The St. Jude investigators warn that although there is excellent influenza vaccine technology available to respond rapidly to an outbreak, the legislative and infrastructure changes needed to translate these advances into public health benefits are extremely slow in coming. Intellectual property laws that limit or slow the incorporation of certain new knowledge into vaccine production add to this problem.
"If an influenza pandemic started tomorrow, we would not be able to head it off with vaccines because the production facilities available to produce them are grossly inadequate," said Robert G. Webster, Ph.D., a member of the Infectious Diseases department and holder of the Rose Marie Thomas Chair at St. Jude. Webster is co-author of the Science article.
In addition to the limited ability to respond to an outbreak with vaccines, the supply of antiviral drugs that might slow a pandemic is in "scandalously short supply," according to the article.
"In the face of a pandemic, the available supplies of antiviral drugs would be used up in days," Webster said. "It would take up to 18 months to make more drugs from scratch. Stockpiling is the only answer."
The warning of a potentially imminent influenza pandemic (worldwide epidemic) is based in part on the occurrence this year of two different outbreaks of avian (bird) flu that jumped to humans, causing fatal infections each time. The sudden occurrence of avian-to-human transmission could indicate that certain flu viruses are evolving quickly enough to pose a serious threat to human health. Such direct avian-to-human influenza virus transmissions were unknown before 1997.
The outbreaks caused by avian flu viruses that jumped to humans this year, designated H5N1 and H7N7, occurred in Hong Kong and the Netherlands, respectively. The H5N1 virus killed a man in Asia, while the H7N7 virus infected 80 people on chicken farms and killed a veterinarian. Influenza viruses are classified according to which type of proteins, called hemagglutinin (H) and neuraminidase (N), appear on the virus' surface. The viruses use the H protein to infect cells in the body, in which many copies of the virus are made; N proteins help the newly made viruses escape from the cells and spread throughout the body.
If either H5N1 or H7N7 had acquired the ability to jump from person to person, the result could have been a pandemic, according to Webster. Moreover, the long time now required to develop and mass produce a vaccine in enough quantity to protect large populations would be a serious vulnerability in any strategy for responding to such an outbreak.
The customary way to make a vaccine against a specific influenza virus is to let viral genes mix inside chicken eggs that include genes from a virus known to be safe to use in humans. Viruses arising from this mixing that are both safe to use in humans and carry hemagglutinin (H) and neuraminidase (N) proteins that trigger immune system responses in humans are used to make vaccines.
"In the event of a pandemic, the process of initially developing a "seed" virus suitable for mass production as a vaccine would be too slow and too dependent on a steady supply of eggs," said Richard Webby, Ph.D., assistant member of the St. Jude Division of Virology and co-author of the Science article. Particularly worrisome is the fact that the highly pathogenic H5 and H7 subtypes of the flu virus kill embryonated chickens eggs.
However, Webster's laboratory demonstrated earlier this year that it is possible to dramatically reduce the overall vaccine development time by using a new technique to develop the seed virus.
Led by Webby, the St. Jude team successfully modified a technique called reverse genetics to develop a seed vaccine against H5Nl. The researchers mixed two genes from H5Nl with six genes from a second virus (A/PR8/34)[HINI]) to produce a seed vaccine virus that was safe in humans but that carried the H and N proteins that stimulated the immune system.
"Although the viruses still have to be grown up in eggs to make vaccines, the initial process of making the seed vaccine is much quicker using reverse genetics," Webby said.
But reverse genetics requires specific populations of animal cells in which to grow the viruses, and there are only a few lines of cells suitable for this process. Most of those cell lines are owned by large pharmaceutical companies rather than academic research laboratories such as St. Jude.
"Laboratories that produce seed vaccines for influenza might need access to cell lines that are privately held," Webby said. "In the event of a pandemic, we'll need international collaboration between government, industry and academia, as occurred successfully in the worldwide response to SARS earlier this year."
"We also need to make sure that we can quickly test vaccines for safety and get them to the public in time to stop a developing pandemic," Webster said. "Fortunately, W.H.O. (World Health Organization) is already establishing guidelines for rapidly determining the safety of vaccines that should help us balance the needs for speed and vaccine safety in the event of a pandemic."
Such an outbreak could be significantly worse than those previously caused by SARS and West Nile virus.
An important factor driving the evolution of influenza viruses is the ongoing mixing of human and lower-animal influenza virus genes inside infected birds and swine kept in close quarters in markets or farms. The animals serve as "mixing bowls" in which influenza viruses swap genes, increasing the chance that some viruses will obtain the ability to spread rapidly among infected humans, according to Webster.
"A major challenge in the control of influenza is the sheer magnitude of the animal reservoirs," Webster said.
Overall, the authors of the paper conclude, the state of preparedness for an influenza pandemic in the United States is "far from optimal."
Influenza research at St. Jude is supported by the Public Health Service, National Institutes of Health and ALSAC.
St. Jude Children's Research Hospital
St. Jude Children's Research Hospital is internationally recognized for its pioneering work in finding cures and saving children with cancer and other catastrophic diseases. Founded by late entertainer Danny Thomas and based in Memphis, Tennessee, St. Jude freely shares its discoveries with scientific and medical communities around the world. No family ever pays for treatments not covered by insurance, and families without insurance are never asked to pay. St. Jude is financially supported by ALSAC, its fundraising organization. For more information, please visit www.stjude.org.