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May
24, 25 - 2006
H5N1 Sequence Analysis of North
Sumatra Cluster
Recombinomics
Commentary
The
CDC head said the genetic sequencing of viruses from the cluster so far has
yielded four main findings:
The
isolates are all "virtually identical," implying a single source. They are
susceptible to the antiviral drug Tamiflu (oseltamivir).
"There is no
evidence of motif changes in the particular areas of the genes that are
responsible for how the virus binds to the respiratory tract of people."
The
isolates are very similar to viruses previously collected from poultry in the
region.
The
above comments from the CDC are similar to comments
from Hong
Kong.
Both groups receive human samples from
Indonesia
as indicated in the WHO
update.
However, as with the earlier WHO updates, more information is available from
what is not said in the reports. Since only part of human
sequence
has been made public (HA and NA from the first confirmed case in July of 2005),
more sequence interpretations come from short and well parsed comments, such as
those above.
The first two confirmed cases in
Indonesia
were associated with short descriptions which contained subtle
differences. The released sequence from the first
case in 2005 has a novel cleavage site (RESRRKKR),
which is why it was not called virtually identical but was said to have high
homology with poultry sequences, which have the more common cleavage site
(RERRRKKR). The second
sequence in 2005 was called essentially the same as poultry (as opposed to
essentially the same as the first human sequence), indicating it had the
RERRRKKR cleavage site.
Thus, there were two sequences in human cases in the
Jakarta
area.
A subsequent
report
indicated all human sequences from the area had RESRRKKR
which did not match any known poultry source, which
created a problem since all WHO updates indicated the human cases were linked to
H5N1 in poultry.
The only animal in the
Jakarta
area with a sequence with RESRRKKR was not a bird, but a cat,
raising serious questions about origins and transmission, since many of the
patients in the area were from familial
clusters
with 5-10 day gaps, indicating human-to-human transmission
(H2H).
These clusters included both of the above sequences, indicating both cleavage
sites were linked to H2H, but only one was linked to
poultry.
The
comments above indicating that the sequences from the Sumatra cluster were
virtually identical to each other and very similar to poultry isolated
previously from the area indicates a poultry source infected the index case, but
the subsequent infections were from
the index case or other family members and the normal incubation time of 2-5
days
suggests that there were multiple transmissions within the family that were not
linked to the index case.
The
cleavage site would be the common poultry sequence of RERRRKKR, but the failure
to mention amantadine sensitivity suggests the cluster sequences were amantadine
resistant, as has been seen previously in poultry isolates from Indonesia.Thus,
the only antiviral mentioned was Tamiflu susceptibility, and the
United
States
is shipping
Tamiflu
to Asia.
However. local media reports indicate that the
patients in the cluster were treated with 3 X 75 mg Tamiflu, and all but one
died, even though the later cases seem to have been hospitalized shortly after
developing symptoms.
The exact times are not clear because the onset dates for all relatives other
than the last fatality, who refused Tamiflu treatment, were not
included
in the WHO update. The resistance to
the Tamiflu treatment may have been due to another change, which is not related
to the receptor binding domain, which the above comments indicate the human
isolates match an avian motif.
That change, which has been seen in H5N1 human cases in Asia as well as
dog
and wild
and domestic cat sequences in Thailand, is PB2
E627K,
which may be why the cluster sequences are virtually identical to each other,
but very similar to the poultry sequences, which have not been reported to
have PB2 E627K.
The only
bird H5N1 sequences with E627K are the Qinghai strain,
which is quite distinct from Indonesian bird or human HA and NA
sequences
(no other human genes have been released from
Indonesia)..The
accuracy of the above analysis can be easily determined by simply releasing the
full Indonesian sequences, which have been sequestered at the private WHO
database at Los
Alamos
since August of 2005
Flawed
Surveillance of H5N1 Human Transmission Chains
Recombinomics
Commentary
WHO
assumes that the incubation time for bird flu in humans is 7 to 10 days, longer
than that of regular flu, she said.
Henry
Niman,
who runs recombinomics.com, a Web site tracking the genetics of flu cases,
argues that the incubation period is
closer to the two to four days of regular flu, so the boy may have been infected
by another family member, meaning that the virus may have made three consecutive
human-to- human jumps.
But Cheng said the health agency's
"working hypothesis" was still that it had jumped only twice.
The WHO
working hypothesis on a limited transmission chain is similar to its
investigations of earlier clusters, which focused on common sources other than
humans, leading
to a gross underestimate of the number of cases of human-to-human transmission
(H2H) and length of transmission chains. The clusters in
Turkey
and Azerbaijan
also involved long transmission chains, but the WHO used tortured arguments to
eliminate H2H, which created faulty data, which then created additional faulty
data such as the 7 to 10 day incubation time.
The
two clusters
that WHO linked to duck blood pudding are good examples.
None
of the H5N1 positive patients had the meal within the common 2-4 day incubation
period. In the cluster in
Hanoi
in 2004/2005, the time between the meal and symptoms was 1 and 17 days. A WHO
committee review of
H5N1
in the New
England
Journal of Medicine stated "The
case-to-case intervals in household clusters have generally been 2 to 5 days,
but the upper limit has been 8 to 17 days, possibly owing to unrecognized
exposure to infected animals or environmental sources".
However, this
upper limit of 17 days is due to WHO's efforts to link the brother to the meal,
instead of the index case.
The
brother developed symptoms when the index case died, which is a common feature
of the familial clusters that involve H2H. Moreover, the use of 7-10 days as
indicated above, reduces the number of links in the transmission
chain.
The
shorter incubation time of 2-5 days also explains the 5-10 day gap between the
onset date for the index case and other family members. H5N1
is still not efficiently transmitted H2H, so transmission peaks several days
after disease onset, which when coupled to the incubation time, creates the 5-10
day gap between the index case and other family members, which was common in the
first 15 clusters which were documented in an H5N1 familial cluster
paper
by WHO and the CDC.
These
shorter incubation periods not only support H2H in the smaller cluster of 2 or
3, but also indicate that the
clusters that have long intervals between the first and last member involve a
number of transmission. These long intervals were clearly present in the
larger clusters in Turkey
and Azerbaijan.
à
However,
the current
cluster in north
Sumatra is the
deadliest. Only one of the eight members
has survived, raising concerns in the changes in the eight H5N1 gene
segments.
Those sequences have been sequestered at a private WHO database. Two
sequences from the first confirmed case in
Indonesia
were released, but the sequences of the other six gene segments, as well as full
sequences from the other H5N1 cases in
Indonesia
should be release immediately.
At
least two distinct H5N1 sequences are co-circulating in
Indonesia,
creating conditions fro dual infections and
recombination.
Therefore
the sequences should be available to the scientific community for detailed
analysis
H5N1
Bar Headed Geese Migrate Through Tibet China
Recombinomics
Commentary
A
total of 399 bar-headed geese and ruddy shelducks had died from the virus in
outbreaks in Tibet's Naqu district and the Guoluo Tibetan Autonomous Prefecture
in neighboring Qinghai province,
the agriculture ministry said.The ministry reported on its website that the
outbreaks, which it said had happened 'recently,' were confirmed as the deadly
H5N1 virus earlier today. Although the two outbreaks had occurred in separate
locations, they were linked by migration route. The route also linked the
outbreaks to two other recent incidents in the area, the ministry said.
According to earlier reports, 123 birds had died in the previous
outbreaks.
The
above description increases the number of locations central
China
with H5N1. Bar-headed geese winter in
India
and then migrate to Qinghai
Lake
for the spring.
A year ago China
filed a report on 519 dead waterfowl at
Qinghai
Lake.
The majority of the dead birds were bar-headed
geese
and the migration pattern is repeating
this year, although the reports of H5N1 infections have
increased.
These
data suggest that H5N1 will retrace its path from last year, but this year the
reports are earlier and more widespread.
Russia
has also reported outbreaks
in the southern Siberia
region infected by H5N1 in mid-July last year.
The early citing suggests
outbreaks will be more severe next year. In addition to birds migrating
out of India,
the widespread H5N1 in Africa,
the Middle
East,
and Europe
will bring H5N1 to southern Siberia
from these new locations, allowing for more dual infections and more
recombination.
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