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Catherine Brahic reports on a scientific conundrum with profound implications for developing nations — how to make large supplies of a vaccine against a pandemic flu virus that does not exist yet.

Scientists and policymakers often differ, but they do agree on two points: the inevitability of a flu pandemic, and the need to produce as much vaccine as feasible in the shortest time.

Pandemics are global disease outbreaks that can occur when a microbe infects people for the first time. Disease can spread rapidly around the world because people's immune systems struggle to fight something they have not encountered before.

A flu pandemic would be doubly bad news for developing countries, as they are the least prepared to detect and deal with one emerging and will probably be last in line for any vaccine that can be made.

Vaccines can protect people from infectious diseases. They present our bodies with a 'sneak preview' of a dangerous microbe, allowing our immune systems to prepare defences.

But researchers simply do not have the ingredients needed to make a pandemic flu vaccine ahead of time. "Production cannot start before a pandemic strain of flu emerges," explains Klaus Stöhr, head of the World Health Organization's (WHO) global flu programme.

The missing ingredient

If one of the dozens of bird flu viruses that occasionally infects humans changes, becoming able to spread easily between people, it could spark the next flu pandemic. But until that happens, the pandemic virus does not exist. So what is there to give a sneak preview of? And would it ever be possible to produce enough vaccine to protect everyone at risk?

"We would be guilty of negligence if we just sat on our hands and waited," says John Oxford, a professor of virology at Queen Mary School of Medicine in London, United Kingdom.

Oxford is referring to the H5N1 bird flu virus that first killed a person in 1997 in Hong Kong, resurfacing in Asia in 2003. H5N1 has killed fewer people in the past three years — just over 100 people — than seasonal flu kills every day.

More alarming is that over half those infected have died — and that the virus is so widespread among birds.

Governments and international agencies are preparing for the possibility of H5N1 getting better at infecting people and spreading between them. Even though this could take years, at least 12 companies and 17 governments are developing potential vaccines in 28 different clinical trials.

Gambling on similarity

Researchers are gambling that the pandemic flu virus will at least resemble H5N1, and that a vaccine based on the virus circulating now will provide some protection. Such a pre-pandemic vaccine could buy time during an initial outbreak, while researchers rush to produce a true pandemic vaccine from the new virus.

What a race it would be. Based on 20th century flu pandemics, computer models suggest that within three months of emerging, a pandemic virus could have reached every continent. Within 6–9 months, it could have reached every country.

Yet, according to Stöhr, it will take at least three months from the virus's emergence until full-scale vaccine production can begin. "Over the next nine months, vaccine production would increase until, if everything went well, one billion doses were produced one year after the virus was first identified," he says.

Flu vaccine is traditionally
made in eggs
Credit: Morguefile

Because flu vaccines are made from the virus itself, making a global or even national supply requires first producing large amounts of virus. Traditionally, researchers mass-produce the viral component of vaccines by injecting the virus into chicken eggs, where it replicates within the embryo.

But the method is slow, needs a lot of space and requires a large supply of chicken eggs, usually 1–2 eggs per dose of vaccine — something that could be problematic if H5N1 continues to plague the poultry industry.

A win-win answer?

As a partial solution, the WHO is urging countries to make more seasonal flu vaccine. "The seasonal flu vaccine is underused," says Stöhr, "Yet it is cost effective and cost limiting."

Stöhr points out there will always be the threat of another pandemic, even though it could be years before one emerges. He says boosting production and use of the seasonal flu vaccine would be a "win-win solution" because by the time a pandemic hits, "there would be enough production capacity for pandemic flu vaccine too".

Licensing a vaccine based on one already approved — such as a pandemic flu vaccine modified from the previous year's seasonal flu vaccine — is relatively straightforward. But building more egg-based production plants would mean putting precious funds into a method that most flu experts consider antiquated.

Cell solutions

There could be another, more long-term solution. It involves infecting mammal cells suspended in a liquid with the virus. Cell suspensions take up less room than eggs and have the added advantage of being able to be stored frozen.

Commercially available vaccines against chickenpox, polio and smallpox are produced in this way. Several companies have used the method to develop seasonal flu vaccines, but none has reached the market.

Getting regulatory approval for a vaccine made using a new method takes time. The US Army warns that research and regulatory hurdles mean that cell-based pandemic flu vaccines are "unlikely to be available for commercial use for at least two to three years".

A living delivery system

Seasonal flu vaccines use either an inactivated or weakened form of the flu virus. An alternative way of boosting supplies of a vaccine is to make it from a live virus.

US-based researchers are developing vaccines made from a relatively harmless cold virus, known as an adenovirus, which they have genetically modified to produce a surface protein from H5N1. They hope this would be enough to prime the human immune system.

The advantage of such 'recombinant' vaccines is that they can be injected live, and replicate inside people's bloodstream, triggering a greater immune response. As the adenovirus can be grown in mammal cells, the method avoids the problems of egg-based production.

The researchers, at the University of Pittsburgh and the US Centers for Disease Control, say their vaccines gave mice and chicken a reasonable degree of protection against H5N1. But work is at an early stage, and such vaccines are unlikely to reach the market for several years.

Researchers are also investigating ways of reducing the amount of flu virus needed to make each dose of vaccine, using 'immune enhancing' chemicals called adjuvants. As Stöhr explains, "It wouldn't make sense to put a lot [of virus] into a vaccine if a little would do the same trick."

Who would be vaccinated?

Virtually all of the flu vaccine research is taking place in industrialised nations. Although the WHO is stockpiling antiviral drugs, there has been no official mention of a vaccine stockpile — partly because that would beg the unanswerable question of what to put in it.

Credit: Wikipedia

If a pandemic flu strain emerged in Asia, where H5N1 has been circulating since 2003, then it would arguably be in the rich nations' interests to provide Asian countries with vaccine, in the hope of keeping the virus well away from their own borders. But with such limited capacity to produce vaccine, this doesn't seem likely.

Ben Schwartz, of the US National Vaccine Program Office, said in June 2005 that it could take 4–8 months from identifying a pandemic virus to the United States producing its first vaccine doses. Even then, the country could only make enough to protect 2.5 million new patients each week.

The Australian company CSL says it could make enough vaccine to protect all Australians if each dose used no more than 7.5 micrograms of virus. Yet early research showed that two doses of a vaccine containing twice that amount were only 50 per cent effective.

Faced with insufficient supply chains to protect their own citizens, it is unlikely that any country with a pandemic knocking at its door will be willing to hand over precious vaccine.

Inevitably, countries with weak healthcare systems will be harder hit by a pandemic. And people in poor health will be more vulnerable to the virus. Because of this, says Stöhr, "it is important that developed and developing countries jointly think about equitable vaccine access".

But he hastens to add, "it goes without saying that if things stay as they are, a pandemic vaccine will be in short supply even in the most developed countries".

According to the US Army: "Without international agreements or access to regional stockpiles, distribution of vaccine will disproportionately favour countries with the greatest production capacity."

Anthony Fauci, director of the US National Institute of Allergy and Infectious Diseases, says developing countries must do what they can to start producing their own vaccine.

China, Thailand, and Vietnam are all either testing pre-pandemic vaccine or will start this year. Even Brazil — far from any confirmed H5N1 outbreaks — has joined in. Like China and Thailand, it is opting for the established egg-based production.

Vietnam, meanwhile, is the only developing country attempting cell-based production, and plans to run its first clinical trials this year. According to the US Army, the Vietnamese method is "unconventional" and uses cancer cells.

And Africa? Living alongside poultry is a way of life across the continent and six countries already have the H5N1 virus. Africa is looking very vulnerable indeed.

Launched today: SciDev.Net's BIRD FLU DOSSIER.

Latest news:On the day this article was published, the US Department of Health and Human Services awarded US$1billion to pharmaceutical companies to develop new, cell-based methods for producing flu vaccine. Click here for more information.

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