Researchers probe pandemic potential of H9N2 virus

Aug 14, 2008 (CIDRAP News) – Scientists have warned it's impossible to predict which avian influenza virus will spark the next pandemic, and while most of the attention has been on highly pathogenic H5N1, one research group is reporting new findings that raise concerns about the threat from the low-pathogenic H9N2 virus.

The international group of researchers, mainly from the University of Maryland, published their findings in the August issue of PLoS One (Public Library of Science One). They used ferrets, which have sialic acid receptors in their respiratory tracts resembling those in humans, to explore how H9N2 viruses replicate and transmit.

The H9N2 subtype has been found in many avian species in Asia, the Middle East, Europe, and Africa over the past decade, the authors write. The virus can cause mild-to-moderate disease in humans. In March 2007, Hong Kong officials reported that a 9-month-old girl was infected with the strain, the fourth time since 1999 that the virus was found in a child from that city.

US officials have worried that H9N2 could evolve into a pandemic strain. In 2004, the National Institute of Allergy and Infectious Diseases (NIAID) contracted with Chiron Corp. (now part of Novartis) to produce a vaccine against the virus. In Sept 2006 researchers reported that the experimental vaccine generated a good immune response in a phase 1 clinical trial. The contract tapped Chiron to produce 40,000 doses of a vaccine containing an inactivated strain of H9N2 developed by the Centers for Disease Control and Prevention.

The PLoS One report says that many H9N2 isolates have acquired human virus–like receptor specificity, preferentially binding alpha 2-6 sialic acid receptors.

The authors write that three other factors also fuel concerns about the potential of H9N2 to evolve into a pandemic strain. Some studies have shown that H9N2 viruses extensively evolve and reassort, while others have shown that the viruses have spread to pigs, which could provide a "mixing vessel" with influenza viruses that are more likely to infect humans. Also, serologic studies have suggested that there may be more human cases of H9N2 than have been detected and reported so far.

"Therefore, avian H9N2 viruses are in an ideal position to undergo further adaptation for more efficient transmission among mammals and humans," they write.

In their study, the searchers first evaluated whether five wild-type H9N2 viruses could infect ferrets and whether infected animals could spread the disease to other ferrets through direct contact and through the air. Lethargy, anorexia, and temperature elevations were noted in some of the ferrets that were inoculated with the virus, and the virus was found in nasal washes from all the inoculated ferrets. Most of the ferrets caged with the inoculated animals showed evidence of viral shedding and had H9 antibodies.

The authors write that the results suggest H9N2 infections in ferrets are similar to those in humans and pigs. "Our findings suggest that the ferret represents a good animal model to study the potential changes that could lead to efficient transmission of avian H9N2 viruses in humans," they state.

Next, they investigated whether one of the H9N2 viruses they used could be transmitted by aerosol to ferrets. Though the virus was found in the inoculated and direct-contact ferrets, they found no seroconversion in ferrets that were kept separate but shared the same air as the other animals. "Taken together, these data indicate that although some H9N2 viruses can transmit to direct contacts, they lack successful aerosol transmission," the report says.

The study also explored genetic-level aspects of H9N2 transmission in ferrets. For example, they found that:

  • A single change of glycine (Gln) to leucine (Leu) at amino acid position 226 in the hemagglutinin receptor binding site enhanced H9N2 replication
  • Leucine residue at position 226 of the hemagglutinin receptor binding site appears to select for human virus–like receptor specificity that enhances replication and direct contact transmission

Another goal was to determine if an H9N2 avian-human reassortment would enhance transmission of H9N2 strains that contained Leu226. Using reverse genetics, they recovered a reassortant that combined surface protein genes from H9N2 with internal genes from an H3N2 virus. Ferrets that were inoculated with the virus, as well as their direct contacts, had high H9 antibody titers, but the aerosol contacts did not.

The authors report that the reassortant virus showed enhanced shedding and transmission, but it lacked the ability to infect aerosol contacts. The reassortant also caused more severe damage in the lungs, replicating in both the upper and lower respiratory tracts, than a wild-type H9N2 virus.

The group concluded that H9N2 viruses are poised for further adaptation that could make transmission more efficient among mammals and humans. Though they did not find aerosol transmission, a key feature of a pandemic influenza strain, an abundance of other risk factors, such as the human virus-like specificity in some avian and swine isolates, build a strong case for H9N2 as a potential public health threat , they assert.

Wan H, Sorrell EM, Song H, et al. Replication and transmission of H9N2 influenza viruses in ferrets: evaluation of pandemic potential. PLoS One 2008 Aug;3(8):1-13 [Full text]

See also:

Mar 20, 2007, CIDRAP News story "Baby in Hong Kong infected with H9N2 avian flu"

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