On Tuesday, highly-anticipated preliminary results from a phase 3 clinical trial of the RTS,S vaccine against malaria found that vaccinated young children had a 56% lower risk of developing the infection. The vaccine’s maker, London’s GlaxoSmithKline (GSK), has been involved with the vaccine since the early 1980s. But its history goes back further to mouse research conducted at New York University (NYU) in the 1960s. Yet, despite a half century of research into malaria vaccines and numerous clinical trials, laboratory models of the disease have changed little — a fact that experts say could be hindering the development of new vaccines.

“The mouse models have not been very predictive,” says Jean Langhorne, an immunopathologist at the MRC National Institute for Medical Research in London. “They’re very good at telling us what vaccines don’t work, but not very good at telling us what vaccines should work.”

When NYU immunologist Ruth Nussenzweig started her hunt for malaria vaccines in the 1960s, mouse models for the disease were brand new. The parasite that causes malaria in humans, Plasmodium falciparum, does not naturally infect mice, so researchers were at a loss for how to study even malaria’s basic immunology. In the 1950s, scientists traveled to the Congo to collect parasites related to malaria from tree-dwelling African thicket rats, and then adapted them to infect mice in the lab. And, thus, scientists developed the mouse model first used for RTS,S: a lab mouse artificially infected with Plasmodium berghei.

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We’ve seen prophylactic use of medicines in the headlines, most recently with the November 2010 news that taking a preventative dose of the HIV drug Truvada cut the risk of infection by 44% among gay and bisexual men. Two studies published yesterday apply the idea of prophylactic drug use to malaria, and suggest that giving young children anti-malarial drugs might outweigh the risk of facing future resistant parasites in malaria-endemic countries.

One study, led by Diadier Diallo of the London School of Hygiene and Tropical Medicine, followed more than 3,000 children in Burkina Faso. It found that those treated with the antimalarial drugs sulphadoxine pyrimethamine and amodiaqune experienced at least 65% fewer malaria episodes than those protected by long-lasting insecticide-treated bed nets alone. The other trial, conducted in Mali by Alassane Dicko from the University of Bamako and his colleagues produced similar results. “Malaria control depends on a combination of strategies,” says Diallo.

Sulphadoxine pyrimethamine and amodiaqune are not the primary antimalarials in use, which makes some experts less worried that prophylactic administration of these particular medicines will result in the explosion of drug-resistant malaria parasites.

“We know there is resistance to both of the components of the drug but they’re still able to deliver this long lasting preventative effect,” says Patrick Kucher, a malaria expert at the US Centers for Disease Control and Prevention.

Christopher Plowe, who studies malaria at the University of Maryland School of Medicine, agrees that this strategy may outweigh the risks. Still, he adds that it’s important that health officials keep an eye out for resistant strains: “To me, if there is a clear evidence of a public health benefit, it may be well worth going from clinical trials to pilot programs with careful monitoring of resistance.”

Image from the CDC

Researchers reported today that the most advanced experimental malaria vaccine developed to date, GlaxoSmithKline’s Mosquirix, provides African children with long-lasting protection against the infectious disease.

In the phase 2 trial, which tracked nearly 900 children in Kenya and Tanzania for 15 months, the risk of infection was cut by about half in those who received the experimental vaccine. The results are comparable with initial findings reported in 2008.

The study authors caution, however, that follow-up trials are still needed to test the efficacy of Mosquirix in children who are malnourished or are HIV-positive, according to Reuters.

With vaccine efficacy hovering at only around 50%, Louis Miller, head of malaria research at the US National Institute of Allergy and Infectious Disease in Bethesda, Maryland, says that a more protective vaccine is still needed. “It’s good, but they can do much better,” he told Nature Medicine.

To increase protection levels against the disease, last April UK-based GlaxoSmithKline announced a partnership with the Dutch biotech Crucell — the manufacturer of another vaccine currently in phase 1 trials in Burkina Faso — to develop a combined vaccine that integrates both companies’ candidate interventions.

Mosquirix is being co-developed by the PATH Malaria Vaccine Initiative, funded in part by the Bill & Melinda Gates Foundation. The vaccine is currently in phase 3 clinical trials in 11 sites in seven countries across sub-Saharan Africa.

For more on the challenges of developing a malaria vaccine, see the Bench to Bedside and Bedside to Bench commentaries from this month’s issue of Nature Medicine.

Image of the malaria-spreading mosquito from the CDC

The World Health Organization (WHO) may be vastly underestimating the number of deaths from malaria in India, according to a report appearing in The Lancet today. Currently, the WHO pegs India’s malaria death rate at 15,000 per year. The authors estimate that the figure is actually thirteen-fold higher, somewhere between 125,000 and 277,000 deaths per year; their best estimate is about 205,000 deaths per year.

The new estimates are based on interviews with family members of more than 120,000 people who died between 2001-2003. Of the 75,000 deaths that occurred before age 70, more than 2,600 were attributed to malaria. Of course, the cause of death was based solely on the judgment of the physicians analyzing the interviews, rather than a clinical test. Many symptoms common to malaria (fever, vomiting, fatigue) can easily be the result of another kind of tropical disease.

Nevertheless, it seems clear that an accurate picture of India’s malaria burden has yet to resolve fully. Part of the problem is that most deaths in the country do not take place in a health care facility, especially in rural areas. Furthermore, in India, the more common malaria parasite is not the widely studied Plasmodium falciparum but the oft-neglected Plasmodium vivax.

Image by The Dream Sky via Flickr Creative Commons

The medication sulfadoxine-pyrimethamine, or “SP”, is currently used to treat malaria in pregnant women in the developing world. It works by disrupting the malaria parasite’s ability to make folic acid, which is a key component of nucleotide synthesis. It’s inexpensive, too, costing 15 cents for a course of treatment as opposed to $1 for a similar course of artemisin-based therapy. This alone should make it an attractive option for widespread use, but for a not-so-slight problem: up until now, research seemed to show that the most common malaria parasite, Plasmodium falciparum, was rapidly becoming resistant to SP.

Now come two papers that challenge that notion. Reporting in the International Journal for Parasitology, researchers from the University of Bamako in Mali working with American and European collaborators suggest that the severity of SP resistance has been overplayed. Although administration of SP does increase the prevalence of SP-resistant genes, it’s possible that SP affects the infectiousness of the malaria parasite to such a degree that the effect of that resistance is negligible.

In the first study, 14 volunteers in Mali who had been previously treated with SP were exposed to the bites of mosquitoes (Anopheles gambiae) uninfected with the malaria parasite. A week after feeding on the participants, the mosquitoes were dissected to look for malaria spores. Out of 928 mosquitoes, only seven had them.

The second article looks closer at the mechanism by which SP affects gametocytes, the sexually reproductive stage of P. falciparum that is transmitted via the gut of mosquitos. They found that SP causes those gametocytes to become deformed, and they don’t mature to the next stage of the parasite’s life cycle.

If the results can be replicated, it could be a strong argument for using SP to treat malaria in infants and children in areas where the drug is effective.

Image: SP-treated Plasmodium falciparum gametocytes from Kone et al.

Currently, the bulk of the scientific community’s firepower is aimed at Plasmodium falciparum, the deadliest of the four known malaria-causing parasites. But researchers are starting to pay closer attention to Plasmodium vivax, which has heretofore lurked in its cousin’s shadow. Both P. falciparum and P. vivax invade liver cells as part of their life cycle, but P. vivax can lie dormant in the liver for much longer periods of time, potentially causing a relapse of malaria years after the initial infection.

Papers on P. vivax malaria frequently carry the word “neglected” in the title — there’s a lack of understanding of just how widespread the parasite is, which would be key to any sort of control or eradication strategy. In a paper published in PLoS Neglected Tropical Diseases, a team of Oxford scientists offers the most up-to-date picture yet of the global burden of P. vivax. Their maps are based on both incidence of malaria cases known to be caused by P. vivax, and also portray the likely dynamics of parasite transmission, which were calculated using factors like climate, proximity to urban centers and parasite-free areas, and the presence or absence of a certain blood genotype— Duffy negative— that is thought to confer resistance specifically against P. vivax malaria.

They found that, in 2009, up to 2.85 billion people had some risk of P. vivax transmission. Previous estimates from 2005 pegged the at-risk population for P. vivax at about 2.59 billion, and for P. falciparum, 2.51 billion. The burden fell overwhelmingly in Central and Southeast Asia, where over 90% of the at-risk population resides. More than half of the at-risk population lives in areas where P. vivax transmission is low or unstable, suggesting that eradication efforts in these areas could have bright prospects. While P. falciparum remains more deadly, the broader range of P. vivax may place a heavier strain on the health of global populations than previously imagined.

Meanwhile, the author of an essay in PLoS Medicine critiques the messianic single-mindedness of malaria eradication campaigns, such as those funded by the Bill and Melinda Gates Foundation. While acknowledging the good faith on the part of these groups, Naman Shah from the University of North Carolina at Chapel Hill writes that the traditional malaria control measures used in eradication efforts may not work in high-transmission zones, which require new tools and a strategy more suited to their varied on-the-ground conditions.

Malaria map courtesy Guerra et al.