SEPTEMBER 30, 2005


Experts warn of looming flu disaster

A single dead bird sets off pandemic alarms.
Canada's readiness called into question

Lab Confirmed Human Cases of Avian Flu as of August 2005 view pdf

Ominous signs are multiplying. Last month, Europe's attention was gripped by the post-mortem of a single dead seagull in the Finnish town of Oulu. And in Russia's Ural mountains, authorities ordered the slaughter of thousands of poultry after making a troubling new finding: the avian flu virus is being spread by migratory birds.

Flu surveillance these days is a strange mix of the familiar and the frightening. On the one hand, there are hopeful signs that this year's batch of influenza vaccine may turn out to be a better match than last year's A/Panama (H3N2)-like strain and that, this time, suppliers will be able to meet demands worldwide. On the other hand, there is growing fear of a pandemic of deadly avian (H5N1) flu that will render all such preparations meaningless.

"I'd be very surprised if we don't see H5N1 in both Europe, and Japan and the Korean Peninsula in the next few weeks," says Dr Henry Niman, developer of the flu monoclonal antibody and founder of US biotechnology company Recombinomics.

Dr Niman says that as migration spreads what he calls "wild bird flu" around the globe, it becomes increasingly likely that these strains, rather than the poultry strains of Thailand and Vietnam, will be the source of a human pandemic that could take millions of lives.

"It's a numbers game. Until now this wild bird flu has been mostly seen in thinly-populated parts of Russia, Kazakhstan and Mongolia," he says. "If we haven't seen human cases it may be because of a lack of opportunity rather than any characteristic of the virus. But it will get plenty of opportunity as it moves into more densely-populated areas like Europe. In fact, it's probably already there."

This year's vaccine mix contains an A/New Caledonia/20/99 (H1N1)-like strain, an A/California/7/2004 (H3N2)-like strain, and a B/Shanghai/361/2002-like strain, or similar equivalents. A/California (H3N2) began to overtake last year's dominant A/Fujian strain in Canada and around the world early this year, and is widely expected to come roaring back this fall. Influenza B strains are also becoming more common, especially in some European countries, while Influenza A (H1N1) strains have remained in the background.

Canada, which leads the world in flu vaccinations per capita, is well stocked with almost 11 million doses of vaccine in public hands — that's enough to permit adding healthy children aged six to 23 months to the list of priority recipients.

The 50-million-dose shortfall in the US that led President Bush to theatrically forego his flu shot last year is unlikely to be repeated. Nonetheless, the Center for Disease Control is taking no chances, delaying vaccination of all but high-risk patients until October 24. One category of people who made it onto the high-priority list at the last minute was Hurricane Katrina survivors. The potential for flu transmission among the displaced is obvious.

But while the world seems reasonably ready to face a normal flu season, it remains woefully ill-prepared to face a catastrophic pandemic of H5N1 avian flu, which some WHO officials now describe as "inevitable". Forty countries have now filed bird-flu response plans with WHO. Unfortunately almost none of them are in the part of the world where H5N1 is endemic.

"There may be some small restrictions imposed in the early days of a pandemic," says WHO's Dick Morris. "But they will fail, because infected people won't yet be showing symptoms."

The world already appears to have had a lucky escape this year when two Thai women were apparently infected by a sick relative. One of the two died. Dr John Oxford, a virologist and instructor at Queen Mary's School of Medicine in London, says the disease appears to have broken down "the final door".

"It sends a cold shiver down the spine," says Dr Oxford. "This is a very important step towards the conclusion that we all wanted to avoid — the spread of this virus from human to human."

If a pandemic begins in the next year, Canada hopes to be able to produce a vaccine in fairly short order. To get a jump on the virus before the exact composition of the strain is known, researchers at the National Microbiology Laboratory in Winnipeg are working on "seed strain" or prototype vaccines.

The plan is to use these as a base from which to customize H5 and H7 flu vaccines for a specific outbreak. The government has contracted with Quebec's ID Biomedical to maintain a production capacity that should allow for vaccination of the whole population within ten months.

It's a good plan that keeps Canada's options open, especially when compared with the slapdash preparations in the US. But it does leave a gap between the initial outbreak and immunization - a gap that Canada's 22.5 million stockpiled doses of Tamiflu aren't going to cover. That's only enough to protect the country's health professionals for about two months. And that's assuming Tamiflu works, which is far from certain.

Even at high doses, Tamiflu has shown little prophylactic efficacy in trials involving mice. An early and aggressive intervention with Tamiflu after an outbreak among tigers at a Thai zoo failed to save a single animal.

That hasn't prevented the growth of a lucrative internet business in Tamiflu. Most sales are going to the US. But there's little doubt that Canadian doctors are writing prescriptions to allow friends and family to build personal stockpiles. The number of Tamiflu prescriptions written in Canada this year more than tripled to 76,000.

Swiss drug maker Roche, the sole manufacturer of Tamiflu, has committed to increase world production eightfold by the end of 2006. New plants are scheduled to open at several locations across the United States. Nonetheless, supply will struggle to keep up with demand.

"We are on a collision course to panic," warns Dr Michael Osterholm, director of the Center for Infectious Disease Research and Policy at the University of Minnesota. "This drug — which has yet to really be demonstrated to have any clinical impact on H5N1 infection — is now going to become an 'I-can't-get-it-therefore-I-must-have-it-right-away' product. The reality is going to come through that there is only so much available."

Virologists say that to protect the general population would require one antiviral dose per person per day for two waves of infection — a tall order for even the richest of nations, and an almost insurmountable challenge for the manufacturer.

But it now seems that an older, cheaper drug may offer some protection against the strain of avian flu recently detected in Russia. Amantadine is an off-patent drug now used mostly for treatment of Parkinson's disease.

Dr Niman says that although the Indochinese strains of H5N1 are clearly amantadine-resistant, wild bird flu does not appear to carry resistant markers. That's good news for Canada, which recently hedged its bets by buying four million doses of the drug.

But Dr Niman cautions that the usefulness of antivirals is so doubtful that the world's best hope remains the aggressive development of a broad range of vaccines, and the capacity to produce a lot of them quickly — in other words, the Canadian approach. But more work also needs to be done on parental strains, he add, to prepare for a pandemic that could now come from almost any quarter.

"For the whole world to be putting all its eggs in one basket, working on vaccines for this one target strain that may or may not be the real threat is an approach that I think is doomed to fail" warns Dr Niman.



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