Thursday, March 16, 2023

Emerging Microbes & Inf.: Prevalence, Evolution, Replication and Transmission of H3N8 Avian Influenza Viruses

Two H3N8 cases in Humans April-May 2022, 400 miles apart 


While most of our attention is currently focused on H5N1, it isn't the only avian flu virus on our radar. In the spring of 2022 China reported the first two known human infections with H3N8 - affecting two small children (one severely) - living roughly 400 miles apart. 

Notably in the first (severe) case, the family dog and cat both tested positive for H3N8, and a full-length HA sequencing revealed the HA to be identical to the boy's. 

Since H3N8 doesn't tend to seriously impact poultry, and until 10 months ago was not considered much of a zoonotic threat, it has received relatively little attention. However:
  • H3N8 remains a plausible cause of a global influenza pandemic that spread out of Russia in 1889-1900 (some researchers now suspect a coronavirus instead).   
  • about 60 years ago H3N8 jumped unexpectedly to horses, supplanting  the old equine H7N7 and is now the only equine-specific influenza circulating the globe
  • in 2004 the equine H3N8 virus mutated enough to jump to canines, and began to spread among greyhounds in Florida (see EID Journal article Influenza A Virus (H3N8) in Dogs with Respiratory Disease, Florida).
  • in 2011 avian H3N8 was found in marine mammals (harbor seals), and 2012’s mBio: A Mammalian Adapted H3N8 In Seals, provided evidence that this virus had recently adapted to bind to alpha 2,6 receptor cells, the type found in the human upper respiratory tract. 
  • And lastly, in 2015's J.Virol.: Experimental Infectivity Of H3N8 In Swine, we saw a study that found that avian (but not canine or equine) H3N8 could easily infect pigs.
Last summer we followed a number of reports on the two cases in China, and somewhat ominously, its detection in Hong Kong's poultry roughly 1000 km away from the first human case. 

IJID: A Review Of The Pandemic Potential Of Avian H3N8

EID Journal: Novel Zoonotic Avian Influenza Virus A(H3N8) Virus in Chicken, Hong Kong, China

Preprint: Human infection With a Novel Reassortment Avian Influenza A H3N8 Virus: An Epidemiological Investigation Study

FAO/OIE/WHO Joint Rapid Risk Assessment Human infection with Influenza A(H3N8)

Our knowledge of how the virus is evolving and spreading in the wild is fairly limited.  This week, however, we get a detailed look at the evolution of H3N8 in Eastern China from 2017 to 2021.  

This is a lengthy, and very detailed report, that provides a lot of insight on the prevalence of other avian flu viruses in Eastern China as well (see graphic below).

I've only posted the Abstract, and some excerpts from the discussion.  Follow the link to read the open-access report in its entirety.  I'll have a brief postscript after the break. 

Prevalence, evolution, replication and transmission of H3N8 avian influenza viruses isolated from migratory birds in eastern China from 2017 to 2021
Article: 2184178 | Received 11 Sep 2022, Accepted 20 Feb 2023,
Published online:13 Mar 2023
The continued evolution and emergence of novel influenza viruses in wild and domestic animals poses an increasing public health risk. Two human cases of H3N8 avian influenza virus infection in China in 2022 have caused public concern regarding the risk of transmission between birds and humans. However, the prevalence of H3N8 avian influenza viruses in their natural reservoirs and their biological characteristics are largely unknown.
To elucidate the potential threat of H3N8 viruses, we analyzed five years of surveillance data obtained from an important wetland region in eastern China and evaluated the evolutionary and biological characteristics of 21 H3N8 viruses isolated from 15,899 migratory bird samples between 2017 and 2021.
Genetic and phylogenetic analyses showed that the H3N8 viruses circulating in migratory birds and ducks have evolved into different branches and have undergone complicated reassortment with viruses in waterfowl. The 21 viruses belonged to 12 genotypes, and some strains induced body weight loss and pneumonia in mice. All the tested H3N8 viruses preferentially bind to avian-type receptors, although they have acquired the ability to bind human-type receptors.
Infection studies in ducks, chickens and pigeons demonstrated that the currently circulating H3N8 viruses in migratory birds have a high possibility of infecting domestic waterfowl and a low possibility of infecting chickens and pigeons.
Our findings imply that circulating H3N8 viruses in migratory birds continue to evolve and pose a high infection risk in domestic ducks. These results further emphasize the importance of avian influenza surveillance at the wild bird and poultry interface.



In recent decades, emerging novel animal influenza viruses and other zoonoses have posed major challenges to the global commercial poultry industry and public health [Citation5Citation43Citation44]. However, H3N8 avian influenza viruses have been ignored due to their low prevalence in chickens and the low risk to public health, although it has become one of the predominant strains in migratory waterfowl and domestic ducks.

Recent human infections with H3N8 viruses in China have promoted interest in and concern about the evolution and cross-species transmission risk of these viruses. In this study, we performed a detailed analysis of the global distribution of H3N8 viruses in different hosts according to deposited sequence data and our surveillance results in eastern China between 2017 and 2021. The summarized results indicated that migratory ducks are the primary natural reservoirs of H3N8 viruses. Here, a total of 162 viruses belonging to 28 subtypes were identified and isolated from 15,899 wild bird samples, which suggested that wild birds are natural reservoirs of different subtypes of avian influenza viruses and play a key role in the maintenance and evolution of such viruses.

H3N8 viruses have been detected in at least 64 kinds of wild birds and have evolved into several phylogenetic lineages, whereas only a few strains were detected in chickens in recent years. The H3N8 viruses analyzed in this study shared similar sequence identities and clustered into the same lineages with some strains isolated from Europe, North America and Africa, suggesting that H3N8 viruses can be transmitted globally with the migration of their natural reservoirs. 

We also found that these H3N8 viruses have undergone complicated reassortment with circulating H5N3, H7N4, H9N2, H10N4 and H10N8-like viruses isolated from Yellow River Delta wetlands [Citation21Citation33Citation34]. Of note, all the H3N8 viruses detected from chicken and humans in China in 2022 share HA and NA surface genes similar to those of duck- and wild bird-origin strains but bear an internal gene constellation from chicken H9N2 viruses [Citation29Citation31]. 

The predominantly prevalent H9N2 viruses have been proven to be ideal internal gene donors for the emerged reassortants, including H7N9, H10N3, and H10N8 viruses [Citation8, Citation13, Citation45, Citation46]. The complicated epidemiology and ecology of avian influenza viruses at the interface of waterfowl and terrestrial birds could have facilitated the emergence of novel H3N8 reassortants in chickens. Therefore, monitoring AIVs in wild and domestic waterfowl and controlling H9N2 viruses in domestic birds will contribute to early warning and reduction in the occurrence of natural avian influenza reassortants.


In summary, we described the distribution of H3N8 viruses and characterized the genetic and biological properties of H3N8 viruses isolated from wild birds in a wetland in eastern China. Our findings emphasize that active surveillance in migratory birds and domestic ducks will contribute to early detection of the emergence and evolution of AIVs in waterfowl and potential threats to the commercial poultry industry and human health.

         (Continue . . . )

While it is somewhat reassuring that we've not heard of any additional human H3N8 infections since last May, that must be tempered by the fact that only cases severe enough to hospitalized, and lucky enough to be properly tested, are apt to be picked up by surveillance. 

And even if a case is detected, China tends to hold virus spillover information close to the vest, often taking weeks or even months before publicly announcing cases (see here, here, here, and here). 

While the number of H3N8 spillover events pale when compared to H5N1, H5N6, or H7N9, it is an important reminder that nature's laboratory is open 24/7, and it has a wide range of experiments going all of the time.