Study: Ebola Virus Is Rapidly Evolving

Credit CDC PHIL

 

# 9015

 

One of the concerns we have when any zoonotic virus spills over into the human population is that over time, as it passes from one person to the next, it could pick up host adaptations – mutations – that could make the virus a greater threat over time.

 

In the laboratory, researchers will often conduct serial passage experiments (see Serial Passage Of H5N2 In Mice) to observe these evolutionary changes, and try to figure out what they mean.

 

Often, these genetic changes are of little or no effect, and can sometimes even be detrimental to the `biological fitness’ of the virus. Those that favor replication in the new found host, however, tend to carry on to produce more progeny, advancing their new lineage forward,  drowning out the earlier `wild type’ virus in the host.

 

A recent concern has been that Ebola - which up until now has never really spread in kind of long chains of human cases that we are seeing now – could better adapt to human physiology over time.

 

Today we’ve a study appearing in the Journal Science where scientists sequenced 99 Ebola viruses taken from 78 people from Sierra Leone during the month of June, and found that the virus is showing a marked propensity to accumulate `interhost and intrahost genetic variation’ as it passages through the population.

 

First a bit from the study, then I’ll be back with more.

Published Online August 28 2014

Science DOI: 10.1126/science.1259657

Genomic surveillance elucidates Ebola virus origin and transmission during the 2014 outbreak

Stephen K. Gire¹,²,*, Augustine Goba³,*,†, Kristian G. Andersen¹,²,*,†, Rachel S. G. Sealfon²,⁴,*, Daniel J. Park²,*, Lansana Kanneh³, Simbirie Jalloh³, Mambu Momoh³,⁵, Mohamed Fullah³,⁵,‡, Gytis Dudas⁶, Shirlee Wohl¹,²,⁷, Lina M. Moses⁸, Nathan L. Yozwiak¹,², Sarah Winnicki¹,², Christian B. Matranga², Christine M. Malboeuf², James Qu², Adrianne D. Gladden², Stephen F. Schaffner¹,², Xiao Yang², Pan-Pan Jiang¹,², Mahan Nekoui¹,², Andres Colubri¹, Moinya Ruth Coomber³, Mbalu Fonnie³,‡, Alex Moigboi³,‡, Michael Gbakie³, Fatima K. Kamara³, Veronica Tucker³, Edwin Konuwa³, Sidiki Saffa³, Josephine Sellu³, Abdul Azziz Jalloh³, Alice Kovoma³,‡, James Koninga³, Ibrahim Mustapha³, Kandeh Kargbo³, Momoh Foday³, Mohamed Yillah³, Franklyn Kanneh³, Willie Robert³, James L. B. Massally³, Sinéad B. Chapman², James Bochicchio², Cheryl Murphy², Chad Nusbaum², Sarah Young², Bruce W. Birren², Donald S. Grant³, John S. Scheiffelin⁸, Eric S. Lander²,⁷,⁹, Christian Happi¹⁰, Sahr M. Gevao¹¹, Andreas Gnirke²,§, Andrew Rambaut⁶,¹²,¹³,§, Robert F. Garry⁸,§, S. Humarr Khan³,‡§, Pardis C. Sabeti¹,²,†§

 

In its largest outbreak, Ebola virus disease is spreading through Guinea, Liberia, Sierra Leone, and Nigeria. We sequenced 99 Ebola virus genomes from 78 patients in Sierra Leone to ~2,000x coverage. We observed a rapid accumulation of interhost and intrahost genetic variation, allowing us to characterize patterns of viral transmission over the initial weeks of the epidemic. This West African variant likely diverged from Middle African lineages ~2004, crossed from Guinea to Sierra Leone in May 2014, and has exhibited sustained human-to-human transmission subsequently, with no evidence of additional zoonotic sources. Since many of the mutations alter protein sequences and other biologically meaningful targets, they should be monitored for impact on diagnostics, vaccines, and therapies critical to outbreak response.

• In Depth Infectious Disease Genomes reveal start of Ebola outbreak

  • Gretchen Vogel
  Science 29 August 2014: 989-990.
  • Summary
  • Full Text
  • Full Text (PDF)

These researchers found that the virus had evolved into three distinct lineages in Sierra Leone during the month of June (one of which appears to have died out), along with accumulating scores of amino acid changes to its genome.

 

It should be noted that while scientists have the ability to sequence and compare these variant viruses, they don’t necessarily know what these individual mutations (or their aggregate) means to the virus, or how it might change its behavior. 

 

Based on the location of some these changes, there are concerns that the PCR primers currently used to detect it patients may need adjusting, and that some of the antiviral drugs being developed could be impacted as well. 

 

And while it is theoretically possible that changes to the genome could affect the transmissibility of the virus, we haven’t seen any evidence of that happening.

 

Unknown at this time are what genetic changes might be occurring in the virus in Liberia and Guinea, or even Nigeria. The bottom line, however, is that the longer this virus circulates in humans, the better chance it has of producing a mutation we really don’t want to see.

 

For some more coverage on this report, NPR’s Goats & Soda Blog has:

 

Ebola Is Rapidly Mutating As It Spreads Across West Africa

by Michaeleen Doucleff

 

 

This from Scientific American:

 

Patient Zero Believed to be Sole Source of Ebola Outbreak

By pinpointing the virus’s source, a new report validates steps health care workers are taking to battle the disease

Aug 28, 2014 |By Dina Fine Maron

And this from Nature News. 

 

Ebola virus mutating rapidly as it spreads

Outbreak likely originated with a single animal-to-human transmission.

Science: H7N9 Transmissibility Study In Ferrets

 

Photo Credit Wikipedia

 

UPDATED: CIDRAP NEWS now has an extensive review of this paper up on their website, with expert commentary provided by Dr. Ian MacKay. 

 

Study: H7N9 highly transmissible by airborne route

  Highly recommended.

 

 

 

# 7496

 

 

While the welcomed lull in avian influenza cases in Eastern China over the past six weeks has taken H7N9 largely out of the daily headlines, history has shown that avian flu viruses often go `quiet’ during the warm summer months, only to reappear again in the fall or winter.

 

Complicating matters, we still don’t know the source of this virus, or exactly how it managed to spread across tens of thousands of square kilometers of Eastern China - and infect at least 132 people - in a matter of a few weeks.

 

So over the summer researchers have continued to examine the H7N9 virus, trying to gauge its pandemic potential should it return with colder weather this fall.

 

Last week we saw two studies in the Journal Nature  (see Nature: H7N9 Pathogenesis and Transmissibility In Ferrets & Mice & CIDRAP NEWS  article New studies on H7N9 raise pandemic concerns) that suggested the H7N9 virus might be better equipped to spark a pandemic than previously thought.

 

Researchers determined that while the virus did not appear to transmit as easily as seasonal flu via respiratory droplets between ferrets, once acquired, the virus replicated at a much higher rate than one normally sees with seasonal flu.

 

Today, we’ve a complex and fascinating new study by scientists from Harbin Veterinary Research Institute and the Gansu Agricultural University appearing in the Journal Science that gives us a detailed look at two critical issues; the pathogenicity and transmissibility of the virus (in mice & ferrets). 

 

Ferrets – whose respiratory system (and susceptibility to flu) are reasonably close to that of humans – are often used in transmissibility and pathogenicity studies of influenza. 

 

Today’s study tested several different H7N9 isolates (acquired from birds, and from humans) for transmissibility, and even though their HA and NA proteins were genetically quite similar, at least one H7N9 isolate transmitted readily via respiratory droplets among ferrets.

 

The abstract (see below), only scratches the surface of research conducted in this study.

 

H7N9 Influenza Viruses Are Transmissible in Ferrets by Respiratory Droplet

Science DOI: 10.1126/science.1240532

Qianyi Zhang, Jianzhong Shi, Guohua Deng, Jing Guo, Xianying Zeng, Xijun He, Huihui Kong, Chunyang Gu,  Xuyong Li, Jinxiong Liu, Guojun Wang, Yan Chen,  Liling Liu,  Libin Liang, Yuanyuan Li, Jun Fan, Jinliang Wang,  Wenhui Li, Lizheng Guan,  Qimeng Li, Huanliang Yang,  Pucheng Chen,  Li Jiang,Yuntao Guan, Xiaoguang Xin, Yongping Jiang, Guobin Tian, Xiurong Wang, Chuanling Qiao, Chengjun Li,  Zhigao Bu, Hualan Chen

Abstract (EXCERPT)

We systematically analyzed H7N9 viruses isolated from birds and humans. The viruses were genetically closely related and bound to human airway receptors; some also maintained the ability to bind to avian airway receptors. The viruses isolated from birds were nonpathogenic in chickens, ducks, and mice; however, the viruses isolated from humans caused up to 30% body weight loss in mice.

 

Most importantly, one virus isolated from humans was highly transmissible in ferrets by respiratory droplets. Our findings indicate nothing to reduce the concern that these viruses can transmit between humans.

 

 

While I’m sure CIDRAP NEWS will have a more detailed look later today (I’ll post a link), a few of the high points in this study include:

 

• Researchers tested more than 10,700 samples taken from poultry farms, live market birds, wild bird habitats, and even poultry and swine slaughter houses and only managed to find 52 samples that were H7N9 positive (all but 2 were found in live-markets)
• Chickens intravenously inoculated with two early strains of the virus showed no signs of illness indicating the H7N9 is largely non-pathogenic in chickens
• Isolates taken from humans appeared to be more pathogenic in ferrets and mice than those taken from birds, suggesting adaptation of the virus may occur after the virus jumps to humans.
• All of the human isolates had either the 627K or 701N amino acid changes in their PB2 (both associated with increased virulence and transmission in mammals) - while the avian isolates did not - again suggesting that adaptive mutations may have occurred during replication of the virus in the human host.
• Mice inoculated with avian H7N9 isolates showed no signs of disease signs or deaths.
• Mice inoculated with human derived H7N9 isolates experienced significant weight loss & pathogenesis.
• In ferret transmissibility studies, four of the five viruses tested could be transmitted between ferrets in direct contact with each other, and one transmitted with high efficiency via respiratory droplets.

 

Being non-pathogenic in chickens, this virus has the potential to spread stealthily, and its rapid spread across multiple provinces in China suggests it transmits efficiently among poultry species.

 

This research suggests that the H7N9 virus already binds pretty well to human-like (a2,6) receptor cells, and it replicates efficiently in a mammalian (ferret) host.

 

Additionally, the H7N9 virus appears capable of accruing adaptive mutations that enhance both its virulence and transmissibility once it starts to replicate within a human host.

 

And perhaps most worrisome of all, at least one isolate tested already demonstrates the ability to transmit readily via respiratory droplets in ferrets.

 

Complicating matters, earlier this week we saw a study (see mBio: Antiviral Resistance In H7N9) suggesting that antiviral resistance may form quickly in patients infected with the H7N9 virus.

 

All qualities that could help make the H7N9 virus a formidable foe should we see it return in the fall.

H7N9: Video Chat Via Science Live

 

 

 

# 7215

 

Each week Science Magazine holds an online chat with top experts on the hottest topics in science as part of their ScienceLive Series. Later this morning (10 am EDT) they will hold a live video Chat on the H7N9 virus, with guests Yuelong Shu, Marion Koopmans, and  moderator Jon Cohen. 

 

Here are the details for what should prove a very interesting discussion.

 

Live Chat: The Threat of H7N9 Bird Flu (Video)

by Jon Cohen on 1 May 2013, 8:47 AM | See below for the chat box. Join us this Thursday at 10 a.m. EDT for a live conversation with leading scientists and expert reporters.

 

Today's Topic

When Chinese public health officials announced last month that people were sick and dying from a bird flu virus never before seen in humans, researchers immediately began hunting for answers to a deluge of pressing questions. How did the humans become infected? How deadly was the bug? Had it spread to people outside of China? Would anti-influenza drugs work? And how long would it take to make a vaccine?

 

Join us at a special time, 10 a.m. EDT, on Thursday, 2 May, on this page for a live video chat when we discuss H7N9 with experts. They’ll tackle the questions above and take yours. Be sure to leave your queries in the comment box below.

Today's Guests

Yuelong Shu

Marion Koopmans

Moderator

ScienceInsider: Laboratory Plans For H7N9 Virus

 

The H7N9 Reassortment – Credit Eurosurveillance

 

# 7151

 

Martin Enserink - contributing editor and writer for Science magazine – together with science journalist Kai Kupferschmidt, have produced a terrific overview of the research plans that laboratories around the world have for using samples of the H7N9 virus.

 

Last Friday the CDC announced that they had received virus samples from China (see CDC Update On H7N9 – April 12th) and were already working on creating a candidate vaccine, diagnostic tests, and serological assay tests.

 

But there is much we don’t know about this virus, including its pathogenicity and transmissibility in mammals. A top priority is to test H7N9 on a variety of lab animals, including ferrets and cynomolgus macaques. 

 

In the following article we learn how small virus samples are grown into useful quantities, and the plans that scientists - including Ron Fouchier at Erasmus MC – have for this enigmatic avian flu virus.  

 

Chinese H7N9 Virus Making Its Way to Labs Around the World

by Kai Kupferschmidt and Martin Enserink, With reporting by Dennis Normile on 16 April 2013, 5:30 PM |

 

 

Research such as described above will not only increase our knowledge of the threat this virus may pose today, but also give us an idea of its potential for evolving into a bigger threat tomorrow.

 

Highly recommended.

Science Live Chat: Are We Doing Science The Right Way?

 

Credit Science Magazine

 

# 6912

 

Over the past few years the topic of scientists behaving badly has come up with increasing frequency.  About a year ago, in Science at the Crossroads, I wrote about the dangerous erosion of the public’s trust in science.

 

Last March In Dysfunctional Science we saw a pair of editorials published in Infection and Immunity (IAI), authored by Dr. Ferric C. Fang, Editor in Chief, Infection and Immunity and Dr. Arturo Casadevall, Editor in Chief, mBio  on the challenges facing researchers. 

 

Copies of these thought provoking editorials can be found online at:

 

http://iai.asm.org/content/80/3/891.full

and

http://iai.asm.org/content/80/3/897.full

 

During a presentation last March before a committee of the National Academy of Sciences, Fang & Casadevall warned that number of retraction notices for scientific journals has increased more than 10-fold over the last decade, while the number of journals articles published has only increased by 44%.

 

And just a few weeks ago, in mBio: Gender Analysis Of Scientific Misconduct, we looked at an analysis written by written Joan W. Bennett, Ferric C. Fang, and Arturo Casadevall, that examined the rise of Scientific misconduct - which includes fabrication, falsification or plagiarism – over the past decade.

 

This is such an important topic that  I’m delighted to report that tomorrow afternoon (Thursday, Feb 7th) at 3pm EST, Science Live  will be holding a live chat with both Dr. Casadevall and Dr. Fang.

Details below, so mark your calendars for what I’m sure will be a lively discussion.

 

 

As much as they love research, many scientists lament the state of their profession these days. A mix of budgetary and other pressures are spawning stress and fear in the community. Bad scientific behavior is not uncommon. Recently, Science described the efforts of two microbiologists, Ferric Fang and Arturo Casadevall, who study how well the enterprise is functioning and how common misconduct appears to be. Is the push to publish ruining scientific discovery? Is science really self-correcting? Does peer review work? Are labs the right size? Does the quest for grants create a climate that encourages misconduct?

 

Join us for a live chat at 3 p.m. EST on Thursday, 7 February, on this page with Fang and Casadevall. Leave your own in the comment box below before the chat starts. The full text of the chat will be archived on this page.

Revisiting The H5N1 CFR Debate

 

 

Source – WHO as of 6/7/12

 

 

 

# 6401

 

One of the more contentious aspects of the H5N1 research debate of the past 8 months has been the argument over the `real’ CFR (Case Fatality Ratio) of the H5N1 virus in humans.

 

The `official’ number – a fatality rate of roughly 60% – is derived from the total known human infections by the virus (606 as of June 7th, 2012), and the total number of fatalities within that group (357)

 

Critics point out that only the sickest of the sick would end up in a testing environment, and that many mild cases would recover and never be counted.

 

The numbers, they maintain, are badly skewed.

 

Last February (see Science: Peter Palese On The CFR of H5N1) the journal Science published a meta-analysis by  Taia T. Wang,  Michael K. Parides &  Peter Palese, that argued that we are likely missing a great many H5N1 infections (perhaps millions), and that the virus is far less lethal than has been assumed in the past.

 

That argument was countered by CIDRAP director Michael T. Osterholm and Nick Kelley in an mBio  article, where they found little serological evidence to suggest that we are missing `millions’ of uncounted H5N1 infections (see mBio: Mammalian-Transmissible H5N1 Influenza: Facts and Perspective).

 

Today, we’ve a new response to the Palese meta-analysis appearing in the journal Science. One with a remarkable pedigree; attached you’ll find some of the biggest names in influenza research:

 

 

Comment on “Seroevidence for H5N1 Influenza Infections in Humans: Meta-Analysis”

Science 22 June 2012:
Vol. 336 no. 6088 p. 1506
DOI: 10.1126/science.1221434

Maria D. Van Kerkhove, Steven Riley,Marc Lipsitch, Yi Guan, Arnold S. Monto, Robert G. Webster, Maria Zambon, Angus Nicoll, J. S. Malik Peiris, Neil M. Ferguson

Abstract

A better understanding of the severity of H5N1 in humans is needed. Wang et al. (Brevia, 23 March 2012, p. 1463; published online 23 February 2012) over interpret the results of seroprevalence studies and take too little account of underlying uncertainties. Although the true risk of death from H5N1 infection will likely be lower than the 60% of reported laboratory-confirmed cases, there is little evidence of millions of missed infections.

 

Their entire rationale may be read here, and it strongly counters the assessment presented by Wang et al. in the original paper.

 

Dueling opinion pieces, regardless of the credentials of those involved, can’t really settle this argument. What we need are more, and better, seroprevalence studies in places where the H5N1 virus is endemic to come to any firm conclusions.

 

While most researchers accept that the 60% CFR number is probably far too high, as the authors of today’s article caution, in the absence of compelling data to the contrary:

 

“The precautionary principle dictates that we continue to assume that natural H5N1 infection in humans carries a high risk of death”

 

A policy I would certainly endorse.

Science Magazine: Public Health, Biosecurity, and H5N1

 

BSL-4 Lab Worker - Photo Credit –USAMRIID

 

 

# 6083

 

 

My thanks to Lisa at CIDRAP for pointing me this morning in the direction of an an avalanche of commentaries on Public Health, Biosecurity, and H5N1 published online ahead of print via Science Magazine’s  Science Express.

These opinion pieces are penned by some of the  most respected names in the world of influenza research.

 

For background on this growing  controversy, you may wish to revisit these earlier blogs:

 

Nature: 10 Expert Opinions On The H5N1 Research Dilemma

WHO To Take Role In Sorting Out Bird Flu Research Controversies

The Furor Over H5N1 Research Continues

 

 

I’ve only just begun to read these papers, but wanted to provide my readers with the links as soon as possible.

 

Public Health, Biosecurity, and H5N1

 

H5N1 Debates: Hung Up on the Wrong Questions

• Daniel R. Perez
• Published online 19 January 2012
• DOI:10.1126/science.1219066]
• Abstract
• Full Text (PDF)

 

Life Sciences at a Crossroads: Respiratory Transmissible H5N1

• Michael T. Osterholm and
• Donald A. Henderson
• Published online 19 January 2012
• DOI:10.1126/science.1218612]
• Abstract
• Full Text (PDF)

 

The Limits of Government Regulation of Science

• John D. Kraemer and
• Lawrence O. Gostin
• Published online 19 January 2012
• DOI:10.1126/science.1219215]
• Abstract
• Full Text (PDF)

 

Restricted Data on Influenza H5N1 Virus Transmission

• Ron A. M. Fouchier,
• Sander Herfst,
• and Albert D. M. E. Osterhaus
• Published online 19 January 2012
• [DOI:10.1126/science.1218376]
• Abstract
• Full Text (PDF)

 

 

You’ll also find a series of news articles that cover this ongoing  controversy, along with a link to Science’s Special Online Collection: Influenza page at THIS LINK.