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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