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US Considers a Third H5N1 Bird Flu Pandemic Vaccine Dose

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.

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