Malaria fight gets fresh lease of life
Australian research is helping to narrow the hunt for a malaria vaccine. Denise Cullen reports
DECADES of concerted research efforts have barely put a dent in the malaria death rate. The World Health Organisation says this blood-borne disease, transmitted by infected mosquitoes, still kills more than 1 million people worldwide each year — and some studies put the figure as high as 3 million. Another 500 million people become severely ill from malaria infection, suffering the excruciating cycle of fever, headache, chills and vomiting that are characteristic of the disease.
But antimalarial drugs, including quinine and chloroquine, have for many years been dogged by reduced effectiveness as the parasite that causes malaria evolves resistance to them. While newer medicines have become available, these too have found themselves fighting a losing battle against resistance.
Even the newer combination therapies based on artemisinin — a chemical derived from a shrub long used in Chinese medicine — could be threatened by the emergence of drug resistance.
This picture of declining antimalarial drug effectiveness makes clear why a vaccine is so urgently needed, but according to a report by The George Institute for International Health in Sydney, released last month, research activity in this area is less promising than it looks.
There are certainly plenty of ideas in the pipeline: today’s global malaria vaccine portfolio is crowded, with 31 new vaccine candidates in preclinical development and 16 in clinical trials.
The vaccine being developed by GlaxoSmithKline nearly halved severe malaria in 2000 children younger than five in Mozambique, according to the findings of a study published in The Lancet (2005;366:2012-8).
Yet despite this apparent progress, and the infusion of cash from large donors such as the Gates Foundation, the George Institute report noted that ‘‘ this apparently healthy global portfolio is deceptive’’.
It suggested researchers were squandering resources on trials of ineffectual vaccines, the vast majority of which failed in clinical trials, and that they should focus instead on generating ‘‘ better candidates’’ in the first place.
Work by Australian experts is providing one promising lead.
Mick Foley, an associate professor with Melbourne’s La Trobe University, explains that one of the reasons why a vaccine has proved so hard to develop is the malaria parasite’s biological complexity, and its capacity to mutate.
‘‘ If you get infected with malaria, or injected with a vaccine, you might be protected for a little while,’’ Foley says.
‘‘ Then a different strain comes along and you’re not protected.’’
In this way, says Foley, it’s a bit like the ever-changing flu virus, but even more complex.
Helping focus the efforts of vaccine-makers is a growing understanding of how the human body naturally fights malaria.
What Foley and a team of researchers have done is home in on the molecular structure of the malaria parasite and the pathways it uses to penetrate human red blood cells.
Their findings on the interactions between our antibodies — proteins our bodies produce in response to the invasion of foreign substances — and the malaria parasite’s antigens, which coat its surface, hold out more than a glimmer of hope for a vaccine that might work.
According to the World Health Organisation (WHO), malaria is caused by four closelyrelated parasites, the most lethal of which is Plasmodium falciparum. The parasites are transmitted to humans in the saliva of infected mosquitoes.
Humans infected with malarial parasites will show an immune response, specifically the production of antibodies, to proteins found on the surface of the parasite. But, contrary to what you might expect, one bout of malaria doesn’t confer lifelong protection.
‘‘ Because all these parasites are constantly changing their surface, you have antibodies which are supposed to kill them, but they will only kill some — not all — and you will end up getting malaria again,’’ Foley explains.
An African child, for instance, has on average between 1.6 and 5.4 episodes of malaria fever each year, according to WHO.
The malaria parasites do their dirty work by hacking into our red blood cells, using the molecular equivalent of a key, which springs open the ‘‘ lock’’ to the door of the cell.
Once inside, they hijack the functioning of the cell and multiply wildly. What prompts the fevers, chills, pains and other life-threatening symptoms of malaria is these hijacked red blood cells bursting open and spawning the next generation of parasites.
Stopping the parasite from entering red blood cells in the first place would stop the disease in its tracks — but locating the key, and stopping it from working, is a whole new story.
The Melbourne researchers took a closer look at one of the proteins, apical membrane antigen 1 (AMA1), which is found on the surface of malaria parasites. AMA1, says Foley, is essential for the invasion of malarial parasites into human red blood cells: ‘‘ If it can’t get into them, it can’t reproduce and it dies.’’
So researchers took a collection of different laboratory and field strains of Plasmodium falciparum and unravelled the genetic code for their AMA1.
‘‘ We and others found that while many parts of the antigen can change, there are some parts that don’t,’’ says Robin Anders, emeritus professor in the department of biochemistry at La Trobe University.
The parasite needs these bits, called ‘‘ conserved regions’’, to survive.
Because conserved regions can’t be varied, the parasite can’t indulge in its usual quickchange capers.
‘‘ These are the regions to which we’d like to induce an antibody response,’’ says Anders.
In collaboration with colleagues at CSIRO, scientists in Foley’s laboratory have identified a variety of molecules that bind to AMA1 and block the invasion into human red blood cells.
All these molecules bind to the same binding groove, or ‘‘ hot spot’’, on the surface of the malaria protein.
AMA1 is currently undergoing clinical trials as a vaccine for malaria.
‘‘ Sometime in the next year we should hear whether an AMA1 vaccine provides some protection for people living in malarious areas,’’ says Foley.
Despite their optimism, researchers are aware it’s early days yet, and that many hurdles lie ahead.
Anders agreed there had been some poor vaccine candidates taken into field trials.
‘‘ But there are also some exciting candidates,’’ he says.
‘‘ AMA1 is one of them and it is necessary to carry out the clinical trials to determine whether AMA1 and other vaccine candidates can provide protection against most of the P. falciparum strains that are circulating.’’
Molecular-level battle: Robin Anders, left, and Mick Foley are in the forefront of an anti-malaria research team