- 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.
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- The results were really telegraphed in
August 2005 when initial results were announced. Although the 'we have
a pandemic vaccine' 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 12X 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 18X 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.
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- Moreover, the end point was a titer of
40, which was no guarantee that patients would not get infected. There
was no 'challenge' top shop 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.
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- 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.
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- 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.
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- 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.
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- Release of the sequences and a review
of WHO's actions are long overdue.
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- © 2006 Recombinomics. All
rights reserved.
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