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H5N1 Pre-pandemic Vaccine Plans in Japan

Recombinomics Commentary 15:33
April 18, 2008

Japan has already stockpiled 20 million doses of so-called "pre-pandemic" bird flu vaccine for use after a major outbreak.

The plan is to initially use 6,400 doses of vaccine to inoculate doctors, quarantine inspectors and other health and immigration officials.

If successful, the government aims to expand the programme to others.

"If we obtain good results over its effectiveness and safety, we want to consider vaccinating (an additional) 10 million people who are in medical occupations" or other key jobs such as at utilities, Mr Masuzoe told reporters.

The above comments describe Japan’s plans to implement a pre-pandemic vaccination strategy.  Although many countries have pandemic vaccines in clinical trials, most have announced plans to stockpile such vaccines, instead of using the vaccine in a strategy targeted at preventing a pandemic or immunizing first responders.

Japan’s decision is not a surprise.  Although they have only confirmed one H5N1 outbreak, neighboring South Korea has now reported H5N1 outbreaks in 3 of the last 5 seasons.  These outbreaks have been linked to wild birds and there is little doubt that the H5N1 in South Korea is also in Japan.

Recent vaccine results for poultry has had mixed results.  One of the more alarming developments has been in Egypt, where H5N1 has been isolated from vaccinated stocks.  The sequence of the HA from these isolates had a large number of non-synonymous changes, which were likely involved in the immunological escape.  The recent H5N1 from Israel had the same series of changes, raising concerns about rapid H5N1 evolution, which may be linked to mismatched vaccines.  However, the mis-matches are more of a concern for poultry vaccination programs, because H5N1 can be efficiently transmitted from bird to bird, especially in domestic poultry.  In addition, the Israeli isolate, like the recent isolate from Saudi Arabia, was amantadine resistant.  Moreover, wild bird isolates from Astrakhan were oseltamivir (Tamiflu) resistant, suggesting that anti-viral may have limited utility in controlling a rapidly expanding pandemic.

Similarly, creating a useful vaccine after the pandemic has gained momentum is also unlikely to be effective.  H5N1 diversity has grown markedly in the past few years.  There are now four distinct sub-clades linked to human cases, and there is further diversity within the sub-clade.  Thus, H5N1 could evolve rapidly during vaccine generation, reducing vaccine effectiveness.  This effectiveness would be further compromised because the target population is immunologically naive and would likely require booster shots.

Thus, plans to create a vaccine after a pandemic has begun are unlikely to be successful.

In contrast, a pre-pandemic vaccine would primer the target population and may protect from an H5N1 that is not efficiently transmitted.  Thus, the vaccine could delay the start of a pandemic.  Moreover, vaccine costs are minimal, as seen in the trivalent vaccine to treat seasonal flu.  That vaccine contains three different viruses and is available at nominal cost.  Due to the rapid evolution of H5N1, a trivalent H5N1 vaccine may be an approach that would produce cross reactive immunity.

The likelihood of a H5N1 pandemic remains high.  The current versions of H5N1 emerged out of China in late 2003/2004.  The movement of H5N1 into long range migratory birds has produced an major geographical expansion, and the clade 2.2 strain has been reported in over 50 countries in he past few days.  Moreover, receptor binding domain changes have been associated with clusters in multiple countries in the Middle East, and these clusters have maintained a high case fatality rate.  Recent data on receptor binding domain changes suggest one or two changes could produce an efficiently transmitted H5N1, which when linked to the current high case fatality, would have catastrophic consequences.

Germany and Switzerland are also considering implementation of a pre-pandemic vaccine, as are Vietnam and Indonesia.  It is likely that such a concept will spread in the upcoming months, as the persistence of H5N1 increases, along with its genetic diversity.

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