Ground shifts in malaria fight: Alan Cowman

from Helen Francombe, The Australian:

This week there was international excitement over news that researchers had discovered how the malaria parasite resists the killing power of chloroquine, once the key drug in the war against the microbe.

Because of work by an Australian National University team, there's hope the previously powerful drug can be redesigned to beat resistant strains of malaria, one of humankind's most formidable foes.

The seemingly inevitable pattern of developing resistance to whatever drugs are aimed its way has made malaria the devastating disease it is, killing up to three million people worldwide every year.

It seems the present linchpin of anti-malarial treatment, artemesinin, a Chinese herbal remedy derived from the wormwood tree, may be headed for the same fate.

Great strides have been made against malaria during the past five years, with a two-pronged approach that involves the use of bed nets impregnated with the insecticide permethrin to prevent mosquito bites and treatment with combinations of drugs based on artemisinin. However, a recent report in The New England Journal of Medicine hit a sombre note.

Artemisinin-resistant strains have emerged along the Thai-Cambodia border, historically the starting point of resistant parasites that then spread to other malaria-prone areas of the world.

This is particularly bad news because if artemisinin becomes ineffective medical science will have nearly run out of options for drug treatment, warns Alan Cowman, a molecular parasitologist with Melbourne's Walter and Eliza Hall Institute.

Despite the bad news, there is progress along the path to a viable malaria vaccine. The decades-long search for an effective vaccine is starting to bear fruit. Together with collaborators from across the globe, Cowman reported earlier this year on the first genetically engineered malaria vaccine in the journal Proceedings of the National Academy of Science. If the vaccine makes it to the clinic it could break the unrelenting progress of the parasite through its victim's body.

The disease begins with a single bite from an infected mosquito. Thousands of Plasmodium parasites are injected into the bloodstream and after about a half hour are settled in the liver.

There they make thousands of copies of themselves and, after another five days or so, they burst out of the liver cells and invade red blood cells, where they do the most damage, says Cowman.
When they're in the blood stage of their life cycle, the parasites cause severe anaemia by not only eating up a huge chunk of oxygen-ferrying haemoglobin but also by destroying large numbers of red blood cells when they burst out to find new cells on which to feed. More dangerous, though, is the way the parasite makes red blood cells sticky so they clog the smallest blood vessels.

This can cause damage to many organs in the body, but it can be fatal when it affects the brain, as in cerebral malaria.

Plasmodium falciparum is the deadliest of the four common types of malaria parasite and the target of Cowman and his colleagues. Supported by a $17 million grant from the Bill and Melinda Gates Foundation's Malaria Vaccine Initiative, they've developed a falciparum parasite missing two genes essential for its growth in the liver. ``So the parasite is still alive. It invades the liver and then dies, so we have a potential live vaccine,'' Cowman says.

The result is that the immune system gets enough of a taste of the parasite to develop an immune response to it. Then, if the body is exposed to falciparum malaria parasites through mosquito bites, the immune system is primed to destroy them. According to Cowman, the vaccine is 100 per cent effective in mice made slightly human by virtue of having human liver cells. The next step will be a trial in 12 human volunteers, planned for February next year in the US, using the engineered parasites manufactured at the Walter and Eliza Hall Institute. If all goes well, larger trials will follow.

This is remarkable progress. While scientists have been working hard for more than 30 years to develop a malaria vaccine, it has proven one of the most elusive goals of medical research. In May this year a phase III trial of the frontrunner in the vaccine race -- called RTS,S -- started in Tanzania and researchers plan to include up to 16,000 children from across sub-Saharan Africa.

If RTS,S passes muster, its deployment in Africa could prevent tens of thousands of infant and childhood deaths, as in some parts of Africa 10 per cent to 20 per cent of children under age five die from malaria, says Richard Carter, an expert in malaria immunity from the University of Edinburgh. Probably one million to three million people die from malaria every year and hundreds of millions suffer its ill effects.

``Relative to its significance in global health there really has, until recently, been a very small amount of money spent on malaria,'' says Carter, who visited Sydney recently. However, a lot of charity money has become available in the past 10 years, he says.

But a lack of money hasn't been the only thing standing in the way of a malaria vaccine. Unfortunately, the malaria parasite is extremely well adapted to its human host, says Robin Anders, a protein chemist at La Trobe University. It cleverly changes itself, so just when the immune system has it tagged for destruction it changes into a new, unrecognisable form. The influenza virus also uses this strategy, the reason new formulations of flu vaccine are developed every year. But Anders says the malaria parasite tosses up far greater numbers of these antigenic forms.

``Progress has been slower than we had hoped,'' says Anders, who has been part of the malaria vaccine effort from way back, having advised the World Health Organisation when the first malaria vaccine trials were carried out in the late 1980s.

Technical advances in the early 80s led to great optimism about the likelihood of developing a malaria vaccine without too much trouble, he says. But because the parasite is a much more complicated creature than a bacteria or virus, it has been difficult to work out which part, or sub-unit, of the parasite causes an immune response in people.

Still, Anders and his colleagues have developed a sub-unit vaccine that has shown promise in early trials. They have funding for further development from the Malaria Vaccine Initiative.
Michael Good, head of the Queensland Institute of Medical Research, is trying a different approach: inoculation with small numbers of dead malaria parasites.

``We give only 1000 or so dead parasites. In fact, the fewer we give the better the response. For comparison, there are between five (million) and 50 million parasites in 10 millilitres of blood from an infected person,'' he says.

This tiny dose seems to be enough to prompt a strong immune response, as all of the mice in Good's early experiments were completely protected from malaria infections for their entire lives. He is applying for a licence to go ahead with human trials.

An effective vaccine could have dramatic effects in humanitarian and economic terms in developing countries, particularly in Africa, Good says, pointing to the Malaria Vaccine Technology Roadmap. Developed in 2006 with input from more than 100 organisations worldwide and co-ordinated by the MVI, the roadmap has set goals of achieving a 50 per cent effective vaccine that lasts more than one year by 2015 and, by 2025, an 80 per cent effective vaccine that lasts for four years.

Good is confident this is achievable, although he is much less certain about the Gates Foundation's ambition of total eradication of malaria: ``It is always good to aim forthe stars, but we need to take it one step at a time.''

Unlocking the mystery of how the malaria parasite develops drug resistance, combined with novel vaccine strategies, must certainly be more than one step in the right direction.

http://www.theaustralian.com.au/news/health-science/ground-shifts-in-malaria-fight-alan-cowman/story-e6frg8y6-1225779304317