Thursday, July 19, 2018

Emerg. Microbes & Infect.: Low Zoonotic Potential Of Clade 2.3.4.4B H5N8 Virus

Asian H5 Evolution Through 2011



















#13,414

While we tend to talk about specific subtypes of influenza (H5N1, H5N8, H7N9, H3N2, etc.) as if they were a single entity, in truth each subtype can contain multiple clades, and within each of these clades there can be numerous subclades, running several layers deep (see H5N1 chart above).
Over time, the complexity and diversity of any successful virus increases, although many of these variants fade away, unable to compete with more biologically fit versions.
Drilling down even deeper, these subclades can be further divided into groups (A, B, C, etc.), - and if that isn't enough complexity for you - there can be significant genetic variation within each of these individual subclades/groups.

Not surprisingly, there can be big differences in the behavior - including the zoonotic potential - of different variants of the same subtype (see 2012's Differences In Virulence Between Closely Related H5N1 Strains).
This likely explains why some countries - like Egypt, Indonesia, and Vietnam - have reported a large number of human H5N1 infections - while other countries where the virus has also circulated have reported few or none.
The evolutionary chart above only deals with H5N1, but since 2011, several new HPAI H5 subtypes - descendants of H5N1 - have emerged, including H5N6 and H5N8.
And like H5N1 before it, these subtypes are building an impressive inventory of genetic variants. 
In 2014 a clade 2.3.4.4A  H5N8 virus - which initially emerged in Chinese poultry - spread like wildfire through South Korea's poultry industry.  Ten months later, it winged its way to North America - where it sparked the biggest avian epizootic in American history.  The virus also made a brief appearance in Europe.
Luckily, we saw no reports of human infection with this new subtype, although South Korea reported a number of exposed dogs developed antibodies  (see MAFRA: H5N8 Antibodies Detected In South Korean Dogs (Again)).
At roughly the same time, a new clade 2.3.4.4.C H5N6 virus appeared in China, Vietnam, and Laos, but unlike its H5N8 cousin, this virus has managed to jump to at least 16 people in China, killing 12 of them.

By the summer of 2015, the H5N8 virus had mysteriously vanished in North America, and it did not return for the winter of 2015-16 (see PNAS: The Enigma Of Disappearing HPAI H5 In North American Migratory Waterfowl). It was also a no show in Europe.

But the following fall (2017), a new - reassorted - 2.3.4.4 group B virus turned up in Germany, and rapidly spread across Europe, and into the Middle East and Africa (see EID Journal: Reassorted HPAI H5N8 Clade 2.3.4.4. - Germany 2016).
This group B version of clade 2.3.4.4. H5N8 virus was much more virulent in birds, spread faster and farther than any HPAI H5 virus we'd seen before, spawned new (H5N5 & H5N6 subtypes) and sparked the biggest epizootic in European history.
While we've seen no reports of human infection with either group A or group B clade 2.3.4.4. H5N8 viruses, we've seen cautionary reports suggesting the potential for zoonotic transmission remains.
J Vet Sci: Evolution, Global Spread, And Pathogenicity Of HPAI H5Nx Clade 2.3.4.4 
Study: Virulence Of HPAI H5N8 Enhanced By 2 Amino Acid Substitutions

Sci Rpts: H5N8 - Rapid Acquisition of Virulence Markers After Serial Passage In Mice
J. Virulence : Altered Virulence Of (HPAI) H5N8 Reassortant Viruses In Mammalian Models

Today we've a new study, published in Emerging Microbes and Infections, which pretty much confirms what we've observed over the past couple of years, finding a low zoonotic potential for clade 2.3.4.4.B H5N8 viruses.

It's a long, and detailed open-access paper, and so I've only included the abstract and a snippet from the discussion section. Follow the link to read it in its entirety, after which I'll return with a postscript.

A novel European H5N8 influenza A virus has increased virulence in ducks but low zoonotic potential

Christian Grund, Donata Hoffmann, Reiner Ulrich, Mahmoud Naguib, Jan Schink├Âthe, Bernd Hoffmann, Timm Harder, Sandra Saenger, Katja Zscheppang, Mario T├Ânnies, Stefan Hippenstiel, Andreas Hocke, Thorsten Wolff & Martin Beer
Emerging Microbes & Infections volume 7, Article number: 132 (2018)

Abstract


We investigated in a unique setup of animal models and a human lung explant culture biological properties, including zoonotic potential, of a representative 2016 highly pathogenic avian influenza virus (HPAIV) H5N8, clade 2.3.4.4 group B (H5N8B), that spread rapidly in a huge and ongoing outbreak series in Europe and caused high mortality in waterfowl and domestic birds.

HPAIV H5N8B showed increased virulence with rapid onset of severe disease and mortality in Pekin ducks due to pronounced neuro- and hepatotropism. Cross-species infection was evaluated in mice, ferrets, and in a human lung explant culture model. While the H5N8B isolate was highly virulent for Balb/c mice, virulence and transmissibility were grossly reduced in ferrets, which was mirrored by marginal replication in human lung cultures infected ex vivo.
Our data indicate that the 2016 HPAIV H5N8B is avian-adapted with augmented virulence for waterfowl, but has low zoonotic potential. The here tested combination of animal studies with the inoculation of human explants provides a promising future workflow to evaluate zoonotic potential, mammalian replication competence and avian virulence of HPAIV.

(SNIP)
Overall, high virulence and transmissibility in waterfowl are biological key features of the examined recent HPAIV H5N8 strain of clade 2.3.4.4 B, and judging on the massive mortality in wild birds in Europe, also of further reassortants of this clade. Interestingly, the augmented virulence for Pekin ducks seems to be connected with a higher virulence in Balb/C mice. Thus, the data from the Balb/C mouse model may be predictive for the virulence of HPAIV H5-viruses in ducks.
The results obtained by the ferret infection model were fully consistent with findings in a human lung explant infection model. The summarizing conclusion of a low zoonotic potential of these viruses is further supported by the observation that up to now no human cases have been reported for the H5N8B strain, despite the very broad distribution in the wild bird and poultry populations in many different countries and the re-emergence of the same strain in the last months in several European countries.
        (Continue . . . . )


Given the lack of reported human cases over the past two years, the above findings are hardly unexpected, but this paper does offer a potential framework for making future risk assessments of HPAIV strains.

If the past 20 years are any indication - there's unlikely to be a lack of new, emerging HPAIV strains to evaluate - and we've no guarantees that the next virus to emerge will have the same low zoonotic potential as the H5N8 viruses we've seen to date.

Because influenza, like time, marches on.

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