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Commentary
WHO H1N1
Vaccine Target Lacks D225G
Recombinomics
Commentary 00:36
February 19, 2010
The above comments from the WHO virtual press release leave little doubt that the 2010/2011 vaccine will include X-181A, which is the version of California/7 current being used for the killed vaccine that has been distributed worldwide. Media reports suggest that 74 million doses of this vaccine have already been produced, indicating this target will be used in the vaccine for the 2010 flu season in the southern hemisphere, as well as the 2010/2011 flu season for the northern hemisphere.
WHO recommendations for both seasons replace the seasonal H1N1 component with the pandemic H1N1 component, which was expected. However, the continued use of Califonia/7 raises concerns that the effectiveness of the vaccine for the next year will be compromised by evolution away from the vaccine.
The original selection of California/7 was controversial, because the vast majority of H1N1 isolates have 5 non-synonymous differences with the vaccine target. Moreover, recent characterization of an isolate from Ukraine had D225G and was designated as a low reactor by Mill Hill. A low reactor designation indicates the titer against the new isolate was at least four fold lower than the reactivity against the vaccine target. This antigen characterization test is dependent on the reference anti-sera, which is traditionally made in ferrets. However, this approach has been generating inter-lab differences, which may also be linked to the target of the anti-sera.
Currently, there are two forms of California/7 in commercial pandemic vaccines. The original California/7 isolate was a mixture with polymorphism at positions 225 and 226 in the receptor binding domain. Most is the killed vaccine which is in the shot is wild type at position 225 and has Q226R at position 226. In contrast, the live attenuated vaccine, which is a nasal spray has D225G at position 225 and is wild type at position 226.
Position 225 has been hyper-variable in pandemic H1N1 isolates. The most widespread change is D225E, but the two changes that have been most concerning are D225G and D225N, which have been linked to fatal cases. In addition D225A has been identified in Ukraine and California, while D225V has been found in swine in Alberta, Canada. These frequent changes at the same position signal strong selection pressure. However, these changes have not been addressed in the vaccine target selection.
WHO did put a D225G report on December 28, which acknowledged the high association of D225G in fatal cases (50% of HA sequences with D225G are from fatal cases). The report claimed that clustering in time, space, or phylogeny was not found. However, sequences released in January from Ukraine and Russia left little doubt that D225G or D225N clustered in all three areas, and the vast majority of such sequences were from fatal cases. More recently D225G and D225N were identified as being in the transmitting death cluster at Duke Medical Center, clearly demonstrating that the reliance on the random mutation paradigm was hazardous to the world’s health.
The lesson on the importance and distribution of D225G/N evolution has not been learned, and the selection of a pandemic target lacking changes at position 225 increases concerns that this failure in learning will seriously jeapordize the efficacy of vaccines for the next 12 months.
Pandemic H1N1 has sent very clear signals on the importance and danger of D225N/G, and WHO’s failure to act on these changes raises serious concerns on its ability to defend the world’s health from pandemic H1N1.
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