Patenting MERS-CoV: no hindrance to diagnosis at all.

Edited by Dr. Katherine E. Arden

This is not the first newly identified virus that researchers at Erasmus, or elsewhere, have patented.

They did the same for human metapneumovirus (HMPV; an endemic respiratory virus and kin to respiratory syncytial virus) after describing its discovery and characterization in 2001.
Another broad-ranging patent also listed on Google is for the human coronavirus (HCoV) NL63, discovered in 2004 by other researchers. Patenting is part of business and today a portion of science research requires proof of the ability of researchers to work with business to help produce real outcomes. Mass-produced diagnostic kits are one outcome - they are made to high standards of quality and distributed worldwide. Research scientists can't do that alone.

Also, the existence of a patent does not prevent or even impede the medical research or public health efforts being undertaken for MERS-CoV now. It also didn't hinder research on HCoV-NL63 or HMPV back when they were discovered. Have a look atPubMED (the Google for scientific research articles) and see how for yourself. There are hundreds of papers there that cover all aspects of each virus - virological, clinical, immunological impact and epidemiology. As a publisher of some of those papers I can assure you I was not asked to pay a cent to the "inventors" and the slowest part of the publication process was my own writing.

Comments to the World Health Assembly today have been interpreted to suggest that a patent on the MERS-CoV has delayed the development of diagnostic tests.

In fact, the necessary parts for leading edge diagnostic testing - sequences for polymerase chain reaction primers - were made available by the researchers (easily contactable thanks to a ProMED posting) as soon as they were developed. They were next made public to the entire scientific community through very rapid publications in leading journals. There are more than 20 papers on the MERS-CoV, or HCoV-EMC as it was known, listed on PubMED already. All a professional, PCR-enabled, public health or research diagnostic laboratory has to do is eMail the discoverers or read the manuscripts and order the reagents.

A true absence of information is unquestionably an impediment to infectious disease research. We saw some great examples of unfettered information from China during the H7N9 outbreak this year. When key information is freely available, as it has been from Prof Zaki and the Dutch researchers at Erasmus for the MERS-CoV, we can rest assured that diagnostic developments are unhindered. Diagnostics are most useful though when they are used to report when and how cases of infection by a new virus occur and spread. Could that area be the next target for more public criticism?

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Flu season isn't the only season.

Its worth noting that when we talk about flu season we are talking about that time of year when flu cases peak. Its not flu season in the US now but there are still cases of influenzavirus spreading among humans. Its just not at epidemic levels (case numbers significantly above the norm).We are entering normal flu season in other parts of the world though, like down here in Aus, although cases are currently sparse. Cases of seasonal flu in one country can be easily spread to other countries by global travel. This is not just the case for influenza viruses of course. Any human respiratory virus ticks over at baseline levels outside of its main "season". Most of the time these infection come and go quickly and with relatively little illness.
Remember, viruses don't know the temperature outside, or the cloudiness - it's the hosts of infection that play the biggest role in virus activity.

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Just normal viruses folks.

It seems that the cluster is a collection of normal respiratory virus infections. Its worth remembering that it is very hard to distinguish between the 200+ different respiratory viruses using signs and symptoms alone. What is usually a common cold virus has been found to trigger asthma attacks and been associated with middle ear infections, pneumonia, bronchitis, influenza-like illness...its a game of probabilities.

Certain viruses are usually cause certain disease. Usually is not always.
In the current climate of MERS-CoV and H7N9 it's understandable that an uptick in acute respiratory illness cases causes alarm but the odds are in favour of one the usual culprits today.

This event is also a reminder of the great job done by expert public disease diagnostic entities like the CDC during times of disease outbreak. Imagine the number of samples that get sent to the CDC for special investigations then scale that up logarithmically during outbreaks. Realistically, even during a pandemic, to find an answer to the type of infectious agent a patient may have requires many separate tests to be conducted on each sample. Time is needed to receive, log and store each patient specimen, to set up, add to and run the diagnostic methods, to carefully interpret the results, sometimes to repeat or add novel testing methods and then to report the results to an increasingly data-hungry public. There's a lot of specialist work in there - even with high throughput system in place these things take some time. We should remember that when reading headlines like "CDC still 'investigating' mystery illness". The implication could be that there is thumb twiddling going because a press releases doesn't appear as quickly as a pirated TV episode on a torrent site. Be assured that there are many steps in a process that seeks to get it right first time.

On a side note, this makes a great case for enhancing diagnostic testing capacity to detect seasonal and endemic respiratory viruses at the local hospital laboratory level. Its surprising how few labs regularly test for the 150+ known rhinoviruses or the 4 non-SARS/MERS coronaviruses for example - together called common cold viruses.

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"Mystery" respiratory illness in Alabama, US.

The past couple of days has seen many reports on a growing number of cases of cluster of acute respiratory illness. The Alabama Dept of Public Health (ADPH) issued an alert yesterday requesting that care providers to be on the lookout for unexplained case of pneumonia.

Cases of interest present with fever, cough, shortness of breath and "something" on their chest x-rays. Upper airway swabs or aspirates have been requested from such cases, regardless of "quick flu" test results. To date, samples have been collected and sent to local labs and to the US CDC.

A total of 10 cases - including 2 deaths (30-40y of age ) - are yet to be linked to a suspected pathogen and are not epidemiologically linked to one another.
Two cases positive for influenza (H1N1 and a seasonal H3) have already been reported (rapid antigen point of care testing?) although the flu season is currently winding down in the US. Two patients have already been discharged.

The cluster of respiratory illness can be traced back to around April 19th. Preliminary testing results should be arriving from the CDC soon.

FluTrackers are keeping a close eye on every report here.

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Making antibodies cross-react with H7N9.

Prof Peter Palese's group has been busy publishing several papers in the Journal of Virology. One report describes the creation of cross-reactive antibodies to H7N9 by making Newcastle disease virus (NDV; a very contagious bird virus that has already been established as a poultry vaccine backbone) produce the H7 haemagglutinin from North American birds (H7N1-3).
They did this by inserting a representative H7 protein coding sequence in between normal NDV genes. The serum collected from mice immunized with this recombinant virus could block a range of H7-containing influenza A viruses. A new vaccine candidate in the making.

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Editor's Note #6.

I've finally started to rebuild the rhinovirus (HRV) page. For someone whose main interest is these little dudes...well, it was in a pretty woeful state. How embarrassment. Expect to see it take shape over the coming weeks.

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H7N9 antibody in Vietnam.

A study by MF Boni and colleagues describe the presence of either specific, or cross-reactive antibodies (which can arise after infection by a different influenza virus, but react with the H7N9 test) to the avian influenza A(H7N9) virus. These antibodies were detected in the sera of a cross-section of people from south Vietnam and were found at higher titres (levels) than antibodies to H5 but below those to H9 viruses. Human seasonal influenzavirus antibody levels were much higher than avian levels.
The protein array method used may not be comparable to haemagglutination inhibition (HI) or neutralization assay.
Results revealed a general increase in the amount of anti-haemagglutinin (HA) IgG antibody with age. This is fairly normal as our exposures to virus accumulate an immune "memory" over time.

There was no significant difference whether the samples came from rural or urban locales or from areas known to often keep chooks in the backyard, versus areas that do not.

The H7N7 and H7N9 avian influenza viruses differ by only ten amino acids in HA so it is likely IgG to H7N7 will cross-react with the H7N9.

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H7N9 comments from ASM 2013.

Prof Albert (Ab) Osterhaus noted during a panel at the American Society of Microbiology 2013 meeting in Denver, that an H7N9 virus capable of spreading efficiently from human-to-human might result in an enormous outbreak.
Prof Osterhaus pointed out that although H5N1 has been around for over a decade (and our research still has not answered all the questions we've raised) it still has not developed the ability to spread efficiently from human to human. He also feels that the "spillover" from birds (likely to be poultry) to humans is via the live bird markets (LBMs) in China-in some way. We must also be mindful of influenza being a seasonal infection so we may see a lull as we enter the warmer months but that it may return as the weather changes.
Prof Osterhaus also reminds us that "low-path" (low pathogenic avian influenza) virus are not necessarily "no-path" and that we shouldn't get too hung up on what may varies among, perhaps within, bird species as noted during lab studies. He also notes that the EMC team has developed a ferret model that provides human-relevant data on influenza infection and he stresses, continually, the importance of good epidemiology underpinned by ongoing surveillance systems.

Prof Robert Webster notes that LBMs may start to be reopened soon. He expressed his concern that H7N9 might re-emerge because of market reactivation. He also notes that poultry vaccines are "second-class" (Prof Osterhaus disagrees, says there arequality animal vaccines; H5N1 vaccines do not provide sterilising immunity - the chickens look good, but they keep shedding viruses - which is a hindrance to further vaccination of apparently healthy animals.

Dr Carole Heilman addresses the possibility of a universal vaccine noting that vaccines very conserved regions show promise in animals models. Current vaccine target the response to hemagglutinin - but what markers will be needed for vaccines focussing on eliciting other responses.

Prof Webster raises the issues of possibly "the most important avian influenza virus" H9N2, a virus spread ubiquitously across Eurasia, evolving in Bangladesh. H9N2 is stealthy in causing no apparent disease but is the backbone of H7N9. It may be the donor virus for many future reassortants.
Prof Osterhaus noted that much of what we have predicted about influenza virus over the years, hasn't happened-so lets keep predicting! However, H5N1 mutations, which are easy for the virus to accumulate, that could create an easily transmissible pandemic virus already exist in nature, some found in H7 and H9 viruses. Inexplicably, these mutations have not come together in humans yet. The potential exists however and complacency must be avoided.

In answer to a question expressing the public's concerns over escape or weaponization of lab-created "frankenflu" (my addition) viruses, Prof Osterhaus notes the high level of scrutiny and containment that these sorts of experiments are conducted under. He also notes that the biggest bioterrorist is nature.
In my opinion, the mutant flu virus research allows us to understand whether these mutations are possible and viable. The new viruses harbouring mutations of interest are "fit", they are able to replicate and transmit efficiently - some mutations make the virus less fit and so are unlikely to survive in nature. Understanding what is likely and what is not, helps researchers and public health officials develop policy, procedures and materials to be on guard for the greatest risks. Knowledge also helps us focus our research towards countering what could happen rather than stumbling around wasting time, effort and money on avenues that will not bear fruit in terms of increased public health and safety in an area that has a ticking clock a

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Imported MERS death and 2 possible family cases in Tunisia.

It seems that up to 3 news cases of the MERS-CoV have

appeared in Tunisia (see updated map).ProMED (Archive# 20130520.1725864) crofsblog(multiple stories) and FluTrackers have more details and specifics.

According to a translated report, a 66M Tunisian citizen died after returning from the Saudi Arabia and Qatar, some of the "gulf states" (includes Bahrain, Kuwait, Oman, Qatar, Saudi Arabia and the United Arab Emirates). His two sons also have influenza-like illnesses, and they are positive for the MERS-CoV (Health Ministry via Kuwait News Agency report).

Its hard to tell but the (?)sons seem to be suffering a milder form of disease than perhaps we are used to hearing about. Which if so, once again raises the issues of how many mild cases are circulating that we are not hearing about, detecting or containing? Also I wonder how "close" these close contacts were in order to acquire infection and are any, more distant, contacts under observation-was 66M coughing and sneezing over his travel mates on the trip back from Tunisia?

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Weekly H7N9 update from China: May 13-20.

No new H7N9 case reported in China!

1 new death of an existing case and 15 more discharges. 130 cases (132 if including the Taiwan import and asymptomatic case), 36 deaths and 72 recovered and discharged patients. No details on the death or discharges unfortunately.

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All Australian bat species, including 1 of the 50 species of microbats (order Chiroptera [bats], suborder Microchiroptera) common in Australia, are considered susceptible to ABLV.

Chief Biosecurity Queensland officer Dr Thompson noted that a dead bat had been found on the property housing the Australian Bat Lyssavirus (ABLV) infected horse, but were not closely associated with any colonies.

All 6 human contacts of the horse have been given preventative treatment including rabies vaccine and rabies immunoglobulin, both of which cross-protect against serious disease caused by ABLV.

The main advice for humans to mitigate risk of infection is to avoid handling bats and flying foxes without appropriate vaccination. Even then, it would be best to report ill or strangely behaving (ill) bats to the authorities. Bats have been the source of a number of virus discoveries (not preventable by specific vaccines) in recent years including influenza virus (H17N10)and coronaviruses (numerous bat-CoVs and possible the MERS-CoV).

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Is this what you think of when you think severe disease?

One of the treasures I've found while tinkering around the edges of H7N9 blogging for just a few weeks - Crawford Kilian's crofsblogs - the flu one in particular. 

I highly recommend this article from 19.05 highlighting the issue of taking MERS the virus and MERS the disease, seriously.

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New MERS-CoV Page takes shape.

VDU is a "work-in-progress" kinda site. The latest work is to develop a new coronavirus page dedicated to the exploits of the latest of the betacoronavirus to infect humans. 

It has a way to go and will probably never have the colourful charts of the H7N9 page - data from the Arabian Peninsula has been nothing like the quality of those from China - but I'll bring it up to speed as I read through the literature, and then leave it as a resource for those wanting a grounding in what used to be (sniff) HCoV-EMC.

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Sunny summer or birds on the wing?

I'm no ornithologist. Week 7 had much to say about the approaching summer scaring away the H7N9 virus and the closure of live bird markets having stunted or stopped entirely the outbreak. 

I'm still not convinced - as I said yesterday. 

A continuation of that line of thinking, posed as question for today then; could the spread of H7N9 have peaked and fallen in relation to the travels of wild birds, not poultry? The paltry number of positive poultry cases could have acquired their virus from wild birds also. 

Also, how many of the males infected with H7N9 kept small birds as pets? Did any of them get those birds recently? Passerine birds, like the brambling, cover some distances when migrating with the seasons. The brambling also turned up amongst as co-contributor (of an H9N2) to H7N9's genetic makeup.

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Denominator example from WHO.

  Thanks to Mike Coston for the heads up on the WHO report resulting form the Influenza-A-team's Joint Mission to parts of China (18/24 April, 2013). They have a nice graphic on pg17 outlining the denominator issue. I've adapted for the H7N9 page.

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