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Widespread Evolutionarily Fit Tamiflu Resistant Pandemic H1N1
Recombinomics Commentary 06:41
July 10, 2009

The NA sequence of the first pandemic isolate in Sapporo, Japan (A/Sopporo/1/2009)  was released at Genbank today.  Since Hokkaido's first report case was June 15, the isolate is relatively recent.  It exactly matches the first isolate from New Jersey, A/New Jersey/1/2009, which was from a patient (22F) in Bergen county (see map) and collected in April.  Both of these isolates match the California traveler who was tested at Hong Kong airport on June 11 and was found to be infected with oseltamivir resistant H1N1 (A/Hong Kong/2369/2009) based on H274Y, which was the only difference between the Hong Kong sequence and those form Bergen, New Jersey and Sopporo.  The same sequence in these three locations indicates the evolutionarily fit H1N1 is widespread and has been circulating for months, but the number of pubic sequences remains low.

The Hong Kong, ex-San Francisco case was mild.  The patient recovered without taking any antivirals, raising concerns that the resistance is circulating worldwide.  The same genetic change, H274Y, has also been reported in patients receiving prophylactic levels of Tamiflu in Denmark and Osaka, Japan.  The Osaka sequence, other than H274Y, matches multiple isolates from Japan, and is distinct from the Hong Kong/San Francisco/Sapporo/Bergen sub-clade.  The sequence from Denmark has not been made public.

However, other countries are reporting suspect Tamiflu resistance in patients who have been treated for at least a month and are symptom free, but shed detectable H1N1.  These reports raise concerns that H274Y is more widespread than the 3 confirmed cases and one presumed case in San Francisco.

The finding of H274Y in all confirmed cases raises concerns that the pattern in pandemic H1N1 will follow the pattern seen for seasonal flu, where H274Y increased to almost 100% in the Brisbane/59 strain of seasonal flu.  The spread of H274Y in the Brisbane strain was facilitated by the acquisition of key polymorphisms from the Hong Kong (clade 2C) strain of H1N1.  However, H274Y had also been reported in clade 1 and clade 2c isolates from patients who were not receiving Tamiflu, and in countries where Tamiflu suage was low.  The H274Y jumped from one sub-clade to another via genetic hitchhiking and recombination explaned the pattern of acquisitions.'

The spread of H274Y in pandemic flu may be accelerated by widespread Tamiflu usage, levels approaching 100% in H1N1 seasonal flu, and the novel H1N1 reported in Canadian farm workers infected with an H3N2 triple reassortant that has acquired Brisbane/59 H1 and N1, with H274Y.

Thus, the detection of H274Y in pandemic H1N1 from patients who were and were not taking Tamiflu, as well as Brisbane N1 in H1N1 seasonal flu and H1N1 novel flu raises concerns that the levels of H274Y will markedly increase in the near term.

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