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WHO H1N1 Vaccine Target Raises Pandemic Concerns
Recombinomics Commentary 22:13
February 18, 2010

One silver lining: US officials hope some of the 74 million doses of leftover pandemic flu vaccine that's sitting in manufacturers' freezers can be used for next fall's vaccine. That would give the nation a big jump in making next fall's vaccine. Which could mean earlier access to flu shots.

The above comments reflect remarks made at WHO’s virtual press conference on recommendations for the vaccine targets in 2010/2011.  The recommendation, like the earlier recommendation for the 2010 season in the southern hemisphere, included H3N2, influenza B, and a California/7-like pandemic H1N1.

The choice of California/7 has been controversial because the widely used X-181A has five non-synonymous HA difference with the consensus H1N1 sequence, including Q226R.  Moreover, unlike the attenuated live virus in the nasal spray, the target does not have D225G.

D225G has been of concern because of its linkage to fatal cases and frequent jumps from sub-clade to sub-clade via recombination.  The sub-clade with the highest frequency of D225G/N includes Ukraine isolates, where most fatal cases have D225G/N and most isolates with D225G/N are from fatal cases.  D225G/N has also been seen in the Duke death cluster, which involves another sub-clade, where three of five sequences from the Duke patients have D225G or D225N.  These sequences were from four patients and three died.  Moreover, the recent vaccine failure associated with a severe cases in Wyoming adds to these concerns.

Concerns rose when Mill Hill did an antigenic analysis on one of the Ukraine isolates and found that it was a low reactor, raising concerns that the frequency of D225G would increase because of selection due to immune responses to wild type H1N1 or the pandemic vaccine.  The CDC test of the same sequence did not produce the four fold or greater decrease in titer, highlight differences that were likely do to use of different anti-sera.  These types of differences were acknowledged by WHO, and anti-sera from pooled patients was created for lab standardization.  However, the affect of this standardization on sensitivity remains unclear.  Thus, such a standard may uniformly fail to detect reductions in titers identified in the Mill Hill assay.  Reports of D225G/N are on the rise suggesting that D225G/N is offering a selective advantage, as predicted by the Mill Hill results.

In addition, N159D is found in two distinct low reactors identified in the CDC assay (A/South Carolina 18/2009 and A/Utah/20/2009) raising concerns that the H1N1 is evolving away from the California/7  target.  Although the WHO report mentioned low reactor isolates, the selection of a vaccine target from April, 2009 which started with 5 non-synonymous changes, the decision to keep the same target through 2011 does not address these changes, and the large stockpiles of this older target suggest that California/7 will be the pandemic target in use in 2011.

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