#17,638
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 (more 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.
Over the second half of 2022 we followed a number of reports on these two cases in China, and somewhat ominously, the detection of H3N8 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)
With China, no news isn't always good news.
Beyond the possibility that H3N8 cases are being under-reported, H3N8 has been on our radar for years because:
- 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.
All of which brings us to a new research article published this past week in Transboundary and Emerging Diseases (which was submitted before the 3rd case in Guangdong Province) that describes the pathogenicity and transmissibility of an H3N8 virus isolated from poultry in Guangdong Province.
This is a lengthy and fairly technical review. I've only posted some excerpts, so those who want a deeper dive will want to follow the link to read it in its entirety. I'll have a postscript after the break.
A Novel Triple Reassortment H3N8 Avian Influenza Virus: Characteristics, Pathogenicity, and Transmissibility
Sheng Chen,1,2,3,4,5Shuqun Shen,1,6Yutao Teng,1,2Ruoying Li,1,2Xinheng Zhang,1,2,3,5Jiajia Liu,1,2Zhiqiang Wu,1,2Zhuanqiang Yan,4Feng Chen,1,2,3,4 and Qingmei Xie1,2,3,4,5
Academic Editor: E. Mateu
Received 20 Oct 2022 Revised 02 Apr 2023 Accepted 18 May 2023 Published 30 Jun 2023
Abstract
An increasing number of new subtypes of avian influenza viruses (AIVs) are reported to be infecting humans, including H3N2, H5N1, H7N9, H10N8, and the recently emerged H3N8 virus in China in 2022. However, the genetic and biological properties of the currently prevalent H3N8 AIVs are not yet fully understood.This study reports the isolation of a novel triple reassortment H3N8 virus (GD-H3N8) from chicken flocks in Guangdong province, China, in 2022. The GD-H3N8 virus contains the Eurasian avian duck-origin H3 gene, the North American avian N8 gene, and dynamic internal genes of the H9N2 virus, and shows high homology with human H3N8 strains. The GD-H3N8 isolate has multiple mammalian adaptive mutations associated with receptor binding and virulence.Growth kinetics assays demonstrate that the GD-H3N8 isolate is capable of efficient replication in avian, mammalian, and human cells in vitro. In vivo, the GD-H3N8 isolate can replicate efficiently in mice without preadaptation, in addition to establishing systemic infection and transmission by direct contact in chickens. These findings underscore the need for continued surveillance of H3N8 viruses to identify circulating strains that may potentially threaten human health.
(SNIP)
Genetic Characterization of Avian Origin GD-H3N8 Virus
All six internal genes of the GD-H3N8 isolate belong to the Eurasian lineage and found to be most closely related to H9N2 virus from birds cocirculating recently in southern and eastern China (Supplementary 4). Furthermore, the high homology observed between the six internal genes of the GD-H3N8 isolate and those of human H3N8 strains suggests that this novel virus has the potential to bind to human sialic acid receptors, which are critical for viral entry and replication in human respiratory cells (Supplementary 5). This raises concerns about the possibility of the GD-H3N8 virus acquiring the ability to efficiently transmit between humans and cause a potential pandemic. Further studies are needed to assess the pathogenicity and transmissibility of this novel reassortant virus in animal models and to monitor its spread and evolution in the natural reservoir.
After conducting a thorough genetic analysis, our findings suggest that the newly discovered GD-H3N8 isolate, which originates from avian species, has undergone multiple reassortment events. Specifically, it appears to have undergone intercontinental reassortment while circulating in the natural reservoir of the virus (Figure 3). Overall, our results indicate that this novel virus is a triple reassortment isolate, containing a Eurasian avian duck-origin H3 gene, a North American avian N8 gene, and dynamic internal genes derived from the H9N2 virus. This genetic makeup gives it a high degree of homology with human H3N8 strains, highlighting its potential to cause illness in humans.
(SNIP)
Notably, mutations associated with mammalian adaptation in PB2, such as G590S, E627K, and D701N, were not observed in the isolate.
However, two other mutations, I292V and A588V, were identified in the PB2 protein, which also represent mammalian adaptive markers [37, 38]. Furthermore, a series of key amino acid mutations (I66M, I109V, and I133V, collectively referred to as MVV) were observed in the PB2 protein, which increase the replication efficiency in both avian and mammalian hosts and are seen as the first step for AIV to acquire mammalian pathogenicity [36].
Regarding the PA protein, several adaptive mutations associated with overcoming species barriers and increased virulence were detected, such as L295P, N383D, V476A, A515T, and V630E, while V100A and E382D mutations were not observed [27–30, 47].
Notably, PB1 protein possesses almost all identified mammalian adaptive mutations, including R207K, 269S, I368V, H436Y, L473V, 563R, 622G, and M677T [29, 31–35]. These substitutions are associated with increased polymerase activity, virulence, and decreased antiviral response. Taken together, these findings suggest that the polymerase of the novel triple reassortment GD-H3N8 isolate may have the ability to replicate and cause pathogenicity in mammals.
To summarize, our study has demonstrated that a novel triple reassortment avian H3N8 influenza virus isolated in Guangdong province has the potential for zoonotic transmission. This virus showed high homology with human H3N8 strains and had multiple adaptive mutations associated with receptor binding and virulence.
Our in vitro experiments revealed that the virus was capable of efficient replication in avian, mammalian, and human cells. In vivo experiments showed that the virus could establish systemic infection and transmission by contact in chickens, and efficiently replicate in mice without preadaptation. Our findings suggest that continued surveillance of H3N8 viruses, especially the newly emerged strains, is essential to identify circulating viruses that may pose a potential threat to human health.
Sheng Chen, Shuqun Shen, Yutao Teng, Ruoying Li, Xinheng Zhang, Jiajia Liu, Zhiqiang Wu, Zhuanqiang Yan, Feng Chen, Qingmei Xie, "A Novel Triple Reassortment H3N8 Avian Influenza Virus: Characteristics, Pathogenicity, and Transmissibility", Transboundary and Emerging Diseases, vol. 2023, Article ID 6453969, 14 pages, 2023. https://doi.org/10.1155/2023/6453969
Despite the `radio silence' from Chinese officials, avian H3 viruses have recently garnered a lot of attention by Chinese scientists, who consistently warn of their zoonotic potential. All of the studies listed below have been featured in this blog over the past 90 days.
Characterization of an Emergent Chicken H3N8 Influenza Virus in Southern China: a Potential Threat to Public Health
EID Dispatch: Replication of Novel Zoonotic-Like Influenza A(H3N8) Virus in Ex Vivo Human Bronchus and Lung
China: Emergence of a Novel Reassortant H3N6 Canine Influenza Virus
EID Journal: Evolution of Avian Influenza Virus (H3) with Spillover into Humans, China
Increased Public Health Threat of Avian-origin H3N2 Influenza Virus During Evolution in Dogs (Revisited)
Add in scores of H5N6 cases reported in China over the past couple of years, a smattering of H10 spillovers, and a growing list of (mostly mild) H9N2 infections, and it is safe to say that H5N1 isn't the only avian threat on our radar.
