Thursday, December 07, 2023

Frontiers Microbiology: China's Growing Concerns Over The H3 AIV


While we rightfully spend a lot of time looking at the global spread and evolution of HPAI H5Nx, to date we've never seen a human pandemic sparked by an H5 avian influenza virus (AIV).  

That doesn't mean it couldn't happen, only that it hasn't (at least, not in the past 130 years). 

All of the known influenza pandemics for more than a century have come from H1, H2, or H3 influenza viruses  (see Are Influenza Pandemic Viruses Members Of An Exclusive Club?), which appear to have fewer barriers to overcome in order to jump to humans.

Twice in my lifetime (1957 and 1968) avian flu viruses have reassorted with seasonal flu and launched a human pandemic.

  • The first (1957) was H2N2, which According to the CDC `. . . was comprised of three different genes from an H2N2 virus that originated from an avian influenza A virus, including the H2 hemagglutinin and the N2 neuraminidase genes.'
  • In 1968 an avian H3N2 virus emerged (a reassortment of 2 genes from a low path avian influenza H3 virus, and 6 genes from H2N2which supplanted H2N2 - killed more than a million people during its first year - and continues to spark yearly epidemics more than 50 years later.

In 2009, a novel swine H1N1 virus jumped to humans, causing a mild-to-moderate pandemic that supplanted the existing H1N1 virus.  Some experts have suggested an H2Nx virus might be next (see H2N2: What Went Around, Could Come Around Again), but H2 AIVs - while they exist - aren't all that common

Increasingly our attention has been drawn to the plethora of H3Nx viruses circulating in China and elsewhere around the globe. 

  • H3 viruses have a wide host range, and are commonly found in wild and migratory birds, poultry, and pigs and they can also infect horses (H3N8),  dogs (H3N8, H3N2 & H3N6), and occasionally marine mammals.
  • H3 viruses are highly mutable, and are able to easily reassort with other viruses to produce numerous genotypes.

A few (of many) recent blogs include:

Emerg. Microb & Inf.: Emergence of Novel Reassortant H3N3 Avian Influenza viruses, China 2023

Eurosurveillance: Analysis of Avian Influenza A (H3N8) Viruses in Poultry and their Zoonotic Potential

Characterization of an Emergent Chicken H3N8 Influenza Virus in Southern China: a Potential Threat to Public Health

EID Journal: Evolution of Avian Influenza Virus (H3) with Spillover into Humans, China

China: Emergence of a Novel Reassortant H3N6 Canine Influenza Virus
The emergence of a novel H3N8 virus last year in China, which has not only spread widely in wild birds and poultry, but has also spilled over into humans (see here, here, and here), has helped to propel H3 viruses back into the limelight. 
All of which brings us to a review article, published today in Frontiers in Microbiology, that looks at growing concerns over the spread and evolution of H3Nx viruses in China.  

This is a lengthy review, so I've only posted some excerpts. Follow the link to read it in its entirety. I'll have a brief postscript after the break. 

REVIEW article
Front. Microbiol., 07 December 2023
Sec. Virology
Volume 14 - 2023 |

Concern regarding H3-subtype avian influenza virus

Jiantao YuQiucheng YaoJing Liu Yan Zhou Miaotong Huo Ye Ge
†College of Coastal Agricultural Sciences, Guangdong Ocean University, Zhanjiang, China

The H3-subtype of avian influenza virus (AIV) is one of the most frequently detected low pathogenic avian influenza virus (LPAIV) subtypes in birds and fowls, causing substantial economic loss to the poultry industry. Most importantly, besides poultry, mammals could also be infected with it, such as swines, canines, equines, felines, and humans, posing a serious public health threat. This allows the virus to persist widely in poultry and wild birds for a long time, where it may mix with other subtypes, providing conditions for viral recombination or reassortment.

Currently, the monitoring of H3-subtype AIV is inadequate, and there is a lack of effective prevention and control measures for H3-subtype AIV. Here, the epidemiology, phylogeny, and genetic variation of H3-subtype AIV were analyzed, and nonsynonymous and synonymous substitution rates (dN/dS) were calculated. Through these steps, we aimed to clarify the current epidemiological feature and evolutionary characteristics of H3-subtype AIV, and provide an operative reference for future scientific control of H3-subtype AIV.

1 Introduction

Avian influenza virus (AIV) is a type A influenza virus and one of the most significant zoonotic diseases that poses a severe threat to both the poultry industry and human health worldwide (Wei-Wen Hsiao et al., 2023; Yang et al., 2023). The AIV genome consists of eight segments of single-stranded negative-sense RNA. Haemagglutinin (HA) and neuraminidase (NA), encoded by segments 4 and 6, respectively, are the main antigenic glycoproteins on the surface of AIV (Jiang et al., 2023; Yang et al., 2023). According to the antigenic differences between HA and NA on its surface, AIV were divided to 18 HA subtypes and 11 NA subtypes (Liu et al., 2019). Except for H17N10 and H18N11, which were isolated from bats (Yang et al., 2021), all other subtypes of influenza A viruses had been identified in wild birds (Kawaoka et al., 1990; RÖHM et al., 1996; Liu et al., 2005; Wang et al., 2014). Different subtypes of AIV have different degrees of pathogenicity to poultry and mainly divided in highly pathogenic avian influenza (HPAI) and lowly pathogenic avian influenza (LPAI). The former is invoked by some H5 and H7 subtype virus strains, while other AIVs usually show low pathogenicity to poultry.

The H3-subtype AIV exists widely in birds, humans, and other mammals. Although its pathogenicity is low, it has many subtype combinations, a wide distribution and complex biological characteristics (Wang et al., 2014). To date, researchers have discovered a total of nine subtypes of H3NX AIV, with H3N2 and H3N8 as the most frequently detected subtypes in birds and canines. And swine and feline influenza were primarily caused by the H3N2 subtype of the influenza A virus, while equine influenza was mainly caused by the H3N8 influenza A virus. In addition, because of the low pathogenicity of H3-subtype AIV, infected animals generally show no symptoms or mild clinical symptoms, so the impact on the breeding industry and human health is often overlooked, which allows H3-subtype AIV to continue to spread and evolve in nature.

H3-subtype AIV has a higher isolation rate in wild birds than in mammals (including humans), especially in wild waterfowl, which are considered its natural hosts. Domestic ducks are considered an important intermediate host for AIV transmission from wild waterfowl to terrestrial fowl and one crucial determinant influencing the genetic diversity of AIV (Huang et al., 2010, 2012; Kim et al., 2012). Avian influenza surveillance data indicate that H3- subtypes of AIV were prevalent in domestic ducks and could be mixed within them, providing good conditions for new subtypes and mutations in genes affecting virulence via antigenic transformation. 

One report showed that H3N8 in wild birds possessed dual-receptor binding properties in the HA protein, which supports the occurrence of this type of AIV interspecies transmission (Tian et al., 2023). Notably, studies had shown that H3NX AIV has the ability to provide genetic fragments for reassortment in other subtypes of influenza viruses, leading to the production of new highly pathogenic strains and thus to influenza outbreaks (Peng et al., 2013; Wenqiang et al., 2017; Zhao et al., 2023). The H3-subtype AIV can also undergo recombination to alter its pathogenicity and has the potential to break through the interspecific barrier to infect humans (Song et al., 2008). 

6 Conclusion

H3-subtype AIV is in a state of evolution and recombination. Frequent recombination occurred between different subtypes, and cross-species transmission occurred. Moreover, multiple mammalian adaptive mutation sites were found on H3-subtype AIV HA protein.

These findings indicate that H3-subtype AIV is gradually adapting to mammals and even humans. Therefore, the monitoring of mutation and recombination in H3-subtype AIVs should be continued, and efficient vaccines should be developed to prevent and control the prevalence of H3-subtype AIV. 


While 1968 was the first time that an H3 virus was confirmed to have sparked a human influenza pandemic, we know very little about the viruses that circulated prior to the 1918 H1N1 pandemic virus, and some researchers have suggested than H3N8 may have emerged in the 1890s (see graphic below). 

Currently the CDC's IRAT (Influenza Risk Assessment Tool) lists 3 H3 viruses as having at least some pandemic potential. 
7/1/2019   A(H3N2) variant [A/Ohio/13/2017]          6.6  (emergence)  5.8 (impact)

12/1/2012 A(H3N2) variant [A/Indiana/08/2011]      6.0 (emergence)  4.5 (impact)

6/1/2016   A(H3N2) [A/canine/Illinois/12191/2015] 3.7 (emergence)   3.7 (impact)

The limited flow of information out of China makes it difficult to fully access the risks, but it would not be terribly surprising to see H3N8 added to this list at some point. New genotypes can emerge at anytime, so there are a lot of possibilities.

While an H5Nx pandemic could easily be more severe, H3 viruses have proven their ability to cause significant morbidity and mortality, and should not be underestimated.