While H5N1 has been at the forefront of this blog since its inception more than 17 years ago, it is far from the only novel flu virus on our radar. H5 and H7 avian flu viruses are of understandable concern due to their high mortality rate in humans, but as we've discussed often, H1, H2, and H3 viruses have been responsible for all human influenza pandemics going back at least 130 years.
The oldest pandemic we can be certain of was the 1918 `Spanish Flu’, which killed anywhere between 40 million and 100 million people, and was caused by an H1N1 virus, followed by H2N2 in 1957, H3N2 in 1968, and H1N1 in 2009.
While none of this means that an H5 or an H7 virus couldn’t adapt to humans (or hasn’t in the past), it does make one take notice anytime we find a novel H1, H2, or H3 influenza virus emerging in the wild.
Despite all of the attention given to H5N1, since 2021 the CDC has ranked a Chinese Swine-variant EA H1N1 `G4' as having the highest pandemic potential of any flu virus on their list (see EID Journal: Zoonotic Threat of G4 Genotype Eurasian Avian-Like Swine Influenza A(H1N1) Viruses, China, 2020).
The emergence of a zoonotic H3N8 virus almost exactly a year ago in China - first infecting 2 children 400 km apart in Henan and Hunan Provinces in April and May of 2022 - and more recently a fatal infection of a 56 year old woman in Guangdong Province, have put yet another H3 virus on our watch list.
While these are the first 3 confirmed 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.
- And just last month, in Emerging Microbes & Inf.: Prevalence, Evolution, Replication and Transmission of H3N8 Avian Influenza Viruses, we looked at the rapid spread of H3N8 (and other) avian flu viruses in Eastern China
They describe a recent reassortment event where H3N8 acquired the internal genes from LPAI H9N2, which has previously contributed genes to H5N1 and H7N9 (see PNAS: Evolution Of H9N2 And It’s Effect On The Genesis Of H7N9).
And lastly, they discuss the growing pandemic potential of H3N8. Due to it length, I've only posted some excerpts, so follow the link to read the report in its entirety. I'll have a brief postscript after the break.
Volume 29, Number 6—June 2023
Evolution of Avian Influenza Virus (H3) with Spillover into Humans, China
Jiaying Yang1, Ye Zhang1, Lei Yang1, Xiyan Li, Hong Bo, Jia Liu, Min Tan, Wenfei Zhu, Yuelong Shu , and Dayan Wang
The continuous evolution of avian influenza viruses (AIVs) of subtype H3 in China and the emergence of human infection with AIV subtype H3N8 highlight their threat to public health. Through surveillance in poultry-associated environments during 2009–2022, we isolated and sequenced 188 H3 AIVs across China. Performing large-scale sequence analysis with publicly available data, we identified 4 sublineages of H3 AIVs established in domestic ducks in China via multiple introductions from wild birds from Eurasia.Using full-genome analysis, we identified 126 distinct genotypes, of which the H3N2 G23 genotype predominated recently. H3N8 G25 viruses, which spilled over from birds to humans, might have been generated by reassortment between H3N2 G23, wild bird H3N8, and poultry H9N2 before February 2021.Mammal-adapted and drug-resistance substitutions occasionally occurred in H3 AIVs. Ongoing surveillance for H3 AIVs and risk assessment are imperative for potential pandemic preparedness.
Avian influenza viruses (AIVs) of subtype H3 are highly prevalent among waterfowl globally, causing mild or no apparent signs of illness in birds (1–5). H3 AIV has shown the potential for cross-species transmission and was the origin of other animal influenza viruses, which caused epidemics in horses, dogs, seals, and pigs (6–9). In 1968, H3 AIV contributed its hemagglutinin (HA) gene to the human influenza (H3N2) pandemic viruses, and it is still unknown whether an intermediate host was involved (10).
In April 2022, the first human infection with AIV (H3N8) was reported; the case was in a 4-year-old boy whose family reared chickens and silky fowls in Henan Province, China (11). After infection, the patient exhibited recurrent fever and severe pneumonia. In May 2022, a second case was identified in 5-year-old boy with mild influenza symptoms, who had visited the live poultry market (LPM) in Hunan Province, China (12). Those cases raised concern over whether H3N8 AIVs will cause a major public health threat (13).
In China, H3 AIVs have been dynamically circulating in poultry and wild birds across multiple regions (14). H3 combinations with multiple neuraminidase (NA) subtypes (N1–N8) were reported, among which H3N2 and H3N8 predominated (14–16). Phylogenetically, those viruses belonged to the Eurasian lineage, which is widespread in wild birds across Eurasia (3,14,17,18). Reassortment events often occurred at LPMs (16,19–22). During 2009–2022, we conducted country-level AIV surveillance in poultry-associated environments and performed a large-scale genetic analysis to provide a comprehensive picture of the evolution of H3 AIVs in China.
H3 AIVs have existed for a long time, but to our knowledge, no human infection had been reported until 2022. After reassortment with 6 internal genes of H9N2, current H3N8 AIVs seem to have the advantage of infecting humans (42). Ongoing adaptation in mammals after continuous human infections may underlie emergence of pandemic strains.
The H3N8 G25 viruses had acquired human-adapted mutations after infecting humans (Appendix Figure 14), such as 228G/S in the HA gene and E627K/V in the PB2 gene, which were also present in 1968 H3N2 pandemic strains (43). This finding indicates the pandemic potential of the newly emerged H3N8 AIVs.
For risk assessment of the pandemic potential, human population immunity to a newly emerged animal virus is a critical parameter. HA inhibition assays among poultry workers (12) and the general population (44) showed seropositivity for the human seasonal H3N2 virus but very low seroprevalence against the newly emerged H3N8 virus. Those results suggest little antigenic cross-reactivity between human seasonal H3N2 virus and the current H3N8 virus and that the human population has little or no preexisting immunity to emerging H3N8 viruses. No drug-resistance mutation to NA inhibitors was observed in H3N8 G25 viruses; therefore, vaccine and drug stockpiles are needed for the potential pandemic preparation.
H3 AIVs have been isolated from asymptomatic ducks (45). Recent studies indicate that the newly emerged H3N8 AIVs are pathogenic to chickens (12,46). Our samples were collected exclusively from avian-linked environments (including LPMs, poultry farms, backyards, and slaughterhouses), according to surveillance guidelines. Thus, we were unable to link the isolated H3 AIVs to specific host information. Poultry sampling might provide helpful information about H3 AIV activity in China. The species of poultry in the LPMs might be confounding factors for the spatiotemporal differences. In this study, the sampling sites were geographically dispersed, and the data were collected from a small number of LPMs. Considering the large number of LPMs in China, especially in rural areas, representativeness of the data might be biased.
AIV surveillance has greatly improved since HPAIV H5N1 infected humans in Hong Kong in 1997 (47). However, gaps still exist, and new virus is unpredictable. The AIVs circulating and evolving in poultry might have a preferential ability to transmit to humans directly across the poultry–human interface (48). The H3N8 G25 viruses, with increased human receptor binding and low population immunity (12), had raised concern for pandemic potential. Dual receptor-binding profiles (49,50) and mutations associated with enhanced virus replication and pathogenicity in mammals were also found in many H3 AIVs. Surveillance and research of H3 AIVs, as well as the drugs and vaccine capacity, should be strengthened for pandemic preparedness.
Dr. J. Yang studies in the Chinese National Influenza Center, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention, and the School of Public Health (Shenzhen), Shenzhen campus of Sun Yat-sen University. Her research interests include epidemiology and evolutionary analysis of influenza viruses.
Our track record in predicting the next pandemic has been 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 appears to be increasing rapidly around the world, all of which makes additional reassortment events - and spillovers - increasingly likely.
While it may take a while, nature will eventually come up with a better flu virus. And when that happens, we'd better be ready for it.