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H5N1 Pandemic Vaccine Progress Well Shy of Half Empty

Recombinomics Commentary
March 31, 2006

The recent New England Journal of Medicine article on results of the US pandemic vaccine trial has been described in some media accounts as half full (half of the subjects responded) or half empty (half of the subjects failed to respond).  However, the data are well shy of the half empty description.

The results were really telegraphed in August 2005 when initial results were announced.  Although the “we have a pandemic vaccine” statement was technically correct, the description of the initial results made it clear that the responses were far from ideal.  The best responses were in subjects receiving the highest dose and two shots were required.  Thus, the amount of antigen was 12 times the level used for a single target in the seasonal vaccine.  This alone would produce a serious production problem, because there were anticipated problems using just 1/12 of the amount.  The problem was also worse than simply the dosage requirement for two injections, because a third injection was mentioned.  This indicated that many failed to adequately respond to two injections.  Three injections using 18 times the expected amount was projected to be VERY unworkable.  In addition to taking 2 months to complete a vaccination course, the amount of antigen required would severely limit the number of subjects that could be immunized.

Moreover, the end point was a titer of 40, which was no guarantee that patients would not get infected.  There was no “challenge” to show that a titer of 40 was sufficient to prevent infection of death.  The minimal immunity might allow the patient to live for two weeks instead of one, but the outcome would still be the same.  Alternatively, the patient might recover, built with permanent neurological damage.  A titer of 40 is a borderline response.  As shown in the NEJM data, a background titer of 10 is present in the placebo controls and even a titer of 20 can be due to nonspecific factors.

Data from the 1918 pandemic indicates that those who survived had titers above 1000, and these titers were present in 2005, over 85 years after the pandemic.  Thus, titers of 40 may simple delay the inevitable and produce additional strain on medical facilities.  Therefore, titers of 40 or more in half of the young healthy adults were well shy of a half empty description.

In addition to the low titer and production issues, the changing specificity was yet another issue.  When the trial began, only Vietnam and Thailand were reporting human H5N1 cases..  The sequences from these isolates were similar, so one vaccine could protect against both H5N1 versions.  However, last summer it was clear that H5N1 was evolving away from the 2004 H5N1 target sequence from Vietnam.  H5N1 was being transmitted and transported by wild birds and it was just a matter of time before these sequences also caused human cases.  In 2005 human cases in Indonesia and China were reported, and sequences from these areas suggested that the cross reactivity between H5N1 from Vietnam/Thailand and Indonesia/China would be poor and the Qinghai sequences were distinct from all of the above.  Now the Qinghai strain has cause human fatalities in Turkey, Iraq, Egypt, and Azerbaijan highlighting the need for multiple vaccines.

Sequence analysis indicates these H5N1’s are evolving via recombination and therefore new versions of H5N1 can be predicted.  However, these predictions are dependent on the sequences of the circulating strains of H5N1 and much of the most recent data is sequestered in a private WHO database.  WHO announcements that H5N1 is evolving via “random mutations” indicates their advice is fatally flawed and the sequestered sequences are not being properly analyzed.

Release of the sequences and a review of WHO’s actions are long overdue.


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