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Although the world is understandably focused on the rapid spread and evolution of HPAI H5N1 clade 2.3.4.4b, it is far from the only novel flu virus with pandemic potential on our list. Even the CDC's IRAT list (with 24 subtypes) is missing some likely suspects.
While avian H5 or H7 viruses are thought capable of producing severe pandemics, they may be far less likely to emerge than an H1, H2, or H3 subtype (see Are Influenza Pandemic Viruses Members Of An Exclusive Club?).
The CDC's IRAT places the EA H1N1 `G4' swine-origin virus well ahead of H5N1 both in terms of likelihood of emerging, and impact. Of course, these assessments are subject to change.
With so many viruses in play, picking the `next pandemic virus' is pretty much a mug's game. Which is why we spend so much time in this blog looking at an array of lesser known threats; even those that might spark less than a `worst case' pandemic scenario.
Over the past couple of years we've seen Chinese researchers raise concerns over the evolutionary trajectory of a number of LPAI viruses in China's poultry and wild bird population, some with occasional spillovers into humans.
H3N8 is of particular interested because:While H4N6, H6Nx, and H9N2 are frequently mentioned, a recent entry in the zoonotic sweepstakes - LPAI 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 in March of 2023, is getting a lot of attention.
- 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.
To this list we can add the following report, published last week in Transboundary & Emerging Diseases, which finds that multiple genotypes (containing internal genes from LPAI H9N2) have become increasingly adapted to poultry, and are now circulating widely - and asymptomatically - in poultry, posing an increasing threat to human health.
First, a link and some excerpts from this study, after which I'll return with a brief postscript.
Genetic Diversity and Biological Characteristics of H3 Avian Influenza Virus Isolated from China in 2021–2022 Showed the Emerging H3N8 Posed a Threat to Human Health
Xin Yin,1Tiantian Wu,1Shuo Liu,1Cheng Peng,1Jinping Li,1Qiuyan Mao,1Yaxin Zhang,1Shuning Zhou,1Wanting Zhou,1Guangyu Hou,1Wenming Jiang,1and Hualei Liu1
Published 05 Mar 2024
Abstract
The H3 influenza viruses are widespread in domestic poultry but have been ignored because their pathogenicity in poultry is low. Three human infections with H3N8 influenza viruses have been reported in China since 2022, raising public concern. Here, we comprehensively analyzed 30 H3 subtype avian influenza viruses isolated from live poultry markets in China between 2021 and 2022.Genetic and phylogenetic analyses showed that the H3 viruses have undergone frequent reassortment and have formed complex genotypes. Notably, the viruses that caused human infections in 2022–2023 were highly homologous to the H3N8 viruses circulating in poultry in 2022, with internal genes derived from the H9N2 viruses.The analysis of chicken infections indicated that the novel H3N8 viruses were more infectious in chickens than those that do not carry H9N2 genes, whereas the H3 viruses detected in China in 2021–2022 showed low pathogenicity in mice.Our findings suggest that the novel H3N8 viruses bearing internal H9N2 genes have adapted to and circulated in chickens and pose a threat to human health. These results highlight the need for continued surveillance of the H3 influenza viruses and their impact on the poultry industry.
1. Introduction
(SNIP)
Low-pathogenic AIVs also pose a threat to human health. In recent years, H6N1, H3N8, H7N4, H9N2, H10N3, and H10N8 AIVs have also been shown to infect humans [11–15]. On April 26, 2022, a novel AIV infecting a 4-year-old boy in Henan Province, China, was identified as the first case of human H3N8 AIV infection. On May 19, 2022, a 5-year-old boy infected with H3N8 AIV was also reported in Hunan Province. On February 22, 2023, H3N8 AIV infection was reported in Guangdong Province in a 56-year-old woman who died on March 16. This was the first human death from H3N8 throughout the world. All three cases had a history of exposure to live poultry [14, 16, 17].
The H3 subtype influenza viruses have a wide range of hosts, including birds, poultry, swine, canines, equines, and humans [18–20]. H3 viral infections in poultry and wild birds rarely cause clinical symptoms, or the clinical symptoms are not obvious (often occurring as recessive infections). Several studies have reported the isolation of H3 subtype AIVs in wild birds, but the H3 subtype AIVs detected in poultry are usually from waterfowl and are rarely isolated from chickens [21, 22]. In this study, we analyzed several of the biological characteristics of 30 H3 subtype influenza viruses isolated during our routine surveillance of live poultry markets in 2021–2022. Our findings provide important information about the evolution and circulation of the H3 viruses in poultry in China and provide insights into the prevention and control of these viruses.
(SNIP)
4. Discussion
The H3 subtype is a low-pathogenic AIV subtype prevalent in domestic poultry. Here, we present a comprehensive analysis of 30 H3 subtype AIVs isolated from live poultry markets in China and have demonstrated that the H3 subtype viruses circulating in poultry have undergone frequent reassortment and formed complex genotypes. Notably, the novel H3N8 viruses circulating in poultry were highly homologous to the human H3N8 isolates, with their internal genes all derived from the H9N2 subtype virus.
Previous studies showed that the H3 influenza viruses did not form a stable lineage in poultry, with their gene segments originating from different subtypes of influenza viruses detected in wild birds or ducks [21]. H9 viruses are widely detected in live poultry markets and farms in China, resulting in the continuous recombination of H9 with other AIV subtypes [35, 36]. It is the optimal internal gene donor for emerging reassortant viruses that cause human infections, such as the H7N9, H10N3, and H10N8 viruses [4, 15, 37].
Therefore, we are concerned that the novel H3N8 viruses bearing H9N2 internal genes may become a stable branch and circulate in chickens or even cause sporadic human infections. Close and continuous surveillance of the H3 subtype of AIVs circulating in nature is required, and we must be aware of the impact of the H3 subtype on the poultry industry in the future.
Over the past 2 years, many agencies have reported the detection of novel H3N8 viruses in chicken farms and live poultry markets in China [14, 16, 17, 23, 38]. All the studies revealed that the novel H3N8 viruses formed independent lineages in the HA gene trees, with their internal genes being from poultry H9N2 viruses. Notably, Chen et al. [38] showed that the novel H3N8 viruses had been circulating in chickens for over a year at a high prevalence and had disseminated to at least seven provinces before detection in humans. We did not isolate the novel H3N8 viruses in 2021, but the two H3N3 viruses bearing the H9N2 internal genes similar to human strains were isolated in April 2021. The H3 subtype viruses, not just H3N8 subtypes, may have mixed with poultry H9N2 viruses very early on. Therefore, a retrospective analysis of H3 subtype strains isolated before 2021 needs to be conducted.
Previous studies have reported that the H3 subtype AIVs detected in poultry were predominantly from waterfowl, were rarely isolated from chickens, and rarely caused clinical symptoms [19, 21, 22]. Our study found that the novel H3N8 viruses bearing the H9N2 internal gene were more infectious in chickens. The virus replicates in more organs, such as the immune organ thymus, than just in the upper respiratory tract. Although challenged SPF chickens rarely show clinical symptoms under laboratory conditions, there have been cases of H3N8-related symptoms during the industrial production of chickens [39]. Recently, Mao et al. [40] reported the novel reassortant H3N3 AIVs bearing the HA gene of novel H3N8 viruses and internal genes of H9N2 showed increased pathogenicity in chicken, with viruses detected in the lungs, trachea, cecal tonsil, spleen, kidneys, pancreas, brain, bursa of fabricius, heart, liver, and thymus [40]. The internal genes derived from H9N2 viruses may play an important role in their infectivity in chickens, and the relevant mechanism requires further research.
The H1N1, H2N2, and H3N2 influenza viruses have caused influenza pandemics in humans, and H1N1 and H3N2 viruses are still circulating seasonally in humans. Guan et al. [21] reported that ferret antisera against human H3N2 viruses did not cross-react with any of the avian H3N2 viruses, suggesting that preexisting immunity does not limit the spread of the H3N2 avian viruses in humans. Sun et al. [16] and Zhu et al. [17] verified that the human population was immunologically naïve to the novel H3N8 viruses.
The E627K mutation of PB2 is known to play a decisive role in the mammalian adaptation of AIVs [41, 42]. The A/Henan/4-10CNIC/2022(H3N8) virus contains the E627K mutation, whereas A/Changsha/1000/2022(H3N8) contains the E627V mutation, which has also been shown to increase the replication or virulence of AIVs in mammals [14, 34, 43]. The E627K mutation of PB2 was not observed in any of the H3 viruses in the present study; two strains that caused large weight loss in mice acquired the 627V mutation of PB2 in our study. Moreover, Cui et al. [23] reported the novel H3N8 isolated from poultry was transmissible between guinea pigs via respiratory droplets. Sun et al. [16] showed that the H3N8 virus isolated from humans had acquired the ability to transmit between respiratory droplets ferrets. Effective control measures must be established to reduce the prevalence of the virus in poultry, which also reduces the likelihood of infection in humans.(Continue . . . .)
In the spring of 2013 a new, LPAI H7N9 virus emerged in China, one which produced few clinical signs in poultry, but could produce serious (even deadly) disease in humans. This was a wake-up call that even LPAI viruses could pose a serious public health threat.
The virus spread stealthily in poultry, with often the first sign of a problem being when people in direct contact with the birds began to fall ill. Over 5 years more than 1,500 people were infected, with > 600 deaths (both likely under-reported).
While H3N8 has yet to demonstrate the sort of threat that we saw with H7N9, it possesses many of the same attributes (stealthy spread in poultry, H9N2 internal genes, zoonotic spillovers, etc.), making it one definitely worth watching for further development.
