#17,657
Although avian HPAI H5 viruses - primarily because of their recent surge and ability to produce severe illness in humans - are currently at the top of our pandemic concern list, over the past 130 years only H1, H2, and H3 viruses have sparked influenza pandemics (see Are Influenza Pandemic Viruses Members Of An Exclusive Club?).
While that doesn't preclude H5, H7, H10, or H9 viruses from adapting well enough to launch the next global health crisis, it does suggest we shouldn't ignore the plethora of H1, H2, and H3 viruses that circulate in birds, swine, and humans around the world.
Just over 16 months ago China reported the first known human infections with H3N8 - affecting two small children (one severely) - living roughly 400 miles apart. Of note - 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 next year we followed numerous reports on these two initial 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)
While these are the only 3 known human infections with H3N8, we've been following its evolution in birds, dogs, horses, and marine mammals for quite some time.
- H3N8 remains a plausible cause of a global influenza pandemic that spread out of Russia in 1889-1900 (although 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.
- 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 June, in Characterization of an Emergent Chicken H3N8 Influenza Virus in Southern China: a Potential Threat to Public Health, researchers reported:
Our experimental studies showed that these H3N8 viruses were transmissible in ferrets, and serological data suggest that the human population lacks effective immunological protection against it. With its wide geographical distribution and continuing evolution in chickens, other spillovers to humans can be expected and might lead to more efficient transmission in humans.
Today we've another study, published in the Journal Cell, which finds that an H3N8 virus isolated from the first patient with severe pneumonia (A/Henan/4-10/2022 [HN/4-10]) had acquired a crucial mammalian adaptation (PB2-E627K) enabling it to spread efficiently between ferrets.
While most of the Cell report is behind a paywall, I found a synopsis published today on the Chinese Academy of Sciences website, which I've translated below:
The Institute of Microbiology and others discovered the airborne transmission mechanism of human infection H3N8 avian influenza virus among ferrets
2023-09-05 Source: Institute of Microbiology
On September 4, Gao Fu's research team at the Institute of Microbiology, Chinese Academy of Sciences and Liu Jinhua's team at China Agricultural University revealed that the human-originated H3N8 avian influenza virus had acquired the ability to spread through the air among ferrets. Related research results were published online on Cell under the title Airborne transmission of human-isolated avian H3N8 influenza virus between ferrets . This work explores the pathogenicity and transmission characteristics of H3N8 avian influenza virus, and provides important clues for us to better understand and respond to possible outbreaks.
Since its first appearance in 2021, the H3N8 virus has continued to show high detection rates in live poultry markets. This continuous evolution and mutation increases the risk of "spillover" infection of the virus to humans.
The team used the human respiratory organoid model to explore the ability of the H3N8 virus to infect humans. The results showed that H3N8 virus could effectively infect and replicate in human normal bronchial epithelial cells (NHBE) and alveolar epithelial cells (Calu-3), and the infection ability of human-derived virus was significantly stronger than that of chicken-derived virus. The results of mammalian model infection experiments showed that compared with chicken isolates, human-derived H3N8 virus strains showed higher toxicity in mice and ferrets, and could even cause severe pneumonia and viral encephalitis.
The ferret transmission model is currently considered the most appropriate animal model to assess whether influenza virus can be transmitted from person to person. Studies have shown that human-origin H3N8 avian influenza viruses can efficiently infect and replicate in ferrets, and that these viruses are more transmissible than chicken isolates. A human-origin H3N8 avian influenza virus (A/Henan/4-10/2022 [HN/4-10]) can spread among ferrets through direct contact or respiratory droplet transmission. This suggests that the virus has adapted to airborne transmission among mammals.
In contrast, chicken isolates cannot be transmitted between ferrets by direct contact or through the air. Further, the study found that the H3N8 virus strain HN/4-10 isolated from patients with severe pneumonia has a key mutation of airborne transmission adaptation, PB2-E627K, and its HA gradually accumulates the G228S mutation during the transmission process, making it dual-infected. body binding ability. Increased polymerase activity and altered receptor binding properties are the molecular mechanisms by which the virus acquires airborne capability. Nevertheless, the HA membrane fusion pH of human and avian H3N8 (pH5.7-5.8) is higher than that of H1N1 seasonal influenza HA (pH 5.2), indicating that its HA is unstable under acidic conditions, which limits its airborne efficiency.
In addition, the antigenic cross-reactivity between the circulating H3N8 avian influenza virus and human influenza vaccine strains is low. No cross-reactive antibodies to the H3N8 virus were observed in individuals who had been vaccinated against the human H3N2 virus vaccine. This suggests that such viruses may pose a potential challenge to human health.
Airborne transmission of human-isolated avian H3N8 influenza virus between ferrets
Honglei Sun, Han Li, Qi Tong, Kin-Chow Chang, George F. Gao , Jinhua Liu
Published: September 04, 2023 DOI:https://doi.org/10.1016/j.cell.2023.08.011
Highlights
- Human-derived H3N8 viruses replicated efficiently in human respiratory epithelial cells
- Human-derived H3N8 viruses caused severe pathology in mice and ferrets
- One human H3N8 isolate acquired efficient respiratory droplet transmission in ferrets
- The PB2-E627K mutation is critical for H3N8 virus airborne transmission in ferrets
Our track record in predicting the next pandemic remains abysmal, and while H5N1 is currently garnering the most headlines, H3N8 (or EA H1N1 `G4', or any of several dozen other avian or swine flu viruses) could easily beat it to the punch.
What does seem certain is that the diversity and geographic spread of novel flu viruses continues to increase around the world, which makes additional reassortment events - and spillovers - increasingly likely.
While it could take years, nature will eventually come up with a better flu virus. And when that happens, we'd better be ready for it.
