While we watch the global spread, and occasional spillover into humans, of HPAI H5Nx viruses with with understandable concern, all of the known influenza pandemics - going back 130 years - have come from H1, H2, or H3 influenza viruses (see ECDC graphic above).
That doesn't mean that an H5 (or H7, H9, H10, etc.) virus couldn't spark a human flu pandemic, only that we haven't seen that happen during our relatively short span (80 years) of being able to identify influenza subtypes.
And as we've discussed previously (see Are Influenza Pandemic Viruses Members Of An Exclusive Club?), novel H1, H2, and H3 flu viruses appear to have fewer barriers to overcome in order to jump to humans - and while they may not prove as virulent as H5 & H7 avian subtypes - that puts them at or near the top of our pandemic threats list.
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 H2N2) which supplanted H2N2 - killed more than a million people during its first year - and continues to spark yearly epidemics more than 50 years later.
Note: The 2009 H1N1 pandemic - although it was a triple-reassortment containing some avian-origin genetic contributions - emerged from swine.
This is the reason why yearly flu vaccination is strongly recommended for people who raise pigs, or work with poultry.
Over the past couple of years we've seen a steady parade of scientific reports coming out of China describing new H3 avian viruses (see EID Journal: Evolution of Avian Influenza Virus (H3) with Spillover into Humans, China), which includes H3N8 which has spilled over into humans at least 3 times, and a Novel Reassortant H3N6 Canine Influenza Virus.)
Today we've another such report in a letter published in Emerging Microbes & Infections, which describes a new reassortant H3N3 virus which includes an HA gene from the H3N8 virus mentioned above, an NA gene from H10N3 (which has also spilled over into humans), and internal genes from H9N2 (which is also zoonotic).
Despite its impressive pedigree, this reassortant H3N3 virus is not yet pathogenic in mice, and still binds preferentially to avian receptor cells. The authors note, however, that it has some concerning traits, describing:
Several mutations that would increase polymerase activity and replication ability and increased virulence in mammalian cell lines or mice were identified, including I292V, I504V and A588V in PB2 and K356R in PA. Several mutations that would especially increase pathogenicity in chickens were identified, including K627E in PB2, I127V, I550L and F672L in PA, P64S and l69P in M2 and A42S and F103L in NS1 [12]. There was also a mutation of S31N in M2 which could increase the resistance to amantadine and rimantadine [13].
Due to its length and technical nature, I've only posted some excerpts from the letter. Follow the link to read it in its entirety. I'll have a brief postscript when you return.
Qiuyan Mao,Shuning Zhou,Shuo Liu,Cheng Peng,Xin Yin,Jinping Li, show all
Article: 2287683 | Accepted author version posted online: 22 Nov 2023
Dear editor,
(EXCERPT)
Since 2023, several large-scale egg farms in Jiangsu province in China have experienced cases of drops in food and water intake, with affected chickens showing respiratory signs including swelling of the sinuses and discharge from the eyes, nares, mouth, severe dyspnea and reduced egg production, with lower mortality rates. The trachea, lungs, liver, and intestines of dead chickens were collected and homogenized to extract DNA and RNA. The egg drop syndrome virus, AIV, Newcastle disease virus, infectious bronchitis virus, infectious bursitis virus and infectious laryngotracheitis virus were tested by real-time polymerase chain reaction methods (national or industry standards), with only AIV being positive. The H3N3 subtype was further identified using HA and NA specific primers [10] and sequencing. The viruses were isolated by inoculation into 10-day-old specific-pathogen-free (SPF) embryonated chicken eggs with homogenate and named A/chicken/Jiangsu/NT322/2023(H3N3) (NT322/H3N3) and A/chicken/Jiangsu/NT308/2023(H3N3) (NT308/H3N3), respectively. Throat and cloacal swabs of chickens from a nearby live poultry market were also sampled and one strain A/chicken/Jiangsu/J1247/2023(H3N3) was isolated.
To investigate the origins of these H3N3 isolates, their genomes were sequenced using Sanger sequencing and phylogenetic analysis was performed. The phylogenetic trees for each gene segment were generated by using the neighbor-joining method in the MEGA 11 package. The bootstrap value was calculated with 1000 replicates. The eight gene segment sequences of the three strains shared 99.5 to 100% nucleotide identity among them, suggesting they were highly homologous.
The HA genes of these viruses were highly homologous to those of H3N8 that caused the three human cases and shared 97.5 to 99.2% nucleotide identity between them (Figure 1(A)). Their NA genes were genetically close to those from H10N3 circulating in poultry in China and including the human case in 2021) in China (Figure 1(B)). The internal genes were genetically associated with the H9N2 circulating in chickens in China.
The internal gene constellation was more similar to that of the human H10N3 isolate than that of the human H3N8 isolates, sharing 95.9 to 98.7% nucleotide homology with A/Jiangsu/428/2021(H10N3), except PA and M genes which were highly homologous with human H3N8 isolates at 98.8% and 99.5%, respectively.
(SNIP)
Discussion
This study presents a preliminary analysis of the isolation and characterization of novel reassortant H3N3 viruses from chickens, which have undergone frequent reassortment. Their HA and NA genes are genetically close to the human infected isolates, H3N8 and H10N3, respectively. Their internal genes are derived from the H9N2 circulating in chickens in China and are more similar to that of the human H10N3 isolate. Our surveillance suggested that H9N2 accounts for about 72% of the AIVs identified in Jiangsu province in 2023 and about 12.3% of birds in LBMs carry H9N2 viruses (unpublished data).
Although these H3N3 viruses preferentially bind to avian-like receptors and were not pathogenic in mice, they were likely to possess molecular markers indicative of potential pathogenicity. Multiple human-infecting AIVs, such as H7N9, H10N8, and the recently emerging H3N8 and H10N3, have been proved to contain the internal genes of H9N2 viruses. Poultry that carry H9N2 AIVs provide a favourable environment for different subtypes of viruses to exchange their gene segments with H9N2 AIVs. Lesions caused by LPAIV, such as H9N2, are difficult to reproduce under experimental settings [14], but the H3N3 viruses isolated in this study exhibited similar clinical signs in SPF chickens as those in domestic production, indicating these H3N3 viruses have increased virulence, unlike the H3 virus in wild birds [15].
Although the H3 subtype is a low-pathogenic AIV subtype prevalent in domestic poultry, the emerging avian H3N3 virus from chicken flocks in China appears to exhibit an increasing pathogenicity. Close and continuous surveillance of the H3N3 subtype of AIVs circulating in poultry is required, their pathogenesis should be continuously investigated and their impact on the poultry industry in the future should be evaluated. Effective control measures including vaccination should also be established to reduce the prevalence and decrease the economic impact of the virus infection in poultry, similar to prevention measures for H9N2 infection.
Ethics statement
The animal study was performed in accordance with the institutional animal guidelines and approved by the Animal Care Committee at China Animal Health and Epidemiology Center.
LPAI (Low pathogenic Avian Influenza) viruses have an advantage, in that they can more easily spread unnoticed in both commercial and backyard poultry, providing them with more opportunities to interact with humans and the influenza viruses we carry.
The H7N9 virus that emerged in China in 2013 was also an LPAI - and while it did not visibility sicken chickens - it could cause severe and often fatal infection in humans.
Whether H3N3 has the `right stuff' to pose a threat to humans is unknown at this time. But it is another example of the rapid evolution of avian viruses in China, and a reminder of why we need to be prepared to meet whatever new challenges nature throws at us.
