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H7N9 poorly adapted to human binding receptors
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Avian influenza A(H7N9) has not acquired the mutations necessary to be transmitted easily from human to human, despite infecting more than 100 people and causing dozens of deaths in 2013, researchers have found.
“Luckily, H7N9 viruses just don't yet seem well adapted for binding to human receptors,” Ian A. Wilson, PhD, of The Scripps Research Institute (TSRI) in La Jolla, Calif., said in a press release.
Until this year, influenza A(H2N9) had never been reported in humans, but in February the virus infected dozens of people in two urban areas in eastern China. The total number of laboratory-confirmed cases reached 132, with 37 deaths as of May.
Data from early studies of H7N9 isolates from the outbreak suggested that the virus had acquired a mutation that substitutes the amino acid leucine for glutamine in the part of the virus that grabs receptors on host cells, making human-to-human transmission possible.
Findings from initial studies of H7N9 isolates in mice, ferrets and monkeys also suggested the virus had limited ability to spread among mammals.
“Because publications to date have implied that H7N9 has adapted to human receptors, we felt we should make a clear statement about this,” said James C. Paulson, PhD, chair of TSRI’s department of cell and molecular biology.
Paulson’s lab evaluated the H7N9 virus’s ability to bind the sialylated sugar receptors, the receptors that flu viruses normally attach on host cells. Subsequently, Wilson’s lab used X-ray crystallography to determine the atomic structures of the H7N9 hemagglutinin protein that bound to the sialic acid receptor molecules, according to the findings published online in Science.
The researchers tested the ability of the virus’s hemagglutinin protein to bind to different human and avian receptor variants.
Influenza A/Shanghai/2/2013 H7N9 demonstrated a strong preference for avian-type receptors and “binds to human-type receptor variants only weakly,” the researchers found.
Specifically, influenza A/Shanghai/2/2013 H7N9 hemagluttinin protein made loose contacts with human-type receptors compared with the snug couplings it makes with certain avian-type receptors.
“These results suggest that we should continue to observe H7N9 and see if it undergoes any changes that make it more likely to spread in the human population,” Wilson said.
If H7N9 acquires the ability to bind with human receptors, it could “potentially spread among humans much better than it does now,” Paulson said.
Disclosure:The researchers report no relevant financial disclosures.
Perspective
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Theodore C. Eickhoff, MD
These studies, carried out at The Scripps Research Institute and using two different laboratory methodologies, show quite clearly that the H7N9 hemagglutinin protein binds only weakly to receptors on human host cells, whereas it bounds quite tightly to avian receptor cell surfaces. Nonetheless, a sufficient inoculum of H7N9 virus is capable of infecting humans, but thus far there has been no absolutely convincing evidence of human-to-human transmission. Though there have been several instances of possible such transmission, there certainly has been no sustained human-to-human transmission. The investigators urge continued close observation for mutation(s) that might facilitate more frequent transmission to humans.
Would it be sufficient to simply watch and observe closely? Absolutely not, and, fortunately, public health authorities are already pursuing vaccine development. Researchers in Australia have already done an immunogenicity trial using an adjuvant from the Commonwealth Serum Laboratories, and reported very promising results (See the Nov. 13, 2013, NEJM Letter to the Editor from Novavax;doi:10.1056/NEJMc1313186).
A trial of Sanofi-Pasteur’s adjuvanted H7N9 vaccine is or will shortly be underway in the United States. When effective vaccines are approved, licensed, and on the shelf, then it might be possible to sit back and observe, hoping that the vaccines will never need to be used.
Meanwhile, this virus has clearly reawakened with the onset of influenza season, and there have been six or seven cases in China in the past 2 months. Of interest is that there have been two cases in Hong Kong, both of whom were probably infected on the mainland at bird markets. Hong Kong authorities have taken the somewhat drastic step of sending a group of about 20 of the closest contacts of the first case off to a vacation spa for enforced isolation and close observation and testing. This was the first time this step has been taken since the SARS epidemic in 2003. Over-reaction? Perhaps most of us in the United States might think so, but remember that infection caused by this virus, infrequent though it might be, still results in an almost 33% mortality rate.
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