Swine-flu viruses (H1, H2, and H3) - while generally less severe in humans - are thought to have less far to `leap' to adapt to human hosts than avian H5 and H7 subtypes (see Are Influenza Pandemic Viruses Members Of An Exclusive Club?)
But in truth, `Swine-origin' viruses are generally an amalgamation of Swine, Human, and Avian flu strains (see above graphic) - since pigs are susceptible to all three types of infections and are often co-infected with two or more strains - which can produce reassortant viruses.
Most of these reassortant viruses are evolutionary failures, unable to compete with existing viruses, but every once in a great while a more biologically `fit' virus emerges. The 2009 H1N1 pandemic virus was one such triple-reassortant virus (see Triple-Reassortant Swine Influenza A (H1) in Humans in the United States, 2005–2009).
While surveillance and reporting on swine-origin viruses is sporadic and woefully inadequate around the globe we continue to get hints - particularly out of China - that when it comes to the next pandemic, time and viral evolution are not on our side.
In late 2015 Chinese and Japanese researchers made headlines when they isolated and characterized a number avian H1N1 virus variants circulating in Chinese pigs that they believed had considerable pandemic potential (see PNAS: The Pandemic Potential Of Eurasian Avian-like H1N1 (EAH1N1) Swine Influenza).The lead author was Chen Hualan - director of China's National Avian Influenza Reference Laboratory - and In the `Significance' section of their report the authors boiled it down to this:
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."
Although information coming out of China is often limited, we've been following the evolution of these EA H1N1 viruses with great interest. Two years ago, 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.
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 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
As recently as last week (see EID Journal: Potential Threats to Human Health from EA H1N1 Viruses and Reassortants) we've looked at the looming pandemic potential of these viruses.
But nothing happens in a vacuum, and at the same time as we've watched the evolution of EA H1N1 viruses in pigs, we've seen evolutionary strides in a number of avian viruses circulating in China, including a ubiquitous - but relatively mild - LPAI H9N2.
Although H9N2 occasionally jumps to humans (probably more than we know), it generally produces mild illness.
Three years ago, in EID Journal: Two H9N2 Studies Of Note, we looked at two reports which suggest that H9N2 continues to evolve away from current (pre-pandemic and poultry) vaccines and is potentially on a path towards better adaptation to human hosts.
Two years ago, the CDC added a new lineage (H9N2 Y280 lineage [A/Anhui-Lujiang/13/2018]) to their short list of novel flu viruses with at least some pandemic potential, although it would not be expected to have anywhere near the impact as an H5 or H7 avian flu.
But H9N2's biggest threat likely comes from its ability to easily reassort with other (avian, human, swine, canine, etc.) influenza viruses, which is believed can increase their ability to infect mammals, including humans.
While not a pandemic powerhouse on its own, H9N2's internal genes have shown up as the backbone of some of the most concerning avian viruses of the past 2 decades (PNAS: Evolution Of H9N2 And It’s Effect On The Genesis Of H7N9).
Natural Reassortment of Eurasian Avian-like Swine H1N1 and Avian H9N2 Influenza Viruses in Pigs, China
Wanying Sun1, Samuel S.M. Cheng1, Kristy N.T. Lam, Tsz C. Kwan, Ricky W.K. Wong, Leo H.K. Lau, Gigi Y.Z. Liu, Leo L.H. Luk, John K.C. Li, Haogao Gu, Malik Peiris, and Leo L.M. Poon
Abstract
Several zoonotic influenza A viruses detected in humans contain genes derived from avian H9N2 subtypes. We uncovered a Eurasian avian-like H1N1 swine influenza virus with polymerase basic 1 and matrix gene segments derived from the H9N2 subtype, suggesting that H9N2 viruses are infecting pigs and reassorting with swine influenza viruses in China.
Swine are regarded as a mixing vessel for influenza A viruses (IAVs) (1). Avian, swine, and human IAVs can co-infect pigs and generate novel reassortants of zoonotic or pandemic potential. The emergence of pandemic H1N1 IAV (pH1N1), containing viral segments from avian, swine, and human viruses, highlighted the key role of pigs in contributing to IAV reassortment and evolution (2). Research in China also showed evidence of avian H5, H7, H9, and H10 influenza infections in pigs (3). Avian IAVs linked to human infection in this region contained internal genes derived from avian H9N2 viruses, indicating that the internal genes of the H9N2 virus might aid zoonotic transmission (4). We report detection of a swine IAV with polymerase basic (PB) 1 and matrix (M) gene segments of avian H9N2 origin.
(SNIP)
The swine H1N1 IAV that we isolated in September 2021, A/swine/HK/NS419/2021, a reassortant between multiple swine influenza lineages (Figure; Appendix Figures 1–6). The PB1 and M gene segments of this virus are of avian H9N2 virus subtype. This virus contains PB2, polymerase acidic, and NA gene segments derived from the pH1N1 lineage. Its HA and NA gene segments are of Eurasian avian-like H1N1 lineage, and its nonstructural gene segment is of a triple reassortant lineage. We further purified the isolated virus by using plaque assays to exclude the possibility of a mixed infection. We confirmed that all plaque-purified viral clones had an identical genotype.
The A/swine/HK/NS419/2021 isolate featured a PB1 gene segment of SH/F/98‐like lineage and an M gene segment of G1-like H9N2 lineage (Figure). Similar PB1 and M sequences have been detected in zoonotic viruses in humans (Figure), PB1 in H10N8 and M in H7N9, but we did not find mutations known for mammalian host adaptation in these 2 segments. The encoded proteins of the PB1 and M gene segments that we isolated featured amino acid sequences rarely observed in mammalian and avian IAVs, including H9 (PB1, 97K, 156N, 397V, 535V, 688I, and 704T; M1, 31I and 46V; and M2, 25S). We could not determine whether these were random or adaptive mutations. The PB1 segment of avian H9N2 is highly compatible to other polymerase genes from mammalian IAVs (8). Such results suggest the need for further characterization of these mutations, particularly those in the PB1 gene.
A recent report in China discussed multiple Eurasian avian-like H1N1 swine influenza reassortants with internal genes derived from pH1N1 and triple reassortant lineages (9). One group of these reassortants (genotype 4) displayed a genotype similar to A/swine/HK/NS419/2021, the only exception being that the virus’s PB1 and M gene segments were of pH1N1 lineage.
That report showed that genotype 4 Eurasian avian-like swine IAVs can bind to human sialic acid receptors (i.e., α2,3), enabling efficient virus replication in human airway epithelial cells, and achieve efficient aerosol transmission in ferrets (9). Serologic surveillance further showed that 10% of studied swine workers were positive for the genotype 4 reassortant (9). Our own sequence analyses suggest that some of the genotype 4 viruses and our Eurasian avian-like H1N1 viruses might share a common ancestry (e.g., A/swine/Shandong/1207/2016; Appendix Figures 1–6). Further risk assessment on the pandemic potential of this genotype and its reassortants is needed (10).
In summary, many zoonotic IAVs in humans have genes derived from H9N2 subtypes. Our results suggest that avian H9N2 IAVs are infecting swine and reassorting with swine IAVs, which indicates the need for continued monitoring of swine IAVs in both China and outlying regions.
Miss Sun is a postgraduate student at The University of Hong Kong, Hong Kong, China. Her primary research interest is bioinformatics.
Until fairly recently, novel influenza viruses were thought to be far-and-away the greatest pandemic threat facing humanity, but with the recent emergence of SARS-CoV in 2002, MERS-CoV in 2012, and SARS-CoV-2 in 2019, it is now apparent that influenza has some serious competitors in the pandemic arena.
Still, if you want to go with the best odds, influenza has a long and distinguished track record (1918, 1957, 1968, 2009, etc.).
The generation of a pandemic-capable strain of influenza in a pig, or a bird, or even a human is admittedly a rare event. But with so many viral contenders, replicating and mutating in billions of hosts around the world each year, eventually one of them is bound to get lucky.
Ten months ago, in PNAS Research: Intensity and Frequency of Extreme Novel Epidemics, we looked at a paper that suggested that the probability of novel disease outbreaks will likely grow three-fold in the next few decades.
Good reasons why we need to be preparing for the next pandemic now - because while our current COVID crisis will eventually recede - it is far from the last global health crisis we will face.
