Bird flu: threat to Australia 'unlikely'

An Australian expert on influenza believes it is unlikely that migratory birds will carry Asia's lethal H5N1 'bird 'flu' strain to Australia.

Dr Alan Hampson, director of the World Health Organisation's Influenza Reference Laboratory in Parkville, Victoria, also downplayed concerns that the virus will become resistant to the front-line flu drugs zanamavir and oseltamavir.

Hampson said the H5N1 strain was so virulent in birds that he doubted infected migratory birds would reach Australia alive, given the normal rigours of migratory flights. "Dead birds don't fly," he said. "The chances are very low, and the poultry industry is well managed.

"It previously dealt very effectively with an outbreak of the highly pathogenic H7 strain of influenza, in a way that prevented it spreading, and with the heightened awareness of the H5N1 threat in the industry, they have increased their level of biosecurity. Any outbreak would be quickly detected and contained."

Hampson said air travel was the most likely means of the virus' entry into Australia in the event an H5N1 strain evolving the capacity for human-to-human infection. Currently, there have been no proven cases of this mode of infection, with all cases probably being due to human contact with infected birds.

Frontline drugs

Commenting on a warning by Hong Kong microbiologist Yi Guan, that misuse of the neuraminidase inhibitor drugs zanamavir (Relenza) and oseltamavir (Tamiflu) could result in the H5N1 strain becoming resistant, Hampson said the two frontline drugs worked by very different mechanisms to earlier drugs like amantidine and rimantidine.

Guan, of the University of Hong Kong, last week warned of the risk of viral resistance after the British medical journal The Lancet published research papers showing that resistance to amantidine and rimantidine had risen by 12 per cent worldwide during the past decade. In some countries, like China, drug resistance exceeded 70 per cent, suggesting that amantidine and rimantidine would no longer be effective in treating or preventing influenza.

Hampson said research had shown that the virus could develop resistance to amantidine and rimantidine relatively easily, and there were reports from China that poultry farmers use the relatively inexpensive drugs to protect their birds, inadvertently applying strong selection pressure for resistance.

The neuraminidase inhibitors were totally different to amantidine and rimantidine in their mode of action, and a Japanese study that had tested children who had taken oseltamavir for influenza had detected only four cases in 2000 where the virus showed a degree of resistance.

Because the drugs target a highly conserved active site in the virus' neuraminidase enzyme, common to all strains of the virus, mutations that confer resistance inevitably reduce the virus' competence to replicate in human cells, so the resistant strains should pose little threat.

Asked about problems developing effective vaccines for the H5N1 strain, Hampson said several vaccines were now moving into clinical trials around the world.

The initial problem had been that the H5N1 virus was so virulent that it killed the embryonated eggs traditionally used to replicate the attenuated virus strains used in vaccines. US researchers had overcome the problem by 'reverse engineering' the virus to reduce its virulence. They used recombinant DNA technology to remove pathogenic segments of the haemagglutinin gene.

But that solution has created a problem of its own: the vaccine requires much larger quantities of the antigen to elicit a protective antibody response, or will require an adjuvant to boost its immunogenicity.

"They're going to have to change the formulation, and they're working to establish an optimal dose," Hampson said. "It will take some time to bed down -- they haven't done a clinical trial yet, so in the event of the pandemic, they may just have to make an informed guess about what will work."

Hampson said that because the attenuated virus is classified as a genetically modified organism, the vaccine will require approval from the Office of the Gene Technology Regulator before it can be used in Australia.

Local vaccine work

Melbourne vaccine manufacturer CSL (ASX:CSL) has been working on a vaccine for some time, but Hampson said its manufacture will probably not begin until late next year.

The major obstacle to producing sufficient quantities of vaccine to counter a pandemic is the necessity to use pathogen-free embryonated eggs to replicate the attenuated virus. Melbourne biotechnology company BioDiem (ASX:BDM) has out-licensed its Russian developed FluVacc technology, which employs a virus strain that can be mass replicated in dog kidney cells.

The 'tame' FluVacc virus was developed by a research team led by internationally renowned influenza researcher Prof Larisa Rudenko, of the Institute of Experimental Medicine in St Petersburg.

BioDiem acquired the commercial rights, and licensed US rights to FluVacc to Merck, which subsequently handed them back. BioDiem has also licensed FluVacc in Europe, to Akzo Nobel subsidiary Nobilon, in the Netherlands. The company is still seeking a north American partner, according to BioDiem's R&D director Dr Peter Hodsman.

Hodsman said BioDiem still has an "ongoing relationship", through Rudenko, with the Centres for Disease Control in Atlanta, Georgia. Rudenko is also a member of several WHO committees monitoring the H5N1 outbreak in south-east Asia.

"The huge advantage FluVacc has over eggs is that vaccine companies have to order their eggs in January, before they're really sure what strains of influenza are going around," Hodsman said. "Once the eggs have been laid and sold, companies can't go back and say they want more -- the whole season is set in stone by January. With our mammalian cell-culture system, we can start later, because we can produce the virus much faster."

The FluVacc virus has been used safely for many years in Russia, with 70 million vaccinations administered," he said. "We know it works, but it really depends on how governments react to any pandemic. In an emergency, we could probably get it up and running very quickly if they waived the regulatory approval process."