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Tamiflu Resistance in Recombined H1N1 in South Africa
Recombinomics Commentary 17:01
August 12, 2008
Recent reports from South Africa indicated that Tamiflu (oseltamivir) resistance was running at 100% in H1N1 isolates. Twenty-three of the first 100 H1N1 isolates had been sequenced, and all 23 had H274Y. Yesterday, HA and NA sequences were released from 13 H1N1 infected patients collected this season in May and June. All eight of the NA sequences had H274Y. The eight HA sequences mapped with Tamfiflu resistant sequences from other countries. Three of the HA sequences mapped to a branch with sequences from French isolates which had H274Y, while the other five mapped with isolates from the United States which had H274Y. Moreover, the NA sequence from at least one South African isolate from each group was released (see red highlighted isolates in list below). Thus, it is likely that all 13 patients from South Africa were infected with H1N1 carrying H274Y.
However, the five isolates which mapped with the US sequences had five polymorphisms clustered together over a stretch of 18 nucleotides. The clustering of 5 changes over such a small region is a signal of homologous recombination, and the changes at the 3’ side of the cluster matched human H1N1 sequences from the 1940’s (see list below). The appending of this group of changes onto a Brisbane/59 genetic background that maps with isolates that have H274Y is cause for concern. The five nucleotide changes lead to three non-synonymous changes (N187S, G189N, A193T - H3 numbering), signaling rapid evolution away from the Brisbane/59 target.
The current vaccine in use in South Africa, like the vaccine for the 2007/2008 season in the northern hemisphere, uses Solomon Island/3 as the H1N1 target, reducing the effectiveness of the vaccine. Although Brisbane/59 will be the target for the upcoming season, the emergence of the rapidly evolving strain in South Africa raises concerns that the newer Tamiflu resistant H1N1 isolates will also escape from the seasonal flu vaccine, which is chasing the H1N1 evolution.
The high frequency of H274Y on N1 in H1N1 and the potential for further evolution away from the soon to be implemented new H1N1 vaccine, raises additional concerns about the utility of using Tamiflu to blunt an H5N1 pandemic. H274Y also produces significant resistance on an H5N1 background, and recombination in N1 involving H1N1 and H5N1 can easily transfer H274Y from one genetic background to the other.
Thus, the emergence of widespread Tamiflu resistance in seasonal flu continues to be cause for concern with regard to the utility of oseltamivir stockpiled worldwide to blunt an H5N1 pandemic.
NA Sequences with H274Y
HA Sequences Mapping with H274Y Positive French Isolates
HA Sequences Mapping with H274Y Positive US Isolates
Recombinomics Paper at Nature Precedings