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H5N1 Pre and Post-Pandemic Vaccine Concerns

Recombinomics Commentary 13:51
June 23, 2008

Both the 1918 and 1968 pandemics showed a wave as lasting 17 weeks with a peak at week 8.

Current estimates for start of vaccine production in the EU from time of identifying the pandemic virus is 22 weeks. This would likely still be of some use but may be better characterized as a 'post pandemic' vaccine or at least post 1st wave.

It would likely be at least 7 months before large amounts of virus is being produced globally to adequately immunize nations. Also the current recommendation is to give 2 doses spaced 3 weeks apart.

They took people from the first trial who had originally had 2 doses of the vaccine 21 days apart and gave them a booster 12-17 months later with a heterologous virus. This booster showed that the immune system had been well primed by the initial series and in 7 days gave good antibody titres to both the new and original virus. This data is supportive of using a prepandemic vaccine followed by a true pandemic vaccine.

The above comments from the International Conference on Infectious Diseases in Kuala Lumpur raise concerns that the current policy of waiting for the emergence of a pandemic followed by the creation of an appropriate vaccine may lead to a post pandemic vaccine, rather than a pandemic vaccine base on the time for manufacturing a vaccine compared to the time for the global expansion of the first wave.  The current approach adopted by most countries is to stockpile vaccines for immunizing first responders at the start of a pandemic.  This approach is based on concerns that early vaccinations may lead to unnecessary side effects if the targeted pandemic does not emerge.

However, a strong case can be made for the emergence of an H5N1 pandemic, and matches with the stockpiled vaccine will decline as the virus evolves.  Although a pandemic H5N1 may be radically different that current circulating strains, H5N1 has been evolving through antigenic drift and changes in a small number of single nucleotide polymorphism can dramatically change transmissibility, in the absence of dramatic antigenic changes.

The evolution and expansion of H5N1 in recent years has been rapid and significant.  The “Asian” version of H5N1 was first reported in 1996 in a Guangdong goose.  The following year it was reported in humans in Hong Kong.  Aggressive culling in Hong Kong created a lull in human cases, although there were repeated poultry outbreaks in the following years.  In early 2003 there were human cases in a Hong Kong family that had visited Fujian province, as well as Beijing resident, who was initially diagnosed as SARS.

However, the explosion in H5N1 began at the end of 2003, beginning of 2004, when H5N1 was reported in countries to the east and southeast of China.  These outbreaks produced human cases in Vietnam and Thailand.  This H5N1 was designated clade 1.  Related clade 2 isolates caused human cases in Indonesia (clade 2.1) and China (Fujian clade 2.3) in 2005, which is when Qinghai clade 2.2 was reported in long range migratory birds.  The movement of clade 2.2 into long range migratory birds in the spring of 2005 led to the global expansion of clade 2.2 into 50 countries in Europe, the Middle East, and Africa and associated human cases in Turkey, Iraq, Azerbaijan, and Egypt in 2006, followed by Nigeria and Pakistan in 2007.  It is likely that the human case in Bangladesh in 2008 was also the Qinghai strain.  Most recently, Fujian clade 2.3 has been found in long range migratory birds in northern Japan, with related isolates in South Korea and eastern Russia.

Thus, the dramatic spread of clade 2 was been recent, and it accounts for virtually all reported human cases in the past few years.  However, most approved pre-pandemic vaccines target clade 1, which was the H5N1 in humans when vaccine development programs began in early 2005.

Stockpiling these vaccines, or those targeting early clade 2 isolates, will not be optimal for the current clade 2 in circulation, as the various sub-clades evolve away from the 2005 isolates.  Thus, these vaccines may be useful for priming patients now, but would have limited utility for a raging pandemic, and may in fact drive H5N1 evolution because of poor matches as seen in poultry vaccines.

However, use of these vaccine now, when H5N1 has not been established in human populations could delay adaptation to humans by reducing the number of human H5N1 infections.

Thus, the current policy of stockpiling older vaccine for use in first responders may have limited value if used after the pandemic begins, and use at that time may lead to a more rapid H5N1 evolution, which will decrease the utility of newer vaccines, which will still be chasing the evolving H5N1, even if the vaccine selection is limited to a pandemic H5N1 which has begun to emerge.

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