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Although H5 and H7 viruses have sparked relatively small epidemics over the past two decades, over the past 130+ years, only H1, H2, and H3 viruses are known to have caused human influenza pandemics (see graphic above).
While it is possible other subtypes reigned supreme before 1890, the assumption today is that H1, H2, and H3 viruses have a competitive edge against others like avian H5 and H7 (see Are Influenza Pandemic Viruses Members Of An Exclusive Club?).
This one of the reasons why we pay so much attention to zoonotic swine (H1, H2 & H3) flu viruses (see Emerg. Microbes & Inf.: Eurasian 1C Swine Influenza A Virus Exhibits High Pandemic Risk Traits).
But twice in my lifetime we've also seen avian influenza viruses reassort and spill over into humans, sparking deadly pandemics.
- 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 a novel H3N2 virus emerged (a reassortment of 2 genes from a low path avian influenza H3 virus, and 6 genes from H2N2) which supplanted H2N2 - killed more than a million people during its first year - and continues to spark yearly epidemics more than 56 years later.
Despite this impressive pedigree, initially this reassortant H3N3 virus was reportedly not pathogenic in mice, bound preferentially to avian receptor cells, and lacked a number of key mammalian adaptations.
A study published a year later (see BMC Genomics: Evidence of an Emerging Triple-reassortant H3N3 Avian Influenza Virus in China) painted a far more concerning picture, finding it had acquired mutations that may` . . . increase viral resistance, virulence, and transmission in mammalian hosts.'
Last March, in Vet. Research: Emergence of a Novel Reassortant H3N3 Avian Influenza Virus with Enhanced Pathogenicity and Transmissibility in Chickens in China, the authors reported that H3N3 could:
- `infect and replicate in the upper and lower respiratory tract of BALB/c mice without prior adaptation'
- replicate `vigorously' within the chicken respiratory & digestive tracts and transmit efficiently and swiftly among chickens through direct contact
- `exhibited high and moderate stability in thermal and acidic conditions and efficient replication capabilities in mammalian cells'
This is a lengthy and detailed review of what is currently known about this subtype, and many will want to read it in its entirety. I've only reproduced the abstract and a few excerpts below.
Assessment of the public health risk of novel reassortant H3N3 avian influenza viruses that emerged in chickens
Authors: Han Li , Qi Tong , Mengyan Tao, Jixiang Li, Haili Yu, Qiqi Han, Jiancheng Wu, Show All (19 Authors) , Honglei Sun
PDF/EPUB
ABSTRACT
Influenza A (H3N2) viruses are historically responsible for the 1968 Hong Kong flu pandemic. Since then, H3N2 has continued to circulate as a seasonal influenza virus in humans. Public health concerns were raised in 2022 when human infections with novel reassortant H3N8 influenza viruses originating from chickens were first reported in China.
Here, we conducted a systematic surveillance of H3 avian influenza viruses (AIVs) circulating in poultry and assessed the public health risk of emergent H3 reassortants. We found that H3 AIVs were prevalent in both ducks and chickens. Notably, in December 2022, a novel chicken-derived H3N3 subtype virus was identified, which gradually replaced the previously predominant H3N8 virus and became prevalent in chickens.
Genetic analysis demonstrated that the novel H3N3 virus is a triple-reassortment strain with the H3 gene segment from chicken H3N8 virus, the N3 gene segment from the H10N3 virus, and internal gene segments derived from H9N2 viruses.
Compared with chicken H3N8 and duck H3N3 viruses, the novel chicken H3N3 viruses produced higher yields and induced greater pathogenicity in human respiratory epithelial cells and mammalian models (mouse and ferret). Importantly, the chicken H3N3 viruses could be transmitted efficiently between ferrets through direct contact.
The polymerase activity of the chicken H3N3 viruses in mammalian cells was markedly increased by the PA gene originating from the H9N2 virus. Our findings indicate that the circulation of novel chicken H3N3 viruses poses a threat to both the poultry industry and human public health.
IMPORTANCE
The H3Ny subtype influenza A virus can infect a wide range of hosts. In addition to circulating among wild birds and poultry, the virus can also infect humans and a variety of mammals. Here, we found that H3Ny subtype AIVs were widely prevalent in domestic chickens and ducks.
Novel H3N3 reassortant viruses emerged as a result of the genetic reassortment of the chicken-derived H3N8 AIVs with H10N3 and H9N2 AIVs. The novel H3N3 subtype AIVs are gradually displacing H3N8 AIVs and becoming prevalent in chickens. Furthermore, these novel H3N3 AIVs exhibited enhanced infection ability and efficient transmissibility in mammalian models, indicating a growing potential public health risk.
(SNIP)
In summary, our study revealed the emergence and increasing prevalence of H3N3 viruses in chicken populations, highlighting their enhanced transmissibility and pathogenicity in human respiratory epithelial cells and mammalian models compared to chicken H3N8 viruses.
Notably, H3N3 viruses demonstrated efficient direct-contact transmission in ferrets, indicating their potential for cross-species transmission.
As always, H3N3 isn't a single viral threat, but rather a diverse and evolving array of similar viruses all sharing the same HA/NA gene types. The H3N3 viruses that have been collected and analyzed to date represent only a subset of what is likely circulating in the wild.Collectively, these findings suggest that H3N3 viruses might pose a risk to public health, emphasizing the urgent need for comprehensive surveillance and control of the spread of H3Ny reassortant viruses in poultry.
While many of the findings cited above are of obvious concern, perhaps the biggest red-flag is just how much attention Chinese scientists are giving this novel subtype, and how quickly we are seeing reports published.