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New targets in hunt for malaria vax


Multiple studies identify potential new ways to beat disease that affects millions. Paul Biegler reports.


Despite concerted efforts to contain it malaria still takes an appalling toll.
Despite concerted efforts to contain it malaria still takes an appalling toll.
Burrard-Lucas / Getty Images

Mosquitoes are firmly in the crosshairs of scientists this week, with a tranche of articles announcing major advances in the battle against deadly diseases spread by the critters, including malaria, Dengue fever and Zika.

Despite concerted efforts to contain it, including the 2015 Nobel prize-winning research that developed the frontline drug Artemisinin, malaria still takes an appalling toll, mainly in sub-Saharan Africa. The World Health Organisation estimates there were 212 million cases and 439,000 deaths from malaria in 2015, with children under five accounting for 306,000 fatalities.

But there is also worrying news closer to home. Reports this year have detailed a multi-drug resistant strain of “super malaria” in South East Asia, specifically, the Greater Mekong region of southern Vietnam.

Hence the timeliness of two pieces of research, published in the journal Science this week, which identify and exploit key enzymes in the malaria parasite’s life cycle, potentially opening a door to new drug development.

The malaria parasite, plasmodium, is introduced into humans bitten by infected mosquitoes. It multiplies in the liver before being released back into the blood, where it enters, is extruded from, then re-enters red blood cells, key stages in the parasite’s life cycle. Symptoms of the disease range from minor fevers and chills to death from cerebral malaria and organ failure.

A team led by Daniel Goldberg, of the Washington University School of Medicine in Missouri, US, has found two enzymes encoded by the genome of Plasmodium falciparum, the most lethal of the malaria-causing species, are critical to the parasite’s entry and exit from red blood cells.

The function of the enzymes, known as aspartic proteases, had been unknown until the current research, which shows that one, Plasmepsin IX (PMIX), facilitates invasion of the red blood cell, and the second, Plasmepsin X (PMX), is implicated in both ingress and egress.

Enter a class of drug known as aspartic protease inhibitors, already a focus of pharmacological development in the treatment of high blood pressure and HIV. The team found several classes of these drugs had anti-malarial potency in a mouse model.

In closely related research, a team led by Paco Pino of the Department of Microbiology and Molecular Medicine at the University of Geneva, Switzerland, showed that the aspartic protease inhibitor 49c killed 99.9% of P. falciparum parasites in a cell culture in 48 hours.

But the team was also able to show the compound’s effectiveness in vivo. Mice infested with the rodent-preferring malaria species Plasmodium berghei had clear blood films after four days of treatment.

Going further, Pino’s team demonstrated that 49c has efficacy across various stages of the parasite’s complex life cycle, not only preventing it leaving liver cells to infect the blood, but hindering mosquito infection by preventing the parasite’s gametes colonising the mosquito’s midgut.

In an accompanying commentary, Justin Boddey from Australia’s Walter and Eliza Hall Institute writes that, “The discovery of PMIX and PMX as master regulators of egress and invasion opens the door to new biology and drug discovery in the ongoing fight against malaria.”

The Melbourne-based researcher warned, however, that, “It will be imperative to understand whether malaria parasites adapt to aspartyl protease inhibitors by amplifying or mutating their PMIX or PMX genes and whether targeting multiple plasmepsins can help overcome this.”

Prevention, though, is well known to be better than cure, something that is no doubt a source of chagrin to many scientists researching malaria vaccines. Only one vaccine, Mosquirix, has reached Phase 3 trials and even then with limited efficacy: 39% over the course of a four year trial.

At least part of the challenge lies in the complexity of the plasmodium life cycle, and the diversity of its genome, leading to multiple potential targets against which to mount vaccine-induced antibodies.

Research detailed in Proceedings of the National Academy of Sciences this week takes an important step in addressing that challenge.

A team led by Leyla Bustamante from the Malaria Programme at the Wellcome Trust Sanger Institute, Cambridge, United Kingdom, has used a process called “reverse vaccinology” to identify five antigen targets of P.falciparum that hold promise for vaccine development.

The researchers isolated 29 antigens from the parasite, known to facilitate red cell invasion, the point at which the parasite is most vulnerable to antibody attack.

They then raised rabbit antibody – IgG – to each antigen and tested all 29 against African and Asian strains of falciparum malaria. They found five to be effective in limiting red cell invasion, with some combinations being superior.

The team then examined a cohort of people from Mali and found the presence of naturally occurring combinations of those antibodies, but not single instances, was protective against febrile malaria.

Using a technique called video microscopy, the researchers then showed that different antibodies working together (being “synergistic”) were attacking the red cell invasion at distinct steps, leading them to conclude that “next-generation malaria vaccines will need to target multiple antigens, preferably in combinations that induce synergistic responses.”

And a paper published in Nature Communications this week will be welcomed by any science enthusiasts keen to transition from passive observer to active participant in the fight against mosquito-borne disease.

Research led by John Palmer at the Centre d’Estudis Avançats de Blanes, in Spain, has found a smartphone app called Mosquito Alert has comparable effectiveness to a more labour-intensive, and expensive way of monitoring the spread of disease-carrying mozzies.

The team focused on the tiger mosquito, whose cargo of pestilence includes 22 arboviruses, among them Dengue, Zika and the less well known Chikungunya virus. Over the past thirty years the tiger mosquito has spread from the Western Pacific and South East Asia to Europe Africa and the Americas. It was first reported in Spain in 2004.

The traditional way of monitoring mosquito spread is to detect the eggs in water containers known as ovitraps, a technique that relies on trained scientists. The app, however, enlists citizen scientists to call in mosquito sightings, preferably with a photo which is then reviewed by entomologists.

The researchers compared 5000 Mosquito Alert reports with data from 1500 ovitraps across Spain collected between 2014-2015 and found the app performed admirably, concluding that, “citizen science costs less than traditional methods and provides early warning information and human–mosquito encounter probabilities of comparable quality with larger geographical coverage.”

If you happen to be in an infested area, and so inclined, you too can take part – Mosquito Alert is available free for Android and iOS.

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Paul Biegler is a philosopher, physician and Adjunct Research Fellow in Bioethics at Monash University. He received the 2012 Australasian Association of Philosophy Media Prize and his book The Ethical Treatment of Depression (MIT Press 2011) won the Australian Museum Eureka Prize for Research in Ethics.
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