Influenza A(H7N9) vaccine approved by Chinese food and drug administration for use...[UPDATED]

CNTV English language newshour reports that the home-made first influenza vaccine from China has met local safety standards and is ready for mass production. The vaccine was a collaborative development between the First Affiliated Hospital under the School of Medicine of Zhejiang University, Hong Kong University, Chinese Center for Disease Control and Prevention, National Institute for Food and Drug Control, and Chinese Academy of Medical Sciences.

It will be interesting to read about what the virus is comprised of (seems to use the older influenza PR8 strain as a backbone, employing a reverse genetics approach to add in H7N9) and how the vaccine makers got around H7N9's predicted low immunogenicity issue, what the dosing regimen is and what was used as adjuvant (mentioned here, earlier). As Mike Coston notes on Avian Flu Diary, the announcements don't detail much of the preceding safety trials that should have been carried out for a vaccine to have reached this level of development. 

Mike has an earlier post over on Avian Flu Diary that reminds us about the few that are sick enough to be obviously ill....and perhaps the many that do not seek medical attention because infection resulted in relatively mild disease. Largely, as Mike notes, any numbers assigned to infections that result in milder or even asymptomatic disease are guesstimates for now - at least until some actual testing is reported. History supports that mild infections are likely, but every zoonosis is its own beast.

More coming soon on the vaccine's development path and on testing to understand H7N9's reach.

Thanks to @makoto_au_japon for identifying the vaccine story through Twitter

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Monkeys!

A troup of Hamadryas Baboons (Papio hamdryas) outside

of Riyadh, Saudi Arabia. Hamadryads live for 30 to 35-years

Image from Northwest Wildlife Homepage.

Monkeys I tell ya, monkeys!

Alsharq.net notes that baboons are such a problem in the Kingdom of Saudi Arabia's southwest that electric fences are being erected to keep them out of certain areas.

Is anyone testing baboons for MERS-CoV? Or any other virus hunting going on in them for that matter? 

I've posted on the movements and interactions of these furry troublemakers before, and they also feature in the VDU model of MERS acquisition.

If they are even infrequently in contact with humans, bats and camels - then perhaps we should give them the laboratory once-over. 

Some serology and some next generation sequencing would be a good place to start.


Thanks to FluTracker's Tweet and post on this.

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MERS update: WHO catches up but passes along no detail - and Hajjis look clear

The World Health Organisation updated it's MERS-CoV tally. The total (144 cases) is the same except for the confirmation of 2 deaths (to 62) hinted at in my last update. 

Disappointingly and once again, the update doesn't allow any analysis because there are no specific details with which to cross-check against our case lists.

Even CIDRAP is heading to the newspapers to try and identify which existing cases have died.

With my arbitrary deadline for emergence of new MERS cases being the 27th of October (this Sunday)  only 2-days away, I think its pretty safe to say that there has been no major symptomatic MERS-CoV transmission event associated with the peak assembly period of the Hajj in 2013 (just like there was none in 2012 when MERS-CoV was already in play). 

The United Arab Emirates is reportedly not checking pilgrims for symptoms, although they have their own 2-week clock running to monitor for signs and symptoms of new cases of flu-like illness in pilgrims.

Thankfully, there are studies performing actual laboratory testing, although the details remain unclear. Such studies will tell us whether MERS-CoV is among us already, but not causing the serious disease we've become used to associating with the virus.

Dr Jake Dunning (@OutbreakJake) noted on Twitter...

@MackayIM We're testing here in London. Trying to raise awareness, but needs to be balanced against more typical local infections e.g. flu.

� Dr Jake Dunning (@OutbreakJake) October 22, 2013

He also went on to say that...

@MackayIM We also have an active MERS observational study in UK, ready to recruit willing patients. @ISARIC1 protocol can be used by anyone.
� Dr Jake Dunning (@OutbreakJake) October 22, 2013

ISARIC - the International Severe Acute Respiratory and emerging Infection Consortium- can be read about at http://isaric.tghn.org/about/.
So my next question becomes, have we been watching the emergence of a new endemic human coronavirus? That question is based on a hypothesis that we have a lot more undetected cases and on Dr Ziad Memish's earlier assertion that MERS-CoV cases are already out and about in other countries. Time, and some testing, will tell.

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Influenza A(H7N9) in Zhejiang, Dutch DURC and dogs..

With the second H7N9 case (see FluTracker's thread) in Zhejiang, located only 13km from the earlier case, things seem to be picking up where they left off in late April. Poultry exposure seems key to this latest case who was a farmer who engaged in poultry trading. That word, trading, also sparks concern. It suggests that the farmer was exposed to poultry coming from, or going to, somewhere else. H7N9 is on the move. Both patients are very unwell.

Zhejiang province had the steepest rate of case acquisition back then and reached the highest H7N9-confirmed case number as well. 

Looks like this province is going to be a key battleground for the next wave of H7N9.

Meanwhile, Eurosurveillance continues its fantastic coverage of this and the Middle East respiratory coronavirus  and H7N9 outbreaks. It already has a paper online (less than a week turnaround) of the earlier Zhejiang H7N9 case in a 35-year old male (35M) which includes a note about the subsequent Zhejiang case! Outstanding work to the researchers and the publishing team. Quality publication almost in the time it takes to write blog post!

This journal certainly highlights how quickly detail research results and analysis, when submitted to peer review, can be published. 

Click to enlarge. The laboratory turnaround
times for H7N9 detection (where suitable date
data exist) since the outbreak began in early 2013. 

• 35M was identified though the surveillance system for unexplained pneumonia
• He was not a farmer and had not had close contact with another probable case. The laboratory turnaround times on this case was 7-days. A 2.2 day improvement on the rolling average I stopped calculating May 6th.
• The most likely source of exposures was a trip to rural region of  Ningbo city where he may have been in contact with animals. But that was 10-days prior to onset which would make it a long incubation period. 35M remains unconscious so further detailed tracking of exposures is not possible
• The virus was >95.5% identical to H7N9 from earlier in the year but with 5 hitherto unreported mutations in the neuraminidase (NA) gene. 2/9 bird market samples were also H7N9 PCR-positive but could not be sequenced due to low viral load

Meanwhile, Reuters reports on Albert Osterhaus and Ron Fouchier at the Erasmus Medical Center who are firing up the "gain-of-function" studies to look at what would be required for H7N9 to become a pandemic virus; essentially changing the virus to look for increased transmission. This work will be performed in an highly secure, enhanced biosafety Level 3 lab. Which of course doesn't change the subject matter - but does define how difficult it would be for that to escape. It's not convincingly clear why this virus needs to be given an evolutionary push, rather than "reverse-engineering" those influenza viruses that have previously been pandemic viruses - or some other approach with less risk of creating a virus that if it escaped, would cause a pandemic. Well, to me at least...but I'm no flu expert. You can find much more on dual-use research of concern (DURC) in Laurie Garrett's latest writing over at Foreign Affairs.

And to add to general influenza virus concerns, Sun and colleagues report in Infection, Genetics and Evolution, that infectious H9N2 (isolated using embryonated chicken eggs), strains of which has been implicated in providing genetic material to H7N9, can be isolated from dogs. The isolate was called A/Canine/Guangxi/1/2011 (H9N2). Between 20% 45% of dogs were found to be antibody-positive to H9N2. A range of dogs seem to have been virus-positive with signs and symptoms including loss of appetitie, cough, sneeze, nasal discharge and raised temperture. Some were asymptomatic. Cats next please?

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DENV-5: virus from the jungle comes to humans?

Earlier today I posted on a conference announcement by Dr Nikos Vasilakis of a 5th human dengue virus (DENV) discovery, "the first new dengue virus type in 50 years"

Click to enlarge. An alignment of the prototypical known 4 dengue virus 
complete genome sequences. The GenBank accession number is shown next 
to the serotype's name. They share 68.9% oligonucleotide identity. 
Aligned using Geneious 6.1.6. Thanks to Prof Paul Young for identifying prototypes. 
Feel free to use the graphic with acknowledgement to VDU.

Weeeell. There is more to understanding that headline than I initially thought. 

Turns out, and please excuse the complete ignorance of dengue literature in my earlier post, dengue coming to humans from the jungle (mosquito to non-human primate, occasionally spilling over to humans; the so-called sylvatic cycle) is not an entirely new thing. Jungle? What am I on about? DENV-5 is a new sylvatic serotype, and it must be a pretty genetically and antigenically distinct one at that, in order to get a new number. 

Dr Vasilakis has written about sylvatic spillovers previously and in great detail - see this article in Nature Reviews|Microbiology from 2011. One comment was particularity interesting...

...recent experimental evidence indicates that little or no adaptive barrier exists to the emergence of sylvatic DENV in the human population

Whether this holds true for DENV-5 remains to be defined but we know this new serotype (it elicted a very distinct antibody response in infected monkeys from that due to DENV1-4) was isolated from a human in Malaysia during 2007.

Sylvatic dengue viruses have infected humans before but there have been no sustained epidemics and they seem to have been related to 1 of the 4 serotypes currently endemic in humans. 

One example, published in PLoS Neglected Tropical Diseases, sequenced the complete genome of a distinct sylvatic DENV-2 serotype isolate that caused dengue haemorrhagic fever (DHF) in a male in Malaysia in 2008. This was the first report of a sylvatic DENV causing DHF in a human. This ancestor of the human lineage DENV-2 was genetically related to a 1970 isolate (P8-1407) also obtained from Malaysia (where Gulden is endemic), after it infected a "sentinel" monkey. Such animals are kept in an area and sampled to see if they have become infected - a way of measuring mosquito and haemorrhagic virus activity in this case.

Another example includes a sylvatic DENV-1 from 2005 isolated in Malaysia and similar to a 1972 sylvatic DENV-1 isolate (P72_1244). 

I hope that adds some value to my earlier post.

Also see Crawford Killian's post on this topic from 2011.

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Hajj pilgrims return around the world...is lab testing happening?

Media and Ministry reports are filtering in from many different countries that their Hajj pilgrims have been safely returning from their pilgrimage. 

To date there have been no reports of Middle East respiratory syndrome (MERS) disease in any pilgrim. 

I presume this is all observational diagnosis? It would be very interesting to read whether any actual laboratory testing is occurring in any of these States. If it is, are the pilgrims PCR-negative?

What observation alone cannot tell us is whether a pilgrim infected but not showing signs. 

Self-reporting of mild disease without overt signs, can be problematic and may bias away from capturing all cases in the absence of laboratory testing. If cases do enter a State "under the radar" they may still shed virus to others in their new locale. Some of those others may be older males with comorbidities; the MERS coronavirus's (MERS-CoV) highest impact population. Of course we don't really know if mild and asymptomatic cases can transmit effectively. We might if their was more widespread testing. Since we haven't seen that level of testing coming from the site of most MERS-CoV infections, the Kingdom of Saudi Arabia, perhaps there is an opportunity for other States to step up and test not just returning pilgrims but their families and other contacts and see whether their upper respiratory tract's are free of MERS-CoV RNA?

These media reports also don't tell us what definitions are used by each State to define a pilgrim as being free of MERS-free. It may be the absence of any sign of any respiratory disease, or it be just absence of severe signs and symptoms, or perhaps a combination of signs and symptoms e.g. fever+cough or cough+difficulty breathing.

Too many knowledge gaps. 

One thing's for sure. The headlines are only scratching the surface.

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Break out the bug zapper: DENV-5 is the new dengue virus in town!

A report from the Third International Conference on Dengue and Dengue Haemorrhagic Fever describes the discovery, by researchers from the University of Texas Medical Branch, of a new type of dengue virus (DENV). he virus was found during screening of samples from 2007, collected from Malaysia's northern Sarawak state.

Click to enlarge. An alignment of the previously known 4 dengue virus complete genome sequence. 
The GenBank accession number is shown next to the serotype's name.
They share 68% olignucleotide identity. Aligned using Geneious 6.1.6.

Dengue viruses have an ~11 kilobase, positive-sense, RNA genome enveloped in a lipid bilayer membrane (taken from the host cell upon virion exit) resulting in a 50 nanometer particle. 

Dengue viruses belong to the Family Flaviviridae, Genus Flavivirus and belong to the Species Dengue virus. The viral genome produces a single polyprotein that is cut into 10 proteins (called C, M, E, NS1, NS2A, NS2B, NS3, NS4a, NS4b, NS5). M and E are embedded in the viral membrane.

New virions are assembled on the surface of the endoplasmic reticulum. Dengue virus is transmitted to non-human primates and humans via a mosquito vector (primarily of the genus Aedes) and infection can result in dengue haemorrhagic fever.

This virus, DENV-5 (preusmably), was discovered by Dr Nikolaos Vasilakis and colleagues. It is the 5th member of the species and the first addition in 50-years. DENV-1 to DENV-4, called serotypes (because they interact differently with our immune response to them) are approximately 65% identical in sequence.

How this latest discovery will impact on existing efforts to interrupt, treat or prevent infection and disease remain to be seen. As does a full research publication.

Thanks to FluTrackers for their earlier post on this.

Further Reading:

1. http://www.nature.com/scitable/topicpage/dengue-viruses-22400925

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Australia on watch for illness among Hajj pilgrims

A report from Radio Australia highlight the ongoing need to be watchful for acute respiratory infections developing among pilgrims returning from Hajj.

Gregory H�rtl (spokesperson, World Health Organisation) noted the need to keep an eye out... 

It could well be that a returning pilgrim gets back, starts feeling sick and is found to be diagnosed with MERS, and what we consequently are asking countries to do is to increase their surveillance and to know what symptoms to look for on the one hand, and for pilgrims to be on alert and to tell their doctors they were on Hajj if they start to feel sick.

Professor Charles Watson (Curtin University) noted that disease is most likely to be an issue when pilgrims return to their countries rather than while they were within the Kingdom of  Saudi Arabia.

Thanks to Crawford Kilian for bringing this report to my attention via Twitter and on his blog.

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Latest MERS-CoV cases

The 1st of the 3 most recent cases were from Qatar (6 in total) and the other 2 seem to have originated in or around Riyadh in the Kingdom of Saudi Arabia (KSA). 

Some details on each case are below (preceded by the FluTrackers' number):

1. FT#144. 61-year old male (61M) with comorbidities, hospitalized October 11th with influenza-like symptoms, no travel outside Qatar in the preceding 2-weeks. Owner of a farm, he had significant contact with camels, sheep and chickens. Some animals were tested but were not MERS-CoV POS
2. FT#145. 73M with comorbidities and no specific travel history outside of Riyadh. ICU.
3. FT#146. 54? No travel history outside the eastern region of KSA/Riyadh. ICU.

There are now 144 cases - remembering that 2 Italian cases have been moved from confirmed to probable. Their numbers are retained although not counted in the lab confirmed tally. This maintains list integrity for all the cases numbered prior to that change. 

Click to enlarge.

Of the 144, 60 (perhaps 62) have died, a proportion of fatal cases of 42%. Age distribution among fatal MERS-CoV cases is shown in the chart. There are some missing data on sex/age but it shows that the median age of cases is still skewed toward those >55-years of age and that males predominate. The median age of fatal cases lies above that of the total case population (including fatal and surviving cases).

As noted by Helen Branswell today on twitter (@HelenBranswell) and Crawford Kilian on his blog - the English version of the KSA Ministry of Health website has not been updated with its Arabian-language data in 22-days. 

It's becoming very hard to find 2 sources of MERS case information to trust these days. There has been no World Health Organization (WHO) confirmation of the 2 recent KSA cases and there are possibly 2 outstanding fatal cases in the wind. The WHO did pass along the Qatari case details, plus a little more. Communication between the KSA MOH  and WHO (and us) seems to have slowed to a trickle.

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MERS-CoV cases begin to tick over again after the Hajj....but not related right?

So by all accounts, Hajj2013 was a very successful event. A lot of lifelong wishes may have been fulfilled and the event went off without any apparent major hitch. A huge undertaking on many fronts.

However, during the Hajj it was hard to avoid seeing  Middle East respiratory syndrome (MERS)-related headlines like...

No cases of MERS virus among pilgrims so far

and my particular favourite...

No infectious disease found

...at all that is. None. Not even bad influenza-like illnesses. No coughs or colds among 2,000,000 people gathered together; 1,300,000 having at some level, shared transportation into the Kingdom of Saudi Arabia (KSA)?

Seriously?

That second quote makes me realise just how important it was for the KSA ministry of health to control this aspect of the Hajj's message; no MERS-CoV disease here. So important, that the message was, to say the least, a little heavy handed.

But now, coinciding with the Hajj ending, we see MERS-CoV detections popping up (3 in 3-days). It's very hard to take seriously the MERS-message. Rest assured we're told, those cases are not at all linked to the Hajj - no travel to that region (now so specific that we are told there is no travel outside of Riaydh) in the previous 14-days. Ironic how that longer incubation period is useful in these happy reports, but not remembered in others, such as when the press note:

Saudi Hajj ends successfully with no reports of MERS virus

Click to enlarge. This graph is from September - highlights a similar case
reporting lull around umrah which then climbed rapidly and steadily
immediately afterwards.

The (longest) 14-day incubation period means we're not out of the woods yet (see my earlier post on timelines). 

Maybe we'll see no new cases among any of the pilgrims. Cool. I doubt that. We have seen 7-day or more breaks in reporting of new MERS-cases before, so this past week is not "out of character". Time will tell, especially from now on for a week or so. Watch that curve closely.

I still wish we could lay off the "everything is fine here right now" message, and instead tell us what's happening to find the host or what testing is being done among those who are not severely ill (take a look at China and H7N9 - include MERS-CoV in your regular respiratory virus testing panel for a little while and see what comes of it). That would be treating us a little less like we are so easily distracted by shiny baubles.

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