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