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H1N1 Low Reactor Recombinants Raise Pandemic Concerns
Recombinomics Commentary 13:26
February 23, 2010

Of interest, all the escape mutant viruses generated with either 1918- or 2009 HA-specific mAbs carried mutations in the antigenic site Sa (Table 5; Fig. 5). The escape mutants that arose in the presence of the 1918 specific mAb 6B9 and 39E4 contained mutations G172E (G158E by H3 numbering) and K171E (K157E by H3 numbering), respectively. The escape mutants generated by selection with the 2009 H1N1 specific mAb (29E3) carried either a K171E or K171Q or K180N mutation (residues K171 and K180 correspond to K157 and K166 in H3 numbering). These results indicate that all the mAbs bind to the conserved antigenic site Sa

The above comments are from the PLOS paper, Protection of Mice against Lethal Challenge with 2009 H1N1 Influenza A Virus by 1918-Like and Classical Swine H1N1 Based Vaccines, and describe changes found in escape mutants when exposed to monoclonal antibodies directed against the 1918 pandemic H1N1 or 2009 pandemic H1N1.  All three changes map to the same antigenic site, and two,
K157E and G158E, match changes found in low reactors.  Moreover, in lethal challenge experiments, involving A/Netherlands/602/2009, anti-sera against pandemic H1N1 or seasonal H1N1 circulating in the 1930’s and 1940’s was more protective than anti-sera directed against A/California/7/2009, highlighting concerns that the 5 amino acid differences between California/7 and the H1N1 consensus sequences reduces the effectiveness of the vaccine against most circulating H1N1, and a minimal number of additional changes can produce low reactors, which generate titers that are at least 4 fold lower than the target sequence.

G158E is found in two German isolates with a low reactor status as detemined by the CDC and Mill Hill.  Although the isolates are easily distinguished at the nucleotide level, both have only one change at the protein level, G158E.  Thus, one nucleotide change can push the target into the low reactor category.  This change has been of particular concern, because of sequences in Russia and Italy which had G158E and D225G.  D225G represents another single nucleotide change that creates a low reactor.  These two polymorphisms can merge into the same sequence via recombination, and the identification of two isolates with G158E and D225G on two distinct genetic backgrounds indicates both polymorphisms are jumping from background to background via recombination.

The recent recommendation of a California/7-like target for the 2010/2011 season, and additional comments that the existing anti-sera against X-181A will be used in vaccinations throughout 2010, raises concerns that frequent drift away from the current vaccine target will quickly compromise the efficacy of the vaccine.

Thus, the selection of California/7, and plans to use stockpiles of X-181A, continues to raise serious questions about the vaccine selection process.

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