Nature: Dissemination, Divergence & Establishment of H7N9 In China

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On a day that has hardly lacked for avian flu news (see APHIS: HPAI H5N2 Confirmed In Arkansas Turkey Flock & WHO: Updated H5N1 Cumulative Case Count Table), perhaps the most eagerly awaited story has been the publication of an analysis of the H7N9 virus in China, authored by a veritable `Who’s Who’ of virology.

Since both Declan Butler and Debra Mackenzie have already published overviews, I’ll avoid re-inventing the wheel and post the link to the article followed by links to both of their reports.

 

Dissemination, divergence and establishment of H7N9 influenza viruses in China

Tommy Tsan-Yuk Lam, Boping Zhou, Jia Wang, Yujuan Chai, Yongyi Shen, Xinchun Chen, Chi Ma, Wenshan Hong, Yin Chen, Yanjun Zhang, Lian Duan, Peiwen Chen, Junfei Jiang, Yu Zhang, Lifeng Li, Leo Lit Man Poon, Richard J. Webby, David K. Smith, Gabriel M. Leung, Joseph S. M. Peiris, Edward C. Holmes, Yi Guan & Huachen Zhu

 Since 2013 the occurrence of human infections by a novel avian H7N9 influenza virus in China has demonstrated the continuing threat posed by zoonotic pathogens^{1, 2}. Although the first outbreak wave that was centred on eastern China was seemingly averted, human infections recurred in October 2013 (refs 3, 4, 5, 6, 7). It is unclear how the H7N9 virus re-emerged and how it will develop further; potentially it may become a long-term threat to public health. Here we show that H7N9 viruses have spread from eastern to southern China and become persistent in chickens, which has led to the establishment of multiple regionally distinct lineages with different reassortant genotypes. Repeated introductions of viruses from Zhejiang to other provinces and the presence of H7N9 viruses at live poultry markets have fuelled the recurrence of human infections. This rapid expansion of the geographical distribution and genetic diversity of the H7N9 viruses poses a direct challenge to current disease control systems. Our results also suggest that H7N9 viruses have become enzootic in China and may spread beyond the region, following the pattern previously observed with H5N1 and H9N2 influenza viruses^{8, 9}.

 

Declan Butler’s piece in Nature News:

 

Flu genomes trace H7N9's evolution and spread in China

But surveillance of avian influenza viruses is patchy and slow.

• Declan Butler

11 March 2015

No one knows whether the H7N9 avian influenza that has infected more than 560 people in China and killed 204 might yet evolve to spread easily among people. But the largest-ever genomic survey of the virus in poultry now provides a more detailed picture of its evolution and and spread.

(Continue . . .)

And from Debra McKenzie at New Scientist has this take:

 

Threatwatch: Bird flu's back and it's brought friends

• 18:00 11 March 2015 by Debora MacKenzie
• For similar stories, visit the Bird Flu Topic Guide

Threatwatch is your early warning system for global dangers, from nuclear peril to deadly viral outbreaks. Debora MacKenzie highlights the threats to civilisation – and suggests solutions

H5N1 bird flu burst out of China in 2003 and stormed across Eurasia and into Africa three years later. It's been there ever since and this week its victims are Egyptians. Now another strain of bird flu, H7N9, is spreading in China and the signs are that it might soon rampage across the continent just like H5N1.

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The growing diversity of – and perceived threat from – the H7N9 virus isn’t new.  We’ve been following its progress for several years, in studies such as:

 

PNAS: Evolution Of H9N2 And It’s Effect On The Genesis Of H7N9

Eurosurveillance: Genetic Tuning Of Avian H7N9 During Interspecies Transmission

EID Journal: H7N9 As A Work In Progress

And practically each step along the way, we’ve been warned:

Overall, due to the genetic tuning procedure, the potential pandemic risk posed by the novel avian influenza A(H7N9) viruses is greater than that of any other known avian influenza viruses.

While today’s study in Nature supports this notion, coming up from behind are a plethora of HPAI H5 viruses (H5N1, H5N2, H5N3,H5N6, H5N8), which have made a dramatic showing the past few months, particularly in Egypt, where we are seeing the worst human outbreak of H5N1 since that virus emerged more than a decade ago.

 

Add in the continually reassorting HPAI H5 variants spreading rapidly around the globe, and 2 weeks ago we saw a statement from  WHO: H5 Currently The Most Obvious Avian Flu Threat.

While we can debate whether H7 or H5 has the greatest chance of sparking a pandemic, the bottom line is that with this large of a novel flu field in place, the risks of having one of them make that leap are probably better than they have been in years.

Nature: 100% Of Ebola Infected Macaques Recovered With ZMapp

 

 

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The wires are buzzing this afternoon with details on a freshly published study in the Journal Nature that looks at the outcome of 21 Ebola-infected Rhesus Macaques – 18 of which received the ZMapp monoclonal antibody cocktail. Incredibly, 100% of the treated monkeys – even those treated 5 days post exposure and already symptomatic – recovered.

 

First a link to the study, then I’ll be back with more.

 

Reversion of advanced Ebola virus disease in nonhuman primates with ZMapp

Xiangguo Qiu, Gary Wong, Jonathan Audet, Alexander Bello, Lisa Fernando, Judie B. Alimonti, Hugues  Fausther-Bovendo, Haiyan Wei, Jenna Aviles, Ernie Hiatt, Ashley Johnson, Josh Morton,  Kelsi Swope, Ognian Bohorov, Natasha Bohorova, Charles Goodman, Do Kim, Michael H. Pauly, Jesus Velasco, James Pettitt, Gene G. Olinger, Kevin Whaley, Bianli Xu, James E. Strong, Larry Zeitlin et al.

 (2014) doi:10.1038/nature13777

Published online 29 August 2014

ABSTRACT

Without an approved vaccine or treatment, Ebola outbreak management has been limited to palliative care and barrier methods to prevent transmission. These approaches, however, have yet to end the 2014 outbreak of Ebola after its prolonged presence in West Africa. Here we show that a combination of monoclonal antibodies (ZMapp), optimized from two previous antibody cocktails, is able to rescue 100% of rhesus macaques when treatment is initiated up to 5 days post-challenge. High fever, viraemia and abnormalities in blood count and blood chemistry were evident in many animals before ZMapp intervention. Advanced disease, as indicated by elevated liver enzymes, mucosal haemorrhages and generalized petechia could be reversed, leading to full recovery. ELISA and neutralizing antibody assays indicate that ZMapp is cross-reactive with the Guinean variant of Ebola. ZMapp exceeds the efficacy of any other therapeutics described so far, and results warrant further development of this cocktail for clinical use.

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Quite simply, a remarkable success rate by any measure. And while you can’t guarantee you’d see the same kind of results in human patients, it is highly encouraging.

 

That said, this news must also be tempered by fact that the existing limited supply of ZMapp has been exhausted, and it is expected that it will take weeks or even months to produce even a small quantity of the drug.

 

A pair of reports on this from two of the best science writers in the business. First this from Maggie Fox of NBC news.

 

ZMapp Saves Sick Monkeys From Ebola, Study Finds

By Maggie Fox

An experimental treatment used to treat two sick American missionaries saved a batch of monkeys infected with Ebola virus, even days after they got sick, researchers reported on Friday.

What works in monkeys doesn’t always work in humans, but it’s a piece of good news for the makers of ZMapp, a cocktail of engineered antibodies meant to boost the body’s defenses against the virus. ZMapp, made by California-based Mapp Biopharmaceutical, is grown in tobacco plants and is meant to improve on an old-fashioned approach that uses transfusions of blood from people who have survived an infection.

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And this from Helen Branswell of the Canadian Press.

 

Winnipeg lab created, tested Ebola drug ZMapp

By Helen Branswell The Canadian Press

 TORONTO – The experimental Ebola drug ZMapp was able to save infected monkeys even when treatment was only begun five days after the animals were infected, a new study shows.

This is the first research to demonstrate that an Ebola therapy could save primates if given so late in the course of their illness — a circumstance that more closely reflects how an Ebola drug would be used in people in an outbreak.

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For more on ZMapp you may wish to revisit  CDC FAQ On Experimental Ebola Treatments & Vaccine Development.

Nature Comms: A Chimeric Bat Flu Study

Credit CDC

 

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Two and a half years ago the influenza world was rocked by news of the detection of a new subtype of influenza A (H17N10), found to reside in little yellow-shouldered bats captured in Guatemala (see A New Flu Comes Up To Bat).  While bats are known to carry other zoonotic diseases,  this was the first time that bats were linked to influenza A.

Since then, another previously unknown subtype (H18N11) has been identified, again in South American Bats (see PLoS Pathogens: New World Bats Harbor Diverse Flu Strains), leading to speculation that these mammalian-adapted flu viruses might someday jump to other species – including man.

 

The most likely scenario for this to occur would be through the reassortment of a bat and a human virus in an intermediate host, such as a pig. 

 

The CDC’s Bat Flu Q & A has this to say about the possibility of such a reassortment occurring:

 

However, the conditions needed for reassortment to occur between human influenza viruses and bat influenza virus remain unknown. A different animal (such as pigs, horses or dogs) would need to serve as a “bridge,” meaning that such an animal would need to be capable of being infected with both this new bat influenza virus and human influenza viruses for reassortment to occur. Additional studies are needed to determine the likelihood that reassortment would occur in nature between bat and human influenza viruses.

 

We’ve some reassuring news via Nature Communications on this front, suggesting that Bat Flu – at least from the H17N10 subtype – may have a difficult time making the leap from chiropterans to humans.

Since researchers have been unable to isolate and replicate the full H17N10 virus from bats, a chimeric (hybrid) virus was created for this study utilizing six internal genes from the bat virus, combined with the HA and NA or prototypic influenza A viruses

.

 

An infectious bat-derived chimeric influenza virus harbouring the entry machinery of an influenza A virus

Mindaugas Juozapaitis, Étori Aguiar Moreira, Ignacio Mena, Sebastian Giese, David Riegger, Anne Pohlmann, Dirk Höper, Gert Zimmer, Martin Beer, Adolfo García-Sastre & Martin Schwemmle

Published  23 July 2014

In 2012, the complete genomic sequence of a new and potentially harmful influenza A-like virus from bats (H17N10) was identified. However, infectious influenza virus was neither isolated from infected bats nor reconstituted, impeding further characterization of this virus.

Here we show the generation of an infectious chimeric virus containing six out of the eight bat virus genes, with the remaining two genes encoding the ​haemagglutinin and ​neuraminidase proteins of a prototypic influenza A virus. This engineered virus replicates well in a broad range of mammalian cell cultures, human primary airway epithelial cells and mice, but poorly in avian cells and chicken embryos without further adaptation.

Importantly, the bat chimeric virus is unable to reassort with other influenza A viruses. Although our data do not exclude the possibility of zoonotic transmission of bat influenza viruses into the human population, they indicate that multiple barriers exist that makes this an unlikely event.

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The past few years have been busy ones for Chiroptologists.

 

Roughly 1/4th of all mammal species on earth are bats, and they are increasingly being viewed as naturals hosts for, and potential vectors of, a number of newly recognized emerging pathogens.

 

Once mainly feared for carrying  rabies, in the 1990s bats gained notoriety with the emergence of the Hendra virus in Australia in 1994 (see Australia: Hendra Vaccine Hurdles) and Nipah in Malaysia in 1999 (see MMWR Update: Outbreak of Nipah Virus -- Malaysia and Singapore, 1999).

 

The emergence of the SARS coronavirus in 2003 – ultimately linked to bats – and most recently, to the MERS coronavirus in the Middle East (see EID Journal: Detection Of MERS-CoV In Saudi Arabian Bat), has served to cement their reputation as important carriers of emerging infectious diseases.

 

None of this is meant to demonize bats, as they play an important role in our ecosystem. However, bats are increasingly being associated with diseases deadly to humans, so a degree of caution is warranted. 

 

To learn how you can stay safe around bats, the CDC offers the following advice.

 

Take Caution When Bats Are Near

Vietnam Girds Against H7N9 As H5N1 Spreads

Photo Credit – FAO

 

 

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Vietnam has dealt with the deadly H5N1 avian flu virus for more than a decade, winning temporary battles, but never the war. In recent weeks we’ve seen a steady resurgence in the number of  provinces reporting infected poultry, which I last blogged about on the Feb. 15th (see Vietnam: H5N1 Poultry Outbreaks Spread To 8 Provinces).

Although media sources are reporting a range of figures, today the Bernama news agency is reporting that the avian virus has spread to 21 provinces:

 

Bird Flu Hits 21 Provinces In Vietnam

HANOI, Feb 26 (Bernama) - Bird flu has hit 21 provinces and cities across Vietnam with around 64,000 infected chickens culled, according to latest statistics from the Animal Health Department.

The number of birds killed in the central province of Khanh Hoa and the northwestern province of Lao Cai has reached almost 20,000, members of the National Steering Committee for Bird Flu Prevention and Control heard at a meeting here on Wednesday.

Vietnam News Agency (VNA) reports the outbreak was attributed to the complicated weather in the first two months of the year, and the increase in shipping and trading of poultry during the recently-ended Lunar New Year (Tet) festival.

(Continue . . .)

 

Complicating matters, less than a month ago we learned that the H7N9 virus had shown up in Guangxi Province, expanding its range southward, and moving it closer to Northern Vietnam (see  Guangxi Province Reports Their First H7N9 Case). 

 

This prompted the FAO earlier this month to issue a statement on H7N9’s Cross Border Threat advising neighboring countries to act now to prepare for possible outbreaks

 

Today, veteran science writer Declan Butler has a cautionary piece appearing in Nature News on Vietnam’s vulnerability to this new avian threat, and the steps they are taking to combat it.  Follow the link below to read:

 

 

Vietnam on high alert over flu risk

H7N9 avian influenza may spread from China for first time.

• Declan Butler

26 February 2014

The H7N9 avian-influenza virus that has killed more than 100 people in China in the past year has for the first time been detected in a province bordering Vietnam, raising the prospect that the disease may take hold across Asia and beyond. It was found in poultry in the live-bird markets of southern China’s Guangxi province in late January, and has caused three known human cases in the region.

The news comes as a surge in human H7N9 flu cases in China since the start of the year shows signs of abating, possibly because of the re­introduction of control measures. Vietnam, which had already prepared response plans for such an H7N9 outbreak, has placed itself on high alert. “There is a very high likelihood of H7N9 entering the poultry sector in Vietnam,” says Peter Horby, a researcher at the Oxford University Clinical Research Unit in Hanoi.

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In a related story, Thanh Nien News is reporting:

 

Vietnam fears lack of equipment to cope with H7N9

Wednesday, February 26, 2014 10:24

Vietnamese health authorities have expressed concerns over the lack of equipment to cope with the possible outbreak of the new virulent H7N9 strain of bird flu.

Health Minister Nguyen Thi Kim Tien told an online conference Sunday that nine of the 28 thermometers at border gates across the country used for anti-bird flu work are currently out of order.

Meanwhile, H7N9 can enter the country at any time, she said.

According to a representative from the US Food and Agriculture Organization (FAO), the shut-down of poultry markets in China has led to poultry being sold to other countries at low prices, while it is difficult for Vietnam to control the imports of poultry via the border with China.

Takeshi Kasai, World Health Organization (WHO) representative to Vietnam, said H7N9 can enter Vietnam via smuggled poultry or humans.

Authorities in Lang Son Province, which borders China, said they are maintaining 14 checkpoints to control the import of poultry around-the-clock at border areas.

Currently, 17 provinces around Vietnam have reported outbreaks of the H5N1 strain of bird flu.

 

 

Given the history of a porous border with China, considerable illicit poultry trade, and the devastating effects from the introduction of the H5N1 virus more than a decade ago,  Vietnamese officials are understandably on guard against this new virus.

 

The history with avian flu viruses has been, that once they become entrenched in a region’s poultry population, they can be extraordinarily difficult to eradicate.

 

And while H5N1 and H7N9 are currently the two viruses that are viewed with the most concern, we’ve seen evidence of other novel reassortants appearing in Chinese poultry (H10N8, H5N5, even a new version of H7N7, etc) which conceivably could eventually spread beyond their borders as well.

The Call For Urgent Talks On `GOF’ Research Projects

BSL-4 Lab Worker - Photo Credit –USAMRIID

 

 

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It’s been more than two years since Dutch Virologist and flu researcher Dr. Ron Fouchier announced, at the  2011 ESWI Influenza Conference in Malta, that he’d created a `more transmissible’ form of the H5N1 virus (see Debra MacKenzie’s New Scientist: Five Easy Mutations).

 

That, combined with a similar announcement from Yoshihiro Kawaoka, a highly respected virologist at the University of Wisconsin-Madison School of Veterinary Medicine, set alarm bells ringing in the biosecurity community. 

 

In the months that followed we saw a protracted, and at times rancorous, debate over the merits and safety of so-called `Gain of Function’  (GOF) research on dangerous pathogens. GOF research involves the creation of viruses and/or  bacteria with enhanced virulence, transmissibility, or host range. 

 

By December of 2011 The Biosecurity Debate On H5N1 Research reached fevered pitch, which led to a group of internationally renowned Scientists to Announce a 60 Day Moratorium On Some H5N1 Research in January, 2012. That moratorium was subsequently extended until January of 2013 (see NIH Statement On Lifting Of The H5N1 Research Moratorium).

In March of 2012 the NIH - which funds many of these research projects - promulgated new DURC Oversight Rules (Dual Use Research of Concern), which also includes some types of GOF research. For those unfamiliar with the lexicon of biomedical research, DURC in this new policy is defined as:

 

. . . life sciences research that, based on current understanding, can be reasonably anticipated to provide knowledge, information, products, or technologies that could be directly misapplied to pose a significant threat with broad potential consequences to public health and safety, agricultural crops and other plants, animals, the environment,

 

After much heated debate, during the summer of 2012 Science Published The Fouchier Ferret Study and Nature Published The Kawaoka H5N1 Study.  But the debate over the safety, merits, and wisdom of conducting these sorts of experiments has continued.

 

Researchers in favor of GOF studies argue against undue restrictions and `censorship’ of science (see mbio Science Should Be in the Public Domain by Vincent R. Racaniello), while critics point out that the benefits of such research have been overstated (see Options VIII: Dr. Marc Lipsitch Argues Against HPAI GOF Experiments) and the risks have been downplayed.

 

All of which serves as prelude to an article over the weekend in in the Journal Nature (and SciAm) regarding a letter – signed by 56 scientists – sent to the European Commission, calling for `urgent talks’ over the future course of GOF research on influenza viruses, and other pathogens.

 

Scientists call for urgent talks on mutant-flu research in Europe

Benefits and risks of ‘gain-of-function’ work must be evaluated, they say.

Heidi Ledford

20 December 2013

A group of over 50 researchers has called on the European Commission to hold a scientific briefing on research that involves engineering microbes to make them more deadly.

In an 18 December letter to European Commission president José Manuel Barroso, the scientists — including representatives from the non-profit Foundation for Vaccine Research in Washington DC — urged the commission to organize the briefing, and to formally evaluate the risks and benefits of such 'gain-of-function' research.

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Although initial concerns were that the publication of the Fouchier or Kawaoka papers could serve as a blueprint for `bad actors’ to create a bio weapon, of even greater concern is the possibility of a laboratory accident that could result in the release of an `enhanced pathogen’.    

 

While accidents in well regulated Bio-level 4 labs are rare, they are not unheard of.  And many researchers doing GOF studies only have access to Bio-level 3 or 3+ labs, where safety standards are not as rigorous.

 

Last November, in BMC Medicine: Containing Laboratory Escape Of Pandemic Viruses, we looked at a report that found the risks of seeing an accidental release from one of these labs is far from zero.

 

They calculated a .3% chance of release from any given lab each year, which works out to be roughly one every 100 years of lab operation.  With hundreds of of BSL-3 and BSL-4 labs around the world, the odds of seeing an accident in any given year somewhere in the world go up substantially.

 

Between 2003 and 2009, US government laboratories had 395 incidents that involved the potential release of select agents, according to this report from CIDRAP NEWS.  While only 7 related infections were reported, this does add weight to some of the concerns being expressed by GOF research critics.  

 

Whether `an urgent meeting’  will help resolve  this controversy is difficult to predict, as there are strong feelings on both sides of this issue.  But as I wrote nearly 2 years ago, in Science At The Crossroads, one need only look at the public’s reaction to vaccines, GMO foods, and nuclear power to see that their trust in science, and scientists, continues to ebb badly.  

 

While seemingly a debate for Academia, how this debate is conducted, and how this issue is resolved, has to potential  to greatly affect the public’s perception – for better or worse – of the entire scientific community.

 

Stay tuned.

Nature: Receptor Binding Of H7N9

Flu Virus binding to Receptor Cells – Credit CDC

 

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For an influenza virus to infect a host, the virus must bind (attach) itself to the surface of a cell.  To do that influenza viruses have an RBS - Receptor Binding Site (the area of its genetic sequence that allows it to attach to, and infect, host cells) that – like a key slipping into a padlock -`fit’ the host’s receptor cells.

 

Avian adapted flu viruses, like the H5N1 virus, bind preferentially to the alpha 2,3 receptor cells found in the gastrointestinal tract of birds.  While there are some alpha 2,3 cells deep in the lungs of humans, for an influenza to be successful in a human host, most researchers believe it needs to a able to bind to the α2-6 receptor cell found in the upper airway (trachea).

 

We’ve seen studies over the summer that the emerging H7N9 virus in China – unlike the H5N1 virus – has shown signs of adapting to mammalian physiology (see Nature: Biological Features Of H7N9).   Among the findings:

 

• Unlike the H5N1 virus – which binds preferentially to avian receptor cells (a2,3-linked sialic acid) -  H7N9 binds to both the avian and human (a2,6-linked sialic acid) receptor cells.

• This dual receptor cell binding ability likely enhances the virus’s ability to transmit from birds to humans.

• The virus appears to replicate well in the lower human respiratory tract - but less well in the trachea – which may have helped to limit its ability to spread from human-to-human.

• Once infected, the virus often produces severe illness in humans, and patients tested showed increased serum levels of chemokines and cytokines, suggesting the possibility of infection inducing a `cytokine storm’.

• There appears to be little  or no community immunity to H7 viruses.

 

Today, we’ve another study appearing in the Journal Nature that looks at the ability of the H7N9 virus to bind to human receptor cells (in vitro), that finds the virus better adapted to human receptor cells than earlier H7N9 viruses, but perhaps still not quite ready for prime time.

 

 

Adaptation of novel H7N9 influenza A virus to human receptors

J. C. F. M. Dortmans, J. Dekkers, I. N. Ambepitiya Wickramasinghe, M. H. Verheije, P. J. M. Rottier, F. J. M. van Kuppeveld, E. de Vries & C. A. M. de Haan

ABSTRACT

The emergence of the novel H7N9 influenza A virus (IAV) has caused global concerns about the ability of this virus to spread between humans. Analysis of the receptor-binding properties of this virus using a recombinant protein approach in combination with fetuin-binding, glycan array and human tissue-binding assays demonstrates increased binding of H7 to both α2-6 and α2-8 sialosides as well as reduced binding to α2-3-linked SIAs compared to a closely related avian H7N9 virus from 2008. These differences could be attributed to substitutions Q226L and G186V. Analysis of the enzymatic activity of the neuraminidase N9 protein indicated a reduced sialidase activity, consistent with the reduced binding of H7 to α2-3 sialosides. However, the novel H7N9 virus still preferred binding to α2-3- over α2-6-linked SIAs and was not able to efficiently bind to epithelial cells of human trachea in contrast to seasonal IAV, consistent with its limited human-to-human transmission.

 

 

The entire study is open-access, and quite detailed regarding methods and materials.  The authors sum up their findings in the discussion:

 

The results indicate that, in comparison to avian H7N9 virus, the human H7N9 virus displays increased binding to α2-6 as well as α2-8 sialosides and reduced binding to α2-3-linked SIAs. Still, whereas all seasonal/pandemic IAVs bind more efficiently to α2-6- than to α2-3-linked sialosides, the human H7 protein binds more efficiently to α2-3- than α2-6-linked SIAs and is not able to efficiently bind to epithelial cells of human trachea. From these results we conclude that the human H7N9 virus has not (yet) adapted its HA protein to such an extent that it results in a receptor-binding profile similar to that of pandemic/seasonal IAV.

 

For more on the evaluation of the emerging H7N9 virus, you may wish to revisit:

 

Nature: H7N9 Pathogenesis and Transmissibility In Ferrets & Mice

Nature: Limited Airborne Transmission Of H7N9 Between Ferrets

Eurosurveillance: Genetic Analysis Of Novel H7N9 Virus

Nature: Mapping The Spread & Risk Of H7N9 In China

 

 

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With H5N1 still in the wings, and the upstart H7N9 and MERS coronavirus making menacing overtures, infectious disease watchers and public health authorities have their hands full right now, just trying to keep track.  This week we’ve seen the CDC issue new guidance on MERS-CoV along with an IHR Emergency Committee meeting, and warnings from the Chinese government to remain alert for the H7N9 avian flu virus.

Despite these warnings and preparations, no one knows if any of these viruses will pose a serious public health risk this fall and winter.  Officials just know they could.  And while we watch this trio of emerging diseases, we could easily get blind-sided by something else.  

As Yogi Berra famously said - Prediction is very hard, especially about the future.

 

But hard or not, scientists are working to model and predict the spread of these diseases in order to help guide surveillance and containment efforts.  Which brings us to an open-access report, published this week in Nature’s Scientific Reports, that attempts to map and predict future outbreaks of H7N9 in China.

 

These researchers, from China and from the University of Florida, found that human cases last spring tended to occur near irrigated land, suggesting that ducks and geese may play a role in its transmission, even though the virus has not been isolated in either species. 

A bit surprisingly, they also found - `high humidity and an atmospheric temperature around 15°C were predictive factors for the risk of avian influenza A’.

This runs counter to other studies on influenza viruses that show moderately low relative Humidity (< 40%) as being more conducive to viral survival and transmission (see PLoS One: High Humidity Reduces Flu’s Infectivity & NIH Study: Climate & Influenza Transmission).

.

Although the methods section of this study will likely be tough sledding for those without a background in statistics, the Introduction and Discussion are both particularly well written, and well worth reading in their entirety.

 

Scientific Reports | Article Open

Mapping Spread and Risk of Avian Influenza A (H7N9) in China

Li-Qun Fang, Xin-Lou Li, Kun Liu, Yin-Jun Li, Hong-Wu Yao, Song Liang, Yang Yang, Zi-Jian Feng, Gregory C. Gray & Wu-Chun Cao

doi:10.1038/srep02722

Published  26 September 2013

The outbreak of human infections with an emerging avian influenza A (H7N9) virus occurred in China in early 2013. It remains unknown what and how the underlying risk factors were involved in the bird-to-human cross-species transmission. To illustrate the dynamics of viral spread, we created a thematic map displaying the distribution of affected counties and plotted epidemic curves for the three most affected provinces and the whole country. We then collected data of agro-ecological, environmental and meteorological factors at the county level, and used boosted regression tree (BRT) models to examine the relative contribution of each factor and map the probability of occurrence of human H7N9 infection. We found that live poultry markets, human population density, irrigated croplands, built-up land, relative humidity and temperature significantly contributed to the occurrence of human infection with H7N9 virus. The discriminatory ability of the model was up to 97.4%. A map showing the areas with high risk for human H7N9 infection was created based on the model. These findings could be used to inform targeted surveillance and control efforts in both human and animal populations to reduce the risk of future human infections.

 

First, from the Introduction (and reparagraphed for readability), a concise summary of where things stand right now with the H7N9 virus:

 

A novel avian influenza A (H7N9) virus infecting humans has emerged in mainland China¹, causing global concerns about its potential to start an influenza pandemic^{2, 3}. Since the National Health and Family Planning Commission of China (NHFPC) announced the emerging infectious disease on March 31, 2013, a total of 131 confirmed cases, with 39 deaths have been reported in eight provinces and two municipalities as of May 30⁴. Fortunately, thus far there has been no evidence of sustained person-to-person transmission⁵.

 

However, unlike the high pathogenic avian influenza A viruses such as H5N1 and H7N7, in which outbreaks in poultry precede human infections and imply where the public health threat lies^{6, 7}, the novel H7N9 virus causes no or only mild disease in birds^{8, 9}. This means that the virus is likely to spread silently in birds or other animal reservoirs. Human infections are therefore the sentinel events, and the quick geographical expansion of human cases indicate that a hidden epidemic in birds is well underway³, and many parts of the country offers a favorable breeding ground for the virus to circulate.

 

So far, however, apart from birds and the contaminated environments at the live poultry markets^{9, 10}, the sources of infection remain elusive¹¹. It is unclear how the emerging avian influenza A (H7N9) virus is spreading in China³, and what and how the underlying risk factors are involved in the cross-species transmission.

 

From the discussion section, a brief excerpt (but follow the link to read it in its entirety).

 

The outbreak of human infections with the novel avian influenza A (H7N9) virus lasted for over three months since it emerged in mainland China. Fortunately, thus far there has been no sustained human-to-human transmission⁵, although the virus has genetic characteristics that suggest it could effectively replicate in mammals^{1, 15}. Currently, H7N9 virus infection is primarily zoonotic. In this study, we used GIS-based spatial analysis to map the spatial distribution of human infections with H7N9 virus. The thematic map displaying the distribution of human cases indicates that although most human cases were concentrated at the Yangtze River delta on China's eastern seaboard, sporadic cases were distributed in large areas of adjacent provinces, even spreading northward to Beijing and being exported to Taiwan (Fig. 1).

 

As a final note, last March – and published before we learned of the outbreak of H7N9 in China – the CDC’s EID Journal carried a study (see Predicting Hotspots for Influenza Virus Reassortment) that attempted to map those areas of the world most likely to spawn new influenza strains.  

 

This study identified a number of key geographic locations  -  the northern plains of India, the coastal and central provinces of China, the western Korean Peninsula and southwestern Japan in Asia, and the Nile Delta in Egypt - as likely hotspots. 

 

Their H5N1 risk map of China (see below), matches pretty closely to the H7N9 risk map in today’s study.

 

Of course, the last pandemic reassortment originated in the Americas, and no one is quite sure where the devastating 1918 `Spanish’ flu evolved.  While scientists can find and predict patterns, Nature often goes its own way. 

 

But models like these – while far from fully predictive – can help guide us as to where we should be looking for the next novel flu outbreak.

 

And with two dangerous avian flu strains in Asia and an emerging coronavirus in the Middle East, we can use all the help we can get.

Nature: Animal Testing Of Drug Combo Shows Potential For Treating MERS

Coronavirus – Credit CDC PHIL

 

 

# 7743

 

One of the more worrisome aspects of the recent emergence of MERS coronavirus has been the lack of a specific and effective treatment.  Unlike influenza, there are currently no coronavirus-specific antivirals available.

 

Treatment has basically been supportive (e.g. fluids, vasopressors, ventilators and/or ECMO, dialysis, and antibiotics for secondary infections). 

 

Today, in a letter that appears in Nature Medicine, we learn that a drug combination (Interferon-α2b & ribavirin) – which showed promise earlier in the year in in-vitro experiments -  `reduces virus replication, moderates the host response, and improves the clinical outcome’ of rhesus macaques experimentally infected with the MERS coronavirus.

 

While welcome news, a few caveats are in order.

 

• First, the macaque model is not a perfect substitute for humans, as they tend not to be as severely impacted by the MERS virus. 
• Second, treatment was initiated 8 hours post infection, which is an earlier pharmacological intervention than most humans could hope to see. 
• And third, most severe human infections have been seen in people with co-morbidities like COPD, cancer, diabetes, asthma . . . variables this study does not attempt to replicate.

 

Still, this has to be seen as progress. I’ve a link to the Abstract, a brief announcement from NIAID, then a link to Helen Branswell’s article on this announcement.

 

Treatment with interferon-α2b and ribavirin improves outcome in MERS-CoV–infected rhesus macaques

Darryl Falzarano, Emmie de Wit, Angela L Rasmussen, Friederike Feldmann, Atsushi Okumura,Dana P Scott, Doug Brining, Trenton Bushmaker,  Cynthia Martellaro, Laura Baseler, Arndt G Benecke, Michael G Katze, Vincent J Munster& Heinz Feldmann

ABSTRACT (Excerpt)

The combination of interferon-α2b and ribavirin was effective in reducing MERS-CoV replication in vitro⁶; therefore, we initiated this treatment 8 h after inoculation of rhesus macaques. In contrast to untreated, infected macaques, treated animals did not develop breathing abnormalities and showed no or very mild radiographic evidence of pneumonia. Moreover, treated animals showed lower levels of systemic (serum) and local (lung) proinflammatory markers, in addition to fewer viral genome copies, distinct gene expression and less severe histopathological changes in the lungs.

 

Taken together, these data suggest that treatment of MERS-CoV infected rhesus macaques with IFN-α2b and ribavirin reduces virus replication, moderates the host response and improves clinical outcome. As these two drugs are already used in combination in the clinic for other infections, IFN-α2b and ribavirin should be considered for the management of MERS-CoV cases.

From NIAID:

Sunday, September 8, 2013

MERS-CoV Treatment Effective in Monkeys, NIH Study Finds

WHAT:

National Institutes of Health (NIH) scientists report that a combination of two licensed antiviral drugs reduces virus replication and improves clinical outcome in a recently developed monkey model of Middle East respiratory syndrome coronavirus (MERS-CoV) infection. Their study, which appears as a letter in the Sept. 8 edition of Nature Medicine, expands on work published in April showing that a combination of ribavirin and interferon-alpha 2b stops MERS-CoV from replicating in cell culture. Both antivirals are routinely used together to treat viral diseases such as hepatitis C.

 

In the latest study, investigators at NIH’s National Institute of Allergy and Infectious Diseases (NIAID) infected six rhesus macaques with MERS-CoV and, eight hours later, treated half of them with the two-drug regimen. Compared to the untreated animals, the treatment group showed no breathing difficulties and only minimal X-ray evidence of pneumonia. The treated animals also had lower amounts of virus and less severe tissue damage in the lungs.

 

As of Aug. 30, 2013, the World Health Organization has reported 108 human cases of MERS-CoV infection, including 50 deaths. Given the current lack of treatment options, the authors of this study conclude that combined ribavirin and interferon-alpha 2b therapy should be considered as an early intervention. 

(Continue . . . )

And finally, from Helen Branswell, a detailed and informative report, with comments from Matthew Frieman, Professor of Virology at the University of Maryland medical school in Baltimore.

 

Drug combo helps reduce MERS virus in animals: study

Helen Branswell, The Canadian Press
Published Sunday, September 8, 2013 1:16PM EDT

TORONTO -- New research is adding weight to the idea that a combination of existing drugs may help some patients infected with the new MERS coronavirus.

 

The findings could prove to be important because there is no vaccine to prevent the infection and no drugs specifically designed to mitigate the damage it does in severe cases.

 

Infections with the new virus continue to pile up, particularly in Saudi Arabia.

 

(Continue . . . )

Nature: Genesis Of The H7N9 Virus

Reassorted viruses can result when two different flu strains inhabit the same host (human, swine, avian, or otherwise) at the same time. Under the right conditions, they can swap one or more gene segments and produce a hybrid virus.

# 7589

 

 

It’s certainly been a busy day in Flublogia.

 

Out next stop is a study in the Journal Nature, off embargo about an hour ago (1pm EDT), that looks at the genesis of the H7N9 avian influenza virus in China, and along the way finds a previously unrecognized lineage of the H7N7 virus circulating in poultry as well.

 

Both the H7N9 and H7N7 viruses appear to be reassortants with the H9N2 virus, which is widespread in poultry throughout Asia. 

 

Preliminary experiments with this newly discovered H7N7 strain show that this virus has the ability to infect, and replicate reasonably well, in ferrets – raising concerns that we may need to be watching more than just the H7N9 virus.

 

First a link to the Nature Article (alas, behind a pay wall), then a press release from the NIH which helped to fund this research, after which I’ll be back with more on H7 viruses.

 

   Nature | Letter

The genesis and source of the H7N9 influenza viruses causing human infections in China

Tommy Tsan-Yuk Lam, Jia Wang, Yongyi Shen, Boping Zhou, Lian Duan, Chung-Lam Cheung, Chi Ma, Samantha J. Lycett, Connie Yin-Hung Leung,  Xinchun Chen, Lifeng Li, Wenshan Hong,  Yujuan Chai, Linlin Zhou, Huyi Liang, Zhihua  Ou, Yongmei Liu, Amber Farooqui, David J. Kelvin,  Leo L. M. Poon, David K. Smith, Oliver G. Pybus, Gabriel M. Leung, Yuelong Shu, Robert G. Webster et al.

ABSTRACT (EXCERPT)

The H7N9 outbreak lineage has spread over a large geographic region and is prevalent in chickens at live poultry markets, which are thought to be the immediate source of human infections. Whether the H7N9 outbreak lineage has, or will, become enzootic in China and neighbouring regions requires further investigation.

 

The discovery here of a related H7N7 influenza virus in chickens that has the ability to infect mammals experimentally, suggests that H7 viruses may pose threats beyond the current outbreak. The continuing prevalence of H7 viruses in poultry could lead to the generation of highly pathogenic variants and further sporadic human infections, with a continued risk of the virus acquiring human-to-human transmissibility.

 

 

From NIAID, we get the following press release.

 

NIH-Funded Scientists Describe Genesis, Evolution of H7N9 Influenza Virus

WHAT

:
An international team of influenza researchers in China, the United Kingdom and the United States has used genetic sequencing to trace the source and evolution of the avian H7N9 influenza virus that emerged in humans in China earlier this year. The study, published today in Nature, was supported by the National Institute of Allergy and Infectious Diseases (NIAID), a component of the National Institutes of Health, and other organizations.

 

Working in three Chinese provinces, researchers led by Yi Guan, Ph.D., of the University of Hong Kong collected samples from the throats and digestive tracts of chickens, ducks, geese, pigeons and quail. Fecal and water samples from live poultry markets and the natural environment were also collected. From these samples, the researchers isolated several influenza viruses and genetically sequenced those of the H7N9 subtype as well as related H7N7 and H9N2 viruses. These sequences were compared with archived sequences of the same subtypes isolated in southern China between 2000 and 2013. The researchers compared the differences between the two sets of sequences to reconstruct how the H7N9 virus evolved through various species of birds and to determine the origin of genes.

 

According to their analysis, domestic ducks and chickens played distinct roles in the genesis of the H7N9 virus infecting humans today. Within ducks, and later within chickens, various strains of avian H7N9, H7N7 and H9N2 influenza exchanged genes with one another in different combinations. The resulting H7N9 virus began causing outbreaks among chickens in live poultry markets, from which many humans became infected. Given these results, the authors write, continued surveillance of influenza viruses in birds remains essential.

 

 

While we’ve been watching the H5N1 virus with great care for more than a dozen years, scientists have also kept one eye on the H7 lineage of viruses (along with H9N2) as possible avian flu pandemic contenders.

 

We’ve been somewhat reassured because – at least until the H7N9 virus emerged this past spring –  other H7 strains that have infected humans have typically only caused mild illness; often little more than sniffles and conjunctivitis. 

 

Ten years ago, the largest known H7 cluster was recorded in the Netherlands. In that outbreak, the culprit was H7N7 (albeit from a different lineage than the H7N7 virus described in this Nature Journal letter).

 

Details on that cluster were reported in the December 2005 issue of the Eurosurveillance Journal.

 

Human-to-human transmission of avian influenza A/H7N7, The Netherlands, 2003

M Du Ry van Beest Holle, A Meijer, M Koopmans³ CM de Jager, EEHM van de Kamp, B Wilbrink, MAE. Conyn-van Spaendonck, A Bosman

 

An outbreak of highly pathogenic avian influenza A virus subtype H7N7 began in poultry farms in the Netherlands in 2003. Virus infection was detected by RT-PCR in 86 poultry workers and three household contacts of PCR-positive poultry workers, mainly associated with conjunctivitis.

 

Roughly 30 million birds residing on more than 1,000 farms were culled to control the outbreak. One person - a veterinarian who visited an infected farm – died a week later of respiratory failure.

 

The rest of the symptomatic cases were relatively mild.

 

The Fraser Valley H7N3 outbreak of 2004 resulted in at least two human infections, as reported in this EID Journal report:

 

Human Illness from Avian Influenza H7N3, British Columbia

Abstract

Avian influenza that infects poultry in close proximity to humans is a concern because of its pandemic potential. In 2004, an outbreak of highly pathogenic avian influenza H7N3 occurred in poultry in British Columbia, Canada. Surveillance identified two persons with confirmed avian influenza infection. Symptoms included conjunctivitis and mild influenza like illness.

 

More recently, in Mexico we saw two mild human cases last summer (see see MMWR: Mild H7N3 Infections In Two Poultry Workers - Jalisco, Mexico).  The World Health Organization published this Summary and assessment as of 10 September 2012.

 

Sporadic human cases of influenza A(H7N3) virus infection linked with outbreaks in poultry have been reported previously in Canada, Italy and the UK, with H7N2 in US and the UK, and with H7N7 in the UK and the Netherlands. Most H7 infections in humans have been mild with the exception of one fatal case in the Netherlands, in a veterinarian who had close contact with infected birds.

 

Of course – H7 flu strains - like all influenza viruses, are constantly mutating and evolving. What is mild, or relatively benign today, may not always remain so.

 

In 2008 we saw a study in  PNAS that suggested the H7 virus might just be inching its way towards better adaptation to humans (see Contemporary North American influenza H7 viruses possess human receptor specificity: Implications for virus transmissibility).

 

You can read more about this in a couple of blogs from 2008, H7's Coming Out Party and H7 Study Available Online At PNAS.

 

The discovery of another H7 reassortant virus sharing some of the same parentage as H7N9 circulating in China isn’t terribly surprising, given the multitude of opportunities that flu viruses have to co-mingle among Chinese livestock.

 

Last March, in EID Journal: Predicting Hotspots for Influenza Virus Reassortment, Eastern China was highlighted as one of the most favored areas in the world for seeing new influenza reassortants.

 

The study cited:

Potential geographic foci of reassortment include the northern plains of India, coastal and central provinces of China, the western Korean Peninsula and southwestern Japan in Asia, and the Nile Delta in Egypt.

 

All of which highlights the need for comprehensive and continual surveillance of farmed animals and wild birds, particularly in those regions of the world where these sorts of reassortments are most likely to occur.

Nature: Limited Airborne Transmission Of H7N9 Between Ferrets

Photo Credit Wikipedia

 

# 7556

 

Yesterday’s report on Omani camels carrying antibodies to the MERS Coronavirus (see Lancet: Camels Found With Antibodies To MERS-CoV-Like Virus) pretty much dominated the headlines in the flu world, but another study deserving our attention appeared in the Journal Nature as well.

 

Researchers from the Erasmus Medical Center in the Netherlands University of Cambridge in the United Kingdom infected four ferrets with the Anhui/1/2013 strain of H7N9, and then placed  uninfected ferrets in cages next to them.

 

Three of the four unexposed ferrets became infected, demonstrating limited airborne transmission (efficiency estimated somewhere between that of seasonal flu and avian flu). Genetic sequencing showed the virus they carried to be identical to the original test virus.  

 

These researchers did find that after ferret passage, variants with preferential binding to avian (a2,3) receptor cells, higher pH of fusion, and lower thermostability were selected, which potentially could reduce ongoing transmissibility of the virus in mammals.

 

Overall, these findings are similar to other ferret transmissibility studies we’ve seen published over the summer (see Science: H7N9 Transmissibility Study In Ferrets).

 

The link to the Nature Abstract follows:

 

Limited airborne transmission of H7N9 influenza A virus between ferrets

Mathilde Richard, Eefje J. A. Schrauwen, Miranda de Graaf, Theo M. Bestebroer, Monique I. J. Spronken, Sander van Boheemen, Dennis de Meulder, Pascal Lexmond, Martin Linster, Sander Herfst, Derek J. Smith, Judith M. van den Brand, David F. Burke, Thijs Kuiken, Guus F. Rimmelzwaan, Albert D. M. E. Osterhaus & Ron A. M. Fouchier

ABSTRACT (Excerpt)

Here we show that although the A/Anhui/1/2013 A(H7N9) virus harbours determinants associated with human adaptation and transmissibility between mammals, its airborne transmissibility in ferrets is limited, and it is intermediate between that of typical human and avian influenza viruses. Multiple A(H7N9) virus genetic variants were transmitted.

Upon ferret passage, variants with higher avian receptor binding, higher pH of fusion, and lower thermostability were selected, potentially resulting in reduced transmissibility. This A(H7N9) virus outbreak highlights the need for increased understanding of the determinants of efficient airborne transmission of avian influenza viruses between mammals.

 

 

While laboratory experiments have consistently shown the H7N9 virus can transmit reasonably well from ferret-to-ferret via direct contact or respiratory droplet, thus far the Chinese have reported no signs of sustained human-to-human transmission in the field.

 

The reasons behind this disparity, and whether this apparent lack of transmissibility in humans will continue, are among the many questions on the list of researchers studying the virus.

CIDRAP: Yesterday’s H7N9 Studies In Nature

 

 

# 7469

 

 

Last night, in Nature: H7N9 Pathogenesis and Transmissibility In Ferrets & Mice, we looked at the first of two H7N9 studies that appeared yesterday in the journal Nature.  

 

This morning my intent had been to examine the second paper, but quite frankly, Lisa Schnirring at CIDRAP News did such a great job covering both studies last night, the only sensible thing is to direct you to her report.

 

Lisa includes expert commentary on these two studies by Marion Koopmans, DVM, PhD, with the National Institute of Public Health and the Environment in the Netherlands and Michael T. Osterholm, .PhD, MPH, Director of CIDRAP.

 

 

New studies on H7N9 raise pandemic concerns

Lisa Schnirring | Staff Writer | CIDRAP News

Jul 10, 2013

 

iStockphoto

Two new studies found limited spread of the new H7N9 flu virus via respiratory droplets. About a third of ferrets were infected via that route.

Two research teams that conducted a massive number of experiments on the new H7N9 influenza virus found more signs that it could be a pandemic virus, though their animal tests showed that its ability to spread through coughs and sneezes isn't as robust as seasonal flu.

 

The two studies are among several recent efforts to assess the threat from the new virus, which infected 134 people, 43 of them fatally, before tapering off in early June. Experts aren't sure if the virus has died out or if it has temporarily retreated due to warmer weather and perhaps the effects of outbreak response measures aimed at live-poultry markets in some of China's biggest cities.

 

Both studies were published in the same issue of Nature. One of the teams is from Japan and the University of Wisconsin, Madison, lab of Yoshihiro Kawaoka, DVM, PhD. That team conducted several types of tests and comparisons on two novel H7N9 strains from China, an earlier avian H7N9 strain, and the 2009 H1N1 virus. They also examined how the new virus behaves in mice, ferrets, miniature pigs, macaques.

 

The second group includes scientists from the US Centers for Disease Control and Prevention (CDC), which also studied two novel H7N9 strains from China, focusing on how it infects human cells and how it spreads in ferrets and mice.

 

(Continue . . . )

 

Watanabe T, Kiso M, Fukuyama S, et al. Characterization of H7N9 influenza A viruses isolated from humans, letter. Nature 2013 Jul 10 [Abstract]

 

Belser JA, Gustin KM, Pearce MB, et al. Pathogenesis and transmission of avian influenza A (H7N9) virus in ferrets and mice, letter. Nature 2013 Jul 10 [Abstract]

 

Nature: H7N9 Pathogenesis and Transmissibility In Ferrets & Mice

Ideally, the well-protected HCW (Health Care Worker) working in an H7N9 environment would be wearing an N95 mask, gloves, gown and eye protection.

 

 

# 7467

 

The Journal Nature has published two H7N9 studies today, each providing a look at just how well adapted the H7N9 virus is to mammals, and offering clues as to what capabilities it still needs to acquire in order for it to become a genuine pandemic threat.

 

One of the studies was conducted by researchers at the CDC, while the other was conducted by an international team led by Yoshihiro Kawaoka of the University of Wisconsin-Madison and the University of Tokyo.

 

I’ll address the CDC study in this post, and will do the Kawaoka study in later tonight or in the morning. Sadly, much of this study is behind a pay wall, but we do have the abstract, and a fairly detailed summary posted on the CDC’s Website.

 

Pathogenesis and transmission of avian influenza A (H7N9) virus in ferrets and mice

Jessica A. Belser, Kortney M. Gustin, Melissa B. Pearce, Taronna R. Maines, Hui Zeng, Claudia Pappas, Xiangjie Sun, Paul J. Carney, Julie M. Villanueva, James Stevens, Jacqueline M. Katz & Terrence M. Tumpey

(Excerpt)

Here we assess the ability of A/Anhui/1/2013 and A/Shanghai/1/2013 (H7N9) viruses, isolated from fatal human cases, to cause disease in mice and ferrets and to transmit to naive animals. Both H7N9 viruses replicated to higher titre in human airway epithelial cells and in the respiratory tract of ferrets compared to a seasonal H3N2 virus. Moreover, the H7N9 viruses showed greater infectivity and lethality in mice compared to genetically related H7N9 and H9N2 viruses.

 

The H7N9 viruses were readily transmitted to naive ferrets through direct contact but, unlike the seasonal H3N2 virus, did not transmit readily by respiratory droplets. The lack of efficient respiratory droplet transmission was corroborated by low receptor-binding specificity for human-like α2,6-linked sialosides.

 

Our results indicate that H7N9 viruses have the capacity for efficient replication in mammals and human airway cells and highlight the need for continued public health surveillance of this emerging virus.

 

Of particular interest, while the virus did not transmit easily via respiratory droplets between ferrets, once acquired, the virus replicated at a much higher rate than one generally sees with seasonal flu. 

 

And while not a complete surprise, this study also seems to confirm the potential for transocular transmission of the H7N9 virus. 

 

We’ve known for more than a decade that H7 viruses often cause conjunctivitis (see MMWR: Mild H7N3 Infections In Two Poultry Workers - Jalisco, Mexico), and other studies have suggested possibility of acquiring influenza virus infection through the eyes.

 

We looked at transocular influenza transmission studies in both 2010 (see I Only Have Eyes For Flu) and again in  2011 (see PPEs & Transocular Influenza Transmission).

 

The  CDC’s Interim H7N9 Infection Control Guidelines, released last April, called for fitted N95 respirators, gowns, gloves, and eye protection as a minimum level of PPEs (personal protective equipment) for all HCWs who may have contact with potential or confirmed H7N9 patients.

 

Here is the CDC’s summary of the findings:

 

CDC Study Analyzes H7N9 Viruses’ Disease Characteristics and Transmissibility

A study published today in Nature by CDC researchers presents findings from animal studies conducted by CDC to better understand the transmissibility and disease characteristics of influenza A (H7N9) viruses isolated in China in late March. Understanding the properties of H7N9 viruses that contribute to human disease and the capacity of these viruses to spread between people is a critical component of the public health response to this emerging disease threat.

 

The study’s key findings indicate that H7N9 viruses are capable of causing infection in a direct contact animal model, but the viruses would need to undergo additional adaptation to spread more easily by droplets or through the air. Person to person transmission, especially by respiratory droplet transmission (such as through coughs and sneezes) is a necessary precondition for the virus to become capable of causing a pandemic.

 

These findings support the conclusions drawn from China’s investigations of human H7N9 cases so far. China has found no clear evidence of sustained human-to-human spread of the H7N9 virus. Human cases of H7N9 virus infection in China reported have been primarily associated with exposure to infected poultry. Currently no human cases of H7N9 virus infection have been reported in the United States.

 

The paper describes the results of multiple studies conducted on two H7N9 viruses obtained from fatal human H7N9 cases from China. The studies were conducted in ferrets, mice and human epithelial cells. Ferrets are considered the best small mammal for studying flu virus infection and are commonly used as a tool for the risk assessment of emerging flu viruses that may pose a risk to public health.

 

The ferret studies revealed that the H7N9 viruses spread readily among ferrets placed in the same cage. However, the viruses were less capable of respiratory droplet transmission, which the researchers tested by placing infected ferrets in cages adjacent to cages housing naive ferrets. Compared to a human seasonal flu virus from last season, the H7N9 viruses were considerably less capable of transmitting by the respiratory route.

 

Other study findings indicated that the H7N9 virus did not cause severe disease in the ferrets and did not spread systemically to the spleen, kidney, liver, or intestinal tract. The lack of systemic spread by H7N9 is different from H5N1 (another avian influenza virus that can cause severe disease in humans). Systemic spread is considered an indicator of severe disease.

 

In addition to ferrets, CDC researchers also studied the H7N9 virus in mice. Compared with ferrets, the virus caused more lethal illness in the mice, and the virus was more capable of replicating in the lungs of mice compared with other avian and human seasonal viruses tested in the study. Also notable, the H7N9 virus was able to easily infect mice, whereas human seasonal flu viruses typically require prior host adaptation to be able to efficiently infect mice.

 

The mouse studies also revealed that H7N9 virus can pass through the eyes to infect the respiratory tract. As a result, the eyes represent a possible portal of entry for the H7N9 virus. This finding supports CDC’s existing flu recommendations to avoid touching the eyes, nose or mouth to help prevent spread of germs. It also supports the recommendation for health care providers to wear eye protection when caring for patients with confirmed or suspected H7N9 infection.

 

The remaining study findings analyzed the H7N9 virus’s ability to replicate in cells derived from human epithelial cells. Epithelial cells are found in the human respiratory tract and are the primary site where flu viruses replicate in humans. CDC researchers found that the H7N9 virus demonstrated a 20- to 400-fold increase in replication at the two-day mark when compared with a human seasonal flu virus and two other avian flu viruses genetically related to the H7N9 virus. Compared with a human seasonal H3N2 virus, the H7N9 virus exhibited an 80,000-fold increase in replication at 24 hours.

 

The studies in mice and ferrets corroborated this finding, as considerably more H7N9 virus was produced and detected in the respiratory tracts of ferrets and mice compared with the amount of virus produced by seasonal flu virus infection. This suggests the H7N9 viruses have the capacity to reproduce quickly and produce a large amount of virus within the cells of mammals and human airway cells. However, the viruses’ ability to replicate was determined to be better suited to the higher temperatures found in the lower airways (lungs) versus the lower temperatures found in the upper airways of mammals.

The study, entitled “Pathogenesis and transmission of A (H7N9) avian influenza virus in ferrets and mice” is available for online viewing via Nature’s website.