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Paradigm Shift Intervention Monitoring
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
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.