Tuesday, September 06, 2022

IJID: A Review Of The Pandemic Potential Of Avian H3N8

First two H3N8 cases in Humans April-May 2022,
Henan Province roughly 400 miles apart


We've been following the evolution and frequent species jumping of avian, equine, and canine H3N8 influenza A viruses since this blog began in 2006, but it wasn't until April of this year (see China: NHC Confirms Human Avian H3N8 Infection In Henan Province) that we saw it infect humans. 

Six weeks ago, in Preprint: Human infection With a Novel Reassortment Avian Influenza A H3N8 Virus: An Epidemiological Investigation Study, we learned that a household dog and cat were also infected in the first (of two) cases.  The authors wrote:

Positive detection of the novel A(H3N8) RNA was obtained from nasopharyngeal swab of a dog, anal swab of a cat, and environmental samples collected in the patient’s house. The full-length HA sequence from the dog and cat was identical to sequence from the patient.

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 the growing host range and versatility of this novel H3N8 avian virus. 

A week ago we learned that avian H3N8 was already well established in Hong Kong's poultry (see EID Journal: Novel Zoonotic Avian Influenza Virus A(H3N8) Virus in Chicken, Hong Kong, China), roughly 1000 km from the first reported human infection in Human Province last April. 

As it is likely being spread by wild or migratory birds (see Adaptation of Two Wild Bird-Origin H3N8 Avian Influenza Viruses to Mammalian Hosts), it has probably already spread across much of Eastern and Southern China.  

While influenza viruses are notoriously unpredictable, this recent surge in activity is a concern because: 

  • 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 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. 
  • 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.
All of which brings us to an excellent review article in the International Journal of Infectious Diseases that examines the pandemic potential of H3N8. Follow the link for the full article and references. I'll have a bit more when you return.
Will the influenza A(H3N8) cause a major public health threat?
Hadi M. YassineMaria K. Smatti

Open Access Published:September 05, 2022
• On April 27, 2022, China reported the first-ever human infection with influenza A(H3N8).
• Earlier studies indicated a possible circulation of the H3N8 in humans in the 1890s.
• Urgent studies are needed to understand H3N8 pathogenesis in humans.
• Cross-reactivity studies of different H3N8 lineages are also needed.

The diversity of zoonotic influenza viruses and their ability to cross the species barrier have been always alarming and required a continuous surveillance in both human and animal populations. Avian A(H3N8) influenza viruses are frequently detected in animals and represent one of the most common subtypes in wild birds. Cross-species transmission of avian A(H3N8) influenza viruses have been reported for multiple mammalian hosts, including the outbreaks in horses and dogs by the equine and canine lineages of A(H3N8), respectively.
In humans, there was no evidence of influenza A(H3N8) infection until 25 April 2022, when the Chinese health authority reported the first-ever human H3N8 case in a 4-year-old boy from Henan Province. Although there are no information that this virus has the ability to sustain human transmission, additional epidemiological and virological studies are needed to better assess the replication potency of the virus in human cells as well as the risk posed to public health. Here, we briefly discuss the influenza A(H3N8) virus interspecies spread, with the focus on transmission in humans.


Since the start of the COVID-19 pandemic, influenza has recorded the lowest numbers in decades worldwide. Currently, two influenza A subtypes (H1N1 and H3N2) and two influenza B lineages (Victoria and Yamagata) circulate in the human population. H2N2 is another influenza subtype that circulated in humans between 1957 and 1968, causing what is known as the Asian flu pandemic. All three subtypes (H1, H2, and H3) have originated from birds, resulting in three pandemics that claimed the lives of millions of people. In addition, sporadic cases with other subtypes, specifically H5, H6, H7, and H9, are reported from time to time. Most of these cases are reported in individuals who work in close contact with infected birds. 

The latest sporadic case was on April 28, 2022, where the CDC confirmed the detection of the first avian influenza A(H5) virus case in the U.S., in a person who had a direct exposure to poultry (U.S. Case of Human Avian Influenza A(H5) Virus Reported. 2022). So far 863, 1, 1568, and 74 cases, were reported for H5, H6, H7, and H9 worldwide, with a fatality rate ranging from 2.7% to 53% for H9 and H5, respectively (Reported Human Infections with Avian Influenza A Viruses 2022). 

Fortunately, none of these subtypes has gained the ability to sustain human-to-human transmission, although several studies have identified mutations that might promote better transmission among humans. Swine also harbor viruses (H1 and H3) that may infect humans, one of which was the origin of the latest H1N1 2009 pandemic.

Influenza A(H3N8) in Humans

On April 27, 2022, China reported the first-ever human infection with H3N8 in a four-year-old boy from in the Henan province. This raised a major public health concern worldwide. Similar to the above scenarios, the boy had been in contact with chickens and crows raised at his home. None of the patient's close contact was infected with the virus, providing a relief sign for public health officials. The boy developed flu-like symptoms before getting hospitalized ten days after the onset of the symptoms.

 Of interest, H3N8 is known to infect horses (equine influenza), dogs (equine origin), and seals in addition to waterfowls which are the natural reservoir of the virus (He et al., 2019). The equine influenza lineages seem to have diverged from avian influenza lineages of the same subtypes (Chambers, 2022). Hence, this subtype, in particular, has shown flexibility to cross the species barrier and infect mammals, which raises public health concerns.

More importantly, according to the sequence analysis of the hemagglutinin (HA) protein, the sequence of the HA from the recent human H3N8 virus was found to be most closely related to avian H3 sequences. Amino acid sequence comparison of the HA from human H3N8 with that from H3N2 (avian and human), H3N1 (avian), and other H3N8 viruses (avian, horse, equine, canine, and swine) is presented in Figure 1a. Sequence similarity index of the HA aa sequences from different H3 hosts is shown in Figure 1.b.


Figure 1 Comparison of the full-length HA protein sequence of the human H3N8 with the HA form H3N1, H3N2, and other H3N8 viruses. A) Summary of selected unique amino acids (aa) that are present in different H3 hosts: Representative protein sequences (n=142) from H3N1 (avian), H3N2 (avian and human), and H3N8 (human, avian, horse, equine, canine, and swine) were obtained form the Influenza Research Database (IRD) and GISAID. Alignment was done using CLC software. The highest similarity was found between the HA from human H3N8 and avian H3N2, which differed at only eight aa sites (marked with red borders). A representation of cross-species sequence conservation of the full-length H3 is shown at the top. B) Similarity statistics of H3 from different influenza strains and hosts. Protein sequences (n=142) from H3N2 (avian and human), H3N1 (avian), and H3N8 (human, avian, horse, equine, canine, and swine) were aligned separately and the consensus sequence of each group was used to calculate the similarity index (SIAS tool, provided by UCM).View Large Image

Influenza-like illnesses have been reported in horses since 1870s. However, the first actual isolation of the H3N8 from horses was in mid 1950’s. The capacity of H3N8 transmission from horse to dogs have been reported in several occasion. However, its transmissibility to humans has been debatable.
In 1965, seroarchaelogy studies revealed the presence of reactive antibodies to H3N8 in an elderly population, whose exposure must have occurred in ∼1890, hypothesizing that H3 had entered humans from horses to cause the 1889 (or 1896) human influenza pandemic. It is worth noting here that the antigen used in these studies was of equine H3N8 origin, as the H3N2 has not emerged in humans and swine until 2011 and 1998 respectively. Although this finding has not been validated by phylogenetic evolution analyses, it still indicates a possible circulation of an H3 subtype virus in humans in 1890s.

In experimental studies (1965-1966), low to subclinical level of infection was reported in about two-thirds of equine type A influenza virus inoculated volunteers, indicating possible infection of human with the H3N8 (Alford et al., 1967). Further, recent serological studies from different nations, including the USA, Australia and others, revealed the presence of anti-equine H3N8 antibodies in 3-10% of the participants, mainly in those exposed to horses (Burnell et al., 2014;Larson et al., 2015).

However, the level of measured antibodies was low to indicate an acute infection with the virus and could be due to cross-reactivity with human H3 influenza. Still, equine H3N8 was shown to infect pig cell lines and in respiratory explants (Patrono et al., 2015). Further, clade II equine H3N8 strains were isolated from pigs in China in 2009 (Tu et al., 2009). Experimentally, equine and canine H3N8 viruses did not replicate well in the respiratory systems of pigs, while avian and seal counterparts replicated substantially and caused noticeable lesions in inoculated pigs. The viruses were used to inoculate pigs without any previous adaptation (Sol├│rzano et al., 2015).

These results indicate that mammals are prone to infection with avian H3N8 viruses, knowing that the distribution of sialic acid receptors in pig's respiratory tissue resembles that in humans, with abundance of ╬▒-2,6-linked sialic acid receptors in the trachea and other parts of the respiratory tract. This similarity has been clearly demonstrated with the emergence of the novel pandemic H1N1 virus in 2009.
Concluding Remarks

In summary, the ability of the H3 influenza subtype to infect humans is documented. This subtype has been shown to infect different mammalian species, including pigs. The ability of avian H3N8 to infect pigs raises significant concern about its ability to infect humans.
Urgent studies are needed to understand the phenotypic characteristics of the recent H3N8 in humans, including receptor specificity, as well as the replication in human airway cells. It is unlikely that immunity against H3N2 will protect from H3N8, considering the significant antigenic changes. Cross-reactivity studies of the different H3N8 lineages are needed in this regard. Currently, an inactivated vaccine against H3N8 is available for use in horses. Whether this vaccine produces immunity against avian H3N8 shall be studied. The availability of such resources might speed up the production on human vaccines if needed.
         (Continue . . . )

H3N8 isn't the only novel flu virus with pandemic potential (see CDC IRAT List) - and while it would probably not produce the most severe pandemic - it does tick a lot of the boxes.

Not the least being, it is an H3 virus - and as we've discussed often (see Are Influenza Pandemic Viruses Members Of An Exclusive Club?) - the progression of human influenza pandemics over the past 130 years appears to have been H2, H3, H1, H2, H3, H1, H1 . . . .


Credit ECDC – 125 years of  Pandemic  History

Simply put, 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 makes them more likely to spark a pandemic. 

H3N8 isn't the only H1, H2, or H3 virus we are watching, however.   

In early 2021 the CDC ranked a Chinese Swine-variant EA H1N1 `G4' as having the highest pandemic potential of any flu virus on their list, and we keep a very close watch on sporadic human infections with swine variant viruses (CDC HAN #00473: Variant Influenza Virus Infections: Recommendations for Identification, Treatment, and Prevention for Summer and Fall 2022) in North America. 

Regardless of the subtype, another influenza pandemic is inevitable. Historic accounts suggest at least a dozen `influenza-like’ pandemics occurred in the 400 years prior to the 20th century. 

Making it a matter of when, not `if', the next influenza pandemic will arrive.