Thursday, October 19, 2017

Cell Host & Microbe: HPAI H7N9 Lethality & Transmission In Ferrets

Credit CDC MMWR Sept 2017


Since if first emerged in China in early 2013, LPAI (low path) H7N9 has been viewed as having enhanced pandemic potential - at least compared to other avian flu viruses.  While H7N9 appeared on the decline in its 3rd and 4th epidemic waves, last winter the number of cases in Mainland China literally exploded (see chart above), nearly equaling the total of the first four epidemic waves combined. 
The CDC's Influenza Risk Assessment Tool (IRAT) ranks the newly emerged Yangtze River Delta lineage along with the original Pearl River Delta Lineage (see Updating the CDC's IRAT (Influenza Risk Assessment Tool) Rankings) at the top of their list of viruses with the greatest pandemic potential.
But along with these LPAI viruses, a new HPAI (highly pathogenic) H7N9 virus emerged in Gaungdong province last winter, and quickly began to spread to other provinces. Although case reports are limited, there has been some early evidence suggesting this HPAI version might pose an even greater threat to human health (see Eurosurveillance: Epidemiology of Human HPAI H7N9 Infection - Guangdong Province).

So concerned have Chinese officials been over this HPAI version, this summer - for the first time -  China's MOA Ordered An HPAI H7N9 Vaccine Deployed Nationwide This Fall. It isn't known how effective this new vaccine will be, how well it can be deployed this winter, or what the fallout from using this vaccine might be (see New Scientist: The Downsides To Using HPAI Poultry Vaccines).
While avian influenza viruses have been a concern for nearly two decades, their public health impact has been limited by their inability to spread efficiently or in a sustained manner from human-to-human.  
Infections are generally (but not always) acquired from exposure to infected birds (or their environment) and are only rarely passed on. Avian flu viruses remain better adapted to avian hosts, rather than mammals. 
That said, we've seen increased signs of mammalian adaptation over the years (see Eurosurveillance: Genetic Tuning Of Avian H7N9 During Interspecies Transmission and Nature Comms.: NS Mutation Enhances H7N9's Ability To Infect Humans).
Although we've seen some preliminary analyses of this new HPAI H7N9 virus, today we get our most detailed look at how well it infects, and can be spread by, mammalian hosts.  And the headline is: HPAI H7N9 appears to be better adapted to mammalian hosts - and potentially a bigger pandemic threat - than its LPAI precursors.

Not only is this new HPAI H7N9 virus lethal in ferrets, it transmits well between them via respiratory droplets, and has shown an elevated level of resistance to oseltamivir (aka Tamiflu).
While not unexpected, these are the sorts of evolutionary changes in an HPAI virus that no one wants to see.
The study, conducted by an international team of researchers led by Yoshihiro Kawaoka, came off embargo today at noon. They tested a wild type HPAI H7N9 virus - along with two nearly identical lab created variants - one sensitive to oseltamivir and one with a mutation to make it resistant to the antiviral.
While the resistant strain wasn't quite as robust (or pathogenic) as the others, they all infected, replicated in, and caused varying degrees of illness in mice, ferrets and macaques.
First, some excepts from the press release provided by the University of Wisconsin-Madison, followed by a link to the 21 page, highly detailed and (fair warning) often technical study.

There's a lot here to absorb, and I've only included some excerpts, so you'll want to download and read both in their entirety. 

H7N9 influenza is both lethal and transmissible in animal model for flu
University of Wisconsin-Madison

MADISON, Wis. -- In 2013, an influenza virus that had never before been detected began circulating among poultry in China. It caused several waves of human infection and in late 2016, the number of people to become sick from the H7N9 virus suddenly started to rise. As of late July 2017, nearly 1,600 people had tested positive for avian H7N9. Nearly 40 percent of those infected had died.

In early 2017, Yoshihiro Kawaoka, professor of pathobiological sciences at the University of Wisconsin-Madison School of Veterinary Medicine, received a sample of H7N9 virus isolated from a patient in China who had died of the flu. He and his research team subsequently began work to characterize and understand it. The first of those results are published today (Oct. 19, 2017) in Cell Host & Microbe.

For the first time, Kawaoka says, his team has identified an influenza virus strain that is both transmissible between ferrets (the best animal model proxy for human influenza infections) and lethal, both in the animal originally infected and in otherwise healthy ferrets in close contact with these infected animals.

"This is the first case of a highly pathogenic avian virus that transmits between ferrets and kills them," Kawaoka says. "That's not good for public health."


H7N9 virus is likely to continue to mutate as it infects humans, resulting in adaptations that enhance the viruses' pathogenicity or ability to pass from person to person, Kawaoka adds. In other words, nature is already performing its own gain-of-function experiments, with potentially serious consequences.

It has, however, become a bit easier recently to detect when poultry are infected with H7N9, thereby allowing people to limit their exposure. That's because the virus has begun to kill birds in China, too. But unlike in the U.S., where farmers cull their flocks to limit the spread of infectious disease, China relies on vaccines. This worries Kawaoka, given how well the virus has been shown to grow.

For now, he says: "We should improve our surveillance."
(Continue . . . )

A Highly Pathogenic Avian H7N9 Influenza Virus Isolated from A Human Is Lethal in Some Ferrets Infected via Respiratory Droplets

Masaki Imai8,'Correspondence information about the author Masaki ImaiEmail the author Masaki Imai, Tokiko Watanabe8, Maki Kiso8, Noriko Nakajima8, Seiya Yamayoshi8, Kiyoko Iwatsuki-Horimoto8, Masato Hatta8, Shinya Yamada, Mutsumi Ito, Yuko Sakai-Tagawa, Masayuki Shirakura, Emi Takashita, Seiichiro Fujisaki, Ryan McBride, Andrew J. Thompson, Kenta Takahashi, Tadashi Maemura, Hiromichi Mitake, Shiho Chiba, Gongxun Zhong, Shufang Fan, Kohei Oishi, Atsuhiro Yasuhara, Kosuke Takada, Tomomi Nakao, Satoshi Fukuyama, Makoto Yamashita, Tiago J.S. Lopes, Gabriele Neumann, Takato Odagiri, Shinji Watanabe, Yuelong Shu, James C. Paulson, Hideki Hasegawa, Yoshihiro Kawaoka9,'

Correspondence (M.I.), (Y.K.)

In Brief

Highly pathogenic avian influenza (HPAI) H7N9 viruses have emerged and raised concerns of a pandemic. Imai et al.characterized an HPAI H7N9 virus isolated from a human. This virus transmitted among ferrets without prior adaptation and caused lethal infection in animals, demonstrating its pandemic potential and the need for surveillance.


    • Highly pathogenic avian influenza (HPAI) H7N9 viruses replicate efficiently in mammals
    • HPAI H7N9 viruses are more pathogenic than low pathogenic H7N9 viruses in mammals
    • HPAI H7N9 viruses transmit via respiratory droplets among ferrets
    • HPAI H7N9 viruses show low sensitivity to neuraminidase inhibitors in mice

(Continue . . . .)

While concerning, none of this guarantees that H7N9 will spark a human pandemic. There may yet be some species specific barrier - or some other obstacle - that could prevent that from happening.
What this study does suggest is that the recently emerged HPAI H7N9 virus appears further along the evolutionary path that could eventually take it in that direction than the other viruses we've been following.
I expect this study will spark a good deal of discussion in the coming days, along with renewed calls for pandemic preparedness. Because - while the cause of the next pandemic may still be in doubt - another pandemic is considered more or less inevitable.

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