Evolution of H7 Avian Influenza: Another Pandemic Candidate?
By Matthew Watson, June 6, 2008
Since 2002, H7 strains of influenza virus have caused both highly pathogenic (HPAI) and low pathogenic (LPAI) avian influenza outbreaks in poultry in North America and Eurasia.* To date, almost all human cases of H7 infection have manifested as conjunctivitis, rather than as respiratory infection. Now, a study just published by Belser and colleagues1 provides evidence that recent H7 strains from Canada and the northeast U.S. have acquired host binding receptors with an increased affinity for the type of binding sites found in the human respiratory tract. This adaptation of viral attachment sites to human respiratory tract receptors is thought to be an essential step in the evolution of a pandemic virus. The researchers also found that at least one H7 strain is now able to spread efficiently between ferrets, which have receptors similar to those in humans.
Adaptations in Viral Receptors May Alter Host Range
Like all avian influenza viruses, including the highly virulent H5N1 subtype, H7 avian influenza strains are not easily transmitted from birds to humans. When human infections do occur, the viruses are rarely transmitted from person to person, in part because sialic acid (SA) receptors in the human respiratory tract are not the same as those in birds: birds have αlpha 2-3 SA receptors in their guts, whereas humans have αlpha 2-6 SA receptors in their respiratory tracts. Viruses adapted to attach well to one type of SA receptor generally cannot attach well to the other. Binding to SA receptors occurs via specific sites present on the viral hemagglutinin surface glycoprotein, and the hemagglutinin of most H7 strains displays a high affinity for αlpha 2-3 SA receptors.
Using glycan microarray to quantify receptor affinity, Belser and colleagues analyzed 9 distinct H7 strains. They determined that two recent H7N7 strains from Europe did have classic affinity to αlpha 2-3 SA receptors, as did a North American strain from 1993. However, moderate to strong binding to αlpha 2-6 SA receptors was observed in all 5 North American strains obtained after 2002.
Transmissibility in One Strain Observed in Ferret Model
To assess the effect on transmissibility of these alterations in receptor affinity, the researchers tested 6 strains in ferrets to see if infection could be passed from one animal to another. Although 3 of the 6 stains had enhanced affinity for αlpha 2-6 SA receptors, only one strain, A/NY/107/03, was able to spread from inoculated to naïve animals. This spread occurred by direct contact and not by respiratory transmission. Unlike the others, this strain had caused respiratory rather than conjunctival infection in man, and it showed the greatest affinity for αlpha 2-6 SA receptors and the least affinity for αlpha 2-3 SA receptors in all of the viruses that were tested. Thus, both strong αlpha 2-6 SA affinity and weak αlpha 2-3 SA affinity seem to be required for transmission. Acquisition of this trait may be one step in the evolution of a virus with pandemic potential.
Increased Surveillance and Cross-Protective Vaccines Needed
Belser and colleagues conclude that increased disease surveillance and clinical vigilance are needed for rapid identification of further viral evolution. Their results also suggest significant implications for pre-pandemic influenza vaccine development. Because it is unclear whether either seasonal or HPAI H5N1 vaccines currently in development would provide cross protective immunity to an H7 challenge, the need for broad spectrum influenza vaccines is more apparent. Toward this end, the U.S. Department of Health and Human Services is funding the development of H7 influenza vaccine candidates2.
*Isolated human infections have been reported in British Columbia3 (HPAI H7N3, 2004), the United Kingdom4 (LPAI H7N2,2007) and New York(LPAI H7N2, 2003). In 2003, at a poultry farm in the Netherlands, an epidemic of HPAI H7N7 caused more than 80 human cases and one death5.
Belser JA, Blixt O, Chen LM, et al. Contemporary North American influenza H7 viruses possess human receptor specificity: Implications for virus transmissibility. ProcNatl Acad Sci. 2008;105:7558-7563.
Joseph T, McAuliffe J, Lu B, et al. Evaluation of replication and pathogenicity of avian influenza a H7 subtype viruses in a mouse model. J Virol. 2007;81(19): 10558-66.
Hirst M, Astell CR, Griffith M, et al. Novel avian influenza H7N3 strain outbreak, British Columbia. Emerg Infect. 2004;10:2192-2195.
Avian influenza A/(H7N2) outbreak in the United Kingdom. Euro Surveill. 2007;12(5):E070531.2
Fouchier RA, Schneeberger PM, Rozendaal FW, et al. Avian influenza A Virus (H7N7) associated with human conjunctivitis and a fatal case of acute respiratory distress syndrome. Proc Natl Acad Sci.2004;101:1356-1361.