#18,583
In late 2015, in PNAS: The Pandemic Potential Of Eurasian Avian-like H1N1 (EAH1N1) Swine Influenza by Chen Hualan (et. al) - director of China's National Avian Influenza Reference Laboratory - described a new, rising swine flu threat in China.
EAH1N1 is a reassortant virus, with elements from H1N1 avian influenza, human H1N1pdm, and swine-origin influenza viruses. Despite sharing the same subtype designation as a currently circulating seasonal strain, it was genetically different enough to pose a genuine public health threat.
Here, we found that, after long-term evolution in pigs, the EAH1N1 SIVs have obtained the traits to cause a human influenza pandemic.
"Based on scientific analysis and comprehensive comparison of the main animal flu viruses: H1N1, H3N2, H5N1, H7N9, H9N2 and EAH1N1, we found the EAH1N1 is the one most likely to cause next human flu pandemic. We should attach great importance to the EAH1N1."
So far its hasn't sparked that feared pandemic. It remains, however, high on just about everyone's watch list, including our own CDC, which lists it at the top of their IRAT list.
In 2020, another study appeared in PNAS (see Eurasian Avian-like H1N1 Swine Influenza Virus With Pandemic Potential In China) that reported a greater than 10% seroprevalence for the EAH1N1 virus among swine workers tested, suggesting that EAH1N1 is gaining human infectivity.
This sparked a series of high profile risk assessments being published by the CDC, ECDC, WHO (and others).
The CDC's Responds to the PNAS EA H1N1 `G4' Swine Flu Study
ECDC Risk Assessment: Eurasian avian-like A(H1N1) swine influenza viruses
WHO Novel Flu Summary & Risk Assessment - July 2020
FAO/OIE/WHO Tripartite Statement on the Pandemic Risk of Swine Influenza
While it has been largely overshadowed by the H5N1 virus the past couple of years, but it continues to simmer and evolve in Chinese pigs - mostly out of our view - and it remains a genuine concern for Chinese researchers.
Unlike avian flu viruses, which bind preferentially to avian α2,3 receptor cells, these swine H1 viruses are already adapted to mammalian α2,6 receptor cells, removing at least one major barrier to infecting humans (see Are Influenza Pandemic Viruses Members Of An Exclusive Club?)
While we await release of new information on HPAI H5, it is worth remembering that avian flu isn't the only viral threat we face. This update, published today in the Journal Viruses, describes 11 H1 subtype swine influenza viruses (SIVs) - both H1N1 and H1N2 - which bear watching.
This is a lengthy report, and I've only posted some excerpts below. Follow the link to read it in its entirety. I'll have a postscript after the break.
Isolation and Characterization of H1 Subtype Swine Influenza Viruses Recently Circulating in China
by
Minghao Yan, Tianxin Ma, Xiaona Shi, Qin Chen, Luzhao Li, Bangfeng Xu, Xue Pan, Qiaoyang Teng,
Chunxiu Yuan, Dawei Yan, Zhifei Zhang, Qinfang Liu * and Zejun Li *Viruses 2025, 17(2), 185; https://doi.org/10.3390/v17020185 (registering DOI)
Published: 27 January 2025
Abstract
Pigs serve as a mixing vessel for influenza viruses and can independently promote the emergence of pandemic strains in humans. During our surveillance of pig populations from 2021 to 2023 in China, 11 H1 subtype swine influenza viruses (SIVs) were isolated. All viruses were reassortants, possessing internal genes of identical origins (PB2, PB1, PA, NP, M: pdm09/H1N1 origin, NS: North American triple reassortant origin).
The H1N1 isolates were all the dominant G4 EA H1N1 viruses in China. Two H1N2 isolates carried early human pdm09/H1N1 HA genes, suggesting a possible pig-to-human transmission route.
Mutations that dictate host range specificity were identified in all isolates, a phenomenon which may enhance the affinity to human receptors. These H1 subtype viruses effectively replicated both in vivo and in vitro without prior adaptation and exhibited different pathogenicity and growth characteristics. Some of the H1 viruses were even found to cause lethal infections in mice.
Taken together, our study indicates that the H1 subtype SIVs recently circulating in China pose a potential threat to human health and emphasizes the importance of continuing to closely monitor their evolution and spread.
(SNIP)
Discussion
Currently, pigs worldwide have been found to harbor a range of influenza A viruses, including avian/human, human/swine, and human/avian/swine strains [50]. China stands out as having the most diverse ecosystem of SIVs. Since the emergence of the 2009 pandemic H1N1 viruses (pdm/09), there has been frequent reassortment with local SIVs, some of which acquired the ability to infect humans [51,52].
Our recent surveillance study conducted from 2021 to 2023 identified 11 H1 subtype strains, including nine H1N1 (81.82%) and two H1N2 (18.18%) subtypes. The H1N1 SIV remains the predominant circulating subtype in China.
(SNIP)
Species barriers prevent the influenza virus from infecting one host from another. The influenza virus must overcome this host range barrier to effectively infect and spread [54]. Normally, human influenza viruses prefer to bind to α-2,6 receptors, while avian influenza viruses have a greater preference for α-2,3 receptors. Therefore, it is generally accepted that an HA receptor-binding preference for a-2,6-linked sialylated glycans is the initial key step for a novel influenza virus causing a pandemic [55].
In our study, all H1 subtype viruses exhibited the E190D and G225D/E mutations. These mutations confer the ability to bind to human-type receptors with high affinity [36,37], indicating that the virus may have the potential to infect humans.
In recent years, concerns regarding low-pathogenic influenza have grown, as it may be able to replicate efficiently in vitro and in vivo and have the ability to infect humans. Our study found that all H1 subtype viruses were able to replicate effectively in MDCK cells without the need for prior adaptation. The combination of 271A, 590S, and 591R is known to be crucial for the efficient replication and adaptation of SIVs in cultured cells [42]. This genetic polymorphism was confirmed in our isolates, which provided the conditions for the virus to replicate effectively in the cells.
The pathogenicity of the viruses in mice was assessed, and the results indicate that the circulating SIV strains carrying avian-sourced HA genes typically exhibit higher virulence. Mice infected with four H1N1 subtype strains (BJ/F3/22, JS/F2/21, JS/02/21, and SH/2/22) experienced rapid weight loss, severe illness, and 100% mortality. Infections with other H1 subtype viruses resulted in moderate weight loss and partial mortality in mice. The R251K substitution in PB2 increases viral replication and pathogenicity of EA H1N1 SIVs [44].
These low-virulence mutations may have been the reason for the lower mortality rates observed in mice infected with certain EA H1N1 viruses. The two H1N2 viruses, JS/235/23 (H1N2) and ZJ/284/23 (H1N2), demonstrated similar replication capabilities in vivo to their genetic ancestors, yet there was a significant difference in their pathogenicity.
Compared to highly pathogenic viruses, the covert transmission characteristics of these viruses with low virulence and high replication levels may increase their risk of adaptation and spread in humans, making them more difficult to detect and control in a timely manner. Interestingly, none of the viruses caused systemic infections in mice, and the viruses effectively replicated only in the lungs and nasal turbinates of the mice. Significant histopathological damage was observed in lungs with high viral loads, marked by widespread epithelial cell necrosis and recruitment of inflammatory cells.
In summary, our findings suggest that the H1 subtype swine influenza viruses which have been recently circulating in China demonstrate efficient replication capabilities in mammalian hosts. It is challenging to predict whether, through additional adaptation and reassortment, they might evolve into viruses capable of efficient transmission among human populations in the future. Given the potential public health threat posed by these circulating SIVs, it is essential to conduct continuous surveillance and genetic characterization to inform vaccine strain selection and update strategies.
While global surveillance is limited - and in some places non-existent - where research is being done we see a lot of potential for swine flu viruses to spillover into humans. A few recent blogs include:
Nature Comms: Zoonotic Transmission of Novel Influenza A Variant Viruses detected in Brazil during 2020 to 2023
The CDC's IRAT (Influenza Risk Assessment Tool) lists 3 North American swine viruses as having at least some pandemic potential (2 added in 2019).
H1N2 variant [A/California/62/2018] Jul 2019 5.8 5.7 ModerateH3N2 variant [A/Ohio/13/2017] Jul 2019 6.6 5.8 Moderate
H3N2 variant [A/Indiana/08/2011] Dec 2012 6.0 4.5 Moderate
Since 2010 we've seen more than 500 scattered reports of human infection with swine variant influenza viruses (H1N1v, H1N2v & H3N2v) in the United States, often associated with agricultural exhibits at county and state fairs.
With this much viral diversity - whether it takes the long way through birds, or finds a short-cut in pigs - another pandemic is inevitable.
It is just a matter of time.
