Recombinomics Commentary
August 7, 2005
Medical experts in Asia, where all of the human and poultry cases of bird flu have occurred, cautioned on Sunday that formidable obstacles remained before the new vaccine would become a useful tool in preventing a pandemic.
The biggest impediment may be the rapid evolution of the virus itself.
Dr. Guan Yi, a Hong Kong University microbiologist, said that the flu virus that has just appeared this summer among migratory birds roosting on an island in Qinghai Lake in western China had quite a few genetic differences from previous viruses that had circulated in Southeast Asia.
The previous viruses appear to have been used in the successful vaccine tests this spring and summer in the United States.
"It keeps changing, it keeps evolving," he said. "We don't know how much the vaccine matches."
The above comments confirm the concerns about the ability of the pandemic vaccine that is being developed worldwide to have utility against the H5N1 that has emerged from Qinghai Lake and is now rapidly spreading across southern Russia and northern Kazakhstan.
This version of H5N1 is considerably different than the H5N1 in Vietnam and the current vaccine is unlikely to have significant activity. The new vaccine requires at least 2 injections of 90 micrograms. The 180 micrograms is 12 times higher then the amount used for a human flu isolate. Moreover, the dose response is border-line, so a third injection may be required. Thus, almost 20 times the normal dose may be necessary, and the H5N1 has a tendency to kill the chicken eggs, reducing the yield. Thus, the availability of chicken eggs could severely limit the amount of vaccine produced and could conceivable require 50 times the number of eggs required to make a vaccine against one human isolates (the current human trivalent vaccine is made against three viruses using 15 micrograms each).
These data suggest that the vaccine under development may not work well against the 2005 H5N1 in Vietnam, which only has 4 amino acids changes in HA, because the vaccine against the immunizing isolate is so weak.
As H5N1 closes in on Europe and threatens to spread throughout Asia and beyond, it is clearly time to rethink and retool vaccine development, which uses technology developed shortly after the first human flu virus was isolated in 1933. The techniques used in 2005 are strikingly similar to the technology of the 1940's, and the case fatality rate of the 2005 H5N1 is 10 to 20 times higher than the 1918 pandemic virus.
Although efficient human-to-human H5N1 transmission has not been confirmed, the rapid evolution of H5N1 and its increased host and geographical range, creates a very unstable genetic situation.
This instability could have dire consequences in the very near term.
http://www.recombinomics.com/News/08070504/H5N1_Vaccine_Outpaced_By_H5N1.html
Recombinomics Commentary
August 8, 2005
Doctors at these centers drew blood from the volunteers to document that they had no antibody to A(H5N1) before they received the first of two injections of the vaccine. Then the doctors drew another blood sample four weeks later when the volunteers received a second injection of the vaccine.
Fauci said his team was considering drawing a fourth blood sample to measure the antibody response over a longer period. He also said that the team was considering adding a third dose of vaccine to determine the maximum response that the vaccine could elicit.
The consideration of a third dose strongly suggests that two doses of 90 micrograms each, generated a response that was far from ideal. This is of concern for a number of reasons.
The above data was generated using younger adults injected with a 2004 reverse engineered version of H5N1 from Vietnam. The group tested will likely generate the best response, so the response in the over 65 group or children may be weaker. Since this is a pandemic vaccine, requiring three shots over an extended time period is also less than ideal, especially if the vaccine has to be used under pandemic conditions.
The borderline response is also of concern with regard to supply. The amount of an individual virus required in the human flu vaccine is 15 micrograms. At the highest doses tested, 180 micrograms were used, which is 12X the amount used for a human virus. A third shot would raise that total to 18X per person. Since the FDA approved method of antigen preparation involves growing the reverse engineered virus in chicken eggs, the number of eggs currently limits supply. This limitation may be exacerbated by poor growth of the virus, which has a tendency to kill the chicken embryo.
A borderline response also raises concerns about utility of the vaccine against an evolving H5N1. Sequences from early 2005 isolates from Vietnam show that HA has 4 amino acid differences with the vaccine prototype strain and NA has 3 differences. Although these differences are modest, they could be enough to make the border line pandemic vaccine ineffective.
Of even greater concern, however, is the H5N1 traveling and transmitting in Russia, Kazakhstan, and Mongolia. These strains almost certainly are linked to the Qinghai Lake outbreak. Isolates from Qinghai Lake have been sequenced and they differ from the pandemic strain at 18 amino acid positions in HA and 13 positions in NA. These changes a similar to differences between the 1997 H5N1 from Hong Kong and 2004 H5N1 from Vietnam. Because of these large numbers of changes, the 1997 pandemic vaccine was not considered a candidate for development against the 2004 H5N1 outbreak.
Thus, the pandemic vaccine results are similar to the results from treating mice with oseltamivir (Tamiflu). The treatment did generate a dose response curve, but even though the amount of Tamiflu used was 5X the FDA approved amount for treatment (and 10X the amount approved fro prevention, 50% of the mice died, even though they were infected after the Tamiflu flu treatment had been initiated.
Therefore, both pandemic vaccine and H5N1 anti-viral data indicate significantly more work is required and the existing treatments will do little to blunt a raging pandemic.
As H5N1 approaches Europe and the summering migratory birds in northern China and southern Russia prepare to head south to recombine with endemic H5N1 in areas like southeast Asia and probably China and India, there is considerable cause for concern.
http://www.recombinomics.com/News/08080501/H5N1_Vaccine_Third_Dose.html