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H1N1 G158E Low Reactors In Germany Raise Vaccine Concerns
Recombinomics Commentary 23:01
February 21, 2010

Sequence analysis of pandemic A(H1N1)2009 viruses indicated that they were genetically homogeneous.  A small number of viruses showed reductions in their reactivity with some ferret antisera (raised against a panel of representative viruses including the vaccine virus) in HI assays.

The above comments from the WHO report on the selection of 2010/2011 targets acknowledge the detection of low reactors. Low reactors have been a concern because the vaccine target, A/California/7/2009, has a number of amino acid differences with the vaccine target.  The original isolate was a mixture and most or all killed vaccine targets use X-181A, which has 5 differences with the H1N1 consensus sequence.

Recently the CDC and Mill Hill released sequences at GISAID from Germany that were designated as low reactors, indicating that the titers against these isolates were at least four fold lower than the vaccine target. One isolate, A/Bayern/69/2009 was sequenced by the CDC. The HA sequence only had one change, G158E.  Similarly, Mill Hill released another sequence from Bayern, A/Bayern/62/2009, which was also designated a low reactor and also had the same one change.  The finding of isolates with a single HA change which created a low reactor designation is cause for concern.  This change is adjacent to N159D, which has been reported in low reactors in the United States.

Currently, the number of publicly reported sequences is limited because in the early wave(s) most humans do not have antibodies, and the pressure for H1N1 genetic change is limited.  However, as more develop immunity to the wild type sequences, there will be more pressure for variants to escape the immune response.  Such isolates are designated as low reactors.

Mill Hill also identified one of the isolates from a fatal Ukraine case as a low reactor, and it only had a single amnio acid change, which was D225G.  This change is strongly linked to fatal cases and there is concern that its designation as a low reactor will drive the frequency higher.

This concern was increased by additional recent isolates which had G158E and D225G.  Such sequences have been found in Russia,
A/Salekhard/01/2009 and Italy, A/Roma/ISS1941/2009 .  The Russian isolate was from a fatal case.

These combinations of changes linked to low reactor status are generated by recombination, and the linkage of two low reactor polymorphisms in the same virus increases concerns that the H1N1 evolution will outpace vaccine targets.  These concerns were increased markedly by the WHO vaccine target for 2010/2011, which allows for usage of existing targets which do not have D225G or G158E.

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