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H5N1 Bird Flu Evolves Away From Pandemic Vaccine
August 6, 2005
An earlier human vaccine against A(H5N1) avian influenza virus was prepared after it first appeared in the world, in Hong Kong in 1997. That vaccine was never fully developed or used, and the strain has mutated since then.
In interviews over recent days, Dr. Fauci has said that tests so far have shown that the new vaccine produced a strong immune response among the small group of healthy adults under age 65 who volunteered to receive it, although the doses needed were higher than in the standard influenza vaccine offered each year.
The above comments on the development of a pandemic vaccine are overshadowed somewhat by the rapid spread of H5N1 across Russia, Kazakhstan, and Mongolia. Although the sequence of the rapidly spreading H5N1 has not been published, descriptions of the sequence sound much like the recently published H5N1 sequences from Qinghai Lake. Those sequences suggest that the current pandemic vaccine being tested worldwide will not be effective against the H5N1 expected to spread throughout Asia and Europe in the upcoming weeks.
As noted above, the vaccine produced against the 1997 H5N1 that infected 18 people in Hong Kong was not developed because the 2004 H5N1 had evolved away from the vaccine. The pandemic vaccine uses 2 of the 8 genes from H5N1 and analysis of the HA and NA shows why the 1997 vaccine was not effective. There were 20 amino acid differences between 1997 and 2004 in the HA protein and 26 differences in the NA protein.
Consequently, the pandemic vaccine that is currently in clinical trials was developed. Sequences from HA and NA of some of the 2005 H5N1 from Vietnam have been deposited at the Los Alamos National Labs Flu Database and there are just 4 differences between 2004 and 2005 in HA and 3 differences in NA. Consequently an earlier announcement indicated that there was no need to switch vaccine targets.
However, the sequence of the isolates from Qinghai Lake indicates that there will be a specificity problem using the new vaccine against the H5N1 being spread by migratory birds. As noted above, the new vaccine requires more virus than the human vaccine. The new trial used several dosages to determine that a higher dose was required. In addition, a booster shot was necessary. Thus, the response was not robust and two shots were required. These data suggest that the vaccine requires a close match to be effective and thus far the effectiveness has only been tested in young adults. Although 2005 isolates out of Vietnam may be genetically close enough, isolates from Qingahi clearly are not.
The differences between 2004 H5N1 form Vietnam and 2005 H5N1 from Qinghai Lake are 18 amino acids in HA and 13 amino acids in NA. Thus, the number of differences between H5N1 in 2004 in Vietnam and 2005 in Qinghai Lake is almost as great as the number of differences between 1997 and 2004, which covers 7 years.
Moreover, as H5N1 migrates back to Vietnam and other Asian countries where H5N1 has become endemic, there will be more recombination and more change, further limiting the usefulness of the current vaccine.
Although the suspect cases in Kazakhstan have yet to be confirmed, and Russia has yet to report a human cases, the sequence data suggest that H5N1 from Qinghai will cause significant problems in the upcoming months. Boxun reports indicate that these isolates have already caused significant numbers of deaths in humans, and China has admitted to testing only two people exposed to H5N1 at Qinghai Lake.
The rapid spread of H5N1 across Asia and the expected spread through Europe dictate that a new pandemic vaccine effort be initiated, because it seems likely that the current vaccine will offer little protection to emerging recombinants in the upcoming months.