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Amantadine H5N1 Bird Flu Pandemic Containment

Recombinomics Commentary

July 18, 2005

The latest in vivo data on use of Tamiflu to treat H5N1 bird flu suggests pandemic use may be limited, especially at the recommended dose and duration.  When mice were treated at the recommended dose for 5 days, 50% died.  This outcome was not unexpected base on prior in vitro data, but discouraging with regard to pandemic containment because the mice had treatment started before infection.  Most patients would not be treated until after symptoms developed, which is usually 2-4 after infection.  The mice did fare somewhat better if treated for 8 days, but 20% still died and more may have had H5N1 brain infections since the strain used is neurotropic, as are many of the more lethal strains of H5N1.

The most recent confirmed human H5N1 fatalities have been in Vietnam, Cambodia, and Thailand.  All public H5N1 sequences from Vietnam and Thailand since 2004 have two resistance markers in the MP gene, precluding the use of amantadine.  Thus, pandemic preparedness plans have focused on Tamiflu, but most plans do not consider the likelihood that the recommend dose of Tamiflu will be ineffective if the pandemic is cause by H5N1 closely related to the isolates from Vietnam and Thailand.

However, recent boxun reports describe several H5N1 strains in China that can infect humans and most strains in China are amantadine sensitive, based on wild type polymorphisms at positions 26 and 31 of  their M2 protein.  The most virulent strain is RK7, which appears to correspond to the recent isolates from Qinghai Lake. These isolates have been described in recent Nature and Science reports and there was no mention of amantadine resistance markers.  The Qingahi MP gene is most closely related to a chicken isolate from Shantou, which is amantadine sensitive.  The other parental sequence, from a peregrine falcon in Hong Kong, is also amantadine sensitive.

Recent reports from Indonesia suggest that the fatalities of three family members may be due to H5N1, which may be transmissible human-to-human and lethal in all three family members.  The family lives near H5N1 positive swine.  Isolates from the swine are similar to Yunnan isolates, and all Yunnan H5N1 sequences at GenBank are amantadine sensitive.

As the number of reported H5N1 cases outside of Vietnam, Thailand, and Cambodia grow, the likelihood that an exported H5N1 will be amantadine sensitive also grows,

Amantadine is approved for prophylactic treatment of adult influenza infections.  It is less expensive and more available than Tamiflu and may soon be stockpiled also.

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