Malaria bug an elusive adversary
After 30 years of disappointing results, research into a malaria vaccine is looking more hopeful, writes Lynnette Hoffman
THIRTY years into the worldwide search for a vaccine to fight malaria, the most advanced vaccine candidate to date, known as RTSS, has been found to reduce the chances of malaria infection in children aged 1 to 4 by a mere 35 per cent.
It’s better than nothing, but hardly a miracle cure, says professor Alan Cowman of the Walter and Eliza Hall Institute in Melbourne, which is among the key players in the search for a vaccine to prevent one of the world’s most pervasive diseases.
‘‘ The parasite has the mechanisms to change itself and make itself invisible — it’s a bit like Harry Potter,’’ Cowman says. ‘‘ So making a suitable vaccine has been very complex.’’
Malaria kills at least 1 million people a year, and infects another 500 million, in mostly subSaharan Africa. Every day 3000 children under 5 die as a result.
Although rare in Australia, it’s far from unknown: the National Communicatable Diseases Database records 570 cases of malaria in Australia in 2007 — less than the five-year average of 642. About one-third of the cases in 2007 were in Queensland.
While treatments and countermeasures in Australia are easily accessed, efforts to control the disease in developing countries through means such as drugs and mosquito nets have been hampered by poor infrastructure. It’s difficult to get the necessary products into remote areas, a problem exacerbated by increasing resistance to drugs and insecticides.
But despite the slow going, researchers say there is reason for hope.
Earlier this year Queensland Institute of Medical Research student Alberto PinzonCharry was awarded a $25,000 grant by GlaxoSmithKline, the same pharmaceutical company behind the RTSS vaccine.
The vaccine that Pinzon-Charry and his QIMR colleagues are developing differs from most of the 80-odd others being developed around the globe in a major way.
Malaria is caused by a tiny parasite, called plasmodium, which is transmitted by the bites of infected mosquitos. The parasites multiply in the liver, before infecting the red blood cells which they destroy.
The World Health Organisation lists symptoms of infection as including fever, headache, and vomiting. These symptoms usually appear between 10 and 15 days after the mosquito bite.
Without treatment the disease can be lifethreatening, and while preventive drugs are available, the parasites have developed resistance to these in many parts of the world.
In their quest for a vaccine, the Queensland researchers are using the dead whole parasite itself to elicit an immune response, rather than a synthesised version that uses selected proteins.
Most effective vaccines work by exposing the healthy person to a small amount of the infectious agent so that the body mounts an immune response. But plasmodium is extremely complicated, and sneakier and more elusive than most.
Malaria parasites go through three different stages of replication and alter their genetic profile at each one. So one set of genes is expressed in the liver, while an entirely different set is expressed in the blood, for example.
‘‘ It’s like a moving target. The natural evolution of the parasite means it’s able to escape whatever we try to do to it,’’ PinzonCharry says.
On top of that, the parasite has some 5500 genes or proteins, so creating a vaccine that targets only one or two or a handful has a high chance of failure, he says.
‘‘ Synthetic vaccines only target a few components of the parasite, so the chances that it will work are low. By using a whole parasite that has been killed we’re giving the immune system more to work with,’’ PinzonCharry says.
Natural immunity to the malaria parasite is slow to develop and incomplete — even after years of continuous exposure. Adults living in malaria-endemic areas who are successfully treated, leave, and return, are often rapidly reinfected.
‘‘ The immunity that we achieve is mostly short-lived. We don’t know how to achieve long-standing immunity to a moving target — we don’t even know if that is achievable,’’ Pinzon-Charry says.
The first stage of clinical trials are expected to begin within 12 to 18 months, but no doubt there will be more hurdles to come.
Safety is one issue: to make the vaccine, the parasite is grown in the test tube using blood from a universal donor and then purified and injected into recipients. But it has yet to be tested in humans, and raises questions: what are the risks of giving blood-derived products to people who are healthy? Could the vaccine produce adverse immune response against normal red blood cells?
There are also logistical issues in distributing vaccine around a continent such as Africa — high costs, the need to keep it refrigerated, and access to the most remote areas.
But as the search for a vaccine slowly progresses, other Australian research is inching us closer to newer medications which are needed in the meantime, says University of Melbourne professor Geoff McFadden, a botanist at the forefront of some of that research.
‘‘ The malaria problem is getting worse. A vaccine is the ultimate solution, but it has got a long way to go, and millions of people are dying in the meantime — so we also really need to be expanding our drug capability,’’ McFadden says.
The best way to combat resistance is have at least 10 different drugs in the available arsenal that can be rotated or used in different combinations in different regions, so that any emerging resistance can’t establish itself.
‘‘ The original resistance to our best drug — chloroquine — spread worldwide before we responded, and the drug now has virtually no use,’’ he says.
Back in 1996 scientists discovered that some 500 of the genes in the malaria parasite were actually the same genes found in plant chloroplasts. It’s likely that plasmodium began as a microscopic plant hundreds of millions of years ago, and then somehow evolved into a parasite, McFadden says.
That discovery is the basis of McFadden’s research over the last decade which is looking to convert non-toxic herbicides, originally made for the agricultural industry, into antimalarial drugs. If it works, McFadden says using herbicides would address one of the biggest challenges to treating malaria: cost effectiveness, which is a particularly important issue given that malaria disproportionately affects the developing world.
‘‘ Herbicides have the advantage of being cheap to manufacture. It costs about $50 a tonne and you only need a couple grams per hectare to kill all the plants, so it’s extremely potent,’’ McFadden says.
That’s important because while effective anti-malarials do exist, they are so expensive to make that they would never work in Africa.
So far the herbicides have been found to reduce malaria in mice, and a trial in northern Thailand last year offered hope that it will work in people too. Researchers took infected blood out of people, and treated the blood samples with the herbicides. What they found was that the parasites died, just like they did in the lab.
Again though, there is still a considerable way to go — not least to ensure that these herbicides would not harm a living patient. McFadden says they are still adjusting the potency before the compound will be ready for clinical trials.
‘‘ The herbicide approach is one of a number of useful angles to try. Like the others, it can’t guarantee avoiding resistance, but it does have an advantage that we know how the compounds work and what strategies plants came up with to develop resistance already,’’ he says.
‘‘ To get 10 useable drugs we may need to start with as many as 100 good leads.’’
Long haul: Alberto Pinzon-Charry is trying a new approach in the hunt for a malaria vaccine.