Completion of the genetic sequencing of the 1918 influenza A virus

An article by Robert Belshe, M.D., of Saint Louis University School of Medicine in the New England Journal of Medicine reviews recent "spectacular achievements of contemporary molecular biology" that hold great importance as the world prepares for a possible flu pandemic.

These achievements, including a recent genetic sequencing and recreation of the virus from the 1918 flu pandemic, "may enable us to track viruses years before they develop the capacity to replicate with high efficiency in humans," Belshe writes.

The new knowledge of the genetic sequences of influenza viruses that predate the 1918 epidemic will be "extremely helpful in determining the events that may lead to the adaptation of avian viruses to humans before the occurrence of pandemic influenza."

And as the virus continues to adapt, scientists now know what to look for. Belshe said scientists should conduct worldwide surveillance to monitor this adaptation process.

"It gives us some reassurance that by continuing to monitor the current virus in birds, we can get a sense as to when it'll be an efficient virus," Belshe says. "We may have some time to develop new vaccines and better therapies."

Belshe reviews recent articles in Science and Nature as part of his perspective article "The Origins of Pandemic Influenza â€" Lessons from the 1918 Virus."

The lead author of the research in Nature was Jeffery Taubenberger, M.D., Ph.D., of the U.S. Armed Forces Institute of Pathology, and the research in Science was led by Terrence Tumpey, Ph.D., of the Centers for Disease Control and Prevention.

"These recent research findings involving avian flu are startling, and they tell us that there are at least two mechanisms by which a pandemic influenza epidemic could emerge," Belshe says. "This research provides critically important insight into the origin of pandemic influenza."

Both mechanisms described in the articles were observed during worldwide pandemics of the 20th century. Scientists now conclude that the prospect of a new worldwide pandemic during the 21st century could involve either of two possibilities:

• A direct spread of an entirely avian virus from birds to humans. This is what happened during the 1918 Spanish flu, the deadliest of last century's three pandemics.
• A "reassortment" virus that mixes bird flu with already circulating human influenza strains to create a new strain. This was the case during the 1968 Hong Kong flu pandemic and the 1957 Asia flu pandemic. (Most of the flu strains of today are genetically related to the 1968 outbreak, which as a reassortment virus is genetically related to both the 1957 and 1918 viruses.)

Belshe said the question of the moment involves which mechanism a future pandemic could involve. "Are we going to see an event like 1918, an avian virus adapting to man, or will it be an event like 1957 or 1968, where an avian virus contributes some genetic material by mixing in with a current strain of the human virus?" Belshe says. "We don't know what will happen or when it will happen, but we know it will happen."

And although it can't be said for sure whether the current avian flu virus can adapt readily to the point where human-to-human transmission is possible, the recent research findings do provide some clues as to what genetic changes are necessary for such an event to occur. In fact, several additional genetic changes must occur in the currently circulating bird flu viruses before these viruses will begin to spread efficiently from person to person and this can be monitored closely by scientists.

"Taubenberger estimated that based upon the rate of evolution, the 1918 epidemic had circulated in man since 1900," Belshe says. "So it took a while to become highly efficient as a pandemic virus."

A copy of the full article can be found in the Nov. 24 issue of the New England Journal of Medicine (2209-2211).

Belshe is director of the Center for Vaccine Development at Saint Louis University School of Medicine. He has conducted research related to influenza for more than two decades, and he has previously published articles in the New England Journal of Medicine on the influenza anti-viral Tamiflu, on the nasal spray influenza vaccine FluMist, and last fall on intradermal administration of flu vaccinations. He has authored dozens of papers on influenza that have been covered in various scholarly journals, including a 1998 commentary in The Lancet article that warned of a coming global flu pandemic and of the necessity of preparing for one.

http://www.slu.edu/ and http://content.nejm.org/cgi/content/extract/353/21/2209