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H1N1 RBD Changes at 225 Create Vaccine Mismatch Concerns
Recombinomics Commentary 14:22
November 29, 2009

Originating Laboratory provider of clinical specimen(s)
and/or virus isolate(s)
 [Ukraine, Kiev] Ministry of Health of Ukraine
Central Sanitary Epidemiological Station 41 Yaroslavskaya str. 04071 Kiev Ukraine
Sample ID given by the sample provider
Submitting Laboratory generator of data
 [UK, London] WHO Collaborating Centre
 The National Institute for Medical Research (NIMR) The Ridgeway - Mill Hill London NW7 1AA, UK
Sample ID given by the sequencing lab:
Antigenic characterisation:
 A/California/7/2009 like. Low reactor
The above characterization of A/Lviv/N6/2009, which was placed on deposit at GISAID by Mill Hill, raises concerns about the evasion of pandemic H1N1 sequences which change position 225.  The above isolate has only one amino acid change in HA, D225G, which strongly implicates D225G in the low reactor results.  A low reactor reduces the titer by four fold or more, which signals a mismatch. Mismatched vaccine create the potential for the section of the variant, which could create problems since D225G was found in four of four fatal cases in Ukraine, and several countries (Brazil, Ukraine, Norway, France, China) found D225G in fatal and or severe cases.

Moreover, since D225G changes receptor specificity, it may transmit undetected because of an emphasis on nasal pharyngeal samples where levels would be expected to be lower.  This was seen in five additional nasopharyngeal washes from Ukraine survivors, who were infected with a sub-clade that matched the fatal cases, but lacked the D225G.

Similarly, the first matching sub-clade isolate in Norway was a mixture of D225G and wild  type. Public sequences from subsequent sub-clades were negative, but the sequence from the first reported fatal cases appears to be one of multiple collections, and the WHO briefing on the situation in Norway stated that D225G was detected in the first fatal cases, suggesting this case was also infected with a mixture.  The ratio of D225G to wild type would increase under vaccine selection pressure, as indicated by the "low reactor" status of the isolate above.  Although the sequence databases under-represent the transmitting levels of D225G, the positive samples have been collected throughout the world, and these levels may be increasing.

Moreover, position 225 has undergone additional changes in pandemic H1N1. D225E and D225N have been detected worldwide also raising concerns that these isolates will also be low reactors and also increase because immunological escape.  Similarly, mixed signals have been seen for D225E and multiple codons encode D225E, suggesting it too may be selected by immune response.  Since most of  these isolates were collected prior to the distribution of the exiting vaccine, it is likely that selection was being driven by host's immune e response.

More information on the antigenic characterization of additional receptor binding domain isolates, especial those that alter postion 225, would be useful.

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