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Tamiflu Resistant H1N1 Vaccine Failures Raise Concerns
Recombinomics Commentary 16:53
March 24, 2009

Deb Brandt, a physician assistant at Rapid City Medical Center's Urgent Care, said that on Wednesday, the clinic checked in 106 people in 11 hours. There were cases of strep, mono and plenty of influenza. Three other Rapid City clinics report a similarly busy schedule.

Brandt said about half of her patients who tested positive for influenza had their shots, but "most of the flu shots were early."

The above comments suggest that 50% of the flu patients in the Rapid City area served by the medical center had been vaccinated this season, and the vaccine failed to prevent infection.  This figure is alarming, since the vaccination rate of the population is likely much lower than 100%, so the failure rate in those receiving the vaccine would be much higher than 50%.

The article suggested that the high failure rate was due a reduction in antibody levels in vaccinated patients, but vaccines fail because the circulating virus evolves away from the vaccine strain.

A media report on the article suggested that the failure rate may have been due to a resurgence of influenza B, which is not well matched with the current vaccine.  However, South Dakota influenza data indicates that the level of influenza A is about 10 fold higher than influenza B for the season, and in the week prior to the report, the level of influenza A was still five fold higher than influenza B, suggesting that most patients were influenza A infected.  Moreover, since the level of H1N1 is ten fold higher than H3N2, most of the cases would be oseltamivir resistant H1N1, because the levels of H274Y in H1N1 are near 100%.

Vaccine failure for H1N1 is supported by reports from other countries.  In Italy, the first five confirmed H1N1 cases were Tamiflu resistant, and three of the five isolates were from vaccinated patients, supporting the failure rate described above in South Dakota.

Indirect evidence came from South Korea, were the vast majority of influenza cases were oseltamivir-resistant H1N1.  Influenza exploded at the beginning of 2009, with ILI visits jumping to levels that were twice as high as last season.

Similar results were also reported in Japan, were school closings were widespread, and investigations in the fall identified oseltamivir resistant H1N1 as the etiological agent.  Moreover, H1N1 testing of isolates produced reduced titers relative to Brisbane/59, the vaccine strain for this season.

Reports from Taiwan also indicated that vaccines failed in 70% of the H1N1 cases and Tamiflu resistant H1N1 dominated in collections after December, 2008.

Although vaccine failures in H1N1 have not been discussed in weekly reports from the CDC, a disclaimer was added in 2009, noting that cross reactivity with ferret reference sera was not always predictive of vaccine protection.  This disclaimer came after failures had been reported in Asia.

These failures were not unexpected.  Last season the H1N1 vaccine target changed from New Caledonia/20/1999 (clade 1) to Solomon Islands/3/2006 (clade 2A).  However, last season circulating clade 2A had been replaced by clade 2B (Brisbane/59/2007) and clade 2C (Hong Kong/2652/2006), but the vaccine was called a “match” because the ferret reference sera was made against the Solomon Islands virus grown in eggs, and there was significant cross reactivity with clade 2B and 2C.  Consequently, all of the clade 2 viruses were called “Solomon Islands-like” and antigenically indistinguishable.  However, the three clade 2 sub-clades were easily distinguished phylogenetically because of a large number of synonymous and non-synonymous changes, and the antigenic differences were confirmed when a new reference sera was made using Brisbane/59 grown in mammalian cells.  That reference sera had a titer of 320 against Brisbane, which fell to 40 for Hong Kong, and was <40 for Solomon Islands.  Consequently, virus that was called “Solomon Islands-like” at the beginning of last season, was called “Brisbane-like” in early 2008.  In addition, the vaccine target from this season was changed from Solomon Islands to Brisbane, acknowledging that the targets were anigenically distinct.

However, the Brisbane target was isolated in the summer of 2007 and by the fall, the clade 2B in circulation had already evolved away from the vaccine target, which was likely accelerated by the vaccine mismatch last season.  Included in the evolution was H274Y, which was not present in the Brisbane strain.  In addition, a second NA change, D354G, was also in the dominant strain that was oseltamivir resistant.  Both of these changes had been reported previously in clade 2C, but not clade 2A.

Moreover, a subset in the osletamivir resistant strain also acquired A193T in HA.  This change had been in earlier H1’s, including H1N1 in circulation in the 1940’s as well as H1N2 in 2003.  However, it was also in clade 2C, including the prototype, Hong Kong strain, but none of the recent strains had been selected as the H1N1 vaccine target, so the acquisition of A193T in clade 2B signaled a significant change in US and UK isolates in late 2007.  This change was also spreading to other countries in early 2008, prior to vaccine target selection for this season.

However, the 2007 Brisbane isolate was the target for the current season, as well as the upcoming 2009 season in the southern hemisphere.  The importance of A193T became more obvious in the summer of 2008, when osletamivir resistance went to 100% in South Africa.  The dominant strain evolved from the dominant oseltamivir resistant strain in the northern hemisphere and contained A193T, as well as two adjacent changes, N187S and G189N.  This strain was also widespread in Australia, where oseltamivir resistance was also approaching 100%, yet these changes were not incorporated into the 2009 target for the southern hemisphere.

The importance of A193T and adjacent changes were more obvious in isolates from this season.  Oseltamivir resistance in clade 2B was close to 100% and those isolates with H274Y also had A193T as well as 1 or 2 changes at flanking positions (187, 189, and 196).  Each position had two or more changes in the 2008/2009 isolates.  The version dominant in Japan, South Korea, Taiwan, and Italy had A193T paired up with G189A.  The dominant strain in the US had A193T with G189V and H196R.  Other versions were similar to the South African / Australia strain, but had G189S instead of G189N.  Others had A193T with N187D or H196N.  Thus, although all of the reported sequences for H274Y positive H1N1 this season had A193T plus one or two flanking changes, none were in the H1N1 target for 2008 or 2009.  Moreover, the recently announced target for the 2009/2010 season is unchanged.

Thus, the failure to note the significant H1N1 changes last season and this season, in association with H274Y hitch-hiking, and in the selection of the vaccine target for next season, is cause for concern.

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