* Bird flu three steps from potentially lethal human strain
* Threat fuels debate over pre-pandemic vaccination
* Science stacks up but idea hard to sell in austerity era
By Kate Kelland and Ben Hirschler
LONDON, July 11 (Reuters) - Culls of hundreds of thousands of chickens, turkeys and ducks to stem bird flu outbreaks rarely make international headlines these days, but they are a worryingly common event as the deadly virus continues its march across the globe.
As scientists delve deeper into H5N1 avian influenza, they have discovered it is only three steps away from mutating into a potentially lethal human pandemic form, adding new urgency to a debate over how to protect humans.
In 2009, during the H1N1 swine flu pandemic, vaccines only became available months after the virus had spread around the world - and even then there was only enough for one in five of the world's 7 billion people.
Next time, experts say, we need another approach.
Talk is centred on "pre-pandemic vaccination" - immunising people years in advance against a flu pandemic that has yet to happen, and may never come, rather than rushing to create vaccines once a new pandemic starts.
"Even if you change manufacturing to higher-yield technologies, you're still going to be chasing the virus," David Salisbury, Britain's director of immunisation, who chaired a global group on vaccines during the H1N1 flu pandemic, said in an interview.
"The bottom line is that current production will never solve the problem. You'll always get at least one, if not two waves of infection before you can get sufficient quantities of vaccine to do anything significant ... If you want to get ahead of it, you've got to have a different strategy."
Scientists and vaccine makers have already produced pre-pandemic H5N1 vaccines and some are stockpiled by wealthy countries like the United States and European governments for front-line medical staff.
Pharmaceutical companies have also invested heavily in ramping up flu vaccine production capacity - partly due to the H1N1 pandemic and partly in response to World Health Organisation (WHO) calls for better preparedness for next time.
Annual flu vaccination programmes have also gained impetus in recent years, with the result that seasonal campaigns are well-established in many developed and some developing countries and structures therefore exist to immunise lots of people.
So why not bring all those elements together and run a pre-pandemic vaccination campaign to prime potential victims with a preparatory shot?
IMMUNITY COULD LIMIT DEATH TOLL
This could boost the immunity of millions of people to a pandemic bird flu strain that might otherwise kill tens of millions. The 1918-19 Spanish flu outbreak killed an estimated 20 million to 50 million people worldwide.
The last flu pandemic was widely viewed as a mild strain and the WHO, along with drugmakers and governments, was criticised in some quarters for scare-mongering over the threat.
Yet a fresh analysis last month showed it may still have killed as many as 580,000 people, far more than the 18,500 cited as the number of laboratory-confirmed deaths.
A mutated human pandemic form of H5N1 bird flu could be a whole different ball game. H5N1 does not yet pass easily from birds to people but when it does it kills around 60 percent of those infected.
The virus continues to spread among birds in Asia, with China reporting the latest cull of more than 150,000 chickens in the far western region of Xinjiang just last week. As of July 6, the WHO counts 607 cases of people infected by bird flu globally. Of those, 358 died, a fatality rate of 59 percent.
Faced with that risk, Rino Rappuoli, a scientist at the Switzerland's Novartis - one of the several drugmakers including Sanofi and GlaxoSmithkline that have H5N1 vaccines approved for use - made the case for pre-pandemic vaccination in a paper in the journal Science last month.
"Given that licensed H5N1 vaccines are available, we have the option to vaccinate individuals at greatest risk or to vaccinate more broadly, including the populations of individual countries, of continents, or even the entire globe," he wrote.
"It is just a question of evaluating the cost, the logistics and the risk of implementing such a vaccination campaign. It is not impossible."
A global campaign might take three to five years, he said.
Pharmaceutical companies would certainly like a new opportunity to put their flu vaccine manufacturing capacity to better use - potentially triggering a re-run of the $7 billion-plus sales windfall seen in 2009-10.
During that pandemic, industry capacity was ramped up to around 900 million doses, but to sustain this drug companies need a regular flow of business and demand for flu vaccines is only around 480 million doses right now.
The scientific case for pre-pandemic vaccination looks sound, given studies led by Karl Nicholson of Britain's Leicester University showing that even people immunised with a different flu strain still had "immune memory" and some protection from a new virus many years later.
"It's called the priming effect," said Nikki Shindo, a medical officer in the department of pandemic and epidemic diseases at the WHO in Geneva.
In theory, at least, she said pre-pandemic vaccination was "a great idea".
Shindo and other experts believe priming the immune system has the potential to make the illness suffered by those who catch pandemic flu far less severe, cutting the number of hospital admissions, reducing death rates and possibly also slowing onward transmission of the virus.
Getting the idea off the drawing-board, however, is another matter and there appears to be limited appetite in government circles right now for costly insurance-policy type vaccination.
That is perhaps understandable. Spending cash on a health emergency that hasn't yet happened is politically tricky, particularly in an age of austerity.
"I don't think the world would be ready to pay for something like that now. The time is just not economically right," said Mark Clark, a pharmaceuticals industry analyst at Deutsche Bank.
As well as paying to protect against an as yet non-existent disease, governments might also have an uphill battle persuading the public to have a shot that could potentially cause mild fever, injection site pain and the occasional allergic reaction.
"All of these strategies are worth thinking about," said Salisbury, who like Clark thinks governments are a long way yet from making a decision.
"It's got loads of common sense about it and it's got loads of science behind it," he added. "But it is a big step." (Editing by Philippa Fletcher)