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H1N1 RBD Changes - D225N and Q226R In Egg Isolates

Recombinomics Commentary 22:40
June 23, 2011

The CDC has released a series of 2011 H1N1 sequences (largely from Feb – April isolates) at GISAID, which have an unusually high frequency of receptor binding domain changes.  The 42 HA sequences have four examples of D225N and eight example of Q226R (several are reported as mixture with wild type at position 226).  Much of this increase is linked to selection of virus grown in eggs, which have gal 2,3 receptors, which would select for the above changes, which have increased affinity for such receptors.  This increased affinity has significant clinical consequences, since gal 2,3 receptors are also at high concentrations in human lung, so samples with D225N or Q226R would have a greater likelihood of causing severe or fatal cases, as has been reported for D225G and D225N, and D225N in Chihuahua sequences led to a new 2011 pandemic alert.

Several of the recent sequences are from samples which have used previously to isolate virus on mammalian (dog kidney MDCK cells), which have gal 2,6 receptors (found in high concentrations in the human upper respiratory tract).  Thus, H1N1 that is wild type at positions 225 or 226 will be selected when grown on MDCK cells, but those samples with the more clinically relevant changes (D225G, D225N, or Q226R), will be most easily detected when isolated in eggs.  The isolation using the earlier samples yielded sequences that matched the mammalian isolates at the other positions, but had changes at position 225 or 226 (D225N and Q226R detected in A/Mississippi/07/2011, with two Chihuahua sub-clades, A/Pennsylvania/02/2011 and A/Maryland/04/2011, having Q226R).

These receptor binding domain changes appended onto the sequence identified in mammalian cell isolates raises serious concerns that the number of receptor binding changes on mammalian cell isolates (the vast majority of CDC isolates) are significantly undercounted and these false negatives support the data suggesting that these changes are spontaneous and poorly transmitted.

The data using egg isolates highlights the increased frequency of these changes and raises serious pandemic concerns associated with the significant undercount.

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