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Amantadine Resistance in Bird Flu Vietnam and Thailand

Recombinomics Commentary
June 18, 2005

>> Zhang and other animal health experts said the drug was used by small, private farms and larger commercial ones. Amantadine sells for about $10 a pound, a fraction of the drug's cost in Europe and the United States, where its price would be prohibitive for all but human consumption.

Su Lijian, vice president of Zhejiang Kangyu Pharmaceutical Co. in southeastern China, said amantadine was introduced into China in the 1970s for human use before being extended to poultry in the 1990s.
Two months before China first reported a bird flu outbreak in poultry to the World Animal Health Organization in February 2004, officials had begun a massive campaign to immunize poultry against the virus. They have now used at least billion doses of a vaccine. 2.6

But researchers in Hong Kong have reported that the H5N1 flu virus has been circulating in mainland China for at least eight years and that Chinese farms suffered major outbreaks in 1997, 2001 and 2003. Scientists have traced the virus that has devastated farms across Southeast Asia in the past two years to a strain isolated from a goose in China's Guangdong province in 1996…….

In the United States, amantadine was approved in 1976 by the Food and Drug Administration for treating influenza in adults. Amantadine and it sister drug, rimantadine, work by preventing a flu virus from reproducing itself. Both are now ineffective against the H5N1 strain.

Even before, these drugs had limitations in treating an ongoing human flu outbreak because of the speed at which the virus would become resistant in humans. But international health experts stressed that amantadine could have been vital in stanching the spread of the bird flu virus in the early weeks of an epidemic.

Now, the only alternative is oseltamivir and closely related zanamivir, which work by hampering the flu virus from leaving infected cells and attacking new ones. Of the two, oseltamivir is easier to use and has far greater sales. <<

The genetic trail of Amantadine resistance is a bit more complicated than many realize.  The isolates from Vietnam and Thailand actually have two Amantadine resistance markers in the M2 protein.  One, L26I, is found only in the isolates from Vietnam and Thailand.  It is not in isolates from China or anywhere else, yet is in all Vietnam and Thailand isolates.

The other M2 mutation, S31N, is much more common, but traces back to lab isolates from the 1930's  It is in  WSN/33 (also found in swine isolates in South Korea) and PR-8 (used to make vaccines worldwide).  These may be related to growing these viruses in tissue culture.  The mutation is also in a variety of human isolates (including those from New York last year).

In Asia, the first H5N1 isolates were from Hong Kong in 2002,  It is also present in isolates from two patients in 2003 and they presumably were infected in Fujian province.  There is also an isolate from Shantou Province and Indonesia.  However, most of the isolates from each of these areas do not have the mutation (but ALL 2004 isolates from Vietnam and Thailand do).

Earlier bird isolates can be found in China.  The earliest H9N2 isolates were in northern China in 1998 (Shanghai and Beijing).

However, the mutation is also found in swine isolates, and the earliest swine isolates are in the US and Europe.  The mutation began appearing in Asian swine in 1999 (in Hong Kong).

Thus, one of the markers is probably traced to treating humans or pigs with Amantadine years ago in the west (US and Europe) and the second mutation may well have arisen in Vietnam or Thailand fairly recently.

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