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Evidence For Sustained H7N9 Human Transmission
Recombinomics Commentary 03:15
April 30, 2013

The Zhejiang Provincial Center for Disease Control and Prevention has released full sequences from two H7N9 bird flu cases, A/Zhejiang/1/2013 (37M) and A/Zhejiang/2/2013 (64M), and they are to be commended for the rapid release of these important sequences.  The age, gender, and collection dates suggest these sequences originated from the cases that generated A/Hangzhou/1/2013 (by the Hangzhou Center for Disease Control and Prevention) and A/Zhejiang/DTID-ZJU01/2013 (by the State Key Laboratory of Diagnosis and Treatment of Infectious Diseases at Zhejiang University).  The recent sequences confirmed that the earlier case (37M) had H7 L226I and PB2 E627K, while the second case (64M) had H7 Q226L and PB2 D701N, all of which are mammalian adaptation markers.  Both of these cases were fatal and detail was provided in the recent Lancet paper  These sequences were from Patient #1 and Patient #3, respectively (see map).

The recently released avian sequences had Q226L, which had not been reported previously in H7  (or H5).  However, Q226L has become common in avian H9N2 sequences and the close relationship of the six H7N9 internal genes to H9N2 sequences suggests these internal genes were compatible with Q226L in avian hosts.  However, the PB2 changes (E627K and D701N) have not been identified in any of the recent H7N9 sequences from live markets in and around Shanghai, and some have speculated that these mammalian adaptations happened in the human cases.  However, the presence of E627K in six of the seven human cases, and the absence in any of the avian cases does not support the repeated acquisition E627K in each human case.  The presence of L226I, another mammalian adaptation, in the two sequences from the earlier case (who has been described as 39M, 38M, and 37M) raises serious questions about a recent avian source, since this adaptation has not been reported in any of the avian sequences.

Moreover, the recently released  H7 sequence from a Jiangsu case (45M), A/Jiangsu/01/2013, also has L226I, and the H7 sequence is identical to A/Hangzhou/1/2013 and A/Zhejiang/1/2013.  Although the PB2 sequence from A/Jiangsu/01/2013 has not been released, N9 and MP sequences are public and both sequences exactly match A/Hangzhou/1/2013.  The H7 and N9 sequences have synonymous changes (A1215C and T409C, respectively), which are also not present in other human or avian sequences, strongly supporting clonal expansion.

However, there is no reported contact between the two cases.  The earlier case is a chef who lived in Jiande, Hangzhou, but worked in Taicang, Jiangsu, while the second case was from the Jiangning District of Nanjing, Jiangsu, which is not near Taicang (see map).  The identity in the three sequences from cases without contact with each other strongly supports sustained human to human transmission, which is also supported by the presence of PB2 E627K in 6 of the 7 human cases (and absence in all five if the avian PB2 sequences).

This sustained transmission contradicts WHO statements, which rely on testing of upper respiratory tract samples, which have produced frequent false negatives.  In contrast to the negative data cited by WHO, the exact matches in the two cases above provides clear evidence for sustained human transmission.  Release of a full set of sequences from the Jiangsu case would be useful (and quite doable since the sequences from the first three gene segments were from an egg isolate).

The WHO claims of no evidence of H2H transmission, and the failure to address the identities in the human H7N9, continue to raise serious pandemic concerns.

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