EID Journal: The Transmission Potential Of A(H7N9) In China

 

 

# 9892

 

Whether you cast your gaze towards Egypt (H5N1), or China (H7N9), recent outbreaks of avian flu among humans continue to raise concerns over their pandemic potential.  Neither virus has demonstrated an ability to spread efficiently from human-to-human, but both continue to get fresh opportunities to try to figure us out.

Last month, in WHO: H5 Currently The Most Obvious Avian Flu Threat, the World Health Organization – while not ignoring H7N9’s potential - weighed in on the risks posed by the recent and dramatic surge in both the variety, and spread, of HPAI H5 viruses around the globe.

 

A couple of weeks later, in Nature: Dissemination, Divergence & Establishment of H7N9 In China, we saw renewed warnings over the evolutionary path that the H7N9 virus has been taking over the past two years.  A topic we revisited the next day, in H7N9: Primus Inter Pares?

 

To this short list, we must also add a growing variety of reassortant avian and swine viruses (H5N8, H5N6, H5N2, H10N8, H3N8, H3N2v, etc.), many of which have at least some potential to adapt to humans. 

 

Today the EID Journal has published a new review of the transmissibility of the avian H7N9 virus in China, and while no evidence of sustained transmission was detected, they found:

• `evidence of a small but significant amount of transmission between humans in the first and second waves’
• `evidence of increased transmission potential in the second wave’

First a few excerpts from the study (follow the link to read it in its entirety), after which I’ll be back with a bit more.

 

Volume 21, Number 5—May 2015

Dispatch

Transmission Potential of Influenza A(H7N9) Virus, China, 2013–2014

Adam J. Kucharski¹ , Harriet L. Mills¹, Christl A. Donnelly, and Steven Riley

Abstract

To determine transmission potential of influenza A(H7N9) virus, we used symptom onset data to compare 2 waves of infection in China during 2013–2014. We found evidence of increased transmission potential in the second wave and showed that live bird market closure was significantly less effective in Guangdong than in other regions.

From February 19, 2013, through April 22, 2014, a total of 429 cases of influenza A(H7N9) virus infection in humans in China were reported and occurred in 2 outbreak waves. During the first wave in spring 2013, live bird markets were closed in several parts of China (1,2); these market closures substantially reduced the risk for infection in affected regions (3). During a second wave in autumn 2013 (4), markets were again closed in some provinces (5–7). Analysis of the largest clusters of subtype H7N9 virus infection in 2013 suggested that the basic reproduction number (R₀, the average number of secondary cases generated by a typical infectious host in a fully susceptible population) was higher in some clusters than in others (8,9), although the absence of sustained transmission implied that R₀ was less than the critical value of 1. To determine the transmission potential of influenza A(H7N9) virus in the first and second waves in 2013, we compared symptom onset data. We also measured the extent to which market closures in 2014 reduced spillover hazard (i.e., risk for animal-to-human infection).

<SNIP Study Details>

Conclusions

We found no evidence of reduced human-to-human transmission between the 2 waves. For a serial interval of 7 days, we estimated that R₀ increased in Zhejiang. Furthermore, the effectiveness of live bird market closures varied between regions; short-term closures were substantially less effective than interventions in other regions. These results emphasize the value of prompt and sustainable control measures during outbreaks of influenza A(H7N9) virus infection.

 

 

Last summer, in Eurosurveillance: Genetic Tuning Of Avian H7N9 During Interspecies Transmission, we saw evidence of the genetic diversity, and continual evolution, of the H7N9 virus in Mainland China.  Researchers found that at least 26 separate genotypes had emerged, mostly during the first wave, through a process they called `genetic tuning’.

 

The Nature report, mentioned above, expands that H7N9 universe to 48 genotypes, spread across three major clades.

 

Not only are the incarnations of H7N9 continuing to grow, the H7N9 virus has also reassorted into at least two new subtypes on the Chinese mainland; H7N7 (see  Nature: Genesis Of The H7N9 Virus) and a new H7N6 virus described in the recent Nature report.

 

This malleable H7N9 virus, which is spreading asymptomatically and stealthily in China’s poultry, could also potentially reassort with a human influenza virus like H3N2 or H1N1.  Something that Hong Kong’s CHP Director has discussed repeatedly this winter (see  HK’s Dr. Ko Wing-man On Flu Reassortment Concerns).

 

While there are seemingly a lot of ways for H7N9 to become a pandemic threat, it is also possible that there is some – as yet unidentified - `species barrier’  that prevents avian flu viruses from adapting well enough to humans to pose a serious threat.

 

The progression of human influenza pandemics over the past 130 years has been H2, H3, H1, H2, H3, H1, H1 . . . .  and while that doesn’t prove that  an H5 or an H7 virus couldn’t adapt to humans (or hasn’t in the past), it has led some researchers to wonder whether a non H1, H2, or H3 virus has the `right stuff’ to spark a pandemic.

 

While some scientists believe that may be a possibility (see Are Influenza Pandemic Viruses Members Of An Exclusive Club?), few are willing to bet the farm on our being that lucky.

CDC: Review of Human-to-Human Transmission of Ebola Virus

Credit CDC PHIL

 

 

# 9211

 

My reasoning behind why I don’t believe that Ebola is an `airborne’ virus in the `classic sense’ (although short-distance droplet transmission appears possible) is pretty simple: 

 

If it was truly airborne, we’d be digging mass graves all around the globe by now.

 

Whether it could someday achieve airborne transmissibility is a debate I’ll leave to real scientists to wrangle over. While I suspect that it is probably a long shot, I try never to say `never’.

 

What we know about the transmissibility of Ebola come mostly from anecdotal reports from earlier outbreaks, along with some limited laboratory experimentation. There are certainly gaps in our knowledge, but thus far – as is stated in the following CDC detailed review  - Airborne transmission of EVD among humans has never been demonstrated.

 

The following is an excerpt from a much larger synopsis of the Ebola Virus, which was published yesterday.  The entire document is worth reviewing.

Review of Human-to-Human Transmission of Ebola Virus

 

• Introduction
• Evidence Summary
• Epidemiologic Data
• Laboratory Data
• Transmission among Healthcare Personnel and Patients
• Transmission Studies
• 2014 EVD Outbreak
• Summary
• References

This document is a concise summary of published information on the current science about human-to-human transmission of Ebola virus. It is developed for use by healthcare personnel and public health professionals to use. It is a complement to the many guidance documents that CDC has issued already online at www.cdc.gov/ebola .

<SNIP>

Transmission Studies

Airborne transmission of Ebola virus has been hypothesized but not demonstrated in humans. While Ebola virus can be spread through airborne particles under experimental conditions in animals, this type of spread has not been documented during human EVD outbreaks in settings such as hospitals or households.¹ In the laboratory setting, non-human primates with their heads placed in closed hoods have been exposed to and infected by nebulized aerosols of Ebola virus.^28,29 In a different experiment, control monkeys were placed in cages 3 meters away from the cages of monkeys that were intramuscularly inoculated with Ebola virus.³⁰ Control and inoculated monkeys both developed Ebola virus infection. The authors concluded that “fomite and contact droplet” transmission to the control monkeys was unlikely, and that airborne transmission was most likely,³⁰ but they did not discuss the potential behaviors of caged non-human primates (e.g., spitting and throwing feces) that might have led to body fluid exposures.³¹ Similarly, an outbreak of Reston virus (Reston ebolavirus species, which does not cause EVD in humans) infection occurred in a quarantine facility housing non-human primates in separate cages and the transmission route could not be confirmed for all infected primates. Multiple animal handlers developed antibody responses to Reston virus suggesting asymptomatic infection was occurring in humans with direct animal contact and implicating animal handling practices in transmission between primates.³² In a different study, piglets that were oronasally inoculated with Ebola virus were able to transmit infection to caged non-human primates that were placed 20 cm from the piglets.³³ The piglet and primate cubicle design did not permit the investigators to distinguish among aerosol, small or large droplet, or fomite transmission routes, and it was noted that pigs are capable of generating infectious short range aerosol droplets more efficiently than other species. A more recent experiment that was specifically designed to further evaluate the possibility of naturally-occurring airborne transmission of Ebola virus among non-human primates showed no transmission of Ebola virus from infected to control primates placed 0.3 meters apart in separate open-barred cages and ambient air conditions, but with a plexiglass divider that prevented direct contact between the animals.³⁴

In outbreak investigations, some EVD patients have not reported contact with another EVD patient, leading to speculation regarding transmission via aerosolized virus particles. In the Kikwit outbreak, 12 (3.8%) of 316 EVD patients did not report high-risk contact with a known EVD patient.⁷ EVD was not laboratory-confirmed in any of these 12 patients, however, and exposure histories for 10 of the 12 patients were provided by surrogates (because the 10 patients died before they could be interviewed); direct contact with EVD patients could have been missed because of wording of the study instrument, and transmission via droplets or fomites were also not ruled out. All 74 patients with EVD confirmed by RT-PCR testing or an Ebola antibody or antigen detection assay in this outbreak had high-risk exposures to Ebola patients.⁷ Similarly, in the 2007-2008 Uganda outbreak, although some probable (not virologically-confirmed) cases did not have a reported contact exposure, all 42 laboratory-confirmed cases had contact with a known EVD case.¹³ Also, in a separate analysis of the Kikwit outbreak, the presence of cough (19% of primary cases within households) did not predict secondary spread of EVD.³

2014 EVD Outbreak

Most of the evidence regarding human-to-human transmission of Ebola virus is derived from investigations of previous Ebola outbreaks. Although the current EVD epidemic in West Africa is unprecedented in scale, the clinical course of infection (i.e., incubation period, duration of illness, case fatality rate) and the transmissibility of the virus (i.e., estimations of the basic reproductive number [R0]) are similar to those in earlier EVD outbreaks.² In addition, genetic analyses of 99 Ebola virus genomes sequenced from 78 patients from the 2014 outbreak in Sierra Leone³⁵ suggest that the 2014 EVD outbreak strains are very closely related to viral strains from the two most recent Ebola outbreaks in Central Africa.³⁵ As has been observed in previous Ebola outbreaks, the genomic sequences from the 2014 EVD outbreak have a small number of distinct genetic changes, but it is not known if these changes have an impact on disease severity or transmissibility.³⁵

Summary

EVD among healthcare personnel and other persons is associated with direct contact with infected persons (or the bodies of persons who have died from EVD) and direct contact with body fluids from EVD patients. CDC infection control recommendations for U.S. hospitals, including recommendations for standard, contact, and droplet precautions for general care, reflect the established routes for human-to-human transmission of EVD and are based on data collected from previous EVD outbreaks in Africa in addition to experimental data. Airborne transmission of EVD among humans has never been demonstrated in investigations that have described human-to-human transmission although hypothetical concerns about airborne transmission of EVD have been raised.^3,10

Nature Communications: Respiratory Transmission of Avian H3N8 In Ferrets

Photo Credit Wikipedia

 

# 9035

 

For those who aren’t completely overwhelmed by the plethora of zoonotic pathogens that have been coming out of the woodwork over the past few years, we’ve a new study today on an avian influenza virus – first isolated in New England seals back in 2011 (see New England Seal Deaths Tied to H3N8 Flu Virus)  –  that finds it is not only well adapted to mammalian hosts, that it can also be easily transmitted between ferrets via the respiratory route.

 
This H3N8 virus is of a different lineage than the Equine/Canine H3N8 virus, although they are cousins. 

 

Until it landed in seals, this H3N8 strain was an avian adapted virus.  That is, that it bound preferentially to the kind of receptor cells commonly found in the digestive and respiratory tracts of birds; alpha 2,3 receptor cells.

 

In 2010, in mBio: A Mammalian Adapted H3N8 In Seals, we saw the first hints that this virus had recently adapted to bind to alpha 2,6 receptor cells, the type found in the human upper respiratory tract.

From the accompanying mBio press release New influenza virus from seals highlights the risks of pandemic flu from animals.

 

The mBio® study analyzed the DNA of a virus associated with a die-off of 162 New England harbor seals in 2011. Autopsies of five of the seals revealed they apparently died from infection with a type of influenza called H3N8, which is closely related to a flu strain that has been circulating in North American birds since 2002. Unlike the strain in birds, this virus has adaptations to living in mammals and has mutations that are known to make flu viruses more transmissible and cause more severe disease. The virus also has the ability to target a receptor called SAα-2,6, a protein found in the human respiratory tract.

Moscana says the study raises two concerns about flu. First, this strain is a novel virus that infects mammals and may well pass from animal to animal, a combination of traits that make it a potential threat to humans. Also, the possibility that a bird flu virus would infect seals hadn't been widely considered before, highlighting the fact that pandemic influenza can crop up in unexpected ways. She emphasizes the need for readiness.

 

Fast forward a couple of years, and today we have a study conducted by the USGS and St. Jude Children’s Research Hospital  appearing  in Nature Communications, that looks at the transmissibility of this emerging virus. 

 

In their words, they found  `the virus has an increased affinity for mammalian receptors, transmits via respiratory droplets in ferrets and replicates in human lung cells.’

 

A triple threat, in any league. And if that weren’t enough, testing of human sera for neutralizing antibodies finds little evidence of population wide immunity to this strain. 

 

All of this becomes even more concerning when you consider the history of H3N8 in humans.

 

The H3N8 virus is thought to have sparked the 1900 influenza pandemic. Since then it has continued to circulate in birds and pigs, and is considered a prime candidate to mount a return engagement someday again (see Are Influenza Pandemic Viruses Members Of An Exclusive Club?).

 

First the Abstract (the full article is behind a pay wall), then a press release with additional details from the USGS.

 

Respiratory transmission of an avian H3N8 influenza virus isolated from a harbour seal

Erik A. Karlsson, Hon S. Ip, Jeffrey S. Hall, Sun Woo Yoon, Jordan Johnson, Melinda A. Beck, Richard J.  Webby & Stacey Schultz-Cherry Article number:

doi:10.1038/ncomms5791

Published 03 September 2014

The ongoing human H7N9 influenza infections highlight the threat of emerging avian influenza viruses. In 2011, an avian H3N8 influenza virus isolated from moribund New England harbour seals was shown to have naturally acquired mutations known to increase the transmissibility of highly pathogenic H5N1 influenza viruses. To elucidate the potential human health threat, here we evaluate a panel of avian H3N8 viruses and find that the harbour seal virus displays increased affinity for mammalian receptors, transmits via respiratory droplets in ferrets and replicates in human lung cells.

Analysis of a panel of human sera for H3N8 neutralizing antibodies suggests that there is no population-wide immunity to these viruses. The prevalence of H3N8 viruses in birds and multiple mammalian species including recent isolations from pigs and evidence that it was a past human pandemic virus make the need for surveillance and risk analysis of these viruses of public health importance.

 

From the USGS we have the following press release.

 

 

Avian Flu in Seals Could Infect People

Released: 9/3/2014 5:00:00 AM

Contact Information:
U.S. Department of the Interior, U.S. Geological Survey
Office of Communications and Publishing
12201 Sunrise Valley Dr, MS 119
Reston, VA 20192
 

The avian flu virus that caused widespread harbor seal deaths in 2011 can easily spread to and infect other mammals and potentially humans.

A new study by the U.S. Geological Survey and St. Jude Children’s Research Hospital shows that the avian influenza H3N8 strain that infected New England harbor seals could be transmitted to other mammals through the air without physical contact. Transmission by respiratory droplets through coughing, for example, is the main way influenza viruses spread among people. The study also showed that current seasonal flu vaccines do not protect against this seal virus, meaning a new vaccine would be necessary if there ever was an outbreak in humans.

"The ability to transmit through the air is an important step in the path toward any influenza virus becoming pandemic," said USGS scientist Hon Ip. "The lack of protection against the seal virus from the annual seasonal vaccine highlights the risks posed by this H3N8 group of viruses."

The article, led by St. Jude in collaboration with the USGS and the University of North Carolina at Chapel Hill, was published today in the journal Nature Communications and is available online.

The scientists tested a sample of the influenza virus taken from an infected harbor seal in New Hampshire in 2011, and found that the virus was closely related to influenza viruses from wild birds. However, the H3N8 virus isolated from the seal contained mutations that allowed it to reproduce efficiently in human lung cells, cause disease in mice and infect ferrets through the air.

"Findings from this study highlight the need for continued surveillance and study of avian influenza genetics, particularly in areas like coastal regions where wild birds, wild mammals and human populations come into contact with each other,” said USGS scientist Jeff Hall.

H3N8 viruses, common in wild birds, have been associated with ongoing outbreaks in dogs and horses and have also been detected in pigs, donkeys and now seals. Beginning in September 2011, more than 160 young harbor seals were found dead or dying along the New England coast as a result of this infection. In previous H3N8 mortality events, up to 20 percent of the local seal population died.

For more information on zoonotic diseases, or diseases that spread between animals and humans, please visit the USGS National Wildlife Health Center website.

 

Up until a few years ago most researchers would have said that birds and pigs are the most likely source of the next global health threat. Today, we look at bats, horses, dogs, camels and yes – even seals - as possibly sparking the next pandemic.

 

For more on the different strains of H3N8 (including canine and equine versions), and influenza in seals,  you may wish to revisit:

 

EID Journal: Equine H3N8 In Mongolian Bactrian Camel

Study: Dogs As Potential `Mixing Vessels’ For Influenza

The 2009 H1N1 Virus Expands Its Host Range (Again)

The Elusive R0 of MERS

 

# 8601

 

Yesterday, the International Journal of Infectious Diseases published an `article in press’ peer-reviewed manuscript that attempts to quantify the risks from the MERS coronavirus, entitled:

 

Middle East Respiratory Syndrome Corona virus, MERS-CoV. Conclusions from the 2nd Scientific Advisory Board Meeting of the WHO Collaborating Center for Mass Gathering Medicine, Riyadh.

Ziad A Memish^a,,  Jaffar Al-Tawfiq^b,  Christian Drosten^c,  Abdullah Assiri^a,  Rafaat Alhakeem^a, Ali Albarrak^{a, d},  Saber Yezli^a,  Malak Almasri^a,  Alimuddin Zumla^{a, e},  Eskild Petersen^f

After reviewing what is known about the outbreak, animal reservoirs, human transmission and the management of hospital patients with MERS, the authors enumerate 13 conclusions.

Conclusions

1. Sequencing of MERS-CoV isolates from Jeddah patients who’s the virus seems stable, showing no signs so far of mutations which indicate an adaption to humans with increased risk of human to human infections.
2. The primary animal reservoir is camels and dromedars. Transmission is thought to be due to close physical contact or due to consumption of camel products.
3. The epidemiology since the virus was first found in 2012 is compatible with multiple introductions into humans from the animal reservoir, with no long-term sustained human-to-human transmission.
4. There is no human reservoir of cases with few or no symptoms.
5. The basic reproductive rate of the virus (R0) is definitely below 1 and probably below 0.5 clearly showing that the virus has no pandemic or even local epidemic potential.
6. The incubation period was between 2 to 16 days? Period of infectivity was?
7. Nosocomial infection is an important risk factor for human to human transmission. Thus infection prevention and control measures are crucial to prevent the possible spread of MERSCoV within health care facilities. Hospital infection control procedures needs to be emphazised and enforced. The Jeddah outbreak showed that it is not always possible to identify patients with MERS-CoV early because some have mild or unusual symptoms.It is important that health-care workers apply standard precautions consistently with all patients irrespective of the diagnosis. Droplet precautions should be undertaken when providing care to patients with symptoms of respiratory tract infection. Contact precautions including eye protection should be added when caring for suspected or confirmed cases of MERS-CoV infection. Airborne precautions should be taken when performing aerosol generating procedures
8. In patients suspected of MERS-CoV, if initial tests using nasopharyngeal swab is negative, repeat testing should be performed, and other specimens from the lower respiratory tract should be obtained if possible.
9. Awareness of MERS-CoV is important in countries where camels and dromedars are a common livestock.
10. The importance of educational campaigns for educating health care workers, the general public, family contacts and travelers to the Middle East was emphasized. General hygiene measures such as regular hand washing, antiseptic before and after handling animals Owners of camels and dromedars should use gloves and mask when handling ill animals.
11. There is no evidence that camel's milk tested positive for MERS, however, milk has the potential of transmitting other infections. Camel milk should be boiled before consumption. Unpasteurised milk should not be consumed
12. There was no grounds for preventing children attending schools and closing schools
13. For the forthcoming Hajj, camel sacrifice or contact with camels should be avoided.

 

While all significant points of interest, from an epidemic standpoint, #5 in the list above would seem to have the most importance:

 

The basic reproductive rate of the virus (R0) is definitely below 1 and probably below 0.5 clearly showing that the virus has no pandemic or even local epidemic potential.

 

A definitive, and highly reassuring statement.   And hopefully correct.  But as with all reviews, at best reports like this can only tell us where this virus has been, not where it is going.  

 

The R0 (pronounced R-naught) is epidemiological yardstick by which human transmission of an infectious disease is measured. Essentially, the number of new cases in a susceptible population likely to arise from a single infection.

 

With an R0 below 1.0, a virus (as an outbreak) begins to sputter and dies out.

 

Above 1.0, and an outbreak can have `legs’.

 

Calculating the R0 is notoriously difficult, even years after an epidemic has passed. Much hinges upon the existence and subtle differences between viral strains, the accuracy of surveillance and reporting, `seasonality’, and individual host responses to the virus (i.e. number of `super spreaders’).

 

Like the CFR (Case Fatality Ratio), the R0 can vary considerably over time or geography, often ends up being described as a `range’, and usually isn’t well established (or at least, generally agreed upon) until long after an outbreak has ended.

 

Last July in The Lancet: Transmissibility Of MERS-CoV we saw the first attempts to quantify the basic reproductive number of this virus – at a time when the total number of MERS cases was still under 70 worldwide. Based on an extremely limited data-set, and hobbled by limited surveillance and reporting out of Saudi Arabia, the authors produced an early estimate of the virus’ apparent R0 (which they fixed at between .60 and .69).

 

Too low (at that time) to spark a pandemic.

 

But as Helen Branswell noted in her report - MERS doesn't have pandemic potential – yet  -  experts,  including Drs. Allison McGeer, Marc Lipsitch, and Chris Bauch (who co-authored a commentary on this study) - warned that past performance is no guarantee how this virus will behave in the future.

 

The following November, we looked at a study published in The Lancet Infectious Diseases, that looks at the likely extent of transmission of the MERS virus in the Middle East.

 

Middle East respiratory syndrome coronavirus: quantification of the extent of the epidemic, surveillance biases, and transmissibility

Simon Cauchemez PhD a †, Prof Christophe Fraser PhD a †, Maria D Van Kerkhove PhD a, Prof Christl A Donnelly ScD a, Steven Riley PhD a, Prof Andrew Rambaut PhD b, Vincent Enouf PhD c, Prof Sylvie van der Werf PhD c, Prof Neil M Ferguson DPh

Interpretation

By showing that a slowly growing epidemic is underway either in human beings or in an animal reservoir, quantification of uncertainty in transmissibility estimates, and provision of the first estimates of the scale of the epidemic and extent of case detection biases, we provide valuable information for more informed risk assessment.

The results – that for every case identified, there are likely 5 to 10 that go undetected –  suggest that this virus may be transmitting more efficiently than previously estimated. The authors believed the R0 of the MERS virus is likely close to 1.0, or perhaps even higher, and wrote:

 

We conclude that a slowly growing epidemic is underway, but current epidemiological data do not allow us to determine whether transmission is self-sustaining in man. Our analysis demonstrates that the transmissibility of MERS-CoV in man is close to the critical threshold of R=1 required for self-sustaining transmission. If R is greater than 1, then the number of human cases we estimate to have occurred to date make it highly likely that self-sustaining transmission has already begun.

 

Skipping ahead to February of this year, in mBio: Spread, Circulation, and Evolution of MERS-CoV, we looked at a study (also co-authored by Ziad Memish), that warned:

 

MERS-CoV adaptation toward higher rates of sustained human-to-human transmission appears not to have occurred yet. While MERS-CoV transmission currently appears weak, careful monitoring of changes in MERS-CoV genomes and of the MERS epidemic should be maintained. The observation of phylogenetically related MERS-CoV in geographically diverse locations must be taken into account in efforts to identify the animal source and transmission of the virus.

 

So far we’ve not seen the kind of exponential growth in MERS cases that would indicate that this virus has achieved a high enough basic reproductive number to spark a major epidemic.   Cases are rising, but more in a linear fashion.

 

Whether that equates to an R0 of <.5  or something approaching 1.0, I’ll leave to the epidemiologists of the world to sort out.

 

I would only note that there are still a lot of unknowns with this virus, including the incidence (and causes) of community transmission.  Surveillance outside of the hospital environment is spotty at best, and we really have no idea how many cases go unidentified.

 

The bottom line is that past performance doesn’t guarantee future behavior of this, or any other virus. 

Which means that as long as the MERS coronavirus continues to circulate in humans and animals in the Middle East, its potential to spark a larger epidemic should not be ignored.

Study: Airborne Transmission Of H7N1 in Ferrets After Serial Passage

Classic serial passage study, albeit with ducks instead of ferrets

 

# 8428

 

When novel flu viruses jump species, they rarely do so fully adapted to the new host. There is generally period of transition – which may be measured in days, weeks, years . . . or even decades -  before the virus can adapt to the new host species.

 

Sometimes the gulf between the original host and the new species is too great, and this adaptation never takes place.

 

Even though we don’t fully understand how it works, the concept is fairly simple.

 

When a flu virus infects a cell, it immediately sets upon making thousands of copies of itself.  But single-stranded RNA flu viruses are notoriously sloppy replicators, and some of these copies will invariably carry small transcription errors.   Most of these `variants’  will prove either neutral or detrimental to the survival and propagation of the virus, but occasionally a change will occur increases its biological fitness in the new host.

 

Those, as you might expect, are the ones that thrive and perpetuate themselves. 

 

Which is why we are always concerned whenever a novel flu virus jumps to humans, as each instance is another opportunity for the virus to `figure us out’.

 

One of the classic lab experiments used to `hurry’  this evolutionary process along is called a serial passage experiment (see graphic at top of this post), where an test subject (usually a mouse or ferret) is infected with a virus, and that virus is then collected and used to inoculate another test subject.  This process is repeated a number of times.

 

After 10 or so iterations, the virus is then examined for `adaptive changes’ and/or changes in behavior (ie. virulence, transmissibility).  Sometimes, after multiple passes through a series of hosts, the virus picks up mutations that favor its survival in the new species. 

 

This is essentially how Ron Fouchier created a `mammalian-adapted’ H5N1 virus in the laboratory in 2011, and it mimics what viruses do in the wild, albeit at an artificially enhanced speed.

 

For a flu virus to spark a pandemic, it basically needs to meet three criteria:

 

1. It needs to be able to infect humans
2. It needs to be pathogenic in humans (causes disease)
3. It needs to be efficiently transmitted from human-to-human

 

The avian influenza viruses we’ve been watching (H5N1, H7N9, H9N2, H7N7,  etc) all appear to meet the first two criteria (although severity of disease varies greatly between subtypes), but so far item #3 remains absent.

 

The primarily barrier to a pandemic appears to be a lack of `airborne transmission’  between humans.

 

Since ferrets are highly susceptible to influenza, and exhibit a similar respiratory response to infection to humans (coughing & sneezing), they are often used for transmissibility studies. 

 

Infected ferrets are placed in cages adjacent to healthy ferrets, but any direct contact is prevented.  If the healthy ferrets catch the virus, its a pretty good indication of airborne transmission.

 

Today, we’ve a study appearing in the Journal of Virology that takes the avian H7N1 virus – passes it serially through ferrets 10 times  – and then tests the virus for both transmissibility and virulence.  The end result was an H7N1 virus that was transmissible via the airborne route (in ferrets) with no apparent loss of virulence.

 

 

Airborne Transmission of Highly Pathogenic H7N1 Influenza in Ferrets

Troy C. Sutton1, Courtney Finch, Hongxia Shao, Matthew Angel, Hongjun Chen, Ilaria Capua, Giovanni Cattoli, Isabella Monne and Daniel R. Perez

Avian H7 influenza viruses are recognized as potential pandemic viruses as personnel often become infected during poultry outbreaks. H7 infections in humans typically cause mild conjunctivitis; however, the H7N9 outbreak in the spring of 2013 has resulted in severe respiratory disease. To date, no H7 viruses have acquired the ability for sustained transmission in humans.

Airborne transmission is considered a requirement for the emergence of pandemic influenza, and advanced knowledge of the molecular changes or signature required for transmission would allow early identification of pandemic vaccine seed stocks, screening and stockpiling of antiviral compounds, and focused eradication efforts on flocks harboring threatening viruses.

Thus, we sought to determine if a highly pathogenic influenza A H7N1 (A/H7N1) vrus, with no previous history of human infection, could become airborne transmissible in ferrets.

We show that after 10 serial passages, A/H7N1 developed the ability to transmit to co-housed and airborne contact ferrets. Four amino acid mutations (PB2 T81I, NP V284M, M1 R95K, and Q211K) in the internal genes and a minimal amino acid mutation (K/R313R) in the stalk region of the HA protein were associated with airborne transmission. Furthermore, transmission was not associated with a loss of virulence.

These findings highlight the importance of the internal genes in host adaptation and suggest that natural isolates carrying these mutations be further evaluated. Our results demonstrate that a highly pathogenic avian H7 virus can become airborne transmissible in a mammalian host, and support on-going surveillance and pandemic H7 vaccine development.

Importance: The major findings of this report are that a highly pathogenic strain of H7N1 avian influenza can be adapted to become airborne transmissible in mammals without mutations altering the receptor specificity. Changes in receptor specificity have been shown to play a role in the ability of avian influenza viruses to cross the species barrier and these changes are assumed to be essential. The work herein challenges this paradigm, at least for the influenza viruses of the H7 subtype, which have recently become the focus of major attention as they have crossed to humans.

 

 

A bit surprisingly, four of the five amino acid changes that were associated with airborne transmission were found to occur in the internal genes (PB2, NP, M1) of the virus. Given the history of H9N2 donating its internal genes to novel reassortants (see Study: Sequence & Phylogenetic Analysis Of Emerging H9N2 influenza Viruses In China), these findings may help identify potential surveillance targets in that subtype, and others. 

 

This isn’t the first time we’ve seen evidence of airborne transmission of an H7 virus in ferrets.

 

In 2013, in Nature: Limited Airborne Transmission Of H7N9 Between Ferrets & Science: H7N9 Transmissibility Study In Ferrets), we saw lab experiments that showed this H7 avian flu virus could be transmitted between ferrets (albeit at low levels) via respiratory droplets.

 

So far, while airborne transmission has been demonstrated (in ferrets) in the lab, we’ve yet to see evidence of sustained and efficient airborne transmission of these novel avian viruses in humans.

 

But nature’s lab is open 24/7, new reassortant flu viruses are appearing all the time, and just because it hasn’t happened yet doesn’t mean it can’t happen sometime in the future.

Nature Comms: H7N9 Gains Antiviral Resistance Without A `Fitness Penalty’

 

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If you follow influenza topics closely, you may know that when influenza viruses gain antiviral resistance they often (but  not always) take a performance hit when it comes to transmissibility.  Back in 2007, it was widely held  that the mutation that made the virus resistant to Tamiflu ® (H274Y), also reduced its biological fitness – suggesting that mutated versions of the viruses were unlikely to spread widely.

 

That notion was turned on its head when, a year later, the (old) seasonal H1N1 virus acquired resistance to oseltamivir, `broke with convention’  and spread like wildfire around the globe.

 

Fortunately, that highly resistant strain is no more, having been supplanted by the 2009 H1N1 pandemic virus. And resistant strains of the other two `human’ flu strains (H1N109 and H3N2) have failed to make much of an impact. 

 

But earlier this year we saw signs that at least some of the isolates collected from patients infected with the  H7N9 virus in China were resistant to antiviral medications (see EID Journal: R292K Substitution & Antiviral Resistance & mBio: Antiviral Resistance In H7N9).  Most of these mutations appear to have developed after the patient was placed on antiviral meds.

 

Unlike the H1N1 and H3N2 resistant strains – which picks up resistance from the H274Y (Histidine  to Tyrosine at neuraminidase position 275) – H7N9 resistant strains have the R292K Substitution (Arginine to Lysine at position 292 in the NA) – also known as Arg292Lys

 

Since we’ve no well documented human-to-human transmissions of this virus to look at, we really haven’t known if these resistant H7N9 strains – like their resistant H3N2 and 2009 H1N1 cousins – take a performance hit. 

 

Today, in a report that appears in Nature Communications, we get  evidence that suggests that resistant H7N9 viruses remain biologically `fit’ , competitive, and transmissible.

 

First a link to the Abstract (the full open access report is available at this link), then I’ll be back with a bit more.

 

 

Influenza A(H7N9) virus gains neuraminidase inhibitor resistance without loss of in vivo virulence or transmissibility

Rong Hai, Mirco Schmolke, Victor H. Leyva-Grado, Rajagowthamee R. Thangavel, Irina Margine, Eric L. Jaffe, Florian Krammer, Alicia Solórzano, Adolfo García-Sastre, Peter Palese & Nicole M. Bouvier

Without baseline human immunity to the emergent avian influenza A(H7N9) virus, neuraminidase inhibitors are vital for controlling viral replication in severe infections. An amino acid change in the viral neuraminidase associated with drug resistance, NA-R292K (N2 numbering), has been found in some H7N9 clinical isolates. Here we assess the impact of the NA-R292K substitution on antiviral sensitivity and viral replication, pathogenicity and transmissibility of H7N9 viruses. Our data indicate that an H7N9 isolate encoding the NA-R292K substitution is highly resistant to oseltamivir and peramivir and partially resistant to zanamivir.

Furthermore, H7N9 reassortants with and without the resistance mutation demonstrate comparable viral replication in primary human respiratory cells, virulence in mice and transmissibility in guinea pigs. Thus, in stark contrast to oseltamivir-resistant seasonal influenza A(H3N2) viruses, H7N9 virus replication and pathogenicity in these models are not substantially altered by the acquisition of high-level oseltamivir resistance due to the NA-R292K mutation.

(Continue . . . )

 

We’ve seen conflicting views on this virus’s pandemic potential (see TSRI: H7N9 Virus Still Binds Preferentially to Avian Receptors vs. Lancet: Tropism Of H7N9 In the Human Respiratory Tract vs.Nature: H7N9 Pathogenesis and Transmissibility In Ferrets & Mice ) over the summer and fall.

 

The good news is that  we’ve not seen any evidence that any of the H7N9 viruses to date are capable of efficiently transmitting among humans.

 

That could change, of course. But no one really knows how many adaptations are needed for this virus to become a pandemic contender.  Since human immunity to the H7N9 virus is likely to be minimal, and this virus is capable of producing significant morbidity and mortality, today’s findings are clearly important and a bit worrisome.

 

But none of this increases the odds that  the H7N9 virus will spark a pandemic.

 

It does suggest, however, that our pharmacological options for treating it could be limited, should that ever happen. 

Additional Details On Zhejiang H7N9 Cluster

Zhejiang Province – Credit Wikipedia

 

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Although I’ve yet to see it confirmed via official government channels, local media (including Xinhuanet) are reporting that yesterday’s newly reported H7N9 infection (see Media Reports: New H7N9 Case in Hong Kong & Zhejiang Province) – a 30 year-old male – is a relative of the 57 year-old male hospitalized last week with the virus (see China: Zhejiang Province Reports H7N9 Case). 

 

Whenever we see two or more avian flu infections in close proximity, the question of human-to-human transmission comes up.   

 

As we’ve discussed before, when it comes to proving human-to-human (H-2-H) transmission of an emerging virus, the bar is set pretty high.  When there are other, equally plausible explanations (e.g. shared environmental, or live bird exposures), then H-2-H cannot be assumed.

 

Since we’ve seen suspected limited  H-2-H transmission of the H7N9 virus in the past (see BMJ: `Probable Person-to-Person Transmission’ Of H7N9), another instance – while of epidemiological interest - wouldn’t be a game changer.  We take notice primarily because it could be the first visible step in a chain of transmission.

 

Should we begin to see evidence of efficient ongoing H-2-H transmission (ie. 3rd, 4th, 5th generation transmission) - then things begin to get more interesting.  But even then, it wouldn’t necessarily signal the start of a major epidemic.  

 

In 2006, we saw large clusters of H5N1 infection in both Indonesia and Turkey, and yet, it never managed to gain enough momentum to spark a pandemic (see 2006 Karo Cluster Involved H2H Transmission).  Similarly, a family cluster in Pakistan in 2007 raised concerns, but once again failed to catch fire (see EID Journal: Unraveling Pakistan’s H5N1 Outbreak).

 

Here then, via Xinhuanet, is the latest on the Zhejiang cluster.

 

Added 1 new case of human infection in Zhejiang Province H7N9 avian influenza

December 07, 2013 Source: qianjiang evening news

Inform the PRC Zhejiang Provincial Health Department on December 6, 1 new cases of human infection in Zhejiang Province H7N9 avian flu cases . At risk patients, male, 30 years old. On December 5 confirmed, first affiliated hospital of Zhejiang University School of medicine now.

 

This reporter learned that, the infection H7N9 avian flu virus risk, was in a hospital of Zhejiang University last Wednesday the 57 confirmed Mr Chang's son-in-law.

 

So far, Zhejiang H7N9 avian flu infections increased from 4 in the second half, including jiaxing H7N9 avian flu patients died.

 

Currently, Zhang Yu and father-in-law, lived in a hospital infectious diseases Department of Zhejiang University in isolation wards. Most H7N9 avian flu patients admitted to the ward first half of the year.

 

Zhejiang and a Deputy Director of the infectious diseases Department LEUNG Wai Fung, told reporters last week confirmed a critical condition, is still in the rescue.

 

Last week, Mr fever, pneumonia, home to Zhejiang Anji register for emergency treatment, treatment process, sudden illness, respiratory failure. Were confirmed infected H7N9 avian flu.

 

Relatives told doctors, 6 chickens raised at home, before the disease is usually fed chickens, cleaning the chicken manure. Doctors speculated that Zhang H7N9 avian flu infection, most likely related to these birds carry the virus. Mr CHEUNG was diagnosed shortly after their son-in-law Mr danger symptoms of high fevers. After the examination, the throat swab H7N9 virus were positive, at present, Mr Yu accepted, including antiviral "four against two balancing" treatment, his condition is stable, conscious, do not need the help of ventilators and other equipment assisted breathing.

 

Father-in-law both continuous H7N9 avian influenza viruses, two were exposed to infected poultry, or "person to person" results? Yesterday, after the expert consultation, still do not prove that the two are "person-to-person" infection.

Our correspondent Wang Rui

 

 

The `fitness’ of the H7N9 virus for human (or at least mammalian) hosts has been the subject of a good deal of research and debate over the past 6 months, with conflicting results.  Two days ago we saw research (see TSRI: H7N9 Virus Still Binds Preferentially to Avian Receptors) suggesting that the virus (at least samples taken last spring) isn’t ready for prime time, while other studies (see mBio: H7N9 Naturally Adapted For Efficient Growth in Human Lung Tissue) are less sanguine.

 

Whatever the case (and with influenza viruses, that status can change quickly), thus far we’ve only seen widely scattered, sporadic human infections and a handful of small family clusters in the wild.  The big unknown is the prevalence and significance of mild, or asymptomatic infections, and there we can only guess.

So we watch cases like the ones this week in Hong Kong and Zhejiang province closely, for any signs that this pattern is changing.

 

The good news, so far, is that we haven’t seen compelling evidence that it has.

H7N9 Transmission and Replication In The Guinea Pig Model

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While MERS-CoV has captured most of our attention these past few weeks, we continue to keep a wary eye on the H7N9 avian flu virus in China, which last spring suddenly sprang to the top of our `worry list’.   So far, the number of cases reported this fall have been small, but concerns remain that it could return with a vengeance over the winter and spring (see Chinese CDC: Be Alert For H7N9).

 

Over the summer we’ve seen a parade of studies that have painted this emerging virus as being better suited to mammalian hosts, and possessing greater pandemic potential, than any other avian flu studied to date.  A few examples include:

 

Nature: Limited Airborne Transmission Of H7N9 Between Ferrets

BMJ: `Probable Person-to-Person Transmission’ Of H7N9

Lancet: Tropism Of H7N9 In the Human Respiratory Tract

Science: H7N9 Transmissibility Study In Ferrets

 

Although we normally hear about flu research being conducted on ferrets – due to their human-like response (sneezing, coughing) to influenza infections - in recent years a number of researchers have looked at guinea pigs as alternative mammalian model for influenza studies (see PNAS The guinea pig as a transmission model for human influenza viruses by Peter Palese et al. 2006).

 

Bouvier and  Lowen,  in Animal Models for Influenza Virus Pathogenesis and Transmission, describe the advantages of the guinea pig model below:

 

The strengths of the guinea pig model lie in the natural susceptibility of these animals to human influenza virus isolates, the efficiency with which human strains transmit among guinea pigs and the relative ease of obtaining, housing and working with these animals. The main drawback of the guinea pig model for influenza research is the lack of disease signs exhibited by infected animals.

 

Earlier this year (see CIDRAP NEWS report Study: Lab-made H5N1-H1N1 viruses spread in guinea pigs) we learned that Chinese scientists had recently used guinea pigs to study reassortant viruses, explaining:

 

. . .   guinea pigs are comparable with ferrets as models of human flu transmission. Although guinea pigs have both avian and mammalian types of airway receptors, flu viruses that bind only to avian receptors (alpha2,3-linked sialic acids) don't spread by respiratory droplets in the animals, they report.

 

Which brings us to a study, published this week in the Journal of Virology, that looks at how well the newly emerging H7N9 avian flu virus replicates and transmits in guinea pigs.

 

And the answer . . .  pretty darn well.

 

Novel H7N9 influenza virus shows low infectious dose, high growth and efficient contact transmission in the guinea pig model

Jon D. Gabbard, Daniel Dlugolenski, Debby Van Riel, Nicolle Marshall, Summer E. Galloway, Elizabeth W. Howerth, Patricia J. Campbell, Cheryl Jones, Scott Johnson, Lauren Byrd-Leotis, David A. Steinhauer, Thijs Kuiken, S. Mark Tompkins, Ralph Tripp, Anice C. Lowen and John Steel

ABSTRACT

The zoonotic outbreak of H7N9 subtype avian influenza virus that occurred in eastern China in the spring of 2013 resulted in 135 confirmed human cases, 44 of which were lethal. Sequencing of the viral genome revealed a number of molecular signatures associated with virulence or transmission in mammals.

 

Here we report that, in the guinea pig model, a human isolate of novel H7N9 influenza virus, A/Anhui/1/2013 (An/13), is highly dissimilar to an H7N1 avian isolate and instead behaves similarly to a human seasonal strain in several respects. An/13 was found to have a low 50% infectious dose, grow to high titers in the upper respiratory tract, and transmit efficiently among co-caged guinea pigs.

 

The pH of fusion of the HA and the binding of virus to fixed guinea pig tissues were also examined. The An/13 HA displayed a relatively elevated pH of fusion characteristic of many avian strains, and An/13 resembled avian viruses in terms of attachment to tissues. One important difference was seen between An/13 and both the H3N2 human and H7N1 avian viruses: when inoculated intranasally at high dose, only the An/13 virus led to productive infection of the lower respiratory tract of guinea pigs.

 

In sum, An/13 was found to retain fusion and attachment properties of an avian influenza virus but displayed robust growth and contact transmission in the guinea pig model atypical of avian strains and indicative of mammalian adaptation.

 

The bottom line here is the H7N9 virus behaves more like a humanized flu virus than an avian flu virus in the guinea pig model.  And the AN/13 H7N9 virus actually out performed the H3N2 human virus in some respects, traveling more readily from the upper respiratory system to the lower respiratory tract.

 

This study adds to the growing body of evidence showing that the H7N9 virus is better adapted to mammals than other avian flu strains that we’ve observed.  Adaptations, some researchers believe, the virus most likely acquired while inhabiting an (as yet, unidentified) intermediate mammalian host.

 

Whether this ability means H7N9 will turn into a serious global public health threat, is something we will just have to wait to see.  But its ability to infect mammals, `right out of the box’, is impressive. 

 

One of the big unanswered questions regarding this avian virus is:  how, and from what reservoir(s), it is spreading?

 

Poultry and wild birds are immediately suspect, but out of hundreds of thousands of birds tested, only a handful have proven positive (see Poultry Samples Around Dongguan H7N9 Case Test Negative).

 

Last May, the Lancet published Origin and diversity of novel avian influenza A H7N9 viruses causing human infection: phylogenetic, structural, and coalescent analyses by Liu D et al.,  which looked at the virus’s genomic sequences, and found:

 

The novel avian influenza A H7N9 virus might have evolved from at least four origins. Diversity among isolates implies that the H7N9 virus has evolved into at least two different lineages. Unknown intermediate hosts involved might be implicated, extensive global surveillance is needed, and domestic-poultry-to-person transmission should be closely watched in the future.

 

In recent years we’ve discovered a good many mammalian species are capable of hosting various influenza strains, in addition to humans, swine, and equines. The (formerly) pandemic H1N1 2009 flu virus was documented in  turkeys, skunks, ferrets, cats, elephant seals and dogs. While in That Touch Of Mink Flu I wrote about 11 farms in Holstebro, Denmark that were reported to be infected with a variant of the human H3N2 virus.

 

Less commonly reported - camels, whales and seals have all been shown to be susceptible to influenza viruses (cite Evolution and ecology of influenza A viruses R.G. Webster et al.)  In  2012, an avian flu strain was identified in New England seals (see mBio: A Mammalian Adapted H3N8 In Seals).

 

And last year (see EID Journal: Guinea Pigs As Reservoirs For Influenza by Leyva-Grado VH, Mubareka S, Krammer F, Cárdenas WB, Palese P.), we looked at a serological study that found that Peruvian and Ecuadorian guinea pigs – raised as livestock – are commonly infected by influenza A and B viruses. 

 

Despite finding high seroprevalence results, the authors cautioned:

 

We did not determine whether guinea pigs are an incidental host for influenza virus infection or, if instead, the virus has been adapted to these animals or if guinea pigs are a natural reservoir for some influenza viruses.

 

And lastly, in 2010  I wrote a blog entitled Mixing Vessels For Influenza  which explored research done by two wildlife disease experts from the San Diego Zoo - Mark Schrenzel and Bruce Rideout – who identified the North American Striped Skunk - along with a handful of other small carnivores - as potential hosts for influenza reassortment.

 
None of this brings us any closer to knowing what species – other than avian – might be serving as an intermediate host for H7N9.

 

But it does illustrate that there are a wide range of possibilities that ought to be explored and tested.

Branswell: Transmission Estimates Of MERS-CoV – Lancet Infectious Disease

Photo Credit NIAID

 

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Helen Branswell has the story this evening on a fresh study, just published in The Lancet Infectious Diseases, that looks at the likely extent of transmission of the MERS virus in the Middle East.  The results – that for every case identified, there are likely 5 to 10 that go undetected –  suggest that this virus may be transmitting more efficiently than previously estimated.

 

First, a link to Helen’s excellent review, then a link to the study, after which I’ll return with a bit more.

 

Most MERS cases going undetected, 'Slow moving epidemic underway': study

Helen Branswell / The Canadian Press
November 12, 2013 03:42 PM

 

A new analysis of MERS case data suggests a large number of infections are going undetected, with the researchers estimating that for each case that has been found, five to 10 may have been missed.

The scientific paper, from European researchers, further suggests that transmission of the MERS virus is occurring at a rate close to the threshold where it would be considered able to pass from person to person in a sustained manner.

In fact, the authors say based on the available evidence they cannot rule out the possibility that person-to-person spread is the main mode of transmission of the virus at this point. The other option, they say, is that the virus is spreading via a combination of animal-to-person and then person-to-person transfer.

(Continue . . .)

 

 

 

Middle East respiratory syndrome coronavirus: quantification of the extent of the epidemic, surveillance biases, and transmissibility

Simon Cauchemez PhD a †, Prof Christophe Fraser PhD a †, Maria D Van Kerkhove PhD a, Prof Christl A Donnelly ScD a, Steven Riley PhD a, Prof Andrew Rambaut PhD b, Vincent Enouf PhD c, Prof Sylvie van der Werf PhD c, Prof Neil M Ferguson DPh

Interpretation

By showing that a slowly growing epidemic is underway either in human beings or in an animal reservoir, quantification of uncertainty in transmissibility estimates, and provision of the first estimates of the scale of the epidemic and extent of case detection biases, we provide valuable information for more informed risk assessment.

 

The epidemiological yardstick by which human transmission of an infectious disease is measured is called the R0 (pronounced R-nought) or Basic Reproductive Number.

Essentially, the number of new cases in a susceptible population likely to arise from a single infection.

With an R0 below 1.0, a virus (as an outbreak) begins to sputter and dies out.

Above 1.0, and an outbreak can have `legs’.

 

Last July, in The Lancet: Transmissibility Of MERS-CoV, we looked at a preliminary analysis that calculated the R0 of the MERS virus to be between .60 and .69.   Too low (at that time) to spark an epidemic.

 

But calculating the R0 is notoriously difficult, particularly since much hinges upon the existence and subtle differences between viral strains, the accuracy of surveillance and reporting, `seasonality’’ of the infection, and individual host responses to the virus (i.e. number of `super spreaders’).

 

Like the CFR (Case Fatality Ratio), the R0 can vary considerably over time or geography, often ends up being described as a `range’, and usually isn’t well established (or at least, generally agreed upon) until long after an outbreak has ended.

 

The authors in today’s study  believe the R0 of the MERS virus is likely close to 1.0, or perhaps even higher, and write:

 

We conclude that a slowly growing epidemic is underway, but current epidemiological data do not allow us to determine whether transmission is self-sustaining in man. Our analysis demonstrates that the transmissibility of MERS-CoV in man is close to the critical threshold of R=1 required for self-sustaining transmission. If R is greater than 1, then the number of human cases we estimate to have occurred to date make it highly likely that self-sustaining transmission has already begun

 

Even assuming low levels of sustained transmission –  with an R0 of greater 1.0 – the timely application of control procedures can sometimes contain, and even halt, an epidemic. 

 

The R0 of SARS was estimated to be between 2 and 4, but since patients weren’t infectious prior to developing symptoms, aggressive quarantine efforts were able to quell that outbreak.

 

The question, of course, is whether the current surveillance and testing regimens in place are comprehensive enough to identify and the spreaders of this virus.  And here, the Achilles heel may be asymptomatic or mild cases – which are less likely to be identified and  isolated – but which may still be capable of spreading the virus.

SARS is believed to have had a low percentage of asymptomatic cases (see EID Journal Asymptomatic SARS Coronavirus Infection among Healthcare Workers, Singapore), and they did not appear to be aggressive spreaders of the virus. 

 

Whether that will be the case with MERS remains to be seen.