#17,721
With its rapid geographic expansion and unprecedented spillover into mammals, H5N1 has rightfully captured the world's attention, but it isn't the only zoonotic influenza virus on our radar.
H5N6 has infected more than 60 people in China over the past three years, scores of mostly mild H9N2 infections have been reported in humans, and we've seen several H10N3 cases emerge as well.
But a relative recent entry in the zoonotic sweepstakes is influenza A/H3N8, which infected two children (1 severely, infecting the family dog and cat as well) in China in 2022, and reportedly killed a woman in Guangdong province (1000 km to the south) in March of this year.
H3N8 is of particular interested because:
- H3N8 remains a plausible cause of a global influenza pandemic that spread out of Russia in 1889-1900 (some researchers now suspect a coronavirus instead).
- about 60 years ago H3N8 jumped unexpectedly to horses, supplanting the old equine H7N7 virus, and subsequently jumped from horses to dogs in 2004
- 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.
- And lastly, 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.
Over the past 18 months we've seen a steady stream of cautionary reports (primarily) by Chinese researchers, warning of the zoonotic potential of H3N8. A few recent examples include:
Cell: Airborne Transmission of Human-isolated Avian H3N8 Influenza Virus Between Ferrets
A Novel Triple Reassortment H3N8 Avian Influenza Virus: Characteristics, Pathogenicity, and Transmissibility
EID Dispatch: Replication of Novel Zoonotic-Like Influenza A(H3N8) Virus in Ex Vivo Human Bronchus and Lung
This week the ECDC journal Eurosurveillance has another of these studies, that identifies at least 17 genotypes of H3N8 (G1-G17) circulating in China, but also parses out which ones appear to be best adapted to infecting, and replicating in, humans.
While ostensibly about H3N8, this report is also about the ubiquitous H9N2 virus - an LPAI which is rife in Asian poultry, and is making gains across much of Europe and the Middle East - and which lends its genes (see chart below) in varying degrees to all of these H3N8 genotypes.
While an LPAI on its own, H9N2 is so enmeshed in the growing constellation of emerging flu viruses that I've occasionally called it the Professor Moriarty of the flu world. Often, when new flu strains emerge – if you look deep enough – you’ll find LPAI H9N2 was skulking somewhere in the shadows (see PNAS: Evolution Of H9N2 And It’s Effect On The Genesis Of H7N9).
In May of 2020, 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 gave the same impact as an H5 or H7 avian flu.
While China's national poultry vaccination campaign has nearly eliminated the H7N9 threat, they have been far less successful in controlling H9N2 (see J. Virus Erad.: Ineffective Control Of LPAI H9N2 By Inactivated Poultry Vaccines - China). This 2021 study warned:
The failure of vaccination might be because of inefficient application, low dose, and low vaccination coverage (especially in the household sector).11,12 Moreover, the continuing transmission in combination with the intensive long-term usage of the inactivated virus vaccine may have led to antigenic changes leading to immune escape.
Today's Eurosurveillance report finds that H3N8 viruses with the most genetic contributions from H9N2 appear pose the biggest zoonotic threat.
Due to its length, and technical nature, I've only posted some excerpts, mainly from the discussion. Follow the link to read the study (and its supplementary materials) in its entirety. I'll have a brief postscript when you return.
Analysis of avian influenza A (H3N8) viruses in poultry and their zoonotic potential, China, September 2021 to May 2022
Pengfei Cui1,2,3 , Jianzhong Shi1,2,3,4, Cheng Yan1,3 , Congcong Wang1 , Yuancheng Zhang1 , Yaping Zhang1 , Xin Xing1 , Yuan Chen1 , Jie Zhang1 , Liling Liu1 , Xianying Zeng1 , Guobin Tian1 , Chengjun Li1 , Yasuo Suzuki5 , Guohua Deng1 , Hualan Chen1,2
Key public health message
What did you want to address in this study?(SNIP)
Avian H3N8 viruses constitute an influenza virus subtype mainly detected in birds. In birds, H3N8 viruses usually cause little or no sign of disease. Spill-over infections to people nonetheless sporadically happen and two human H3N8 viral infections were reported in China in 2022. We wanted to investigate H3N8 viruses circulating in poultry and poultry-related environments in China in September 2021−May 2022.
What have we learnt from this study?
We isolated H3N8 viruses from samples collected in various Chinese provinces. In laboratory assays, some of the viruses could bind to both human- and avian-type receptors. Further analyses revealed that a number of viruses, including those having caused human infections, had acquired genes from other influenza virus subtypes called H9N2. These viruses transmitted between guinea pigs via respiratory droplets.
What are the implications of your findings for public health?
Our findings shed more light on how avian H3N8 influenza viruses can evolve in poultry by adopting genes from H9N2 influenza viruses, which are also found in poultry. The results increase our understanding of how H3N8 viruses can infect mammals and potentially pose a human health threat. Careful monitoring of human H3N8 viral infections is important for influenza pandemic preparedness.
Discussion
The H3N8 influenza viruses have been detected in multiple animal species in nature, including different wild birds, domestic poultry, horses, donkeys, dogs, and harbour seals [21-25]. In this study, we detected different genotypes of H3N8 viruses in farmed ducks and different avian species in live poultry markets, and found that some viruses detected in the live poultry markets have acquired the six internal genes of H9N2 viruses.
Previous studies have shown that the H9N2 viruses are widely detected in live poultry markets in China [16], and chickens vaccinated with the H9N2 vaccines can still be reinfected by H9N2 viruses in these markets [26]. Such a situation provides an opportunity for the H9N2 viruses to reassort with other subtype viruses in the markets, as evidenced by the emergence of H7N9 and H10N8 viruses in 2013, H10N3 viruses in 2020, and the 24 H3N8 viruses detected in this study all bearing six internal genes derived from H9N2 viruses [9,10,27].
Moreover, in our investigations, H3N8 viruses bearing the H9N2 internal genes replicated well in the upper respiratory tract of chickens and were efficiently shed by chickens through both the oropharynx and cloaca. These viruses were also transmissible between guinea pigs via respiratory droplets. Importantly, such H3N8 viruses caused two human infection cases in China [11,12]. This suggests that viruses with this gene constellation may be able to circulate in chickens and continue to pose a threat to human health.
An emerging influenza virus that can replicate in humans may acquire key amino-acid substitutions to adapt to humans, and some human-adaptation mutations also play a key role in facilitating the spread of the virus from human to human. One of the best-known substitutions is the E to K substitution at position 627 (E627K) in PB2, which can dramatically increase the virulence and promote the transmissibility of avian influenza virus in mammals. A previous study indicated that over 78% of the H7N9 avian influenza viruses acquired the 627K substitution in PB2 after replication in humans [28]. Liang et al. found that the low polymerase activity attributed to the viral PA protein is the intrinsic driving force behind the emergence of PB2 627K during H7N9 virus replication in mammals [29]. Several studies have reported that the E627V substitution in PB2 increases the replication and lethality of different avian influenza viruses in mice [30,31]. Zhang et al. found that the H3N2 avian influenza virus easily acquires the 226R/L or 228S substitution in HA during its replication in ferrets, and that either of these substitutions can appreciably increase its affinity for the human-like receptor, allowing the virus to be readily transmitted in ferrets via respiratory droplets. Further analysis indicated that the 228S substitution in HA is important and necessary for the H3N2 virus to be a pandemic strain [13].
Both 627K in PB2 and 228S in HA were detected in the A/Henan/4–14CNIC/2022 strain (Table S2), that was isolated from an infected child’s clinical sample, indicating that the H3N8 virus could easily obtain these key substitutions after a single round of replication in humans. In addition, we found that three avian H3N8 viruses (i.e. CK/HuN/S2342/22 (G15), CK/HuN/S2221/22 (G16), and CK/HuN/S2283/22 (G16)) have the E627V substitution in their PB2 (Table S2), which may contribute to their efficient replication in mice (Figure 2). Therefore, we must carefully monitor H3N8 virus infection in humans and evaluate the human-to-human transmission potential of the viruses isolated from humans in order to be prepared for future influenza pandemics.
One limitation of this study is that the two H3N8 viral strains that had infected humans were neither assessed in the receptor-binding assays nor in the animal investigations as we did not have these strains.
Conclusion
Our study detected multiple genotypes of H3N8 viruses in farmed ducks and different birds in the live poultry markets in China, and found that the proportion of H3N8 viruses bearing the six internal genes of H9N2 virus appeared high in 2022 in multiple live poultry markets and caused two human infections. Some H3N8 viruses bind to both avian-type and human-type receptors, and are transmissible in guinea pigs via respiratory droplets, indicating clear pandemic potential.
The low pathogenicity of the H3N8 avian influenza virus in poultry has led to its control being a low priority, which allows the virus to continue to circulate and pose a threat to human health. Carefully monitoring of the H3N8 virus in humans is important to strengthen early warning systems and pandemic preparedness.
Predicting which influenza virus will spark the next pandemic is a mug's game. There are too many candidates, and too many moving viral parts, to confidently pick a favorite. About the only thing we can say with any certainty is another novel influenza virus will eventually emerge and conquer the world.
But - if you wanted to make a case for H3N8 - in 1968 another avian H3 virus (H3N2) emerged out of China, replacing seasonal H2N2 and sparking the 3rd influenza pandemic of the 20th century.
Past performance is no guarantee of future results, of course. But H3 viruses have track record we can't afford to ignore.
