WHO changes H5N1 strains for pandemic vaccines, raising concern over virus evolution

Aug 18, 2006 (CIDRAP News) – The World Health Organization (WHO) today changed the H5N1 avian influenza strains recommended for candidate vaccines for the first time since 2004, causing some experts to question how far the virus has evolved.

The WHO's new prototype strains, prepared by reverse genetics, include three new H5N1 subclades.

The hemagglutinin sequences of most of the H5N1 avian influenza viruses circulating in the past few years fall into two genetic groups, or clades. Clade 1 includes human and bird isolates from Vietnam, Thailand, and Cambodia and bird isolates from Laos and Malaysia. Clade 2 viruses were first identified in bird isolates from China, Indonesia, Japan, and South Korea before spreading westward to the Middle East, Europe, and Africa. The clade 2 viruses have been primarily responsible for human H5N1 infections that have occurred during late 2005 and 2006, according to WHO.

Genetic analysis has identified six subclades of clade 2, three of which have a distinct geographic distribution and have been implicated in human infections:

  • Subclade 1, Indonesia
  • Subclade 2, Middle East, Europe, and Africa
  • Subclade 3, China

On the basis of the three subclades, the WHO is offering companies and other groups that are interested in pandemic vaccine development these three new prototype strains:

  • An A/Indonesia/2/2005-like virus
  • An A/Bar headed goose/Quinghai/1A/2005-like virus
  • An A/Anhui/1/2005-like virus

Report raises alarm, offers opportunities
Michael T. Osterholm, PhD, MPH, a leading pandemic preparedness expert, said recognition of the three subclades demonstrates how diverse the virus is and how dynamically it is evolving. He said the WHO notice is more important for the questions it raises than for the vaccine guidance it contains. "Does that mean H5N1 is closer to becoming an agent that can readily transmit human-to-human? That's the billion dollar question," he told CIDRAP News. Osterholm is director of the University of Minnesota's Center for Infectious Disease Research and Policy, publisher of the CIDRAP Web site.

Many experts who follow the ongoing analysis of the H5N1 virus sequences are alarmed at how fast the virus is evolving into an increasingly more complex network of clades and subclades, Osterholm said. The evolving nature of the virus complicates vaccine planning. He said if an avian influenza pandemic emerges, a strain-specific vaccine will need to be developed to treat the disease.

Recognition of the three new subclades means researchers face increasingly complex options about which path to take to stay ahead of the virus, he commented. Their goal is to develop a vaccine that is effective against a broad array of virus strains, one of which may be the pandemic trigger. "Does that mean one of these subclades is the lucky or unlucky one? That's the key issue," Osterholm said.

Paul Targonski, MD, PhD, a genetics epidemiology expert who works in vaccine research at the Mayo Clinic in Rochester, Minn., said that the WHO's release of the subclade strains is an important, progressive development in vaccine research. What's new for vaccine researchers is seeing the smaller differences between the H5N1 virus clades, he told CIDRAP News.

Though the information makes the development of an H5N1 vaccine more complex, it also provides good information for designing more targeted and effective vaccines, Targonski said.

Next steps for vaccine developers
Some researchers will use the WHO's new prototype strains to develop vaccines to treat regional outbreaks, while others will use them to craft a more global vaccine that addresses the most common H5N1 virus strains, Targonski predicted.

Until now, researchers have been working on prepandemic vaccines for H5N1 viruses in clade 1. In March, the first clinical trial of a US vaccine for H5N1 showed modest results. In May, French researchers showed somewhat better results in a clinical trial of an H5N1 vaccine that included an adjuvant.

Vaccine experts aren't sure if a vaccine effective against known H5N1 viral strains would be effective against future strains. Although the new viruses will now be available for vaccine research, WHO said clinical trials using the clade 1 viruses should continue as an essential step in pandemic preparedness, because the trials yield useful information on priming, cross-reactivity, and cross-protection by vaccine viruses from different clades and subclades.

See also:

Mar 30 CIDRAP News article "H5N1 vaccine trial shows limited benefit"

April 11 CIDRAP News article "Would an imperfect vaccine be useful in a flu pandemic?"

May 12 CIDRAP News article "Sanofi reports results for H5N1 vaccine with adjuvant"

Jul 20, 2005 CIDRAP News article "WHO won't change H5N1 strains picked for vaccines"

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