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Dramatic Spread of H1N1 Tamiflu Resistance Puzzles Experts
Recombinomics Commentary 15:47
August 26, 2008

In a summary of H1N1 resistance to oseltamivir in the the 2007-08 flu season, the WHO said in June that no link between "oseltamivir exposure and resistance at the individual patient level was noted."

The increasing oseltamivir resistance in H1N1 viruses has puzzled experts. In an editorial published by Eurosurveillance in January, authorities said resistant viruses with the H274Y mutation had been seen in previous flu seasons but were rare and did not spread easily. But the more recent H1N1 isolates with the mutation were "fitter" and were spreading in the community, they wrote.

A recent update by the European Centre for Disease Prevention and Control (ECDC) observed, "At this stage the significance of these [resistance] findings remains uncertain. The emergence of drug resistance in the context of limited drug use is unexpected, and the extent of future circulation is difficult to predict."

The above summaries at the end of the most recent CIDRAP report on the spreading Tamiflu resistance, highlight the confusion linked to the reliance of influenza “experts” on a dying paradigm which uses selection of random mutations to explain antigenic drift in influenza.  Consequently there is little understanding of how the resistance became widespread, and why it is unlikely that the trend will significantly reverse in the upcoming season.

The history of the emergence clearly demonstrates that the increasing dominance violates the old paradigm, leading to the conclusion that the recent isolates with H274Y are fit.  However, the lack of the expected selection by Tamiflu use is the most striking aspect of they spread, as is the failure to look at the origins of the outbreak.

The earlier cases are largely ignored, even though the earlier cases were also in patients who had not taken recent Tamiflu.  This condition applies to the wild birds infected with H5N1 in 2005, the clade 2C infected patients in China in the 2005/2006 season, the clade 1 infected patients in the United States in 2006/2007, or the early clade 2B patients in Hawaii in 2007/2008, which includes the region of identity downstream from the H274Y acquisition in all of the above human isolates.

The dramatic spread was not on the radar screen when the earlier cases were infected.  Widespread discussion began after the rate in Norway exceeded 50%, as reported at the beginning of this year.  All cases were H1N1, had the identical genetic change leading to H274Y, and were in patients not taking Tamiflu.

However, the failure to recognize the role of recombination in moving single nucleotide polymorphisms from one genetic background to another created more confusion.  The concept of H274Y moving from a clade 2C background in China, to a clade 1 background in the US to a clade 2B background in the US, followed by movement to the dominant clade 2B background violated the random mutation aspect of the paradigm, and therefore was discounted.

Similarly, the reliance of poor reference anti-sera and target led to a misclassification of the H1N1 clades.  In the past season the H1N1 vaccine target switched from New Caledonia (clade 1) to Solomon Island (clade 2A), but both targets had dead ended and were no longer in circulation.  Instead they had been replaced by Brisbane/59 (clade 2B) and Hong Kong 2652 (clade 2C).  However, Brisbane/59 was being called Solomon Island-like and Hong Kong 2652 was called New Caledonia-like, creating an illusion that the H1N1 was a match, when in fact it was a mismatch.  Later in the season, classification of  new Brisbane/59-like isolates were corrected, creating a second illusion, that Solomon Island was being replace by Brisbane during the season, when in fact Solomon Island was not in circulation anywhere in 2007/2008  and most countries were misreporting Brisbane as Solomon Island-like.  Brisbane/59 grown on mammalian MDCK cells demonstrated the striking differences between immune recognition of Brisbane/59 and the target of the vaccine, Solomon Island/3.  Mammalian Brisbane/59 generated a titer of 320 against the Brisbane anti-sera, which dropped to 40 for Hong Kong 2652, and was below the detection limits for Solomon Ilsand/3 (and New Caledonia/20).  Thus, the use of a New Caledonia target in 2006/2007 and Solomon Island/3 in 2007/2008 helped establish Brisbane/29-like as the dominant H1N1 strain in circulation, including the subset with H274Y.

The most recent sequences from South Africa had a cluster of additional changes near the receptor binding domain (position 190 in H3 numbering), raising concerns that the role out of the new trivalent vaccine, which includes Brisbane/59 as the new H1N1 target, will have limited utility, pushing the evolution of H1N1 carrying H274Y.

This evolution was supported by the Tamiflu resistance level of 100% in South Africa and Australia this season.

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