#18,823
While HPAI H5N1 gets most of the headlines due to its presumed high virulence in humans, it actually ranks #11 on the CDC's IRAT list of most likely zoonotic influenza A viruses to emerge as a pandemic threat.
Above it are 6 avian flu viruses (H7N9, H5N1, H9N2 subtypes), and 4 swine-origin influenza A viruses (H1N1, H1N2, H3N2).EA A(H1N1) `G4' - in Chinese pigs - is ranked #1 with an emergence score of 7.5, nearly 50% greater than the estimated (n=5.1) for the current H5N1 clade 2.3.4.4b threat. It's overall impact score (6.9) is slightly lower than H7N9, but is higher than for all of the remaining viruses on the list.
EA H1N1 `G4' is a reassortant virus, with elements from EA Avian-like viruses, the 2009 H1N1virus, and TR lineage viruses. Despite sharing the same subtype designation as a currently circulating seasonal strain, it is genetically different enough to pose a genuine public health threat.
In the `Significance' section the authors boiled it down to this:The world's attention was first drawn to this emerging swine-origin virus in late 2015, when a group of Chinese scientists (including Hualan Chen) published a paper in PNAS: The Pandemic Potential Of Eurasian Avian-like H1N1 (EAH1N1) Swine Influenza describing its prevalence, genetics, and transmissibility (in ferrets).
Here, we found that, after long-term evolution in pigs, the EAH1N1 SIVs have obtained the traits to cause a human influenza pandemic.
Since then we've followed numerous studies on this emerging virus, including:
EID Journal: Reassortant EAH1N1 Virus Infection In A Child - Hunan China, 2016In 2020, researchers writing in PNAS: Eurasian Avian-like H1N1 Swine Influenza Virus With Pandemic Potential In China, reported > 10% seroprevalence for the EAH1N1 among swine workers tested, suggesting that EAH1N1 was gaining in its ability to jump species.
J. Virology: A Single Amino Acid Change Alters Transmissability Of EAH1N1 In Guinea Pigs
Emerg. Microbes & Infect.: Effect Of D701N Substitution In PB2 Of EAH1N1 Swine Flu Viruses
This report led to a flurry of `risk assessments' by public health agencies on EA H1N1 `G4', including:
The CDC's Responds to the PNAS EA H1N1 `G4' Swine Flu StudyIn early 2021 the CDC ranked a Chinese Swine-variant EA H1N1 `G4' as having the highest pandemic potential of any flu virus on their list, and since then we've seen additional studies that have only exacerbated concerns.
ECDC Risk Assessment: Eurasian avian-like A(H1N1) swine influenza viruses
FAO/OIE/WHO Tripartite Statement on the Pandemic Risk of Swine Influenza
EID Journal: Natural Reassortment of EA H1N1 and Avian H9N2 Influenza Viruses in Pigs, ChinaWhile there are no reports of widespread outbreaks in humans in China, surveillance, testing, and reporting of novel flu viruses remains limited and we often only learn - sometimes only years-after-the-fact (see here, here, and here) - when new discoveries are made.
EID Journal: Potential Threats to Human Health from EA H1N1 Viruses and Reassortants
PNAS: An EA H1N1-Like Swine Flu Virus With Increased Pathogenicity/Transmissibility Due to Mutations In Its PA
Our last in-depth look at this EA H1Nx G4 strain was six months ago, in Viruses: Isolation and Characterization of H1 Subtype Swine Influenza Viruses Recently Circulating in China.
All of which brings us to a new research article, published last week in the Journal of General Virology, by Hong Kong researchers that demonstrates how well this EA H1`G4' Swine influenza A virus has adapted to human physiology.
The authors report that EA H1N1 G4 replicates competently in human bronchial and lung tissue explants, which would allow for both upper and lower respiratory infections.It also binds preferentially to a2,6-linked sialic acid receptors cells, which are abundant in the human upper airway.
They do report a mild cytokine response in human macrophages, which might attenuate the severity in some individual infections, but conversely, could promote faster spread of the virus via mild, moderate, or subclinical infections.
Due to its length, I've only posted the Abstract and a few excerpts. Follow the link to read the report in its entirety. I'll have a bit more after the break.
Research Article
Open Access
Evaluation of pandemic potential of the genotype 4 (G4) swine influenza virus using ex vivo and in vitro cultures of the human respiratory tractJenny C.M. Chan1,2, Rachel H.H. Ching1,2, Hermione H.M. Kock1, Teng Long1,2, John M. Nicholls3, J.S. Malik Peiris1,2, Kenrie P.Y. Hui1,2 and Michael C.W. Chan1,2 View Affiliations
Published: 31 July 2025 https://doi.org/10.1099/jgv.0.002133
ABSTRACT
Recent studies have reported a genotype 4 (G4) reassortant Eurasian avian-like (EA) H1N1 virus in swine, demonstrating a potential pandemic threat in humans.Here, we have compared the tropism, replication competence and pro-inflammatory cytokine and chemokine induction of the two G4 EA H1N1 strains in parallel with 2009 pandemic H1N1 (H1N1/pdm/09) and A/Quail/HK/G1/1997 H9N2 (G1) using ex vivo culture of the human respiratory tract and in vitro culture of human peripheral blood-derived macrophages.
Our results showed that G4 strains could replicate in ex vivo cultures of human lung and bronchus with a similar replication competence to H1N1/pdm/09. The cytokine induction levels of G4 were similar to H1N1/pdm/09 in macrophages.
Taken together, we could extrapolate that the G4 EA H1N1 swine influenza may pose a notable public health threat towards human and should not underestimate this threat.
(SNIP)
Discussion(excerpt)
The ability of the influenza virus to infect the lung is proven to be correlated with the disease severity [44, 45]. It has been previously shown that viruses that infect the alveolar epithelium (lower lung) are less transmissible and are more likely to result in severe viral pneumonia in human, whereas those that replicate better in conducting airway are the opposite [38]. For the two G4 strains, other than replicating productively in ex vivo bronchial explants, we have also revealed their ability to replicate effectively in human lung explants.
The replication competence of the two G4 strains is similar to H1N1/09 pandemic and G1. The trend of generally high viral replication competence in human lung may indicate that the G4 virus can productively replicate in human lung.
A number of human cases caused by EA H1N1 have been reported in Europe and Asia, including the Netherlands, Spain, Italy, Switzerland and China since 2013, indicating an increase in human acquiring EA H1N1 infection. Human cases caused by EA H1N1 have been reported occasionally in Europe and Asia since 2003 [2–6, 46–48].
Fortunately, these cases are still limited to people who are involved in the swine industry. Other than being able to infect human lung and bronchus, population immunity is another common way to determine the pandemic potential of influenza strains. It has been reported that G4 EA H1N1 strains reacted poorly with the currently used H1N1 vaccine by either using ferret’s sera or human serum sample, indicating that the G4 EA H1N1 strains may pose a pandemic risk [42, 49].
(SNIP)
Taken together the effective replication competence of the two G4 strains in both human lung and bronchial explants, we can therefore extrapolate that there is a potential risk of increasing human transmission. The cytokine induction upon infection has demonstrated possibly mild disease severity in human. The two mutations, T588I and 590S/591R, both identified in PB2 of the G4 strains, may favour the adaptation of G4 EA H1N1 strain for human infection and potentially lead to future pandemics.
It is of concern that the G4 EA H1N1 virus may pose a potential public health threat, given they have acquired many of the essential capabilities to be able to infect human conducting and lower airway. Therefore, the risk assessment of G4 in the human respiratory tract remains important. A more physiologically relevant risk assessment platform should apply to validate the data acquired using cell lines and animals (mice and ferrets) to assess the G4 EA H1N1 strains. Routine surveillance and close monitoring of the swine industry may help to prepare us for the noticeable threat.
While the milder cytokine response offers some hope that EA H1N1 G4 might not produce as severe of illness as an H5 or H7 pandemic virus, even a 1%-2% CFR - when combined with a high attack rate - would present a grave threat.
And since these viruses continually evolve, mutate, and reassort, it is always possible that a future iteration could pick up changes - like PB-E627K, HA-H275Y, or HA-D225G - which could increase its impact.
While EA H1N1 G4 is just one of dozens of viral threats simmering in the wild - given the continued warnings from Chinese scientists - we should probably be paying closer attention.
