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Paradigm Shift Intervention Monitoring
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Vaccine Target Selection Failure
For the H1N1 component, a strain similar to A/California/7/2009, replacing A/Brisbane/59/2007
For the H3N2 component, a strain similar to A/Perth/16/2009, replacing A/Brisbane/10/2007
For the B component, a strain similar to B/Brisbane/60/2008-like virus
The above comments list the WHO vaccine target recommendations for the 2010/2011 flu season in the northern hemisphere. Although the recommendation leaves discretionary room for the precise A/California/7-like target, comments at the associated virtual press conference as well as media reports clearly indicate that the recommendations allowed for used of the X-181A version of California/7, which has been used for the killed vaccine worldwide, and the current stockpile has been cited as 74 million doses. This large inventory of X-181A in bulk form virtually ensures its use in the vaccination program for the southern hemisphere, which will begin in the next few months, followed by the 2010/2011 northern hemisphere campaign, which will begin in the fall. This seamless transition from the target selected in April of 2009 through vaccinations in 2011 is cause for concern.
As is well know, influenza A continually evolves away from host immunity, especially when immunity is widespread in the host population. When pandemic was first identified in April of 2009, the human population had little immunity. The elderly who had been exposed to the 1918 H1N1 strain or the seasonal H1N1 strain that followed still had protective immunity that cross reacted with the 2009 swine H1N1 pandemic strain, but most of the population under 65 had no protective immunity. Consequently, there was little selective pressure for the virus to change.
However, as more people developed immunity from infections, more changes began to emerge. Position 225 in the receptor binding domain was of concern because the D225G change had been seen in 1918 H1N1 pandemic isolates from 1918 and 1919, and lab studies had demonstrated a change in receptor binding specificity to increased binding to gal 2,3 receptors which are found in the lower respiratory tract in humans.
Moreover, in the summer of 2009, which is the flu season in the southern hemisphere, D225G and D225N were found in autopsy lung samples from deceased patients in Sao Paulo, Brazil. In addition, the changes were found on additional backgrounds in China and Mexico, signaling movement of position 225 changes via recombination.
Position 225 was also of interest because the first evolutionarily fit isolate with H274Y was from a patient with D225E and an early swine isolate from Alberta had D225V, which indicated position 225 was the most hyper-variable position in swine H1N1.
Thus, when media reports out of Ukraine described high numbers of fatalities with hemorrhagic presentations and rapid lung destruction, the presence of D225G and D225N was predicted. Sequences from Australia had just been released with D225G and D225N on additional genetic backgrounds, demonstrating that these D225 changes were “in play”.
The release of Ukraine H1N1 sequences by Mill Hill confirmed the prediction for D225G, which was found in 4 of the 10 sequences. The six sequences without D225G were from an earlier isolate from Kiev, or nasal washes from 5 milder cases in western Ukraine. The four cases with D225G were from the same clade as the milder cases from western Ukraine, but isolates with D225G were from lung or throat samples from fatal cases. The Mill Hill sequences were followed by sequences by the CDC from two additional patients, which had D225N. The association of D225G and D225N with fatal cases was supported by additional autopsy lung sequences in Ukraine, Russia, and Moldova, raising concerns that increasing frequencies of D225G/N infections would lead to a higher frequency of severe and fatal cases.
This concern was increased by data from Mill Hill, which tested one of the Ukraine samples with D225G. It was designated a low reactor, indicating movement from the immune response generated by the vaccine or infection with wild type D225. Although the CDC failed to find this decreased activity in a sample with the same HA sequence, lab variation linked to difference in reference sera was not uncommon, and WHO recently proposed using reference sera from pooled serum samples from patients instead sera generated in ferrets.
However, the reduced titer reported by Mill Hill was consistent with the high frequency of D225G and D225N in fatal cases in Ukraine and Russia, as well as findings of D225G/N jumping from one genetic background in Ukraine and worldwide, including the Duke death cluster.
Thus, the failure of WHO to address these concerns and to ignore that compelling sequence data generated in January, raises serious concerns about the committee’s abilities to analyze data and anticipate changes in H1N1 antigenicity and associate effects on vaccine efficacy.
These failures continue to jeopardize the world’s health.