Tests home in on new hope against bird flu

Aus­tralian ex­perts are on the trail of a po­ten­tial new weapon against bird flu. Ju­lia Hinde re­ports

The Weekend Australian - Travel - - Health -

AFLOOD of alarm­ing re­ports de­tail­ing the hor­rors the world could ex­pect in the event of an­other bird flu pan­demic swept the globe in 2005 and 2006.

Prompted by cases in Asian coun­tries, and the world­wide spread of the H5N1 virus by mi­grat­ing birds, the cov­er­age left no one in doubt that a new pan­demic could be dev­as­tat­ing. Fur­ther sober­ing de­tails came with the pub­li­ca­tion by Aus­tralian and some other gov­ern­ments of nec­es­sar­ily dra­co­nian plans that would be avail­able to deal with any se­ri­ous out­break — as well as the stock­pil­ing of mil­lions of doses of un­proven an­tivi­ral drugs.

The re­ports about bird flu have slowed to a trickle. But the threat has not gone away.

Now a group of Aus­tralian re­searchers has pub­lished data that might point the way to an al­ter­na­tive — and po­ten­tially cheaper — way to fight the next ma­jor out­break.

Led by Ian Clark of the Aus­tralian Na­tional Univer­sity (ANU), the re­searchers used gem­fi­brozil, a drug al­ready ap­proved for hu­man use as a choles­terol-low­er­ing med­i­ca­tion, to treat mice in­fected with a po­tent in­fluenza virus.

The team re­ports a dou­bling in sur­vival rates for in­fected mice when they were given a course of gem­fi­brozil, start­ing four days af­ter they be­came in­fected.

Ac­cord­ing to ANU post­doc­toral fel­low Lisa All­eva, who is an au­thor on the pa­per, gem­fi­brozil was cho­sen be­cause as well as hav­ing choles­terol-low­er­ing prop­er­ties, it is known to have anti-in­flam­ma­tory ef­fects and re­duces im­mune sys­tem par­ti­cles called proin­flam­ma­tory cy­tokines’’. Cy­tokines are im­por­tant sig­nalling mol­e­cules in the body which, dur­ing an im­mune re­sponse, sig­nal im­mune cells to travel to the site of an in­fec­tion.

But a num­ber of re­cent stud­ies have re­ported pro­nounced in­creases in proin­flam­ma­tory cy­tokines af­ter in­fec­tion with po­tent in­fluenza viruses. This has led many in the sci­en­tific com­mu­nity to sug­gest the high mor­tal­ity as­so­ci­ated with viruses such as avian flu might in fact be the re­sult of a mas­sive im­mune sys­tem over­re­ac­tion — a so-called cy­tokine storm — which in turn trig­gers fur­ther in­flam­ma­tion, lung dam­age and even death.

Hence, the ANU team, rather than tar­get­ing the virus it­self, set out to tar­get the hy­poth­e­sised im­mune sys­tem over­re­ac­tion with an im­mune-mod­u­lat­ing drug.

We trawled through the lit­er­a­ture be­liev­ing that in­fluenza mor­tal­ity is pri­mar­ily caused by an over-ex­u­ber­ant im­mune re­sponse,’’ ex­plains All­eva. We looked for pre-ex­ist­ing drugs used in hu­man pop­u­la­tions that may have side ef­fects which were an­ti­in­flam­ma­tory.

When we tried gem­fi­brozil, it worked so well, we ran with it.’’

In the pa­per — pub­lished in the jour­nal An­timi­cro­bial Agents and Chemo­ther­apy (2007;51(8):2965-2968 — the re­searchers sug­gest that if this prin­ci­ple trans­lates to pa­tients,

a drug al­ready ap­proved for hu­man use... might be adapted rel­a­tively fast for use against in­fluenza, con­ceiv­ably in­clud­ing hu­man in­fec­tion with a deriva­tive of the avian H5N1 strain’’.

If this turns out to be true, gov­ern­ments across the world might have rea­son to breathe a sigh of re­lief. Cur­rent pan­demic plan­ning has largely in­volved stock­pil­ing the ex­pen­sive an­tivi­ral drugs Tam­i­flu and Re­lenza. Th­ese would al­most cer­tainly have to be ra­tioned to work­ers in crit­i­cal in­dus­tries and other key fig­ures, even in the na­tions that could af­ford them; they would prob­a­bly not be avail­able at all to the bulk of peo­ple in the world’s poor­est coun­tries.

Ex­ist­ing plan­ning also as­sumes that as soon as the pre­cise na­ture of the in­fec­tious agent was known, work would start to de­velop a vac­cine. How­ever, this would take months be­fore it was avail­able, and mass vac­ci­na­tion pro­grams would be a lo­gis­ti­cal chal­lenge.

Ac­cord­ing to All­eva, the ben­e­fits of gem­fi­brozil — if it worked in hu­mans — could be sub­stan­tial.

It’s been used in the hu­man pop­u­la­tion for 20 years, hence there is a very long safety record,’’ she says.

There are generic brands which are off­patent, so they are cheap. They are pro­duced all around the world and are likely to be avail­able where they will be most needed.’’

Ad­di­tion­ally, the team’s data sug­gests that en­hanced sur­vival does not de­pend on giv­ing gem­fi­brozil be­fore the on­set of the ill­ness, or even in the very early days, as is the case with an­tivi­rals.

All­eva says this is im­por­tant be­cause we ap­pre­ci­ate there are early im­mune re­sponses which are pro­tec­tive’’. The time de­lay might be cru­cial in a pan­demic where it’s go­ing to be crazy’’.

She says the ANU team’s work fol­lowed a pa­per by David Fed­son, for­mer di­rec­tor of med­i­cal af­fairs at drug com­pany Aven­tisPas­teur, who pro­posed in­ves­ti­gat­ing a group of widely avail­able choles­terol-low­er­ing drugs, called statins, which ex­hibit anti-in­flam­ma­tory and im­munomod­u­la­tory ef­fects. The ANU team is now ur­gently seek­ing fur­ther fund­ing to take for­ward its gem­fi­brozil re­search. Im­por­tantly, says All­eva, they need to redo their stud­ies us­ing the cur­rently cir­cu­lat­ing H5N1 avian flu virus, rather than the H2N2 virus — the strain that caused the 1957 flu pan­demic — which the team used ini­tially. In Aus­tralia, work with live H5N1 can only be un­der­taken at CSIRO’s Aus­tralian An­i­mal Health Lab­o­ra­tory at Gee­long.

How­ever, ac­cord­ing to All­eva, an ap­pli­ca­tion to the Na­tional Health and Med­i­cal Re­search Coun­cil ( NHMRC) for fund­ing for this was re­cently un­suc­cess­ful.

The team also needs to in­ves­ti­gate whether gem­fi­brozil is act­ing as an anti-in­flam­ma­tory or an an­tivi­ral in this case, or as both.

We are still try­ing to un­der­stand the mech­a­nisms,’’ All­eva says. I think this work needs to be taken for­ward.’’

Oth­ers ap­pear to agree. Stephen Turner, se­nior lec­turer in the De­part­ment of Mi­cro­bi­ol­ogy and Im­munol­ogy at the Univer­sity of Melbourne, be­lieves it is likely that the im­mune re­sponse causes much of the dam­age in path­o­genic in­fluenza’’.

He adds that us­ing anti-in­flam­ma­tory drugs, such as statins, is a rel­a­tively new approach in in­fluenza. It’s a worth­while strat­egy,’’ he sug­gests.

Anne Kelso, di­rec­tor of the Mel­bournebased WHO Col­lab­o­rat­ing Cen­tre for Ref­er­ence and Re­search on In­fluenza, notes there is

a lot of in­ter­est in the idea of a cy­tokine storm caus­ing dam­age in in­fluenza’’.

I would not con­sider it a proven mech­a­nism, but it’s an in­ter­est­ing idea which de­serves fur­ther re­search,’’ she says. She adds the idea of us­ing im­mune-mod­u­lat­ing drugs is in­ter­est­ing.

We need all the tools we can find,’’ she says.

But not all of the re­search would sug­gest Pro­fes­sor Clark’s team is onto a win­ner in try­ing to mod­u­late the body’s im­mune re­sponse to path­o­genic in­fluenza.

A team at the St Jude Chil­dren’s Re­search Hospi­tal in Mem­phis in the US — where Aus­tralia’s No­bel lau­re­ate and in­fluenza re­searcher Peter Do­herty also has a lab — has re­cently ques­tioned the no­tion that the cy­tokine storm is the main cause of death dur­ing H5N1 in­fec­tion.

A team at the hospi­tal, led by in­fluenza ex­pert Robert Web­ster, re­ported in July’s Pro­ceed­ings of the Na­tional Academy of Sci­ences (2007;104(30):12479-12481) that in­hi­bi­tion of the cy­tokine re­sponse did not pro­tect mice from dy­ing when in­fected with an H5N1 in­fluenza virus.

Rather, ac­cord­ing to one of the pa­per’s au­thors, Rachelle Salomon, our find­ings, us­ing mice ge­net­i­cally de­fi­cient in hall­mark pro-in­flam­ma­tory cy­tokines, in­di­cated that un­der th­ese con­di­tions there was no dif­fer­ence in mor­bid­ity and mor­tal­ity (com­pared with nor­mal mice) fol­low­ing in­fec­tion with the most highly path­o­genic H5N1 de­scribed to date’’.

De­spite th­ese neg­a­tive re­sults, and the Mem­phis group’s view that stop­ping the virus from repli­cat­ing is a more promis­ing strat­egy than in­hibit­ing the body’s cy­tokine re­sponse, Salomon adds that the ANU team’s re­sults are very in­ter­est­ing’’.

This is a very im­por­tant area of re­search,’’ she says. None of th­ese stud­ies have defini­tively an­swered what the con­tri­bu­tion of the cy­tokines are to the patho­gen­e­sis of H5N1 and whether anti-in­flam­ma­tory drugs will be pro­tec­tive.

The ef­fects of in­ter­ven­ing in the im­mune re­sponse to highly path­o­genic avian in­fluenza virus are not well un­der­stood.

We def­i­nitely think cy­tokines are im­por­tant. We do en­cour­age more re­search into the con­tri­bu­tion of cy­tokines. There are more ques­tions out there.’’

Pic­ture: Gary Ra­m­age

Ad­van­tage: ANU re­searcher Lisa All­eva says new drugs may prove to be cheaper

Newspapers in English

Newspapers from Australia

© PressReader. All rights reserved.