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Northern Hemisphere H1N1 Vaccine Failure
Recombinomics Commentary 23:50
February 17, 2011

Unvaccinated                                     1014/2554 (39.7%)
Vaccinated season 2009/10 only           26/130 (20.0%)
Vaccinated season 2010/11 only           22/100 (22.0%)
Vaccinated both seasons                        21/107 (19.6%)

The above data from table 3 in the Eurosurveillance report, "Effectiveness of seasonal 2010/11 and pandemic influenza A(H1N1)2009 vaccines in preventing influenza infection in the United Kingdom: mid-season analysis 2010/11",  for samples positive for H1N1 between September 2010 to January 2011, demonstrate a vaccine failure rate of approximately 50%, regardless of vaccination schedule.

This high failure rate was expected based upon the reports of widespread infections, as well as the elevated levels of severe and fatal cases in the UK in this period, primarily in December and January.  A vaccine failure was also anticipated due to sequence data which indicated that November cases were almost exclusively due to H1N1 with S186P or S188T, and the presence of S188T in all December sequences from the UK.  This domination is largely dependent on immunological escape from the immune response generated in response to infections during the 2009/2010 season or prior vaccinations.

The results in the UK have been extended to most countries in the northern hemisphere, which have reported a similar domination of sub-clades with S186P or S188T.  This escape however is poorly represented in antigenic characterization tests, which lack reproducibility and sensitivity.  Unfortunately, this outdate procedure is the gold standard for vaccine target selection by the WHO and CDC.  Today the WHO announced that the vaccine target for the northern hemisphere in the 2011/2012 season will again be A/California/07/2009.  Although the recommendation acknowledged that some isolates produced low reactivity in some antigenic characterization tests using ferret anti-sera, the selection of the 2009 target once again demonstrates the failure of this approach.

The track record of this approach in the targeting of H1N1 has been abysmal, and has been largely driven by the poor data generated in the antigenic characterization test.  For the 2007/2008 season, the vaccine target of Solomon Island/03/2006 (clade 2A) was selected.  The prior target, New Caledonia/20/1999 had been circulating since 1999 and anti-sera directed against this target (designated clade 1) produced a low reaction against clade 2.  However, by the fall of 2007, there was virtually no Solomon Islands (clade 2A) H1N1 circulating.  It had been replaced by Brisbane/59/2007 (clade 2B) in Europe and North America, or Hong Kong/2562/2007 (clade 2C) in Asia and western North America.  The Brisbane/59 was a concern because of high frequencies of Tamiflu resistance (H274Y).

However, an insensitive ferret anti-sera was used by the CDC.  Since the anti-sera could not distinguish between the clade 2A, 2B, and 2C, all were said to be Solomon Island-like and a vaccine match.  However, the phylogenetic analysis showed that the three sub-clades were easily distinguished and had multiple amino acid difference.  Moreover, the dominance of 2B and 2C indirectly indicated there were antigenic difference which led to the dominance of 2B and 2C at the expense of 2A.  These difference were confirmed in a subsequent anti-sera generated against Brisbane/59 grown in mammalian cells.  This anti-sera readily distinguished 2A from 2B from 2C and led to the replacement of Solomon Island/3 with Brisbane/59 for the 2008/2009 season.  However, Solomon Island was used in the summer of 2008 in the southern hemisphere, when Tamiflu resistance increased to 100%.
Moreover, the dominant sub-clade of Brisbane/59 also had receptor binding domain changes (A193T and additional changes at positions 187 and 189, allowing the virus to escape immunological responses generated against the virus in the prior season.  Consequently, the Brisbane/59 that emerged not only was Tamiflu resistant with HA A193T and at least one additional change at positions 187, 189, or 196, leading to vaccine failures when Brisbane was introduced in the 2008/2009 season.  Moreover Tamiflu resistance in H1N1 increased to 100% worldwide.

The problems linked to an insensitive and unreliable antigen characterization test continued when pandemic H1N1 emerged in the spring of 2009.  The late appearance led to a delay in the fall vaccine, and the pandemic emerged early, so it had already peaked when the vaccine was distributed widely.  The drop in activity in November signaled an immunized target population, raising questions about the vaccine effectiveness for the following year, since the target was not changed.  Selection of a new target was complicated by an unreliable test.

Initially there was some agreement between testing done by the CDC and Mill Hill.  Both had found a low reactor in Germany and both viruses had G158E.  This result supported data from two other labs testing H1n1 under different circumstances.  MedImmune had tested a clone with G158E which grew well in eggs, but was not selected as a target because anti-sera against wild type produced a dramatically reduced titer (confirming the G158E produced low reactors).  Similarly H1N1 grown in the presence of neutralizing monoclonal antibodies generated low reactors which had changes in positions 156-159 including G158E.
However, subsequent isolates from the US which had G158E were not designated low reactors by the CDC, signaling intra-lab variation. 

These differences were compounded when a Ukraine isolate A/Lviv/N6/2009 was characterized.  Mill Hill designated it as a low reactor, which was a concern because it had D225G.  However, the CDC published a sequence showing that an isolate from the same patient had D225G and G158E, yet it was still not called a low reactor by the CDC.  An isolate from this patient became a lab standard and the WHO regional lab in Australia and the HPA in the UK published data using the standard and both clearly showed that it was a low reactor.  Thus, the CDC data did not match its own data on G158E in Germany or the low reactor designation of the Ukraine isolate generated by three different labs.  Moreover, all US isolates designated as low reactors by the CDC had a change at position 159, strongly suggesting that the assay lacked sensitivity for detection of low reactors in the US that did not have a position 159 change.

These discrepancies continued this season.  Sub-clades with S188T and S186P emerged in the UK and across the northern hemisphere, indicating these changes fuel immunological escape.  These sub-clades became dominant and were tested by the CDC.  The testing of isolates collected from patients outside of the US providing some data signaling immunological escape associated with S188T.  One isolate from Kenya had a mixed signal at position 158, but was called a low reactor, supporting a contribution by S188T.  Similarly, an isolate from India did not have a change in the positions 156-159, but had S188T and S186P and was designated a low reactor.  However, a US isolate, A/Kentucky/09/2009 had S188T as well as G158E and D225G, but was still not designated as a low reactor by the CDC.  Moreover, the CDC has yet to identify a low reactor in the US this season, even though most isolates have S188T or S186P.  This failure of the antigenic characterization test has led to a recommendation of A/California/07/2009 for the 2011/2012 season, even though H1N1 has now become the dominant serotype in the US, influenza is widespread in most of the states, and the pneumonia and influenza death rate for week 6 is 8.9, just shy of the five year high of 9.1 set in week 11 in 2008.
Thus, the CDC and WHO consultants have ignored the emergence of S188T and consistent failures of the antigenic characterization test to generate reliable or predictive data, and selected A/California/07/2009 as the pandemic H1N1 vaccine target for the 2011/2012 season for the northern hemisphere.

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