Malaria fight gets fresh lease of life

Aus­tralian re­search is help­ing to nar­row the hunt for a malaria vac­cine. Denise Cullen re­ports

The Weekend Australian - Travel - - Health -

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.’’

Pic­ture: Chris Crerar

Molec­u­lar-level bat­tle: Robin An­ders, left, and Mick Fo­ley are in the fore­front of an anti-malaria re­search team

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