Why we don't need to do Gain of Function (GOF) influenza transmissibility studies

Professor of epidemiology, Dr Mark Lipsitch, Harvard School of Public Health, presented his views last week at the conference, Options for Control of Influenza VIII. 

His talk, entitled Transmissibility GOF Experiments with HPAI: Interesting Science but not worth the risk of an accidental pandemic, noted that these experiments will not (yet) produce results that are balanced by the risk of an accidental pandemic. An accident that is not beyond the realms of reality since such accidents have happened (FMDV in 2007, SARS in 2004 and possibly H1N1 in 1977) in high level biosecurity laboratories (BSL3/PC3). The required standards for these labs differ from country to country.

Further, Lipsitch noted, we don't need GOF studies for vaccine design when currently effective vaccines target haemagglutinin (HA) and not other influenza segments. Further our influenza surveillance is poor and our primary animal model for use in GOF studies for high-pathogenicity influenza virus, ferrets does not always "perform" as we expect it to.

So Lipsitch summarizes, there is much work still to be done to nail down influenza virus variability, impact of host genetic variation and whether before considering more GOF work. Any real benefit to offset the risk of GOF studies may simply be over-stated.

I enjoyed presentation this very much and it has greatly informed my understanding of the argument. Dr Lipsitch's views are clearly thought out and presented in a logical order intended to address some statements/justifications from the proponents of GOF influenza transmission studies.

Thanks to Avian Flu Diary for posting on this earlier.

Today's MERS tetrad is....

Click on image to enlarge.

Another 4 confirmed MERS-CoV cases and the chart for KSA is exponential. On the plus side, many recent cases have been asymptotic  or symptomatic but mild or stable, which is a change in the recent trend of fatal cases. Of the last 26 cases, 7 have been fatal, and that proportion of 26.9% is well below the overall average, among the 132 global cases, which currently sits at 43%.

Today's case details (not yet on the English MOH site) with FluTracker's case numbering included (as it will be in all my posts from now on) are mostly female (yesterdays seemed to be all male), all in stable condition and they seem to be Riyadh-centric:

1. FT129: 51-year old female (51F), symptomatic female, contact of a mystery case, Riyadh
2. FT130: 47F, symptomatic healthcare worker (HCW), Riyadh
3. FT131: 39F, symptomatic HCW, Riyadh 
4. FT132: 38M, symptomatic HCW, Riyadh

The average age for cases is now sitting at 50-years and the median ages are 39 and 56. 

For fatal cases the average age is 59 and the mode sits at 56.

These represent a reduction in age reflecting the relatively younger cases of late. The younger, predominantly contact-based cases seem to have fewer underlying conditions as a rule - or at least we're hearing of fewer.

So, generalising, severe MERS continues to be an outcome among the older group with comorbidities and less so among contacts and the younger age band.

So, as I like to waste my time asking, I wonder what would happen if prospective testing were to be conducted on a sample of the general population, say in Riyadh, Medinah and Hafr Al Batin, without regard for symptoms? Ideally also in a "control" city from which no cases have been reported. 

My hypothesis is that the average age of MERS cases would drop further and the PFC along with it. In other words there would be more asymptomatic and mild cases detected than we see now. That would really serve the needs of pilgrims and the Kingdom of Saudi Arabia. Maybe such studies are happening right now - who'd know?

Happy Birthday rhinoviruses (RVs) - 60 years old today!

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MERS mounts up...

In a strange coincidence of numerals, the 4th Middle East respiratory syndrome coronavirus (MERS-CoV) report in a row from the Ministry of Health (MOH) of the Kingdom of Saudi Arabia (KSA) contains very little on 4 cases. 

I use below, the FluTracker's (FT) case numbering scheme because frankly, they produce the only numbering schemes for tracking cases of new or returning infectious disease that are systematic, reliable and worthy of our trust. 

It should form the basis for a worldwide numbering system for infectious disease outbreaks because it is also freely and publicly available such that any potential manuscript author can easily check it before submitting a research paper and then we could all know which case is being discussed. And by "we" I mean fellow researchers, not just interested parties. 

The KSA MOH could consider running their own table of data akin to that of FluTrackers, but augmented and using an adapted version of Crawford Kilian's wishlist to the MOH. Each (deidentified) case entry should include the following headings along the top row, filled out if and as they become relevant:

1. A unique, continuous identifying code specific to this emerging virus
2. Sex
3. Age
4. Occupation
5. Co-morbidities
6. Date of illness onset
7. Town of illness onset
8. Town of acquisition
9. Date of hospitalisation
10. Type of laboratory testing
11. Date of laboratory confirmation
12. Date of death
13. Date of release from hospital
14. Treatments/management
15. Town of treatment
16. Relationships to any other cases

Today's MERS-CoV cases are mostly asymptomatic. These cases are announced amid rumours of larger case numbers being tested, panic in hospitals over potential MERS cases, frustration from within KSA over the MOH's poor performance, and of the KSA cracking down on healthcare workers who pass on rumours as well as prosecuting bloggers.

Today we have:

1. FT#125: 22-year old asymptomatic male, citizen of Madinha (Medina), contact of another confirmed case (we shall call him Mr/Mrs/Ms/Dr X)
2. FT#126: 24-year old asymptomatic male healthcare worker in Madinha
3. FT#127: 60-year old asymptomatic male citizen of Riyadh, contact of another case (also unknown)
4. FT#128: 47-year old male citizen of Riyadh, contact of another unknown case, symptomatic but stable

This brings the tally to 128 with 57 deaths (proportion of fatal cases, PFC, at 45%). Where data for sex exists, males comprise 63% of cases and 74% of deaths in people confirmed as positive for MERS-CoV. 82% of cases come from the KSA and, if counting back to the retrospectively identified cases from Jordan, we take the first week of disease associated with MERS-CoV infection as that beginning 19-Mar-=2013, then we are in 78th week of MER. 

FluTrackers: Updating the ordinary about the harmful.

FluTrackers are a rock onto which we bloggers hold for dear life while the torrents of poorly-crafted, or well-crafted but just plain overwhelmingly vast, information break over and around us each day.

It sometimes seems like FT posts before the events even happen. Possibly they do since they also track a lot of related detail and background information so they see trends that may precede the particular case or outbreak "offical" announcement  But they have very strong principles and they clearly discriminate between what is confirmed and what is under investigation  They want you to know what's going on when no-one else has yet got the message to you. 

I think the dedication that this driven band of multi-lingual fact-seekers displays is worthy of honorary doctorates. 

Perhaps they could be made founding members of  a Division, Infection Notification: Forum for Organised Real-time Monitoring - now that's a name by someone who really wanted the initials to spell out I.N.F.O.R.M.

Anyway, I wish the example set by FluTrackers was one that more public health entities followed. Information that is quickly and publicly available, all the time, on everything, from everywhere.

Cheers from VDU.

MERS-CoV fatal cases by week

Click to enlarge. MERS-CoV deaths (red bars) each week against a
backdrop (green) of total cases surviving + fatal, globally.

As requested on Twitter overnight, this shows the confirmed weekly MERS-CoV-positive deaths across time.

Not updated for today's 4 new cases though.

The case against over-interpreting MERS-CoV detection by month...

Click to enlarge. MERS-CoV cases plotted by month of
detection (global data; combining 2012 and
2013 confirmed detections).

There are a number of reasons why I started my post yesterday (my time) with "I'm the first one to say its way to early to be talking about the seasonal distribution". Let's look at some of those reasons today:

1. Where there are few positives in the chart, there has also been very little testing done. The first validated PCR assay was published in 27th September 2012. So Sept-Dec 2012 cases are few and far between for this reason.
2. We are not yet 12-months beyond the announcement of the discovery of MERS-CoV (then nCoV and subsequently HCoV-EMC/2012). It was announced via ProMED on the 20th of Sept and the first genome and clinical study went online 17th October 2012. So no real screening had been done before that time. Cases shown prior to Sept 2012 that identified were retrospectively and not the result of systematic screening
3. As far as I know, screening is still mostly done on a case by case (and contacts thereof) basis. We don't know whether MERS-CoV is circulating endemically in the KSA or any other peninsula country. This is an important data gap since it may be humans that are acting as the reservoir - for all we know
4.  If we look at my post prior to the seasonality chart last night, we can see that cases are climbing steadily - have been since April, and there is no real sign that there is a change in that climb by month. Some reduction of numbers July & August but September is shaping up to be a big month.
5. The spike in cases starting in April was related to a hospital outbreak (the Al-Hasa cluster). And things have rolled on since then. What triggered that outbreak or how the first case(s) acquired the infection remains unknown

So why draw the chart if it is not an accurate representation of true seasonality? Because it gives us an idea of how all the cases officially announced so far are falling out over time, based on the data we have. 

But it should not be over-interpreted. 

We'd need a much greater number of cases and probably a couple of years of surveillance (including community screening) before we could accurately define whether MERS-CoV appears with any seasonal recurrence. Nonetheless, the seasons, or events that happen with seasonal regularity, may influence the risk of exposure and spillover. Also, most of the other seasonal human CoVs occur at their peak every couple of years, and even then, some occur in very low proportions of specimens from people with acute respiratory tract infections. That may be irrelevant to an emerging CoV, or not, so it may take even longer before we can speculate on any seasonal regularity to MERS-CoV infections; if we don't first stamp out the virus altogether as we did with the human SARS-CoV.

So to conclude, before I have to find something and PCR it, given the small amount of data we have, and hints that it might be only the tip of that well referred to iceberg, the more we can extract from what we have the better our chances of finding some clues to the host and some risks for acquiring infection.

Can MERS-CoV seasonality tell us anything about acquisition of MERS?

Click to enlarge. Combined MERS-CoV cases for 2012 & 2013.

I'm the first one to say its way to early to be talking about the seasonal distribution of a new or emerging virus when there are only 124 cases worldwide. 

Right. 

Having said that, I thought I'd plot the cases by date of illness onset or (less satisfactorily) date they were first reported (even if that first was the report of a death). 

When combining the 15-months worth of case data for 2012 and 2013, the graph revealed a single "season" or at least larger numbers around summer in the Kingdom of Saudi Arabia (KSA). Because >80% of cases have occurred in the KSA, I have also listed a few festivals (some of which are frequented by camels) as well as the peak temperature variations and dust storm activity.¹ 

While I have no idea whether weather could be kicking up clouds of infectious CoV, it is an interesting co-occurrence, as are the presence of a number of festivals before case numbers spike. The Saudi Gazette commented that the risk of [acquiring?] bacterial and viral infections increases during dust storm season as do complication due to allergen exposure.

Of course we also know that some large clusters of cases have originated form hospital outbreaks and so environmental factors may play very little role at all. Or they might. Its impossible to say. But it is worth considering what could be happening up 2-weeks prior to a sharp rise in cases - if only to identify 1 index case that then ended up triggering a hospital outbreak.

1. Dust Storms in the Middle East: Sources of Origin and Their Temporal Characteristics. http://ibe.sagepub.com/content/12/6/419.short
2. http://www.magazine.noaa.gov/stories/mag86.htm
3. http://www.saudiaramcoworld.com/issue/200803/heads.high.htm

MERS-CoV cases continue to climb

Click to enlarge. Global MERS-CoV cases by week and
the accumulation of cases.

The latest chart of Middle East coronavirus case spikes by week combined with the accumulating tally of cases.

This paints a picture of unrelenting case growth. The curve took a sharp turn upwards in April and hasn't slowed since. This is in marked contacts to influenza A(H7N9) virus cases which were brought to a screeching halt in south east China earlier in the year.

Combined interferon and ribavirin therapy an option for early MERS-CoV intervention?

Falzarano and colleagues write in Nature Medicine that the combination of ribavirin (an antiviral) and interferon-α2b (a cytokine key to our antiviral defenses) improved the health of MERS-CoV (EMC/2012) inoculated rhesus macaque monkeys. 

This builds on the March Study by Falzarano et al, which reported  the usefulness of this drug cocktail in reducing virus production in a cell culture system.

Treated infected animals did not suffer from increased respiratory rate, breathing difficulties or increased white blood cell counts (mostly due to neutrophils). Treated infected animals also showed no X-Ray changes in their lungs 1-day after infection and little change beyond that. Untreated animals showed mild to marked evidence of pneumonia and also lower levels of markers of inflammation and copies of viral RNA genome.

The macaques were inoculated with 10⁶ tissue culture infective doses (TCID₅₀) by combined intratracheal (lower respiratory tract), intranasal (upper respiratory tract), oral (ingestion) and ocular routes. That seems to represent a fairly "shock-and-awe" cocktail of inoculation routes compared to how humans may get exposed. Viral RNA was detected in spleen, kidney, lymph nodes, upper and lower respiratory tract and airways in the untreated animals - and many of those sites in the treated ones. The relevance of this study to MERS-CoV transmission is probably limited, but then it's not a transmission study, it's a treatment study. There is another article cited as in press from part of this group. It may further address tissue replication; Novel human betacoronavirus causes a transient lower respiratory tract infection in a rhesus macaque model. Proc. Natl. Acad. Sci. USA.

Interestingly, disease in the macaques is at best mild to moderate in severity, so how the drug cocktail would work when faced with severe human disease...which may take longer to develop...remains unclear. Also unclear, is what disease would look like in macaques with a similar degree of comorbidities to those seen in the most severe human MERS cases.

The main proviso is, the cocktail must be administered early; it was administered 8-hours after infecting the monkeys here. 

With a 5-working day to 2-week turnaround in testing for MERS-CoV, treatment would have to be started at first suspicion and even then might not meet this window. Given the Qatar GP story yesterday, that window would be long shut, painted over and boarded up.

Nonetheless, this is a very encouraging finding and a very nice piece of work that adds an important step in the path to providing a therapeutic option to MERS-CoV infections.