Melinda Gates Foundation to MVI.

Looking ahead
Follow-up in this Phase III trial will continue to provide more data for analyses to better understand the different findings between the age categories. These data and analyses should also provide insights into the vaccine candidate’s efficacy in different malaria parasite transmission settings. More data on the longer-term efficacy of the vaccine during 30 months of follow-up after the third dose, and the impact of a booster dose are expected to be publicly available at the end of 2014.

The data and analyses will inform the regulatory submission strategy and, if the required regulatory approvals are obtained and public health information, including safety and efficacy data from the Phase III programme, is deemed satisfactory, the World Health Organization (WHO) has indicated that a policy recommendation for the RTS,S malaria vaccine candidate is possible as early as 2015, paving the way for decisions by African nations regarding large-scale implementation of the vaccine through their national immunisation programmes. An effective vaccine for use alongside other measures such as bed nets and anti-malarial medicines would represent a decisive advance in malaria control.

GSK and MVI are committed to making this vaccine available to those who need it most, should it be approved and recommended for use. In January 2010, GSK announced that the eventual price of RTS,S (also known as MosquirixTM) will cover the cost of manufacturing the vaccine together with a small return of around 5% that will be reinvested in research and development for second-generation malaria vaccines or vaccines against other neglected tropical diseases.

About RTS,S
RTS,S is a scientific name given to this malaria vaccine candidate6 and represents the composition of this vaccine candidate. RTS,S aims to trigger the immune system to defend against Plasmodium falciparum malaria parasite when it first enters the human host’s bloodstream and/or when the parasite infects liver cells. It is designed to prevent the parasite from infecting, maturing, and multiplying in the liver, after which time the parasite would re-enter the bloodstream and infect red blood cells, leading to disease symptoms. In the Phase III efficacy trial, RTS,S is administered in three doses, one month apart. A booster dose administered 18 months after the third dose is also being studied in the trial.

The vaccine, based on a protein first identified in the laboratory of Drs Ruth and Victor Nussenzweig at New York University, was invented, developed, and manufactured in laboratories at GSK Vaccines in Belgium in the late 1980s and initially tested in US volunteers as part of a collaboration with the US Walter Reed Army Institute of Research.

In 2001, the MVI entered into partnership with GSK to study the vaccine candidate’s ability to protect young children in sub-Saharan Africa. Over time, the partnership expanded to include the 11 African research centres and, in some instances, associated scientific institutions from Europe and the United States.

With more than US$200 million in grant monies from the Bill & Melinda Gates Foundation, MVI contributes financial, scientific, managerial, and field expertise to the development of RTS,S. GSK takes the lead in the overall development of RTS,S and has invested more than $300 million to date and expects to invest more than $200 million before the completion of the project.

About the study
The first complete set of results in children aged 5 to 17 months and combined data for severe malaria in the first 250 cases from those aged 6 weeks to 17 months were published in the New England Journal of Medicine in November 2011. The Phase III trial has been designed in consultation with the appropriate regulatory authorities and the WHO. It is conducted in accordance with the highest international standards for safety, ethics, and clinical practices and is overseen by an independent data safety monitoring committee.

About GSK Vaccines
GlaxoSmithKline Vaccines is active in vaccine research and development. Headquartered in Belgium, GSK Vaccines has 14 manufacturing sites strategically positioned around the globe. Of the 1.1 billion doses of our vaccines we distributed in 2011, over 80% went to developing countries, which include the least developed, low- and middle-income countries.

GlaxoSmithKline – one of the world’s leading research-based pharmaceutical and healthcare companies – is committed to improving the quality of human life by enabling people to do more, feel better and live longer. For further information, please visit www.gsk.com.

The PATH Malaria Vaccine Initiative (MVI) is a global program established at PATH through an initial grant from the Bill & Melinda Gates Foundation. MVI’s mission is to accelerate the development of malaria vaccines and ensure their availability and accessibility in the developing world. MVI’s vision is a world free from malaria. For more information, please visit www.malariavaccine.org.

PATH is an international nonprofit organization that transforms global health through innovation. PATH takes an entrepreneurial approach to developing and delivering high-impact, low-cost solutions, from lifesaving vaccines and devices to collaborative programs with communities. Through its work in more than 70 countries, PATH and its partners empower people to achieve their full potential. For more information, please visit www.path.org.

1  Burkina Faso – Nanoro, Institut de Recherche en Science de la Santé (IRSS) / Centre Muraz
Gabon – Lambaréné Albert Schweitzer Hospital, Medical Research Unit
Ghana – Agogo/Kumasi: School of Medical Sciences, Kwame Nkrumah University of Science and Technology; Kumasi Centre for Collaborative Research, Agogo Presbyterian Hospital
Ghana – Kintampo: Kintampo Health Research Centre, Ghana Health Service
Kenya – Kilifi, KEMRI-Wellcome Trust Research Program
Kenya – Kombewa (Kisumu), KEMRI-Walter Reed Project Kenya Medical Research Institute
Kenya – Siaya (Kisumu), KEMRI-CDC Research and Public Health Collaboration
Malawi – Lilongwe, University of North Carolina Project at the Tidziwe Centre
Mozambique – Manhica, Centro de Investigação em Saúde de Manhiça
Tanzania – Bagamoyo, Ifakara Health Institute
Tanzania – Korogwe, National Institute for Medical Research, Tanzania, Kilimanjaro Christian Medical Centre
2  Standard childhood vaccines used were the combined diphtheria-tetanus-whole-cell-pertussis, hepatitis B, and Haemophilus influenzae type b vaccine (DTPwHepB/Hib) and the oral polio virus vaccine (OPV).
3  Based on According To Protocol (ATP) statistical methodology.
4 Average risk for malaria in the control group was 0.9 clinical episodes per child per year and 2.3% of the children experienced at least one episode of severe malaria.
5  A serious adverse event refers to any medical event that occurs during the course of a clinical trial and that results in death, is life threatening, requires inpatient hospitalization, or results in a persistent or significant disability or incapacity needs, regardless of whether the event is considered by the investigator to be caused by the study vaccination. All SAEs are reported to regulatory authorities.
6  Contains QS-21 Stimulon® adjuvant licensed from Antigenics Inc, a wholly owned subsidiary of Agenus Inc. (NASDAQ: AGEN), MPL and liposomes

Source: Malaria Vaccine Initiative. Reproduced from the Malaria Vaccine Initiative website at www.malariavaccine.org, Nov. 9, 2012