Saturday, April 21, 2018

CDC Update: Candida Auris - April 2018


In June of 2016 the CDC issued a Clinical Alert to U.S. Health care facilities about the Global Emergence of Invasive Infections Caused by the Multidrug-Resistant Yeast Candida auris.
C. auris is an emerging fungal pathogen that was first isolated in Japan in 2009. It was initially found in the discharge from a patient's external ear (hence the name `auris').  Retrospective analysis has traced this fungal infection back over 20 years.
Since then the CDC and public health entities have been monitoring an increasing number of cases (and hospital clusters) in the United States and abroad, generally involving bloodstream infections, wound infections or otitis.
Adding to the concern:
  1. C. auris infections have a high fatality rate
  2. The strain appears to be resistant to multiple classes of anti-fungals  
  3. This strain is unusually persistent on fomites in healthcare environments.
  4. And it can be difficult for labs to differentiate it from other Candida strains
The CDC has updated their C. Auris surveillance page, where they show - as of March 31th - 247 confirmed cases and 30 probable cases, across 11 states.

Additionally, based on targeted screening in four states reporting clinical cases, the CDC reports an additional 475 patients have been discovered to be asymptomatically colonized with C. auris.

As mentioned, this isn't just a problem in the United States (see map above), and this week the CDC's MMWR carries a `Notes from the field' report on C. Auris in Colombia that illustrates how easily this fungal infection can fly under the surveillance radar. 
Something that is probably happening in many other places around the world.
I've only included some excerpts, so follow the link to read the report in its entirety.

Notes from the Field: Surveillance for Candida auris — Colombia, September 2016–May 2017
Weekly / April 20, 2018 / 67(15);459–460

Patricia Escandón1*; Diego H. Cáceres2,3*; Andres Espinosa-Bode4; Sandra Rivera1; Paige Armstrong2; Snigdha Vallabhaneni2; Elizabeth L. Berkow2; Shawn R. Lockhart2; Tom Chiller2; Brendan R. Jackson2; Carolina Duarte1

After a 2016 CDC alert describing infections caused by the multidrug-resistant fungus Candida auris (1), the Colombian Instituto Nacional de Salud (INS) queried the country’s WHONET† database of invasive Candida isolates to detect previous C. auris infections.
No C. auris isolates were identified during 2012–2016. However, C. auris is often misidentified as Candida haemulonii (2), a yeast that rarely causes invasive infections, and 75 C. haemulonii isolates were reported during May 2013–August 2016.

These isolates came primarily from patients in intensive care units in the country’s north region, approximately 350–600 km (220–375 miles) from Maracaibo, Venezuela, where C. auris cases were first identified in 2012 (3). Of the 75 reported Colombian C. haemulonii isolates in WHONET, INS obtained 45 isolates from six medical institutions dating from February 2015 through August 2016, all of which were confirmed to be C. auris by matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry.

Based on these findings, INS issued a national alert and mandated reporting of suspected isolates on August 30, 2016§ (3,4). In September 2016, a team from INS, CDC, and medical staff members from hospitals with documented C. auris cases investigated the 45 MALDI-TOF–confirmed C. auris cases identified before the INS alert. This investigation involved two hospitals in the north region and two in the central region. Cases were clustered within specific hospital units, and surveillance sampling demonstrated transmission in health care settings (INS and CDC, unpublished data, 2018).

Infections caused by C. auris are occurring in Colombia; the pathogen has been present in Columbia since at least 2015, and case counts are increasing. The number of reported cases likely does not reflect the true number of infected and colonized persons because of underreporting and underdiagnosis, as well as misdiagnosis as other yeast species (6).

To contain the spread of C. auris in Colombia, INS updated the C. auris national clinical alert in July 2017 specifying which yeast isolates must be sent to INS for confirmation and mandating that medical facilities implement enhanced infection control practices, including using contact precautions and single rooms for patients with C. auris infections, minimizing the number of health care personnel in contact with infected patients, and daily and terminal cleaning of patient rooms and medical equipment with a disinfectant effective against Clostridium difficile spores** (2).

Clinical laboratories should be aware that automated laboratory systems might incorrectly identify C. auris, particularly as C. haemulonii, although the species reported depends on the system (2).
        (Continue . . . )

For more on this emerging fungal pathogen, you may wish peruse the CDC's dedicated web page:

And for some older blogs on the topic, you may wish to revisit:

Friday, April 20, 2018

C.I.D.: Predicting Influenza H3N2 Vaccine Efficacy from Evolution of the Dominant Epitope


After this past winter's severe H3N2 flu season, which was aided and abetted by a seriously disappointing H3N2 component to the seasonal flu vaccine, the last thing anyone wants to see are the headlines from yesterday forecasting another poor vaccine performance this fall.
Rice University study suggests 2018 flu vaccine will have 20 percent success rate -
Rice University study suggests 2018 flu vaccine will have 20 percent success rate - CW39
Fall 2018 flu vaccine will be 20 percent effective, study predicts -UPI
April 19 (UPI) -- This fall's flu vaccine will be 20 percent effective for the dominant circulating strain of influenza A, the same as shots given the past two years, a new study predicts.
        (Continue . . . )

Admittedly, not exactly the message that public health officials want to see splashed all over the media during the run up to next fall's vaccination campaign (or for the Southern Hemisphere's campaign right now).
While the performance of next fall's H3N2 vaccine component - which suffers from mutations generated during its passage through eggs (see PLoS Path.: A Structural Explanation For The Low VE Of Recent H3N2 Vaccines) - seems likely fall short again next fall, that is (thankfully) not the whole story.  
We've had two H3N2 dominant flu seasons in a row.  While it is certainly possible we'll be unlucky enough to see a third, right now H1N1 appears to be picking up steam around the globe, and we may see it become the dominant strain next fall (see WHO Update below)

62.7% of Influenza A  H1N1 / 37.3% H3N2

Although H1N1 cases were few and far between this past winter, the CDC's Interim Vaccine Effectiveness numbers (released in Feb) estimated a 67% (CI = 54%–76%) VE against A(H1N1)pdm09 viruses.
Even assuming that proves optimistic due to the small sample size, the VE against H1N1 has generally run over 50%.
Which means - depending upon the mix of influenza A & B viruses next fall - the vaccine may not prove to be as much of a dud as these headlines would suggest.  Only time will tell.

All of this dire reportage stems from what I'm sure is a fascinating study, published this week in Clinical Infectious Diseases, that is (alas) almost entirely behind a pay wall.  There is not much I can do but provide a link.
Predicting Influenza H3N2 Vaccine Efficacy from Evolution of the Dominant Epitope
Melia E Bonomo Michael W Deem
Clinical Infectious Diseases, ciy323,
Published: 17 April 2018


We predict vaccine efficacy with a measure of antigenic distance between influenza A(H3N2) and candidate vaccine viruses based on amino acid substitutions in the dominant epitopes. In 2016-2017, our model predicts 19% efficacy compared to 20% observed. This tool assists candidate vaccine selection by predicting human protection against circulating strains.
        (Continue . . . .)

What we do have is a press release (below) from Rice University, which provides some pretty good background on the study.  It too, glosses over the possibility that next year could be an H1N1 dominant year, which undoubtedly explains the media's slant.
Study predicts 2018 flu vaccine will have 20 percent efficacy
Jade Boyd – April 19, 2018 David Ruth


Jade Boyd

Study predicts 2018 flu vaccine will have 20 percent efficacy
Rice U. study finds egg adaptations will limit efficacy of new flu vaccine

HOUSTON — (April 19, 2018) — A Rice University study predicts that this fall’s flu vaccine — a new H3N2 formulation for the first time since 2015 — will likely have the same reduced efficacy against the dominant circulating strain of influenza A as the vaccine given in 2016 and 2017 due to viral mutations related to vaccine production in eggs.

The Rice method, known as pEpitope (pronounced PEE-epih-tope), was invented more than 10 years ago as a fast, inexpensive way of gauging the effectiveness of proposed flu vaccine formulations. The latest pEpitope study, which is available online this week in Clinical Infectious Diseases, suggests pEpitope is a more accurate predictor of vaccine efficacy than long-relied-upon ferret tests, particularly for data gathered in the past decade. The pEpitope method accounts for 77 percent of what impacts efficacy of the vaccine in humans.

pEpitope is a computational method that measures critical differences in the genetic sequences of flu strains. In the new study, the method accurately predicted vaccine efficacy rates for more than 40 years of flu records. These included the past two flu seasons in which vaccines offered only limited protection against the most widely circulating strain of influenza A.

“The vaccine has been changed for 2018-19, but unfortunately it still contains two critical mutations that arise from the egg-based vaccine production process,” said Michael Deem, Rice’s John W. Cox Professor in Biochemical and Genetic Engineering and professor of physics and astronomy. “Our study found that these same mutations halved the efficacy of flu vaccines in the past two seasons, and we expect they will lower the efficacy of the next vaccine in a similar manner.”

(Continue . . . )

As I said, this appears to be a fascinating project, and I look forward to seeing more on it.  And until we change the way flu vaccines are produced, it is very likely - particularly with H3N2 - that these VE problems will continue.

By the middle of last summer it was becoming apparent that the 2017-18 H3N2 vaccine component was likely to be `suboptimal' once again (see The Enigmatic, Problematic H3N2 Influenza Virus) and the prospects of a another H3N2 dominated North America flu season were looking pretty good.  
Despite those warning signs, I got the flu vaccine last September and urged others to do so as well, figuring that some protection beats no protection at all.   
While this year's flu vaccine was far less effective than we'd like, the CDC's mid-season estimate of the overall U.S. VE (Vaccine Effectiveness) against both A & B subtypes was 36%. Some age groups however - notably adolescents (9-17), and adults 50 and older - showed no statistically significant protection from the vaccine.
One bright spot is that kids aged 6 months through 8 years saw as much as 59% protection from this year's vaccine.  And in a year where we've seen more than 150 flu-related pediatric deaths, without the vaccine, that number would undoubtedly have been higher.
Although I think the benefits of the flu vaccine are sometimes oversold, it does have genuine value, even in years when its VE is sub-par. A few recent studies showing this include:
CMAJ Research: Repeated Flu Vaccinations Reduce Severity of Illness In Elderly
CID Journal: Flu Vaccine Reduces Severe Outcomes in Hospitalized Patients
More Evidence Flu Shots May Improve Outcomes In Critical Patients
Study: Flu Vaccine May Reduce Heart Attack Risk
Despite being far from perfect, the flu vaccine – along with practicing good flu hygiene (washing hands, covering coughs, & staying home if sick) – still remains your best strategy for avoiding the flu and staying healthy this winter.

Regardless of what the headlines say.

Thursday, April 19, 2018

WHO: Audio Of SAGE Press Conference On Vaccines (including Dengvaxia (tm))


Roughly 5 months ago vaccine producer Sanofi hinted at a safety signal with their Dengvaxia (tm) vaccine (see Philippines Halts Dengue Vaccine After Sanofi Issues Warning) - involving children who had never been infected with dengue, and received the vaccine. 
Recently completed studies suggested that dengue-naive children who received the vaccine were at an increased risk of seeing a `severe dengue infection' months or even years later.  
This news came after roughly 700,000 people received the vaccine in the Philippines, of which as many as 10% may have never been previously infected. Within days of the announcement, the Philippines FDA withdrew the drug from the market amid media reports of potentially injured children.

In December the World Health Organization Unveiled Interim Dengue Vaccine Recommendations, and promised `. . . a full review of the data through the Global Advisory Committee on Vaccine Safety and SAGE, for revised guidance of the use of Dengvaxia®'. 

SAGE has just completed their spring meeting and the audio of a 26 minute press conference discussing that meeting - and their decision on Dengvaxia (tm) - has been posted to the WHO mulimedia web page. 
The upshot is, after reviewing the evidence, SAGE recommends that the Dengvaxia vaccine be given in a`much safer way', meaning that it should only be given to those who can be certified as having previously been infected with one of the dengue serotypes.
Practically speaking, that would require the use of an inexpensive point-of-care rapid test that can be administered just prior to vaccination - a product which is not currently available.     

As we've discussed previously, there have long been concerns over the safety of the dengue vaccine, particularly in regards to a phenomenon called antibody dependent enhancement or ADE.

Generally speaking, a person's first infection with dengue is relatively mild, but with four serotypes, a person can be infected multiple times during their lifetime. A person's second infection with dengue is often more severe due to the body thinking the second infection is the same serotype as the first, and sending inefficient antibodies to fight it.
When given to a dengue-naive individual, the dengue vaccine can substitute for that first infection, and could make a later infection worse.
There were warnings - published in major journals - suggesting just this sort of outcome was possible. One need look no further than a CIDRAP News report from July of 2016, which eerily presages the events of the past few months (see Contrary dengue vaccine response hints at possible problems with Zika).
Regardless of the actual risk of injury from this vaccine (which remains a matter of some debate), Dengvaxia's reputation - and the public's perception of the safety of other vaccines - has taken a significant hit.
Which in the end, could turn out to be the biggest loss of all.

Emerg. Microbes & Infections: Wild Ducks Shed (2014-15) HPAI H5N8 Asymptomatically


During the first two years after it emerged in South Korea in January of 2014, HPAI H5N8 spread rapidly around the globe - turning up in Europe and North America in less than a year - presumably carried in by migratory birds.
Somewhat remarkably, during the six months when H5N8 (and its reassorted offspring H5N2) decimated the US poultry industry (Dec 2014-June 2015), fewer than 100 dead or dying birds were found infected across the United States.
Even more remarkable, by the summer of 2015, the virus had virtually disappeared in both North American poultry and  wild birds (see PNAS: The Enigma Of Disappearing HPAI H5 In North American Migratory Waterfowl).  
While still causing losses in Korea and China, to everyone's surprise H5N8 did not return the following winter to Europe or North America.
When H5N8 did return to Europe in the fall of 2016, it was quickly apparent that something had changed. In November of 2016, in Europe: Unusual Mortality Among WIld Birds From H5N8, I wrote about thousands of wild birds dying from the virus in the Netherlands.

In January of 2017, we would learn that the H5N8 virus had reassorted - either in Russia or China (see EID Journal: Reassorted HPAI H5N8 Clade - Germany 2016) - picking up virulence in wild birds, an expanded avian host range, and unusual environmental persistence.
Despite this increased mortality in wild birds, the virus has continued to spread - first into the Middle East - and then into central and southern Africa, although it was largely supplanted by a reassorted HPAI H5N6 virus in Europe and Asia this past winter. 
All of which brings us to a new research article, published this week in Emerging Microbes and Infections, which looks at the carriage of the (pre-2016-reassortant) HPAI H5N8 virus in wild ducks and finds that it produced far fewer clinical symptoms than did HPAI H5N1.

I've only excerpted the abstract, so follow the link to read it in its entirety.
Wild ducks excrete highly pathogenic avian influenza virus H5N8 (2014–2015) without clinical or pathological evidence of disease 
Judith M. A. van den Brand, Josanne H. Verhagen, Edwin J. B. Veldhuis Kroeze, Marco W. G. van de Bildt, Rogier Bodewes, Sander Herfst, Mathilde Richard, Pascal Lexmond, Theo M. Bestebroer, Ron A. M. Fouchier & Thijs Kuiken

Emerging Microbes & Infectionsvolume 7, Article number: 67 (2018)
Published online: 18 April 2018


Highly pathogenic avian influenza (HPAI) is essentially a poultry disease. Wild birds have traditionally not been involved in its spread, but the epidemiology of HPAI has changed in recent years. After its emergence in southeastern Asia in 1996, H5 HPAI virus of the Goose/Guangdong lineage has evolved into several sub-lineages, some of which have spread over thousands of kilometers via long-distance migration of wild waterbirds.

In order to determine whether the virus is adapting to wild waterbirds, we experimentally inoculated the HPAI H5N8 virus clade group A from 2014 into four key waterbird species—Eurasian wigeon (Anas penelope), common teal (Anas crecca), mallard (Anas platyrhynchos), and common pochard (Aythya ferina)—and compared virus excretion and disease severity with historical data of the HPAI H5N1 virus infection from 2005 in the same four species.

Our results showed that excretion was highest in Eurasian wigeons for the 2014 virus, whereas excretion was highest in common pochards and mallards for the 2005 virus. The 2014 virus infection was subclinical in all four waterbird species, while the 2005 virus caused clinical disease and pathological changes in over 50% of the common pochards. In chickens, the 2014 virus infection caused systemic disease and high mortality, similar to the 2005 virus.

In conclusion, the evidence was strongest for Eurasian wigeons as long-distance vectors for HPAI H5N8 virus from 2014. The implications of the switch in species-specific virus excretion and decreased disease severity may be that the HPAI H5 virus more easily spreads in the wild-waterbird population.
        (Continue . . . )

HPAI H5N8 did in just over 3 years what HPAI H5N1 has yet to do in more than 15 years;  it made the leap to North America, sparked record setting epizootics there and in Europe, and has set recently taken up residence in the Southern Hemisphere (Zimbabwe & South Africa).
Whatever barriers that limited H5N1's spread via migratory birds have been largely overcome by HPAI H5N8. 
A reminder that avian flu viruses - like all viruses - are constantly changing; seeking an evolutionary advantage that will give them greater access to a ready supply of susceptible hosts.

And that we can't necessarily assume that the novel viruses we will face tomorrow will continue to behave as they have in the past.

Multi-State Cluster Of Coagulopathy Associated With Synthetic Cannabinoids Continues

Credit Illinois Department of Public Health


While the vast majority of cases continue to be reported from central Illinois and the Chicago region, cases of severe hemorrhage linked to Spice/K2/`Fake Weed' use in other states continues to rise. 
Spice already had a pretty nasty reputation among mental health professionals and ER staff before these severe cases of bleeding began to appear a little over a month ago.
A few past blogs include:
First, yesterday's update from the IDPH, then we'll move on to Maryland, Indiana and Wisconsin.

Synthetic Cannabinoids 
As of April 18, 2018, IDPH has received reports of 141 cases, including three deaths, linked to an outbreak, since March 7, 2018; cases report using synthetic cannabinoid products before suffering from severe bleeding.

***Numbers are provisional and subject to change; IDPH will update the website everyday at 1:30pm, for the duration of the outbreak***

ases report acquiring the synthetic cannabinoid products in counties across the state.  Individuals reported obtaining contaminated synthetic cannabinoid products (i.e., K2, spice, synthetic marijuana, and legal weed) from convenience stores, dealers, and friends.   
If you have purchased any of this product in the past month, do not use it.  If you have used any of these products, and start experiencing severe, unexplained bleeding or bruising, please have someone take you to the hospital immediately or call 911. Do not walk or drive yourself. Tell your health care providers about the possible link between your symptoms and synthetic cannabinoid use.

Not quite two weeks ago, in CDC COCA Outbreak Alert: Coagulopathy Associated With Synthetic Cannabinoids Use, we learned that a few scattered cases (2 in Indiana, 1 in Maryland, 1 in Missouri, and 1 in Wisconsin) had been reported outside of Illinois.

From the Maryland Department of Health we learn that three more cases have been confirmed.
Maryland Department of Health and Maryland Poison Center Reports Fourth Synthetic Cannabinoids Hospitalization in Maryland
Cases are on the Rise—Effects can be Harmful and Deadly

Baltimore, MD (April 17, 2018) – The Maryland Department of Health and the Maryland Poison Center have reported the fourth hospitalization in Maryland from individuals experiencing risk of severe bleeding after using synthetic cannabinoids, which are often called Spice, K2, Bliss, Scooby Snax, or fake weed.

Clinical signs include bruising, nosebleeds, bleeding of the gums, bleeding out of proportion to the level of injury, coughing up blood, vomiting blood, blood in urine or stool, or excessively heavy menstrual bleeding and back pain.

Synthetic cannabinoids are human-made, mind-altering chemicals that are sprayed onto dried plant material. They can be smoked or sold as liquids to be vaporized in e-cigarettes and other devices. These chemicals are called cannabinoids because they are similar to chemicals found in the marijuana plant. The health effects from using synthetic cannabinoids can be unpredictable, harmful, and deadly. Additionally, it is likely that these products have been contaminated with a product that makes people bleed and there is no way to identify which products are contaminated.

Synthetic cannabinoids are found in places like drug paraphernalia shops, novelty stores, and online. The potential for harm applies to synthetic cannabinoids purchased legally or illegally.
The four cases reported in Maryland have noted similarities to those in Illinois, where 131 cases—including three deaths—have been reported since March 7, 2018.

(Continue . . . )

From Indiana we learn that their number (as of April 12th) had risen to three, with two additional cases under investigation. 

Synthetic Cannabinoids/Spice

Summary of event
​As of April 12, 2018, Indiana State Department of Health (ISDH) has received reports of 3 cases linked to the outbreak. Two additional cases are currently under investigation. Illinois identified the first cases of synthetic cannabinoids/spice use linked with vitamin K dependent coagulopathy (unusual bleeding that requires treatment with Vitamin K). The first case was reported to ISDH on March 27, 2018. 

**Numbers are provisional and subject to change; numbers will be updated on a weekly basis or more regularly, if deemed necessary.**

While providing few details, the State of Wisconsin's Health Department has posted:
As of April 12, 2018, Wisconsin Department of Health Services (DHS) has identified four cases in Wisconsin.
There may well be more cases from other states which I've not stumbled upon yet.  
While 150 cases pales in comparison to the toll of our nation's opioid epidemic, the sale of these drugs is particularly insidious because it plays on people’s perception that marijuana is relatively harmless (and indeed, legal in some states) - and due to loopholes in the law - Spice is often sold `legally'. 
 For more, you may wish to visit:
CDC - Synthetic cannabinoids: What are they? What are their effects?

NIH - Synthetic Cannabinoids (K2/Spice)

Wednesday, April 18, 2018

Cell Reports: A Dominant Gene Constellation Emerged For H7N9 In Wave 5


During the first three waves of H7N9 (which began in the spring of 2013) we saw an explosion in the number of genotypes reported, with literally scores of genetically distinct H7N9 viruses circulating in China.
In the first year alone (Feb 2013 - Feb 2014) researchers identified - out of 146 H7N9 viruses available with full genome sequences - at least 26 different genotypes (see Eurosurveillance: Genetic Tuning Of Avian H7N9 During Interspecies Transmission).
Many of these genotypes proved to be flashes in the pan - detected once or twice - and were quickly supplanted by more biologically `fit' variants. A handful of others were more robust, and widespread.
But this illustrates just how volatile H7N9's evolutionary process really was, and why it quickly sparked concerns that the virus was on a path toward becoming a pandemic virus.
After three impressive waves, the 4th wave in China was markedly smaller, raising hopes the virus was losing steam. But the 5th wave was the largest to date; nearly equaling the total of the 4 previous waves (see graphic at top of blog) combined.
The 5th wave was also notable for the emergence of a new, dominant LPAI lineage (Yangtze River Delta) - dethroning the original Pearl River Delta lineage - and an HPAI variant which surfaced in Guangdong Province and began to spread (see MMWR: Increase in Human Infections with Avian Influenza A(H7N9).
We've also seen a number of mammalian adaptations reported (see J. Virol.: Spread & Evolution of HPAI & LPAI H7N9 During 5th Wave - China) which may have contributed to last year's record-setting epidemic. 

Today we've a new research article which appears in Cell Reports that finds the rapid expansion of H7N9 genotypes during the earlier waves appears to have - at least temporarily - slowed dramatically during the 5th wave.
Moreover, a single dominant gene constellation appears to have been responsible for the bulk of the human infections during the 5th wave. 
We've a very long, detailed, open-access report today from Cell Reports that describes this abrupt change in the evolution of H7N9. Due its length, I've only included some excerpts - so you'll want to follow the link to read it in its entirety. 
A Gene Constellation in Avian Influenza A (H7N9) Viruses May Have Facilitated the Fifth Wave Outbreak in China
Wenfei Zhu3, Jie Dong3, Ye Zhang3, Lei Yang3, Xiyan Li3, Tao Chen, Xiang Zhao, Hejiang Wei, Hong Bo, Xiaoxu Zeng, Weijuan Huang, Zi Li, Jing Tang, Jianfang Zhou, Rongbao Gao, Li Xin, Jing Yang, Shumei Zou, Wenbing Chen, Jia Liu
, Yuelong Shu4,'Dayan Wang  

Open Access
DOI: |


  • H7N9 viruses inherited NP genes from co-circulated H7N9 instead of H9N2 viruses
  • H7N9 viruses appear to have entered a relatively stable stage
  • One gene constellation is identified as having emerged in H7N9 viruses
  • The largest outbreak in wave V may be due to the gene constellation

    The 2016–2017 epidemic of influenza A (H7N9) virus in China prompted concern that a genetic change may underlie increased virulence. Based on an evolutionary analysis of H7N9 viruses from all five outbreak waves, we find that additional subclades of the H7 and N9 genes have emerged.

    Our analysis indicates that H7N9 viruses inherited NP genes from co-circulating H7N9 instead of H9N2 viruses. Genotypic diversity among H7N9 viruses increased following wave I, peaked during wave III, and rapidly deceased thereafter with minimal diversity in wave V, suggesting that the viruses entered a relatively stable evolutionary stage.

    The ZJ11 genotype caused the majority of human infections in wave V. We suggest that the largest outbreak of wave V may be due to a constellation of genes rather than a single mutation. Therefore, continuous surveillance is necessary to minimize the threat of H7N9 viruses.



    The fifth epidemic of H7N9 in China was marked by extensive geographical spread infecting both poultry and humans. The number of human infections reported in the fifth epidemic was almost as many as reported during the previous four epidemics combined.
    Epidemiological characteristics, including age, sex distribution, and exposure history of human infections with influenza A (H7N9) virus in China, reported during the fifth wave were similar to those reported for the previous four waves (Xiang et al., 2016). 

    This indicates that it may, in fact, be the genetic or antigenic characteristics of the viruses that might have changed. After comprehensive evolutionary analysis of the influenza A (H7N9) viruses from all five waves, we found that viral genetic diversity increased dramatically from wave II to wave IV but significantly decreased in wave V. The reduced genetic diversity in wave V and similar inferred evolutionary change rates in H7 and N9 genes during each wave (Figure S3) may indicate slower adaptation of H7N9 viruses.

    Indeed, we found that the ZJ11 genotype viruses were responsible for the majority of human infections in wave V. A gene constellation presented in ZJ11 genotype viruses that we suggest is associated with increased transmission among poultry or from poultry to humans. One of the gene constellation changes, PB2-A588V, had been proven to enhance the pathogenicity of H7N9, H10N8, and H9N2 viruses in mice (Xiao et al., 2016). However, one single mutation was not sufficient to cause the largest outbreak in wave V. 

    The rapidly increased number of human infections in wave V would be expected to be associated with a combination of substitutions. Thus, vigilance and further studies of other gene constellation markers are urgently needed to investigate potential links with increased infectivity and transmissibility of the H7N9 viruses.

    In summary, our study indicates that influenza A (H7N9) viruses underwent a period of rapid adaptation via dynamic reassortment and then entered a relatively stable stage of the evolutionary process.
    Our findings reveal the emergence of a gene constellation that may have been associated with the largest outbreak of wave V. Other uncertainty could also contribute to the increased number of cases in wave V, including the unknown environmental, behavioral, changes in social factors or the poultry trade, etc. 

    While further follow-up on the gene constellation is required, dominant genotype viruses containing the gene constellation found here and the repeated emergence of H7N9 variants may lead to an increased pandemic risk. Field investigations on H7N9 viruses are needed for close monitoring of changes in these viruses. The implementation of effective control measures is also of paramount importance to reduce the opportunity for a pandemic to arise.

    (Continue . . . .)

    While a reduction in the volatility of H7N9's evolution would seem to be a good thing - this stabilization could also mean the virus has optimized itself into a reasonably  robust genotype, and now only needs to accrue some more mammalian adaptations to become a genuine pandemic threat. 
    Another wild card to consider is last summer's introduction of an H5+H7 AI vaccine in China, and their national campaign to inoculate the nation's poultry.
    While we've seen a dramatic drop in poultry outbreaks and human infections this winter, as we’ve discussed previously (see  MPR: Poultry AI Vaccines Are Not A `Cure-all’ & The HPAI Poultry Vaccine Dilemma), poultry AI vaccines can have some serious down sides.
    They often suppress bird flu, but they don't always eliminate it. 
    As avian viruses evolve, poultry vaccines tend to become increasingly less effective; often only masking the symptoms of infection (see Egypt: A Paltry Poultry Vaccine).
    Poor vaccine matches can then allow AI viruses to spread silently among flocks, to continue to reassort and evolve, and potentially lead to the emergence new subtypes of avian flu. 
    A few earlier blogs on that include:
    Virology: Selection Of Antigenic Variants Of An H5N1 HPAI Virus In Vaccinated Chickens
    Subclinical Highly Pathogenic Avian Influenza Virus Infection among Vaccinated Chickens, China).

    Study: Recombinant H5N2 Avian Influenza Virus Strains In Vaccinated Chickens

    EID Journal: Subclinical HPAI In Vaccinated Poultry – China
    The bottom line is, despite the welcome drop in H7N9 this winter, there are too many variables in play to even begin to guess where this virus goes from here.  Or what replaces it if it somehow miraculously fades away.

    Stay tuned.