H5N1 Pandemic Vaccine Selection Trails Clade 2.2 Changes
Recombinomics Commentary 13:27
March 7, 2008
The recently released human vaccine target selections by the WHO, raise concern over timely identification of targets. H5N1 is rapidly evolving and clade 2.2 is rapidly spreading. The spread of the Uvs Lake strain of clade 2.2.3 has been most glaring, yet this strain was not targeted in the February, 2008 update. The strain has spread throughout Europe and is in the Middle East. Movement into south Asia is unclear, because sequences have not been released. However, earlier sequences were clade 2.2.3, so the spread of the Uvs Lake strain to that region is certainly possible. In addition to the lack of targeting of the Uvs Lake strain, the explosion in diversity in Egypt is under-representation. In Egypt human cases have been reported in each of the last three seasons, moving Egypt to the number one position in confirmed human H5N1 cases outside of southeastern Asia.
As seen in the phylogenetic tree in Figure 1 of the report, the Uvs Lake strain, as represented by isolates from Kuwait and Krasnodar has evolved away from the 2006 clade 2.2.3 isolate from India, which has been selected as a target sequence. The evolutionary movement has been noted for some time, and the spread throughout Europe was emerging in the summer of 2007. The emergence and evolution of the strain was evident in wild bird sequences from the massive outbreak at Uvs Lake in northern Mongolia in the summer of 2006. H5N1 was isolated from a whooper swan and golden eye in Mongolia along with isolates from a duck and grebes in adjacent Tyva in southern Siberia. The sequences were 2.2.3, but were distinct from 2.2.3 isolates from Europe earlier in the year.
As seen in the recently released sequences from the 2006 outbreak in south Korea, the Uvs Lake strain migrated southeast to south Korea near the end of 2006. The sequences also migrated to southwest to Kuwait in early 2007, raising the possibility that it also migrated due south into south Asia.
Although the strain was not reported in Europe in late 2006 or early 2007, it appeared in the Czech Republic in the summer of 2007, as confirmed by the recently released sequences. However, movement into Europe was also indicated by the outbreaks in Germany over the summer. Early reports from FLI indicated the sequences in Germany were most closely related to the published wild bird sequences from Uvs Lake. The German wild bird outbreaks were followed by outbreaks in France, which were also characterized as being closely related to the Uvs Lake of Kuwait sequences. Thus, in the summer of 2007 it was becoming increasingly apparent that Uvs Lake H5N1 was widespread in wild bird populations and was spreading across Europe, displacing early clade 2.2.1 and 2.2.2 strains identified in 2006.
Public confirmation of the spread was provided by sequences from Krasnodar, which were released shortly after the September outbreak. This was followed by release of sequences from Germany, as well as sequences from Romania, which were released shortly after the fall outbreak there. More recent sequences from Saudi Arabia and Ukraine confirm the spread of the Uvs Lake strain in Europe and the Middle East, yet there is no representation in the vaccine targets selected in the recent WHO report.
Similarly, the broad diversity of sequences is under represented in the tree and selection of new targets. In early 2006, clade 2.2.1 sequences were detected in Egypt. These sequences were closely related to sequences in Israel, Gaza, and Djibouti. The sequences from the 2006/2007 had the same regional markers, but were markedly more complex due to acquisition of new polymorphisms. These new polymorphisms trace back to early clade 2.2 isolates, including an over representation of polymorphisms in Germany. This diversity is represented in part by the five Egyptian sequences on the tree. However, the initial cases in the 2006/2007 season were fatal and mapped to additional branches which are not represented on the tree in Figure 1. All patients with M230I died, yet the isolates with M230I are not represented in the tree. Included in the fatal cases with M230I were the three family members designated as the Gharbiya cluster. These patients had another receptor binding domain change, V223I, which is also not represented.
The diversity in Egypt may have contributed to the vaccine failure in some flocks. H5N1 from these isolates is also not represented. These isolates had a large number of non synonymous changes, and were geographically diverse, but primarily in northern Egypt. Similarly, a large number of isolates with M230I and V223I were also detected in the current season. Thus, this season H5N1 is more diverse and unlikely to be well represented by the target sequence from Egypt, which is from a mild case that was genetically distinct from the sequences in northern Egypt. The added diversity in Egypt, coupled with more aggressive human cases will create new challenges for effective human vaccines, which is being exacerbated by vaccine failures and growing diversity in Egypt.
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