Friday, January 05, 2018

mSphere: Human Clade A/H5N6 Influenza Virus Lacks Mammalian Adaptation Markers


Given that in the four years since it first emerged in China (and its frequent side trips to Laos, Vietnam, South Korea, Japan, etc.) - we only have 17 confirmed human infections - you can make a pretty good prima facie case for clade HPAI H5N6 not being particularly adept at making the zoonotic leap to humans. 
When it does happen, however, the results have often proved fatal. 
We've a new study with an excellent pedigree (Peiris & Fouchier, among others) that characterizes a specific H5N6 isolate (A/H5N6 A/Guangzhou/39715/2014) retrieved from a human case, in vitro and in ferrets. 

While they find this particular H5N6 isolate to cause more severe disease in ferrets than other clade HPAI H5 viruses, it did not transmit via the airborne route among ferrets, and it lacked two of three recongnized primary mammalian adaptations. 

Human Clade A/H5N6 Influenza Virus Lacks Mammalian Adaptation Markers and Does Not Transmit via the Airborne Route between Ferrets

Sander Herfst, Chris K. P. Mok, Judith M. A. van den Brand, Stefan van der Vliet, Miruna E. Rosu, Monique I. Spronken, Zifeng Yang, Dennis de Meulder, Pascal Lexmond, Theo M. Bestebroer, J. S. Malik Peiris, Ron A. M. Fouchier, Mathilde Richard
W. Paul Duprex, Editor

DOI: 10.1128/mSphere.00405-17


Since their emergence in 1997, A/H5N1 influenza viruses of the A/goose/Guangdong/1/96 lineage have diversified in multiple genetic and antigenic clades upon continued circulation in poultry in several countries in Eurasia and Africa. Since 2009, reassortant viruses carrying clade hemagglutinin (HA) and internal and neuraminidase (NA) genes of influenza A viruses of different avian origin have been detected, yielding various HA-NA combinations, such as A/H5N1, A/H5N2, A/H5N3, A/H5N5, A/H5N6, and A/H5N8.
Previous studies reported on the low pathogenicity and lack of airborne transmission of A/H5N2 and A/H5N8 viruses in the ferret model. However, although A/H5N6 viruses are the only clade viruses that crossed the species barrier and infected humans, the risk they pose for human health remains poorly characterized.
Here, the characterization of A/H5N6 A/Guangzhou/39715/2014 virus in vitro and in ferrets is described. This A/H5N6 virus possessed high polymerase activity, mediated by the E627K substitution in the PB2 protein, which corresponds to only one biological trait out of the three that were previously shown to confer airborne transmissibility to A/H5N1 viruses between ferrets.
This might explain its lack of airborne transmission between ferrets. After intranasal inoculation, A/H5N6 virus replicated to high titers in the respiratory tracts of ferrets and was excreted for at least 6 days. Moreover, A/H5N6 virus caused severe pneumonia in ferrets upon intratracheal inoculation. Thus, A/H5N6 virus causes a more severe disease in ferrets than previously investigated clade viruses, but our results demonstrate that the risk from airborne spread is currently low.

IMPORTANCE Avian influenza A viruses are a threat to human health, as they cross the species barrier and infect humans occasionally, often with severe outcome. The antigenic and genetic diversity of A/H5 viruses from the A/goose/Guangdong/1/96 lineage is increasing, due to continued circulation and reassortment in poultry, posing a constant risk for public health and requiring regular risk assessments.
Here we performed an in-depth characterization of the properties of the newly emerged zoonotic A/H5N6 virus in vitro and in ferrets. The lack of airborne transmission in the ferret model indicates that A/H5N6 virus does not pose a direct public health threat, despite the fact that it can replicate to high titers throughout the respiratory tracts of ferrets and cause more severe disease than other clade viruses.
         (Continue . . . )

Obviously good news, but findings which must be tempered by the knowledge that more than a year ago there were at least 34 known genotypes of H5N6 (see Cell Host Microbe: Genesis, Evolution and Prevalence of HPAI H5N6 In China) - four of which had infected humans - and these results only deal with one.

Last November, in Nature Sci Rpts: H5N6 Viruses Exhibit Varying Pathogenicity & Transmissibility In Mammals, we looked at a Journal Nature (open access) report that compared three genetically similar, but behaviorally different, H5N6 viruses collected in Hubei Province, China.
  • One of the variants (CK918) produced only minor physical effects on inoculated lab mice, and zero mortality, while two others (DK01 and CK165) produced rapid weight loss, and a high mortality rate
  •  In transmission testing (using guinea pigs) CK918 and DK01 did not appear to transmit via direct contact or aerosol route, but CK165 transmitted to 2 out of 3 guinea pigs via direct contact (but not aerosol).
While none of that makes H5N6 ready for prime time, it does illustrate that if you've seen one H5N6 virus . . . you haven't seen them all.  

And in today's mSphere report, the authors note that there is considerable (and growing) diversity among clade H5N6 viruses, and that other strains will need to be checked as well. They write:
To conclude, the results from this study demonstrate that an A/H5N6 virus of the G1 genotype is not fully adapted to mammalian hosts and therefore presents a low risk to humans, although it caused more severe disease in ferrets than other clade viruses.
However, considering the diversity of genotypes among A/H5N6 viruses, more extensive characterization and risk assessment of A/H5N6 viruses of different genotypes is required in order to completely assess the risks. Moreover, owing to its pathogenicity in ferrets and its antigenic divergence from other A/H5 Gs/Gd viruses, A/H5N6 GZ/14 virus could be used as a challenge candidate for vaccination/challenge studies to assess the ability of different vaccination strategies to elicit protective responses to emerging Gs/Gd HPAI viruses.

For some more recent blogs on the evolution of avian H5N6, you may wish to revisit:

Study: Experimental Infection Of Dogs With HPAI H5N1 & HPAI H5N6
Virology: Five Distinct Reassortants of HPAI H5N6 In Japan - Winter 2016–2017

Arch. Of Virology: Novel Reassortant H5N6 Isolated From Cats - Eastern China
Emerg. Microbes & Inf.: Human Infections With A Novel Reassortant H5N6

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