BioEd Online

The US National Institutes of Health (NIH) last weekend announced preliminary results of tests in people of a vaccine against the H5N1 avian flu virus, 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. Vaccines that work at much lower doses are urgently needed, they say.

The National Institute of Allergy and Infectious Disease (NIAID), based in Bethesda, Maryland, tested four concentrations of vaccine on 452 healthy adults. The drug was made by the pharmaceutical company Sanofi Pasteur's facility in Swiftwater, Pennsylvania,.

Preliminary results from 115 subjects were reported at the weekend by Anthony Fauci, NIAID's director. Two shots at 90 µg of flu antigen each were needed to produce an immune response likely to confer protection - the highest concentration tested. Annual flu vaccines typically use a single shot of 15µg.

"It's good news," said Fauci, "We have a vaccine."

But other scientists are less upbeat. "Needing two doses of 90µg is the worst-case scenario," says James Robertson, principal scientist of the virology division of the UK National Institutes for Biological Standards and Control in Potter's Bar. "You are not going to get very far with that."

The world is not enough

If the entire US vaccine production system, which can produce 180 million seasonal flu vaccines, was devoted entirely to making pandemic vaccine at this concentration, it could make enough for 15 million people: barely 5% of the US population.

The US government plans to stockpile the vaccine to protect first-responders in the immediate aftermath of a pandemic. It has bought 2 million H5N1 vaccines from Sanofi Pasteur, and says it intends to buy 20 million more. But given the test results, these would only protect 330,000 to 3.4 million people, far short of the 20 million US goal.

Len Latevan, a spokesman for Sanofi Pasteur, says the company will double its capacity to produce flu vaccine in the United States and France in three or four years time. But that would not be enough to produce sufficient vaccines unless the dose was 15 µg or less.

Low dose

Critics such as David Fedson, a retired former medical director of Sanofi Pasteur's parent company Aventis Pasteur, argue that the vaccine must be changed to work at much lower doses.

This is difficult, as people have no natural immunity to avian flu. Lower doses can be used for seasonal flu jabs, as people have a natural exposure to such viruses in their daily lives, giving them a low level immune response.

Results from earlier trials suggest that low doses might work in combination with an ingredient called an adjuvant. These are chemicals that seem to irritate the immune system, boosting response.

Fedson has long argued that this is the correct approach, and that the NIH should have tested adjuvants from the outset. But it has not yet done so because regulatory agencies treat adjuvanted vaccines as new products, and so require a lengthy approval process.

Moving forwards

John Treanor, a principal investigator in the vaccine trial at the University of Rochester in New York, says that NIAID will now start tests of three adjuvants. They will also investigate other dose-reducing strategies such as injecting the vaccine into skin or muscle.

The institute will also test the vaccine in children and the elderly, Treanor adds. An immune response in healthy adults does not guarantee that the vaccine will work in these other groups.

In the meantime, experts caution that enthusiasm over early results might do more harm than good. "I'm concerned that news of the success may be mistaken, and may make policy makers and others responsible for pandemic preparedness feel optimistic, and reluctant to speed up urgent pandemic preparedness," says Masato Tashiro, a virologist at the National Institute of Infectious Diseases in Tokyo.