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Delay to extension of Hendra virus vaccine period...it's not a ferret's life!

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Based on ABC News, Yahoo News

Who'd wanna be a ferret? 

They are great for growing influenza viruses and testing their ability to transmit between animals as a model for human-to-human transmission. Ferrets are apparently also useful for hosting Hendra virus (HeV) replication. 

Because ferrets are cheaper and easier to test vaccines on than horses, they are used as negative control animals for HeV vaccine studies like the one by Dr Deborah Middleton, veterinary pathologist at Australian Animal Health Laboratory (AAHL), Commonwealth Scientific and Industrial Research Organisation (CSIRO) was conducting (the vaccine was created and developed by CSIRO and Pfizer). 

This study was aiming to confirm that the current Hendra vaccine booster could be given every 12-months, rather than every 6-months, as it currently is. This would be a saving of ~$100/horse/year.

UPDATE: Thanks to Shane Granger, @gmggranger for more realistic costings which equate to $165/horse + microchipping at the first visit (if not already done) or some savings for more than 1 horse: 


Unfortunately, the study failed because the unvaccinated ferret control group did not become ill after being infected. This means the experiment couldn't show that the vaccine was protecting against the virus upon challenge. 

The problem was traced to a bad vial of HeV. The lab virus used to infect the animals was not as potent as expected of a real life, or "wild",  infection of horses.

Vaccination of horses is encouraged by Biosecurity Queensland to fend off the virus is lethal in viruses, in about half of human who come into close contact with infected animals and can infect dogs also as seen recently at an infected property in New South Wales and in August 2011 on a property in Queensland.

This year (2013), the Royal National Agricultural and Industrial Association of Queensland (RNA) has mandated that all horses attending or competing at its Royal Queensland Show (Ekka, held in Brisbane, Queensland) should be vaccinated for HeV. 
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Coronavirusauruses.....

I've always been interested in just how long this virus or that virus have been with us. Have they evolved along with their original animal host, or with humans, or just jumped ship relatively recently - months  rather than millions of years ago.

Well, here is a cool potential answer.

Wertheim and colleagues revisited the age debate with the coronaviruses in their viewfinder, back in April's J Virology.

They looked at genome sequences from the 4 genera, focusing on areas that did not shows signs of having resulted from the mixing of different viruses (recombining) and applied more recently developed models to calculate the time to most recent common ancestor (tMRCA).

Prior to this study, the tMRCA of all four CoV genera was 10,141 years ago (based on Patrick Woo's analysis of all four genera using just one region, published in 2012). In another instance, Pyrc and colleagues noted that HCoV-NL63 diverged from its MRCA around 900 years ago (with a rate of mutation around 3x10-4 changes per nucleotide position per year) based on analysis of the spike protein (S) gene.

This new study concluded that CoVs, like other viruses (which they list in the discussion), appear to be an ancient line of viruses. The average tMRCA was calculated to be 293 million years ago-give or take. Dinosaurs died out 65-million years ago I think.

The authors speculate that this period might also parallel the evolution of the bat and avian host species.

I wonder what their ancestors were infecting before that?
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MERS-CoV cases rise by 3...how is the health of 83M?

The Kingdom of Saudi Arabia's (KSA) Ministry of Health (MOH) has confirmed MERS-CoV in a 67-year old female (67F) with underlying disease. That took 7-days to confirm and announce. 

The MERS-CoV tally is now at 94 cases, 46 deaths (PFC of 48.9%).

The other 2 new cases are both 39Fs and healthcare workers (form Asir and Riyadh) exposed to known cases; both have mild disease. 

This is against a backdrop of a second media report of the earlier described 83M having died. The first report describing his death also mentioned a 63F MERS-CoV case (could this be the latest 67F?) and a male case of unknown age (cannot be a case form today - they were female) as being positive. 

However, despite the wide press reporting of it, the death of 83M remains unconfirmed by KSA MOH or WHO. The last KSA MOH bulletin related to this case described a death without detail...

"Within the framework of the epidemiological surveillance of the novel Coronavirus (MERS-CoV), the Ministry of Health (MOH) has announced that one confirmed case of this virus, aged 83, has been recorded in Asir.
Within the same vein, MOH has announced the death of one case, who had been previously announced to be infected with this virus in Asir, May Allah have mercy upon him."
That does not describe the death of the same person...to me at least. So its been 5-days since the popular media noted the death of a case - a death not confirmed by announcement through official channels. 

The last MERS-related death with any detail was that of 66M in King Fahd Hospital.
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Patients with diabetes or chronic renal failure at high risk for MERS...

A recent New England Journal of Medicine editorial piece, accompanying that huge MERS-CoV case study previously discussed here, notes the immediate concern of October's Hajj pilgrimage to the hot zone, Saudi Arabia.  

Perlman and McCray also note that MERS-CoV is a system-wide infection and that while the average number o new cases from each index case (R0) is reportedly...and so far, practically (tertiary infections seem to be rare)...below 1, there are anomalous super-spreader events that draw attention to healthcare settings as the places to watch in the future. Similarly, those with diabetes or chronic renal failure are the populations to watch. 

The virus itself needs careful observation to see if/when it shows the telltale changes to its cell-binding proteins that indicate it may have shifted gear, becoming a more aggressive spreader among humans.

I have not been able to find much by way of virus epidemiology studies among those with severe illness and underlying conditions like those above, so its still very hard to know whether MERS-CoV is unique and scary in this role, or whether other, more endemic CoVs could wreak the same degree of havoc in this populations.


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Editors Note #10: A re-post of the Zombie comparison....

A local news site, brisbanetimes.com.au has reprinted my earlier article on World War Z being an extreme epidemiology event-giving viruses teeth and legs. For which I am most grateful.

Does that mean 20-years in virology has lead me to being "that zombie guy"??

If you drop by, please also have look through the MERS-CoV and influenza A(H7N9) virus stuff on the blogs here and on Virology Down Under's main site.

Come for the zombies but come back for the virology!
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Reporting on the MERS-CoV event..behind the scenes timeline

In an Eastern Mediterranean Heath Journal (EMHJ) journal issue dedicated to MERS-CoV, there is an article entitled "Novel coronavirus: the challenge of communicating
about a virus which one knows little about" written by Gregory H�rtl, Head of Public Relations/Social Media for World Health Organization.
The article details how the World Heath Organization, educated by the severe acute respiratory syndrome (SARS) event, has responded to MERS-CoV by applying their WHO Outbreak Communications Guidelines:
"These Guidelines stipulated that all acute public health event communications should be planned, organized and executed in keeping with the 5 principles: trust, transparency, announcing early, listening and planning."
The report details the waxing and waning of media interest in the MERS event and the parallel responses of WHO to new reports of cases and clusters which were often interspersed with periods of quiet. It also describes the timeline of providing information to the world about the "novel coronavirus". 

I'd also like to note that WHO, or any institution, can only be as transparent  proactive, timely and informative as the information it receives allows it to be. Sure, a researcher on the ground can report the precise details of their study, cases, symptoms  epidemiology, sequences, assays - they hold all the cards - but global educators and planners like the WHO need that information passed along in order to share it quickly. Only  then can they address its principles.

The paper also notes that Twitter and other social media are the WHO's main means of keeping in contact with the world. This started in 2009-10 and was expanded in 2012 to a dedicated social media function  @WHO now boasts 837,790 followers.

To paraphrase a very nice wrap-comment, the article notes that people want to know what's going on when a disease breaks out and in finding the information they desire, a trust is also built between the person and the institution (and its partners) which provided answers early, simply and transparently. 

Such trust, once built, can then be leveraged to advise a possibly panicky population should a random cluster of cases turn into an outbreak, epidemic or pandemic.

Its a bridge-building process that Mr H�rtl and the WHO are clearly working hard at...and doing very well.

Follow Mr H�rtl global health WHO updates on @HaertlG and the WHO on @WHO.


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Anarchy, air travel and contagion

A new paper by Nicolaides and colleagues looks, in great detail (as this group, who have previously published travel-related contagion modelling, does) at the spread of a disease due to human movement and how the choices made about that movement could help or hinder its spread.

They point to the dilemma of policy makers for the next big outbreak. Should they:

  1. Restrict/redirect the freedom of an individual's movements in order to benefit the whole - limit rapid disease spread and possibly contain its spread
  2. Allow anarchy/a loss of social welfare - in this context, by travelling anywhere during and through regions of transmission - acting as a vector to inoculate susceptible populations as they go.
Trying to implement a system of reduced or rerouted mobility in a heat of a pandemic will probably meet with considerable resistance  

Should policy makers see the benefits to containing a significant disease outbreak in this way, here's hoping for lots of education of the population...starting soon.
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If you gave a virus legs and teeth...

Following on from my post on extreme epidemiology, zombies and World War Z, there is an article today in livescience (yes, it's all in fun).

The article, including some commentary from Prof Robert Smith? (that's an intentional "?"), an expat Aussie mathematician based at the University of Ottawa, and myself, an expat Kiwi. 

Prof Smith even has a book coming out on the subject...so if you're a hardcore maths enthusiast and hey, who isn't?... check out and debate this mathematical model from an earlier publication and other equations relating to zombification...

From: Infectious Disease Modelling Research Progress. (2009). Ch4.p133-150 When Zombies Attack!: Mathematical Modelling Of An Outbreak of Zombie Infection. Munz, Hudea, Imad and Smith. Nova Science Publishers Inc
Smith's modelling has real-world applications,  having been useful in understanding human papillomavirus infections  and in getting the next generation of zombie fighters interested in mathematics.

Alternatively, if maths is not your thing, perhaps you are a genius, billionaire, playboy, philanthropist and developing a suit of armour that protects you from zombie bites is more up your alley.

While the topic of zombies may be a bit much for some, the concepts underpinning the spread of a zombie virus are not very different from those due to any virus infection. More extreme, yes, but human virus infections, transmission conundrums and deaths due to real viruses are happening right now all over the world.


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MERS-CoV case and death confirmed by WHO....from 4-days ago?

The latest Disease Outbreak News (DON; they can be found here prior to archiving here) from the World Health Organisation announces that an 83-year from Asir region is positive for the MERS-CoV and another, previously identified case, died.

This is a great example of why tracking ID can make you think you're in a Doctor Who episode!

I reported these 2 cases (from other's sources) on July 26th...4-days ago. It was on the non-English version of the Kingdom of Saudi Arabia's Ministry of Health (MOH) website.  

Since then however, we have heard of possible death of this case and reference to 2 new cases - neither confirmed. 

Prior to last night, Down Under time, the latest update on the English version of the MOH site was July 18th. The July 25th update appeared yesterday, the 29th. So, I'm hopping in the TARDIS now to see if the death and new cases are confimred on Thursday, the 1st of August.

In the meantime, different media sources and blogs recirculate each others content, often from the earliest source - which makes it very hard to track cases using public data. 

Obviously this is why following trusted public health sources like the WHO, and FluTrackers (who have a policy of confirming using more than a single news report) is so important. 

But it can take longer to get the confirmation and in the meantime you and I will hear it the news from (many) other places.

Confused? Me too!
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Influenza A(H7N9) virus infects cells from the upper and lower respiratory tract...

Chan and colleagues from the University of Hong Kong (HKU) used tissue taken from (explanted) different parts of the conducting airways and respiratory epithelium to demonstrate the ability of H7N9 (A/Shanghai/1/2013 [Sh1],  A/Shanghai/2/2013 [Sh2] and duck) to replicate in different regions and how well it does that compared to highly pathogenic avian influenza (HPAI) A/H5N1,  and HPAI A/H7N7 and pandemic human A/H1N1.

Some key findings...

  • Bronchus, lung nasopharyngeal and tonsil tissues were stained using an antibody to influenza nucleoprotein
  • Lung tissue growth
    • A/Shanghai/1/2013 > A/Shanghai/2/2013
    • A/Shanghai > H5N1
    • A/Shanghai/1/2013 > H1N1pdm
    • Duck/H7N9 did not replicate
    • A/Shanghai/1/2013 > NL/219/H7N7 > H5N1
  • Bronchus tissue growth
    • A/Shanghai/1/2013 similar to A/Shanghai/2/2013
    • A/Shanghai > H5N1
    • A/Shanghai similar to H1N1pdm
    • Duck/H7N9 did not replicate
    • A/Shanghai/1/2013 > NL/219/H7N7 > H5N1
  • Nasopharyngeal tissue (33� C) growth
    • A/Shanghai/2/2013 replicated
  • Primary human pneumocyte growth
    • A/Shanghai/1/2013 similar to A/Shanghai/2/2013 but > H5N1 and H1N1pdm
  • cDNA PCR was used to gauge the changes in mRNA expression of a range of genes related to interferon (IFN) and IFN signalling, after infection of peripheral blood  monocyte-derived macrophages.
    • A/Shanghai upregulated MX1, ISG15, IFI35, IFI44, IFIH1 and OAS1
    • Compared to H1N1pdm, A/Shanghai more strongly upregulated IL20RB, IFNAR1, IL20RA, IL22RA2, IL2RB, IL9R and IRF4
    • Compared to H1N1pdm, A/Shanghai more strongly downregulated IL10RB and IL4R
    • H5N1 & A/Shanghai upregulated IFN�, IL29, CCL5 and CXCL10 >H1N1pdm
    • A/Shanghai upregulated FN�, IL29, CCL5 < H5N1
The cytokine PCR studies revealed an inflammatory potential between H1N1pdm (milder inflammation) and H5N1 (stronger inflammation).

Understanding which cells and tissues the virus grows in provides some clues as to what to expect from this version of H7N9 in terms of how easily it could be spread and how easily our upper airway tissues (the point of likely first contact with virus) they are to support an animal virus, thus providing a mechanism for animal to human transmission.

The team concluded that Shanghai 2/2013-like H7N9 viruses are well suited to infecting humans and that their major role in disease may not be as relatively strong initiators of inflammation as much their initiation of inflammation in the lower airways.

As Zhu and colleagues previously described, Shanghai 2/2013 also hosted infection in 2/3 ferrets who developed antibodies after airborne exposure to an infected ferret. 

Yet more evidence that H7N9 has the right stuff to cause human harm via attack of the lower airways. 

I still wonder whether it starts off down there - being inhaled as small particle aerosols - or whether it ends up there after establishing itself in the upper airways?
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Influenza A(H7N9) virus review of 1st Hangzhou, Zhejiang Province death

Chen and colleagues provide a detailed description of the 1st death in this region (paper accepted in May). I believe this 39-year old male (39M) case was also briefly described in an earlier Lancet article.

Some key facts:
  • The patient had a chronic hepatitis B virus infection
  • Had contact with poultry (he was a cook) prior to presenting with cough and diarrhoea
  • Clinical features also included fever, shortness of breath, weakness, poor appetite, cyanosis and coma
  • Laboratory biochemical and haematological features included raised enzymes (AST, ALT, LDH, CPK), bleeding/clotting times (PT, APTT) and C-reactive protein (CRP)
  • Oxygen saturatiuon decreased with disease progression
  • Was treated with antibiotics but not antivirals
  • Virus was detected using real-time reverse-transcription PCR (RT-rtPCR)
  • Subgenomic (less than full genome; A/Zhejiang/1/2013) sequences were examined for HA (closest relative, A/duck/Thailand), NA (closest relative A/wild bird/Korea) and M (closest relative A/chicken/El-Fayoun) genes and each shared >99.1% nucleotide identity with Anhui/1 and Shanghai/1 and Shanghai/2 strains
  • A pharyngeal swab sample yieled a virus isolate, A/Zhejiang/1/2013, on MDCK cells grown at 37�C, observed fro 14-days, and identified using PCR and a haemagglutination assay after the appearance of cell damage
  • Contacts were all negative by RT-rtPCR

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Human endemic coronaviruses and underlying conditions....

Human coronaviruses (HCoVs), that is, the ones that circulate all the time, not the ones that spillover from an animal host to cause havoc and mayhem, come in four flavours....

  • HCoV-229E
  • HCoV-OC43
  • HCoV-NL63
  • HCoV-HKU1
On the back of my last post, I thought I'd start looking into what HCoVs do among those with some sort of pre-existing disease or condition.

Generally speaking, the HCoVs circulate spasmodically; each peaking every couple years and then often in small numbers.
Clinical studies that include virus testing and with a focus on comorbidities seem rare as are studied focussing on older age groups using PCR to screen for an extended panel of respiratory viruses (beyond the "standard 8 or so).

Some findings below....
  1. Gaunt and colleagues noted in 2010 that 229E was over-represented among the immunosuppressed compared to other HCoVs and respiratory viruses in general. 
  2. El-Sahly and colleagues noted in 2000 that 13/16  HCoV antibody detections occurred among inpatients >35-years of age. Of those infected with an HCoV or a rhinovirus in this age band, 73% had underlying cardiopulmonary disease
  3. Cabeca and colleague noted in 2012 that of the 5/394 mostly paediatric inpatient samples POS for a HCoV, 4 (80%) had a comorbidity
  4. We noted in 2012 that in 13/61 (21.3%) HCoVs positives, chronic underlying disease or immunocompromise was noted. Most (69%) were POS for OC43
  5. Lau and colleagues noted in 2006 that among the 13/4181 samples from mostly child inpatients POS for HKU1, 8 (61.5%) had underlying diseases
  6. Garbino and colleagues noted in 2006 that among 29/540 adult bronchoalveolar lavage samples POS for an HCoV (69% male), 14 (48%) had a comorbidity
  7. Kuypers and colleagues noted in 2007 that among 66/1043 children positive only for an HCoV, were more likely to have a comorbidity than children with with coinfections
  8. Al Hajjar and colleagues noted in 2011 that among 4/489 specimens (0.8% of samples) from paediatric patient samples in the Kingdom of Saudi Arabia that were POS for NL63, all had an underlying condition.
So this snapshot of studies shows that HCoVs do not contribute to a vast number of cases, similar to the MERS-CoV to date, but that there seems, by eyeball alone, to be a bias towards illness in HCoV-POS patients with underlying conditions-age not being limited to those >50-years.

Feel free to add any papers to this list. I'm also looking for papers studying older populations.
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MERS-CoV & SARS-CoV zoonoses....what about the endemic human CoVs?

Hat tip to Crawford Kilian's story...

Arab News carries a piece entitled "Unpredictable MERS �deadlier than SARS�" noting a comment along this line by senior author, Prof Ziad Memish, on the recent Lancet large MERS-CoV case-study. Prof Memish is also senior infectious diseases consultant at King Fahad Medical City, Professor at Alfaisal Univeristy and King Saud University, President of the Saudi Association of Public Health, Adjunct Professor at Emory University, and Ministry of Health's Assistant Deputy Minister of Health for Preventative Medicine in the Kingdom of Saudi Arabia (KSA).

What strikes me as strange is a comment from the news article...
"MERS coronavirus appears to be more deadly, with 60 percent of patients with co-existing chronic illnesses dying, compared with the one-percent toll of SARS"
In the Lancet article, Prof Memish notes that only 1-2% of fatal SARS-CoV cases had comorbidities as opposed to 60% of MERS-CoV fatal cases.

 Some things to think about here.
  1. According to a 2004 paper "SARS: the new challenge to international health and travel medicine" by Venkatesh  and Memish, published  in the Eastern Mediterranean Health journal, the severe acute respiratory syndrome (SARS) disease (caused by another coronavirus), did not enter the KSA. This means we cannot necessarily extrapolate the impact in patient populations in other parts of the world, to what would happen in the KSA if SARS-CoV infection had taken hold.
  2. The 2004 article also noted that it banned entry to KSA of pilgrims from "the 5 SARS-stricken South East Asian countries-China, Hong Kong, Taiwan, Singapore and Viet Nam". That process has not been repeated by any countries outside the KSA, which has most MERS-CoV cases, for Umrah or the Hajj. And the WHO does not support travel restrictions in their latest advisory. Another sign that MERS ain't SARS.
  3. The MERS-CoV has its highest toll in the elderly, a disproportionate effect in this relatively small percentage of the KSA's population (see demographics I described on Friday). The impact is most severe among those with underlying disease...or comorbidities...96% of MERS-CoV cases already had something affecting their health which could have adversely affected the course of their infection compared to healthy people.
So, we don't really know that SARS-CoV wouldn't have displayed the exact same pattern as the MERS-CoV in the KSA but we do know that it is a particular sliver of the population that is affected most by this new coronavirus. Most deaths (>60%) are in males and those aged >50-years.

Could this be used as a clue to the animal host/source? 
Is there something specific that the over-50s do that exposes them to risk or are the worse outcomes because this group is already more ill? 

Is this group's risk increased because they have contact with the natural host animal or areas infested by that animal? Is there any information on common social behaviours among this age/sex group in the KSA? Does this demographic sit around date palms in the evening (fruit bat "hang-outs"?)? Eat certain foods, drink particular drinks? Prepare food or drink a certain way? Do things that they won't talk about because its a taboo subject - that could be putting them at risk? Keep certain animals as pets (a secondary host-intermediate vector?). Kill or have close contact with certain animal?

When you look at MERS-CoV as a virus that mostly causes death in a specific segment of the population, the next question might be, what do the endemic human coronaviruses (HCoV) 229E, OC43, NL63 and HKU1 do to people in the same age and comorbidity-laden populations? 

Stay tuned.
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Possible death of existing MERS-CoV case (83M from Asir) and 2 new cases

Crawford Kilian has an article from the press about the death of an existing case (83M) and 2 new cases - #2 is "a man" and #3 a 63F. 

I'll update this as any detail becomes available. If confirmed by the KSA MOH and WHO will bring the tally of cases (including deaths) to 93 and the deaths to 47.

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The Wolverine: the rebuttal's inner animal?

If World War Z is a tale of extreme epidemiology, then perhaps The Wolverine gives screen-time (and claws) to some of the feelings a Chief Investigator may cycle through, just after reading their Assessment Letters around June each year (Down Under at least). 

Then we put them in a drawer for a day or two while we put the animal away again. 

Or perhaps...as Bruce Banner (The Hulk) said in the Avengers...

"...I'm always angry..."
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