Monday, December 10, 2018

China MOA: ASF Outbreaks In Shaanxi & Guizhou Provinces


In the last week of October, China's southern Guizhou province reported their first 4 outbreaks of African Swine Fever - but in the 6 weeks since, we've heard no new reports.
Today China's MOA reports a new outbreak in Guizhou, along with another outbreak in Shaanxi Province, which reported their first outbreak only a week ago.
Based on OIE reports, ASF reports from China appear to be lagging anywhere from a few days to a couple of weeks after an outbreak is detected, and we've really no good idea of how effective reporting and surveillance - particularly from the more remote areas - really are.

This report from China's MOA:

The detection of African swine fever in the Shenmu City of Shaanxi Province and the Baiyun District of Guiyang City, Guizhou Province

Date: 2018-12-10 11:26 Author: Source: Ministry of Agriculture and Rural Press Office

The Information Office of the Ministry of Agriculture and Rural Affairs was released on December 10, and the African swine fever epidemic was detected in Shenmu City, Yulin City, Shaanxi Province and Baiyun District, Guiyang City, Guizhou Province.

At 18:00 on December 9, the Ministry of Agriculture and Rural Affairs received a report from the China Animal Disease Prevention and Control Center and was diagnosed by the China Center for Animal Health and Epidemiology (National Center for Animal Disease Research).
A farmer in Shenmu City, Yulin City, Shaanxi Province, Guizhou Province A farmer in the Baiyun District of Guiyang City in the province has detected the African swine fever epidemic.
  • Up to now, there are 33 pigs in the farms of Shenmu City, with 19 diseases and 19 deaths.
  • There are 26 live pigs in the Baiyun District, with 5 heads and 5 deaths.
Immediately after the outbreak, the Ministry of Agriculture and Rural Affairs sent a steering group to the local area. The local government has started the emergency response mechanism as required, and adopted measures such as blockade, culling, harmless treatment, disinfection, etc., to treat all the sick and culled pigs harmlessly. At the same time, all pigs and their products are prohibited from being transferred out of the blockade, and pigs are prohibited from being transported into the blockade. At present, the above measures have been implemented.

While ASF does not pose a direct threat to human health, it can be devastating to pork producers, and China is both the largest consumer and producer of pork in the world. 
The continued uncontrolled spread of the virus could seriously disrupt China's economy, exports, and  food security in an already stressed region of the world.
Although ASF has never been reported in North America - given the recent spread of the virus to China, and the return of CSF (Classical Swine Fever) to Japan - the potential exists for their importation from China, Europe, or Africa.

The USDA has released a new African Swine Fever Factsheet that discusses their preparations for a possible introduction of the virus into this country.

Keeping ASF Out

Because of the concern over ASF, USDA recently reviewed and further strengthened its longstanding stringent protections against the spread of the disease.These include:
  • Collaborating with states, industry and producers to ensure everyone follows on-farm biosecurity and best practices (including for garbage feeding in states where that is allowed);
  • Restricting imports of pork and pork products from affected countries; and
  • Working with CBP staff at ports of entry to increase passenger and baggage screening for prohibited products from affected countries.

WHO EMRO: Influenza Activity In The Middle East - November 2018


While we tend to think of the Northern and Southern Hemisphere flu seasons as singular, monolithic events - in truth, we often see large regional differences in the timing and dominant flu strains each flu season.
Last year, during the United State's record setting H3N2-centric flu season, Asia was battling primarily influenza B, while much of Europe and the Middle East were hit by a combination of H1N1 and Influenza B.
Last January, in Eurosurveillance: Changes In Timing Of Influenza Epidemics - WHO European Region 1996-2016, we explored a study that found Western European countries have seen a discernible shift towards later flu season peaks, while the opposite was true in Eastern Europe and Russia.
Although H1N1 appears poised to be the dominant strain across the Northern Hemisphere winter, we monitor all regions for any signs of outliers or unusual activity. 
WHO EMRO has published the following summary of influenza activity reported during the month of November in the Eastern Mediterranean region, which builds on last months report, and shows a continued uptick in (primarily) Influenza A/H1N1 activity.

Epidemic and pandemic-prone diseases
Influenza monthly update, November 2018
In the WHO Eastern Mediterranean Region, influenza activity continues to increase in the month of November in many countries reporting data to FluNet and EMFLU namely, Afghanistan, Bahrain, Egypt, Iran (Islamic Republic of), Iraq, Jordan, Lebanon, Morocco, occupied Palestinian territory, Oman, Qatar, Saudi Arabia, Sudan, Syrian Arab Republic and Tunisia.

Influenza activity by subtype

• In November 2018, no new cases of human influenza A(H5N1) were reported in Egypt.

• In the northern Africa influenza transmission zone, A(H3) virus was detected predominantly in Egypt, while Morocco reported no activity.

• In the western Asia influenza transmission zone, Oman, Qatar and Saudi Arabia reported co-circulation of all seasonal influenza viruses, while in Bahrain influenza A(H1N1)pdm09 and A(H3) virus were detected. Jordan, occupied Palestinian territory and Syrian Arab Republic reported circulation of sporadic cases of the influenza A(H1N1)pdm09, while Iraq and Lebanon reported no activity.

• In southern Asia transmission zone, Iran (Islamic Republic of) reported circulation of all seasonal influenza viruses, while Afghanistan reported no activity.

Circulating influenza viruses by subtype

• During November 2018, national influenza centres and influenza laboratories in the Region tested a total of 10728 specimens for influenza viruses of which 3194 tested positive (30%).

• The average percentage of positivity rates is 30%, with highest positivity rate recorded in Bahrain and Qatar.

• Of the viruses tested; 2659 (83%) were influenza A viruses, including 1235 (39%) influenza A(H1N1)pdm09 virus and 142 (4%) were influenza A(H3) virus. Influenza B (Lineage Not determined) virus accounted for 533 (17%) (Figure 3).

While we're seeing increased flu activity in South Korea, Canada, and the Middle East - influenza activity remains relatively low in Europe, Hong Kong, the United States, and Russia. 

A happy circumstance that is unlikely to persist much longer. 

Japan: Gifu Prefecture Reports A 4th Farm Outbreak Of Classical Swine Fever

Gifu Prefecture - Credit Wikipedia


Japan has been dealing with multiple outbreaks Classical Swine Fever - for the first time in 26 years -  since last September (see Japan: MAFF Confirms Classical Swine Fever Outbreak). So far, the disease has only been detected in Gifu Prefecture.

Five days after reporting their 3rd farm outbreak of Classical Swine Fever (at a Gifu Livestock Research Institute), Japan's MAFF is reporting a 4th occurrence  - this time a wild boar breeding facility in Gifu - about 12 miles distance from last week's outbreak.
While often clinically indistinguishable from African Swine Fever (ASF), Classical Swine Fever is caused by a different virus (genus Pestivirus, family Flaviviridae). Unlike with ASF, there is a vaccine for Classical Swine Fever.
Both diseases - while posing no human health threat - are highly contagious among pigs, and can be economically devastating to pork producers.   Today's statement from Japan's MAFF follows:
Confirmation of suspected slaughter of swine fever in Gifu prefecture (4th case - feeding)

December 10, Heisei 30
Ministry of Agriculture

Today, at the animal feeding facility in Seki, Gifu Prefecture, mock animals of domestic animal infectious disease, swine fever were confirmed.

We will do everything about the epidemic prevention measures of the disease.
We ask for your cooperation so that we can refrain from scrutinizing at the work site, as it may cause the spread of this disease, and it may invade personal privacy.

1. Outline of the occurrence facility

Location: Gifu Prefecture Seki (Facilities about 12 km away from the third generation facility)
Feeding situation: wild boar (22 head)
2. Background
(1) On December 9th, Gifu Prefecture took an on-site inspection for the facility in response to a notification that anagaining exhibits an abnormality.
(2) On 10th December, we conducted a disease assessment at the Central Livestock Health and Sanitation Center in Gifu Prefecture concerning this fun and confirmed that it is a suspected swine of swine fever. (4th example)
3. Future response
Based on "Specific Animal Infectious Disease Control Guidelines on Hog ​​Cholera", we will take all possible measures against the following epidemic measures.
(1) We will promptly and appropriately implement the necessary epidemic measures such as the killing and burning of the breeding of the facility at the facility, the setting of the movement restricted area, etc.
(2) We will promptly check the occurrence status of the farm within the movement restricted area.
(3) In order to prevent the spread of infection, we will strengthen disinfection around the outbreak facility and establish a disinfection point on the main road.
(4) We will send a national epidemiological survey team to investigate the infection route etc.
(5) We will strive to provide accurate information to producers, consumers, distributors, etc. while trying to fully collaborate with related ministries and agencies.
(6) Ensuring guidance on compliance with feeding hygiene management standards such as disinfection of farms and prevention of intrusion of wild animals to farms
(7) We investigate and investigate all possible possibilities for investigation of infection route etc. and prevention of spread.
4. Other
(1) Farmed breeds are subject to epidemic measures based on the provisions of the Livestock Infectious Disease Prevention Law.
(2) Hog cholera is a disease of pigs and wild boars, and it does not infect people.
(3) Thank you for your cooperation so that we can refrain from spreading the scene at the work site, as it may cause the spread of this disease, and may violate the privacy of individuals.
(4) Since we will make efforts to provide information promptly and accurately, cooperation is requested so that stakeholders and consumers, such as producers, will not be confused by unfounded rumors.
Even as Japan attempts to contain this outbreak of CSF, they are keeping a wary eye on the spread of African Swine Fever in nearby China, and are taking steps to try to prevent its import (see Japan MAFF: ASF Virus Detected In Luggage At Hokkaido Airport )

As far as the history of CSF eradication in Japan is concerned, in 2007 MAFF produced the following summary:

The eradication of classical swine fever in Japan
Classical swine fever, which is an acute infectious disease in pigs, existed throughout Japan but the outbreaks had decreased sharply with the improvement of the disease control and herd management technologies and the implementation of a live vaccine from 1969. No outbreak has been observed since 1992.

Under such circumstances, eradication program has been introduced step by step since 1996 to establish control measures without vaccination and thus to fully eradicate this disease with the cooperation of prefecture and local governments, producers and all other related organizations.

As a part of the measures, we have completely banned vaccinations since April 1st, 2006, and watched the disease. One year had passed since then and we had reported the achievement of the eradication program to the Office International des Epizooties (OIE). According to the requirement of the OIE cod
e, Japan had become a classical swine fever free country on April 1st, 2007.

Last September the OIE withdrew/suspended Japan's hard won status as being free of the disease (see OIE Statement), leaving only 34 countries with that coveted designation.

Sunday, December 09, 2018

Study: BMI & Hospitalization For Influenza & Other Resp. Infections


Early on in the 2009 H1N1 pandemic (see H1N1 Morbidity And Previously Existing Conditions) we saw reports of unusual numbers of obese influenza patients - a previously unrecognized risk group - populating intensive care facilities around the world.  
Obesity - and particularly morbid obesity - was increasingly mentioned as a possible risk factor, along with asthma, diabetes, and immune disorders.   
That notion took a hit a few months later, when - during an ACIP meeting held at the end of July, 2009 - evidence was presented that showed that the incidence of hospitalizations among those listed as obese by their BMI was practically the same as their prevalence in society.
Roughly 34% of Americans are obese, and roughly 38% of those hospitalized met that criteria.  While 6% are morbidly obese (BMI > 40), they only made up 7% of the hospitalized cases.
Two months later, in Study: Half Of ICU H1N1 Patients Without Underlying Conditions, it became apparent that while pre-existing risk factors were important, they were not the sole reason behind flu victims ending up in intensive care.

A few months later, Eurosurveillance Journal  published a Study: H1N1 Hospitalization Profiles, reported similar results:
  • The most common risk factor in admission to intensive care was chronic respiratory disease followed by chronic neurological disease, asthma and severe obesity.
  • 51% of hospitalized cases and 42% of ICU cases were not in a recognized risk group.
But the idea that BMI played an important role in influenza morbidity and mortality was far from dead.

In 2011 (see Extreme Obesity: A Novel Risk Factor For A Novel Flu), the IDSA’s journal Clinical Infectious Diseases published a study called  A Novel Risk Factor for a Novel Virus: Obesity and 2009 Pandemic Influenza A (H1N1), that found:
Extreme obesity associated with higher risk of death for 2009 H1N1 patients
[EMBARGOED FOR JAN. 5, 2011] For those infected with the 2009 pandemic influenza A (H1N1) virus, extreme obesity was a powerful risk factor for death, according to an analysis of a public health surveillance database.
In a study to be published in the February 1, 2011, issue of Clinical Infectious Diseases, researchers associated extreme obesity with a nearly three-fold increased odds of death from 2009 H1N1 influenza. Half of Californians greater than 20 years of age hospitalized with 2009 H1N1 were obese.
Despite a lack of consensus, for the past few years the CDC has cited `people with extreme obesity (i.e., body-mass index is equal to or greater than 40)' on their list of High Risk groups for severe influenza.
The controversy continues, however. 
Last February, in Study: Obesity & Influenza-Like-Illness (ILI) Severity, we saw a 2018 paper appearing in the International Journal of Obesity, that found quite the opposite; a four year (2010-2014) study of ER visits for influenza-like-illness (ILI), found that obesity was not linked to a greater risk of hospitalization.
Epidemiology and population health
Is weight associated with severity of acute respiratory illness?
Elizabeth E. Halvorson,Timothy R. Peters, Joseph A. Skelton, Cynthia Suerken, Beverly M. Snively & Katherine A. Poehling Conclusion

Overweight and obesity were not associated with increased risk of hospitalization during winter respiratory seasons in children or adults.

Alas, science isn’t always consistent, neat, or tidy.  Results can vary widely depending upon the design, size, location, and timing of a study (see When Studies Collide (Revisited)), and conflicting findings are more common than one might suspect. 
This is the primary reason why I try to present as much relevant context as possible in these blogs, since it is far too easy to cherry pick studies to back up a particular point. 
Entering the fray this week - this time published in Influenza & Other Respiratory Viruses - is a study that finds both low and high BMI as risk factors for hospitalization with flu or other respiratory infection.

The entire open access study is available online at the link below.  I've only included some pertinent excerpts.

Underweight, overweight, and obesity as independent risk factors for hospitalization in adults and children from influenza and other respiratory viruses

Joe‐Ann S. Moser, Arturo Galindo‐Fraga, Ana A. Ortiz‐Hernández, Wenjuan Gu, Sally Hunsberger, Juan‐Francisco Galán‐Herrera, María Lourdes Guerrero,… See all authors

First published: 04 December 2018

The relationship between obesity and risk of complications described during the 2009 influenza pandemic is poorly defined for seasonal influenza and other viral causes of influenza‐like illness (ILI).

An observational cohort of hospitalized and outpatient participants with ILI was conducted in six hospitals in Mexico. Nasopharyngeal swabs were tested for influenza and other common respiratory pathogens.

A total of 4778 participants were enrolled in this study and had complete data. A total of 2053 (43.0%) had severe ILI. Seven hundred and seventy‐eight (16.3%) were positive for influenza, 2636 (55.2%) were positive for other viral respiratory pathogens, and 1364 (28.5%) had no respiratory virus isolated. Adults with influenza were more likely to be hospitalized if they were underweight (OR: 5.20), obese (OR: 3.18), or morbidly obese (OR: 18.40) compared to normal‐weight adults.
Obese adults with H1N1 had a sixfold increase in odds of hospitalization over H3N2 and B (obese OR: 8.96 vs 1.35, morbidly obese OR: 35.13 vs 5.58, respectively) compared to normal‐weight adults.
In adults with coronavirus, metapneumovirus, parainfluenza, and rhinovirus, participants that were underweight (OR: 4.07) and morbidly obese (OR: 2.78) were more likely to be hospitalized as compared to normal‐weight adults. All‐cause influenza‐like illness had a similar but less pronounced association between underweight or morbidly obesity and hospitalization.

There is an increased risk of being hospitalized in adult participants that are underweight or morbidly obese, regardless of their viral pathogen status. Having influenza, however, significantly increases the odds of hospitalization in those who are underweight or morbidly obese.

As always, it is important to look at the study's design, and its limitations.  The authors caution:
One significant limitation to our study is that it enrolled participants that sought medical care for an influenza‐like illness. It is not a population‐based study that can accurately assess the risk that body mass confers for infection. Additionally, the study cannot differentiate within the NIRV group between those with true infections (but not detected on the multiplex platform), or those with non‐infectious etiologies of the respiratory symptoms.

In conclusion, our findings suggest that adults, who are underweight or morbidly obese, even if they do not have chronic conditions that increase the risk of influenza‐related complications, may be at increased risk of developing severe disease due to seasonal influenza infection as well as other respiratory viral infections. Clinicians should keep a patient's body mass index in mind when evaluating risk and deciding on a course of treatment.
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Despite being personally `gravitationally challenged', I'd never argue that maintaining a `normal BMI' doesn't provide appreciable health benefits.
It also seems likely that those benefits would extend to a lower risk of hospitalization and/or death from influenza and other respiratory infections.
So, despite a string of conflicting studies, I'm assuming my extra weight - along with my age - increase my risk factors, and I'll act accordingly; I get the flu shot every year, use hand sanitizer like I own stock in the company, and will take aggressive steps (i.e. antivirals) should my first two lines of defense fail me.

Saturday, December 08, 2018

Frontiers Cell. & Infect. Microb.: Pandemic Potential Of H7N9 In Humans
Credit FAO - Dec 5th Update


Although you'd scarcely know it by its recent lack of activity (see FAO chart above), China's complex array of avian H7N9 viruses continue to occupy the top spot of our pandemic flu watch list.  
Not only due to its high mortality rate (30%+ among hospitalized patients) and the record number of cases during wave 5, but because of its incredible (and growing) diversity.   
During wave 5 (2016/17) a new LPAI Yangtze River Delta lineage emerged as dominant - dethroning the original Pearl River Delta lineage - and an HPAI variant surfaced in Guangdong Province and began to spread (see MMWR: Increase in Human Infections with Avian Influenza A(H7N9).

We've seen literally scores of H7N9 genotypes created by the prolific reassortment between H7N9, H9N2, H6Nx and H7Nx viruses (see below). 

Add in the emergence of mammalian adapted amino acid substitutions (eg. PB2 E627K and HA G186V and Q226L/I ) and we end up with dozens of viruses with varying  degree of pandemic potential, all on their own evolutionary paths. 

Some past studies & blogs on these changes include:
Arch. Virology: Co-circulation Of Multiple Genotypes of H7N9 in Eastern China, 2016-2017

Cell Reports: A Dominant Gene Constellation Emerged For H7N9 In Wave 5
J. Virol.: Spread & Evolution of HPAI & LPAI H7N9 During 5th Wave - China
PLoS Pathogens: Three Mutations Switch H7N9 To Human-type Receptor Specificity
The dramatic and welcomed drop in H7N9 activity over the past 18 months has been credited to a last-ditch and highly successful nationwide H5+H7 poultry vaccination program over the summer of 2017, which has - at least temporarily - suppressed the virus in poultry. 
The concern is that the effectiveness of this vaccination program may diminish over time as the various strains of H7N9 evolves away from the vaccine.  We've already noted a bit of an uptick in H5N6 activity (also covered by the vaccine) over the past 4 months.
As noted yesterday, in EID Journal: Two H9N2 Studies Of Note, and previously in Vet. Sci.: The Multifaceted Zoonotic Risk of H9N2 Avian Influenza and in PNAS: Evolution Of H9N2 And It’s Effect On The Genesis Of H7N9 (among others), the continued evolution of and genetic diversity of H7N9 has been heavily intertwined with the evolution of LPAI H9N2. 
As H9N2 gains new mammalian adaptations (see Genomic Characteristics Of 2 A(H9N2) Virus Isolates From Humans In Anhui Province - 2015) it has shared them (via reassortment) with multiple strains of the H7N9 virus.  
All of which brings us to a new, open-access study, appearing in Frontiers of Cellular & Infection Microbiology, that looks at H7N9's remarkable evolution - due in large part to H9N2's genetic contributions - towards a more `humanized' virus. 
While the virus isn't quite ready for prime time, the authors warn that a failure to continue to control the virus in poultry could potentially lead to a human pandemic down the road.
Due to its length, I've only posted a few excerpts (bolding mine), so follow the link to read the report in its entirety.

Potential Pandemic of H7N9 Avian Influenza A Virus in Human 

Zhiqing Pu1, Dan Xiang2, Xiaobing Li1, Tingting Luo1, Xuejuan Shen1, Robert W. Murphy3, Ming Liao1,4 and Yongyi Shen1,4* 
1College of Veterinary Medicine, South China Agricultural University, Guangzhou, China
2Joint Influenza Research Centre (SUMC/HKU), Shantou University Medical College, Shantou, China
3Centre for Biodiversity and Conservation Biology, Royal Ontario Museum, Toronto, ON, Canada
4Key Laboratory of Zoonosis Prevention and Control of Guangdong Province, Guangzhou, China

Since 2013, the H7N9 avian influenza A virus (AIV) has caused human infections and to the extent of now surpassing H5N1. This raises an alarm about the potential of H7N9 to become a pandemic problem

Our compilation of the amino acid changes required for AIVs to cross the species-barrier discovers 58 that have very high proportions in both the human- and avian-isolated H7N9 viruses. These changes correspond with sporadic human infections that continue to occur in regions of avian infections. 

Among the six internal viral genes, amino acid changes do not differ significantly between H9N2 and H7N9, except for V100A in PA, and K526R, D627K, and D701N in PB2. H9N2 AIVs provide internal genes to H7N9. Most of the amino acid changes in H7N9 appear to come directly from H9N2. Seventeen amino acid substitutions appear to have fixed quickly by the 5th wave. Among these, six amino acid sites in HA1 are receptor binding sites, and PB2-A588V was shown to promote the adaptation of AIVs to mammals. 

The accelerated fixation of mutations may promote the adaptation of H7N9 to human, but need further functional evidence. Although H7N9 AIVs still cannot efficiently transmit between humans, they have the genetic makeup associated with human infections. These viruses must be controlled in poultry to remove the threat of it becoming a human pandemic event.



Recent research on gain-of-function has identified genetic changes required for AIVs to cross the species-barrier and adapt to replication and transmission in mammals. Our compilation of these genetic changes (Supplementary Table 1) and surveillance data serve to predict that H7N9 poses a great threat to humans.

AIVs must adapt to their new host (humans) to infect successfully. To initiate infection, hemagglutinin (HA), which is the major surface glycoprotein of influenza viruses, binds to host cell surface complex glycans via a terminal sialic acid. The switch of the preference from avian- to human-type sialic acid receptors (α-2,6 sialo-saccharides) is a key element necessary for AIVs to cause human pandemics (Matrosovich et al., 2000).
Amino acid changes S155N, T156A, G182V, S205Y, and Q222L (H5 numbering) in HA increase virus-binding to human α-2,6 sialo-saccharides (Suzuki et al., 1989; Yamada et al., 2006; Wang et al., 2010; Herfst et al., 2012; Imai et al., 2012). These changes occur in very high proportions in both human- and avian-isolated H7N9 viruses (Figure 1). This suggests that H7N9 viruses have an ability to bind to human-type receptors because receptor-binding specificity assays have shown that the human-isolated H7N9 viruses can bind to both avian-type (α2,3-linked sialic acid) and human-type (α2,6-linked sialic acid) receptors (Zhou et al., 2013). 


The 5th wave of human infection saw a rapid growth in the number of cases (Wang et al., 2017). Have H7N9 AIVs experienced an accelerated fixation of beneficial adaptations to the environmental of human? In addition to the known amino acid mutations associated with changes in host tropism or increased pathogenicity in mammals, our analyses detect a trend for the fixation of 17 amino acid changes in the 5th wave (Figure 3). Among these, six amino acids sites substituted in HA1 locate at receptor binding region (Figure 4). Amino acid change PB2-A588V which showed much higher proportion in human-isolated than avian-isolated H7N9 in the 5th wave, was proved to promote the adaptation of H7N9 to mammals (Xiao et al., 2016). This might explain the increased number of human infection cases in the 5th wave. The function of other sites needs further experimental study.

H7N9 AIVs have continuously evolved since 2013. Although they have triggered five epidemics of human infections, they still do not have efficient human-human transmission, and only fix to avian. Our analyses identify a series of amino acid changes that associate with cross-species transmission from avian to human in high proportions in both human- and avian-isolated H7N9 AIVs. Avian-isolated H7N9 viruses have the genetic makeup associated with human infections and this suggests that if we cannot control this subtype in poultry, an impending human pandemic is still on the doorstep.
Author Contributions
YS conceived, designed, and supervised the study. ZP, DX, XL, TL, and XS collected and analyzed the data. YS and RM wrote the drafts of the manuscript. ML commented on and revised drafts of the manuscript. All authors read and approved the final report.
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One of the reasons we spend so much time looking at H9N2 (and other, lesser avian flu threats like H6N1, and H4N6, etc.) is that influenza viruses are a promiscuous lot, and none of them circulate in a vacuum. 
They interact readily, share genetic information, and continually  reinvent themselves into new genotypes - and occasionally - new subtypes. 
And while China's introduction of a new H5+H7 vaccine in poultry has been a great success, these avian flu viruses persist in unvaccinated ducks and other wild birds, and are capable of staging a comeback at any time.

Friday, December 07, 2018

EID Journal: Two H9N2 Studies Of Note


Despite relatively few documented human infections (see FluTrackers List) - and having a reputation for causing generally less severe human illness than its avian H5 & H7 cousins - LPAI H9N2 is still regarded as having some pandemic potential because:
So, while H9N2 may not be at the top of our pandemic threats list, it is regarded as having at least some pandemic potential (see CDC IRAT SCORE), and several candidate vaccines have been developed over the years.
The January 2019 (Volume 25, Number 1) edition of the CDC's EID Journal has two studies on this intriguing long-shot in the pandemic sweepstakes, both of which suggest that H9N2 continues to evolve away from current (pre-pandemic and poultry) vaccines and is potentially on a path towards better adaptation to human hosts.
Due to their lengths, I've only included some snippets from each. Follow the links to read them in their entirety (bolding of text mine)

Volume 25, Number 1—January 2019 


Avian Influenza A(H9N2) Virus in Poultry Worker, Pakistan, 2015
Muzaffar Ali, Tahir Yaqub, Nadia Mukhtar, Muhammad Imran, Aamir Ghafoor, Muhammad Furqan Shahid, Muhammad Naeem, Munir Iqbal, Gavin J.D. Smith , and Yvonne C.F. Su 


Avian influenza A(H9N2) virus isolated from a poultry worker in Pakistan in 2015 was closely related to viruses detected in poultry farms. Observed mutations in the hemagglutinin related to receptor-binding affinity and antigenicity could affect cross-reactivity with prepandemic H9N2 vaccine strains.

Our detection and isolation of H9N2 virus from a poultry worker in Pakistan highlights the potential for cross-species transmission of H9 viruses in the country. The World Health Organization considers avian H9N2 viruses a consistent pandemic threat because they are widespread in poultry and cause sporadic infection in humans.
H9N2 viruses have been central to the generation of other viruses of pandemic concern and have contributed the internal genes to both H5 and H7 viruses in China (15). Although the subtype is relatively well studied in China, investigation in other countries is generally limited in scope. Within Pakistan, H9N2 viruses in chickens have circulated endemically for at least a decade, yet systematic surveillance is lacking.

Our results show continued diversification of H9N2 viruses in Pakistan; viruses isolated during 2015–2016 formed a distinct clade to earlier viruses from Afghanistan, Iran, and Pakistan isolated during 2008–2014. Dating analysis further estimated the tMRCA of the 2015–2016 Pakistan viruses as late 2010, indicating at least 5 years of unsampled virus diversity that circulated in poultry. We also observed mutations in HA related to changes in receptor-binding affinity and antigenicity that could affect cross-reactivity with the World Health Organization–recommended prepandemic H9N2 vaccine strains. None of the 3 G1 candidate vaccine viruses are closely related to strains from Pakistan.

Phylogenetic relationships indicate H9N2 virus transmission across South Asia and the Middle East, where the persistence and circulation of AIV are poorly understood. Increased surveillance in wild bird populations, poultry farms and markets, and occupationally exposed workers are needed in these regions to identify the emergence of antigenic variants and to maintain up-to-date H9 vaccine candidates.
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The second study is considerably more complex, and finds a growing array of H9N2 genotypes in Pakistan, some with improved binding avidity to both avian and human receptor cells, and infers an increased zoonotic risk.

Volume 25, Number 1—January 2019
Association of Increased Receptor-Binding Avidity of Influenza A(H9N2) Viruses with Escape from Antibody-Based Immunity and Enhanced Zoonotic Potential
Joshua E. Sealy, Tahir Yaqub, Thomas P. Peacock1, Pengxiang Chang, Burcu Ermetal, Anabel Clements, Jean-Remy Sadeyen, Arslan Mehboob2, Holly Shelton, Juliet E. Bryant, Rod S. Daniels, John W. McCauley, Munir Iqbal , and Jean-Remy Royal Veterinary CollegeLondonUKSadeyen


We characterized 55 influenza A(H9N2) viruses isolated in Pakistan during 2014–2016 and found that the hemagglutinin gene is of the G1 lineage and that internal genes have differentiated into a variety of novel genotypes.
Some isolates had up to 4-fold reduction in hemagglutination inhibition titers compared with older viruses. Viruses with hemagglutinin A180T/V substitutions conveyed this antigenic diversity and also caused up to 3,500-fold greater binding to avian-like and >20-fold greater binding to human-like sialic acid receptor analogs.
This enhanced binding avidity led to reduced virus replication in primary and continuous cell culture.
We confirmed that altered receptor-binding avidity of H9N2 viruses, including enhanced binding to human-like receptors, results in antigenic variation in avian influenza viruses.
Consequently, current vaccine formulations might not induce adequate protective immunity in poultry, and emergence of isolates with marked avidity for human-like receptors increases the zoonotic risk.
In conclusion, we have assessed the pathogenic and zoonotic risks posed by enzootic influenza A(H9N2) viruses in Pakistan by characterizing field isolates. Because of circulation of viruses with potential to escape vaccine-induced immunity, regular updating of vaccines to match circulating strains and protect poultry is needed in Pakistan. Furthermore, isolation of viruses from the G1 lineage with enhanced human receptor-binding avidity warrants continued surveillance for poultry and persons working with or near poultry.
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Even when we are looking at other novel influenza subtypes, highly promiscuous H9N2 can often be found playing a supporting role in the background, usually by lending genes via reassortment.  A few examples include:
Reassortment After Co-infection Of Chickens With H4N6 and H9N2 influenza Viruses

A Canine H3N2 Virus With PA Gene From Avian H9N2 - Korea

PNAS: Reassortment Of H1N1 And H9N2 Avian viruses.
PNAS: Reassortment Potential Of Avian H9N2

Whether on its own, or as a viral co-conspirator, the continued evolution of H9N2 remains a pandemic threat worth keeping our eye on.