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Vaccine Resistant H1N1 in Japan Raises Concerns
Recombinomics Commentary 21:44
February 2, 2009

majority of separated virus 61 stocks of former Sendai medical institution origin, 1: 80 - 160 and 2 - 3 tubes to be lower than homo- value, in 1: 40 and 1: 20 (each 1 stocks) with, largely there were also some which have slipped. In addition, virus 11 stocks of the Fukuoka medical institution origin which is separated so far all HI values 1: 80 was, had slipped largely. Furthermore, these do not react vis-a-vis the antiserum for a/SOLOMON stocks which are AH1 sub- form chin stocks of last year completely (1: <10)

The above translation is from an NIH Japan report on H1N1 testing from patients in two medial centers (Sendai and Fukuoka).  Japan has just reported an explosion in flu cases last week (see updated map), which are largely H1N1.  Most H1N1 in Japan is Tamiflu resistant, but the latest report looks at reactivity with the seasonal vaccine.

Antisera from ferrets immunized with the trivalent vaccine, which uses Brisbane/59/2007 as the H1N1 target for the current season has a titer of 640 against the target, but that levels drops 4-8 fold when H1N1 from the above medical centers are used.  Moreover, in some cases the levels falls 16-32 fold, which explains why some who were vaccinated are still getting infected with H1N1.  This was recently reported for patients in Italy, and the above cross-reactivity data suggest the protection failure may be widespread.

Earlier studies on H1N1 from elementary school children in Sendai identified H1N1 that was virtually identical to H1N1 in the United States (HI, TX, PA), raising concerns of similar resistance.  An earlier outbreak at a high school in Texas included infection of the school nurse, who had been vaccinated.  Similarly, recent outbreaks at a Texas university (SMU) and boarding school (Texas Military Institute) have been reported, suggesting that outbreaks in the United States are likely.

The vaccine resistance is not a surprise.  Although the Tamiflu resistant H1N1 is the Brisbane strain (clade 2B), it has evolved away from the 2007 target.  H274Y is a genetic hitch-hiker on an H1N1 which ahs acquired a number of HA and NA changes which were on a clade 2C (Hong Kong) genetic background.  However, the Hong Kong strain has also not been a vaccine target, so these components have not been in H1N1 vaccines.

Last season the vaccine target was changes from New Caledonia/20/1999 (clade 1) to Solomon Islands/3/2006 (clade 2A).  Solomon Islands was called a “match” by agencies in the United States and Europe, but last season Solomon Island had been replaced by Brisbane and Hong Kong, but initially all clade 2 isolates were classified as “Solomon Island-like”.  However, phylogenetic analysis easily distinguished each sub-clade and suggested that there would be cross reactivity issues.  Initial reference antisera was made against Brisbane grown in eggs and that antisera cross reacted with all three sub-clades, leading to statements that the clade 2B and clade 2C were antigentically indistinguishable from clade 2A.  However, antisera directed against Brisbane grown in mammalian cells readily distinguished the three sub-clades.

Consequently, the target was changed from Solomon Island to Brisbane this season, but the Brisbane target was from 2007, and the 2008 Brisbane has already evolved away from the 2007 target.  The evolved strain was Tamiflu resistant and had additional changes, which increased this season, which led to even less cross reactivity.

Thus, at this time the H1N1 in Japan has H274Y which creates Tamiflu resistance, but it also has evolved away from the 2007 strain, so it is also vaccine resistant.

Chasing Tamiflu resistant H1N1 with mismatched vaccines is hazardous to the worlds health because of diminished protection and an increased risk if dual infections involving H1N1 and H5N1 leading to Tamiflu resistant H5N1.

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