BioEd Online

Bird flu has wreaked havoc on much of Asia in recent years. Millions of birds have been culled to prevent the spread of the disease, but by the middle of 2005, some 50 people had died from bird flu. Given fears that the virus will mutate to a more contagious form, experts continue to warn of the potential for a full-blown pandemic, much like the 1918 flu epidemic. Here news@nature.com keeps tabs on the situation from day to day.

For a full timeline reaching back to 1890, and monthly summaries of events, click here.

The United States today bolstered its stockpile of countermeasures against an H5N1 influenza pandemic. Health secretary Mike Leavitt announced that they have bought $100 million worth of pandemic influenza vaccine from Sanofi Pasteur, and 84,300 treatment courses of the anti-viral drug zanamivir (Relenza) from GlaxoSmithKline. They already have a small stockpile of the antiviral drug Tamiflu.

US officials have said they intend to buy enough vaccine to protect 20 million people, and enough drugs to treat 20 million more. It's not clear how many people $100 million worth of vaccine will protect at high doses - earlier this summer, the H5N1 generated a protective immune response in trials with healthy adult volunteers, but only at very high doses (see 'Bird flu vaccine not up to scratch'). US officials are also scrambling to test lower-dose versions of the vaccine.

In the United States, top scientists plan to meet with heads of the finance industry and White House officials in New York on 23 September for a symposium on "Preparing the Financial Industry for a Pandemic".

President Georges Bush says he will create "a new international partnership on avian and pandemic influenza". Addressing a high-level UN meeting in New York, Bush gave no details of the proposed coalition, but said that it would "require countries that face an outbreak to immediately share information and provide samples to the World Health Organization". As Nature revealed last May, affected countries are failing, or refusing, to share their human samples with the WHO, the UN agency responsible for coordinating international pandemic flu efforts (see 'Refusal to share' leaves agency struggling to monitor bird flu').

Delegates at the European Influenza Conference largely spent the day pledging money.

Canada reported that it has put aside C$34 million for supporting development of prototype pandemic vaccines.

And Germany reported a fund of €24 million for development of a type of vaccine known as low-antigen, adjuvented, full-virus vaccine. (The inclusion of an adjuvant promotes a stronger immune reaction to the antigen itself and is a favoured strategy in Europe. It should help to protect more people with a limited amount of antigen.)

The European Health Commission also announced a €1 billion fund, which had been approved in early summer, to reimburse member states for expenditure on 'unexpected threats'. The details of who would get paid for what remained unclear to many delegates. But the Commission's general intention was clear: that member states who pledge to buy stockpiles of antivirals, or invest in pandemic vaccine preparedness, will get some level of financial support.

Klaus Stöhr, head of WHO's Influenza team, warned that preparedness for flu pandemics must also prepare for the distant future. Pandemics come along every few decades. So the best thing would be to develop a single vaccine to protect against all pandemics - along with normal seasonal flu viruses. But there is no money available for the long-term research that would be required for the development of such a vaccine.

Stöhr proposed that European governments should turn as a group to an agency like the World Health Organisation to negotiate a single deal with companies for flu vaccines. Such bulk deals should lower the price, said Stöhr, and the money saved could be put into a special fund supporting the development of a general vaccine. There was no public response to this suggestion, which seems to have been discussed in the numerous behind-doors meetings running throughout this congress.

Scientists at the European Influenza Conference report that the H5N1 virus has become much more virulent and pathogenic since began circulating in 1997. Several mutations are probably implicated, they add - not just changes to the genes encoding the surface haemagluttinin (H) and neuraminidase (N) proteins that give the flu strains their code names, but also the genes encoding internal proteins such as polymerase enzymes. These enzymes control the virus's growth rate; mutations, it seems, can allow growth to far outstrip that which a person's immune system can handle.

The researchers also present improved animal models for flu infections in cats and ferrets, showing how H5N1 can be easily transmitted between animals, infecting the brain and gut as well as the lungs. So far, the more than 100 human cases of H5N1 have not been in a form easily transmitted between people. What molecular changes would be required to make human-to-human transmission as easily as cat-to-cat? That's a crucial question in anticipating a pandemic, and scientists are not close to understanding it.

In gloomy discussions with policy-makers and health workers, scientists broach the contentious subject of who should be first in line for treatment with the scarce supplies of vaccines and drugs such as Tamiflu. The unhappy bottom-line message, as voiced by Claude Hannoun, former head of the Influenza National Reference Centre in France, is: don't expect any vaccine to be available during the first pandemic wave. Governments still need to beef up their national stockpiles of Tamiflu.

It will take 4 to 12 months after identifying the pandemic strain for the first batch of vaccines to appear, by which time the virus will have circled the globe. Scientists have some strategies that could eventually shave a few weeks off different parts of the process, but long-term alternatives to avoid such a delay are not being seriously investigated, they complain. Meanwhile, one company is offering meeting delegates free flu jabs to protect against this year's regular flu strain. Not that they will help against a bird flu pandemic.

The Second European Influenza Conference opens in Malta. Bird flu experts confirm that the virus is still sweeping its way across the globe, and still threatens to cause a major and deadly human pandemic for which we remain insufficiently prepared.

Conference organizer Albert Osterhaus notes a small recent turning point, however: some governments are at last beginning to take the issue seriously - almost 50 countries now have provided draft pandemic preparedness plans.

Indonesian authorities have reported what may be the country's fourth victim of avian flu. The 37-year old woman from the country's capital Jakarta died on 10 September. The health minister has said that an initial test was positive for the highly pathogenic H5N1 virus. Samples have been sent to a Hong Kong laboratory for confirmation.

The woman was an immigration official, with little contact with poultry, and the source of infection remains unknown. Health authorities aim to track down and test the woman's contacts.

The first deaths from avian flu in Indonesia were reported in July (see 'Bird flu: crossing borders').

Bird flu spreads to another species: it is confirmed in civets (the animal that famously spread SARS to humans) in Vietnam. Bird flu has previously been found in other mammals, including tigers.

The president of the British Veterinary Association says that bird flu is "inevitably" going to arrive in the UK. Various European officials have decided that poultry flocks should be brought indoors to prevent the possible transmission of the H5N1 virus from migratory birds. Others say this is not necessary.

The US National Institutes of Health (NIH) announce preliminary results for a vaccine against H5N1, showing that two large doses should protect adults from infection. But critics point out that the large amounts needed mean the hundreds of millions of doses needed to tackle a pandemic could never be produced.

See "Bird flu vaccine not up to scratch"

Pharmaceutical giant Roche pledges to make three million courses of its anti-viral drug Tamiflu available to the World Health Organization.

A Maine biotechnology company that makes vaccines for poultry diseases is fined US$500,000 for smuggling a chicken flu virus into the US. The company hoped to use the virus sample to develop a vaccine.

See"Maine company falls a-fowl for smuggling bird flu"

Poultry flocks in Russia and Kazakhstan are hit by H5N1. A suspected human case is also investigated. The outbreak hints that the disease is moving towards Europe.

Bird flu moves towards Europe

At the end of a three-day conference in Malaysia, World Health Organization officials announce that $150 million is needed to fight the spread of the disease in people and another $100 million to stop its spread in animals in Asia.

The Philippines, so far the only Asian country unaffected by bird flu, reports its first case in a town north of the capital, Manila, but officials do not confirm whether it is the H5N1 strain.

Indonesia confirms that a man exposed to sick chickens has been infected with a deadly strain of avian flu virus. The man, a farm labourer, shows no symptoms, but his blood carries antibodies against the H5N1 strain.

Bird flu becomes resistant to the low-cost amantadine family of antiviral drugs. Chinese farmers' use of the compound in chickens is blamed, a claim formally denied by Chinese authorities who pledge to investigate the situation.

Rumours of human deaths in China from H5N1 remain unconfirmed, while the virus has killed more than 1,000 migratory birds. Indonesia's government confirms reports of H5N1 infection in pigs.

The WHO reports 97 cases and 53 deaths from bird flu in Vietnam, Cambodia and Thailand since January 2004.

Vietnam reports a total of 60 laboratory-confirmed human cases of H5N1 avian flu since the outbreaks began, with 35 deaths. Thailand confirms a total of 17 infections of which 12 have been fatal, whereas Cambodia has confirms two fatal cases.

15 additional cases of H5N1 infection in Vietnam, and one additional case in Cambodia, are reported.

Bird flu has spread to 10 countries, including the Democratic People's Republic of Korea, and killed around 50 million chickens.

First report of a bird flu case from Cambodia.

A report of probable person to person transmission of bird flu in Vietnam is published (New Engl. J. Med, 352 333-340)

The WHO makes prototype H5N1 vaccine strains available to several institutions and companies, and a range of vaccines is submitted for clinical testing.

13 additional cases of bird flu have occurred in Vietnam since December 2004, 12 of which have proved fatal.

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