In late April we saw the first confirmed human infection by avian H3N8 reported by Chinese officials in Henan Province (see China: NHC Confirms Human Avian H3N8 Infection In Henan Province). The patient - described as a 4 year-old boy from Zhumadian City - fell ill in early April - and at the time was reported to be in critical condition with respiratory failure.
A month later (May 26th), a second case was announced - also in Henan Province - which was eventually confirmed by Hong Kong's CHP (see Hong Kong CHP Finally Notified Of 2nd H3N8 case).
Although any spillover of a novel influenza virus into humans is worthy of our attention, H3N8 is of particular concern because:
- it 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 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 in 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.
- in 2016, in PLoS One: Evidence of Subtype H3N8 Influenza Virus Infection among Pet Dogs in China, we looked at the species jump and adaptation of (EIV or CIV or AIV) H3N2 to a canine host.
- Ten months ago, in CCDC Weekly: Epidemiological and Genetic Characteristics of the H3 Subtype Avian Influenza Viruses in China, we looked at an overview of H3 viruses in wild birds and poultry across China that warned: Frequent mutations and reassortments increased the genetic diversity associated with altered virus virulence, transmission, and mammalian adaptation of H3 AIVs, posing a potential threat to animal and human health.
- and last May, in Adaptation of Two Wild Bird-Origin H3N8 Avian Influenza Viruses to Mammalian Hosts, we looked at a study investigating the transmissibility and pathogenicity of two H3N8 LPAI viruses (GZA1 & XJ47) isolated from wild birds in China. Both strains were subjected to a serial passage experiment, and both developed much higher virulence, and picked up known mammalian adaptations (PA T97I and D701N in PB2).
Not only is this virus closely related to the Hunan strains mentioned earlier, it also carries some worrisome genetic signatures (e.g. an H9N2 backbone) that we've seen with other zoonotic avian flu viruses (H5N1, H5N6, H7N9, H10N8).
Abstract
Zoonotic and pandemic influenza continue to pose threats to global public health. Pandemics arise when novel influenza A viruses, derived in whole or in part from animal or avian influenza viruses, adapt to transmit efficiently in a human population that has little population immunity to contain its onward transmission. Viruses of previous pandemic concern, such as influenza A(H7N9), arose from influenza A(H9N2) viruses established in domestic poultry acquiring a hemagglutinin and neuraminidase from influenza A viruses of aquatic waterfowl.
We report a novel influenza A(H3N8) virus in chicken that has emerged in a similar manner and that has been recently reported to cause zoonotic disease. Although they are H3 subtype, these avian viruses are antigenically distant from contemporary human influenza A(H3N2) viruses, and there is little cross-reactive immunity in the human population. It is essential to heighten surveillance for these avian A(H3N8) viruses in poultry and in humans.
Diverse influenza A viruses are found in aquatic waterfowl, poultry, swine, horses, aquatic mammals, bats, and domestic pets such as cats and dogs. Although there is a diversity of virus hemagglutinin (H1–H16) and neuraminidase (N1–N9) subtypes in aquatic birds, more restricted numbers of virus subtypes are established in other species, including chicken (1). The high mutation rates associated with an error-prone virus replication complex and the presence of a segmented genome enables genetic reassortment of gene segments of viruses of different species and interspecies transmission and adaptation to new hosts.
Influenza A virus subtypes H9 and H6 have formed established lineages in domestic chicken and game birds (quail, pheasant) farmed for consumption in Asia (2). The internal gene constellation of H9N2 viruses contains hemagglutinin (HA) and neuraminidase (NA) genes acquired from aquatic waterfowl to generate H5N1, H5N6, H7N9, and H10N8 viruses through genetic reassortment, and many of these viruses also became established in poultry, subsequently posing zoonotic and pandemic threats (3–5). A novel influenza A(H3N8) virus has been recently reported to cause zoonotic infection in Henan Province, China (6).
In this context, we report detection of novel H3N8 viruses recently identified in chicken in live poultry markets and chicken farms in Hong Kong, China, that are genetically similar to the zoonotic H3N8 viruses reported in mainland China (6). We also report that these recent H3N8 viruses have arisen in a manner akin to zoonotic H5N1, H7N9, and H10N8 viruses and that there is little cross-reactive immunity in the human population to these chicken H3N8 viruses.
(SNIP)
Discussion
We report detection of chicken influenza A(H3N8) viruses from live poultry markets and farms in Hong Kong. These viruses were genetically similar to each other and to a recently reported zoonotic H3N8 virus in mainland China (6). The viruses were novel reassortants that have virus internal gene segments derived from H9N2 lineage genotype 57 viruses (A/chicken/Zhejiang/HJ/2007-like) established in poultry in mainland China, but the H3 and N8 gene segments were derived from wild aquatic bird influenza A viruses. The H9N2 virus internal gene cassette was previously reported to facilitate the emergence of reassortant influenza A viruses of zoonotic potential (26). These chicken H3N8 viruses in Hong Kong were distinct from H3N8 viruses reported from poultry in mainland China (25), but a A/chicken/China/Guangdong_01/2022 (H3N8) virus genetically similar to these viruses in all 8 gene segments is reported in public databases (Appendix Table). These H3N8 viruses were also distinct from H3N8 viruses reported in horses, dogs and cats (27–29).
These novel H3N8 viruses appear to have arisen in a manner analogous to the emergence of previous zoonotic H7N9 and H10N8 viruses, in which the H9N2 viruses enzootic in chicken and other game birds in China acquired HA and NA gene segments from wild, aquatic bird viruses. Wild aquatic birds share ecosystems with domestic ducks, and it is inevitable that influenza viruses will also be shared in such ecosystems. Subsequent trade systems in which domestic ducks and chickens (and other game birds) are mixed in close proximity within wholesale and retail poultry markets provide the opportunity for H9N2 viruses in chicken to acquire HA and NA gene segments from domestic ducks, as has been postulated in the emergence of H7N9 and H10N8 viruses (4).
Pandemics emerge when influenza viruses of birds, swine, or other mammals adapt to transmission between humans and when the human population lacks immunity to the hemagglutinin of the newly emerged virus. Cross-reactive immunity in humans is 1 parameter that is considered when risk assessing the pandemic threat from a newly emerged animal influenza virus (30).
Our data suggest that there is little antigenic cross-reactivity between contemporary seasonal H3N2 viruses and the H3N8 virus. The overall HI test seroprevalence at a titer >1:40 to H3N8 in age-stratified serum samples collected from blood donors in Hong Kong was 3.2%, and the estimated proportion of the population immune (weighted for age structure) was 2.9% (95% CI 1.2%–5.8%). We estimated that if this H3N8 virus acquired transmissibility between humans and acquired an R0 >1.033, cross-reactive population immunity would fail to impede its onward transmission in the human population. For comparison, similar estimation of the minimal R0 required for the 2009 pandemic H1N1 virus to spread in face of population immunity before its emergence and spread in 2009 was 1.231 (95% CI 1.185–1.292), a markedly higher threshold to cross (22).
In conclusion, we report the emergence of a novel influenza A(H3N8) virus in chickens in Hong Kong. This virus might have major zoonotic and pandemic potential. Our results indicate the need to enhance surveillance for this virus in poultry, carry out comprehensive risk assessment of such a virus, and prepare pandemic seed vaccine strains if justified by such risk assessment.
Dr. Sit is the chief veterinary officer and assistant director of the Agriculture, Fisheries, and Conservation Department of the Government of the Hong Kong Special Administrative Region, Hong Kong, China. His primary research interest is veterinary public health.
A little over a month ago, in Preprint: Human infection With a Novel Reassortment Avian Influenza A H3N8 Virus: An Epidemiological Investigation Study, we looked at some of the findings of China's investigation into the first human H3N8 infection.
It isn't possible to ascertain who infected who. The child could have contracted the virus from an avian exposure, and passed it on to these companion animals. Or, or one of these animals could have contracted it, and passed it on to the child.
But it does speak to both the transmissibility, and host range, of this novel virus. The report also discussed its genetic sequences, which they described as:
Both HA and NA genes of the virus were of avian origin, with the HA gene most closely related to H3N2 and H3N8 viruses detected in ducks in Guangdong Province, and NA gene most closely related to wild bird H3N8 influenza viruses detected in the USA and Japan.
The six internal genes were acquired from Eurasian lineage H9N2 viruses. Molecular substitutions analysis revealed the haemagglutin retained avian-like receptor binding specificity but PB2 genes possessed sequence changes (E627K) associated with increased virulence and transmissibility in mammalian animal models.
Influenza A's superpower is its ability to simultaneously infect an animal (avian, swine, human, canine, etc.) host with two or more subtypes, and by swapping genetic material, create a new hybrid virus (reassortant).
While the future course and impact of H3N8 is unknowable, the fact that similar reassortants have been found in both Hunan Province - and in Hong Kong, roughly 1000 km away - suggests this novel virus has beaten the odds, and has developed some degree of biological fitness.
Which means we need to pay very close attention. Stay tuned.
