Malaria bug an elu­sive ad­ver­sary

Af­ter 30 years of dis­ap­point­ing re­sults, re­search into a malaria vac­cine is look­ing more hope­ful, writes Lyn­nette Hoff­man

The Weekend Australian - Travel - - Health -

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.’’

Pic­ture: Lyn­don Mechielsen­later

Long haul: Al­berto Pin­zon-Charry is try­ing a new approach in the hunt for a malaria vac­cine.

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