Preprint: Fatal Human H3N8 Influenza Virus has a Moderate Pandemic Risk

Credit NIAID

#18,897

While much of the world thinks primarily of HPAI H5 when it comes to avian flu threats, China's researchers have been unusually preoccupied of late with the emergence and spread of a number of H3Nx viruses. 

Avian H3 viruses have sparked human pandemics before; most recently in 1968. Nearly 6 decades later H3N2 continues to circulate in humans, and is often the cause of the most severe flu seasons.

While not considered a `reportable' virus in poultry or wild birds, H3Nx viruses have been making considerable inroads into mammalian hosts in recent years.  A few (of many), include:

• In July, in Emerg Microbes Infect: A fatal Case of Acute Encephalitis Associated with a Novel influenza H3N2 Recombinant Virus Possessing Human-origin H7N9 Internal Genes we learned of the death of a 7-year old child from a novel swine H3N2 reassortant virus,

• Last June, in Virology: Assessment of the Public Health Risk of Novel Reassortant H3N3 Avian Influenza Viruses That Emerged in Chickens, which reported the H3N3 subtype in China already `. . . exhibits abundant genetic markers for mammalian host adaptation'.

• And last May we saw a remarkable, albeit belated, incident described in Preprint: Fatal infection of a novel canine/human reassortant H3N2 influenza A virus in the zoo-housed golden monkeys, where yet another novel H3 subtype (H3N2) jump species in China.

As worrisome as these H3 subtypes might be, H3N8 viruses (avian, canine and equine) are of particular interest 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 virus, and subsequently jumped from horses to dogs in 2004

• 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 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.

Since 2022 China has confirmed at least 3 avian H3N8 infections in humans, causing severe illness and at least 1 death. In the first spillover, the family dog and cat both tested positive for the H3N8 virus.

Notably that first virus carried the PB2-E627K mutation along with N30D and T215A in its M gene and P42S in the NS. All known or suspected markers of mammalian adaptation. 

While the third (fatal) infection in 2023 did not carry those mutations, the recovered isolate bound to both avian-type and human-type receptors with a preference for (α2-6 linked sialic acids) human-type receptors.

Since H3N8 has become widespread in China's poultry, it is important to try to gauge its pandemic potential. Which is what researchers from the University of Pittsburgh, Emory University, and The Scripps Research Institute endeavor to do in the following preprint.

Due to its length (31-pages), I've just posted the abstract and a small excerpt from the discussion. Follow the link to read it in its entirety.  I'll have a brief postscript after you return.

Fatal Human H3N8 Influenza Virus has a Moderate Pandemic Risk

Valerie Le Sage, Michelle N. Vu, Maria A. Maltepes, Shengyang Wang, Brooke A. Snow, Grace A. Merrbach, Alexandra J. Benton, Kylie E. Zirckel, Sarah E. Petnuch, Carly N. Marble, Lora H. Rigatti, James C. Paulson, Elizabeth M. Drapeau, Anita K. McElroy, Scott E. Hensley, Louise H. Moncla, Seema Lakdawala
doi: https://doi.org/10.1101/2025.10.02.679960
This article is a preprint and has not been certified by peer review  
 
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Abstract

In China, low pathogenic avian influenza (LPAI) H3N8 virus is widespread among chickens and has recently caused three zoonotic infections, with the last one in 2023 being fatal.

Here we evaluated the relative pandemic risk of this 2023 zoonotic H3N8 influenza virus, utilizing our previously published decision tree. Serological analysis indicated that a large proportion of the human population does not have any cross-neutralizing antibodies against this H3N8 strain.

LPAI H3N8 displayed a dual affinity for a2-3 and a2-6 sialic acids and replicated efficiently in human bronchial epithelial cells. 

Furthermore, we observed H3N8 transmission via direct contact but not aerosols to ferrets with pre-existing H3N2 immunity. Although pre-existing H3N2 immunity resulted in a shortened disease course in ferrets, it did not reduce disease severity or replication in the respiratory tract.

This study suggests that this zoonotic H3N8 strain has moderate pandemic potential and emphasizes the continued need for avian influenza surveillance.

       (SNIP)

The risk of an emergent IAV is increased when there is a lack of existing human immunity. Although a serosurvey of farm poultry workers in China would indicate that there is a low prevalence of H3N8 virus exposure in this population (11), these data also demonstrate a lack of cross-reactive antibodies in people at this high-risk human-animal interface.

 

Similarly, our representative US population had virtually no cross-reactive neutralizing antibodies above the limit of detection, except for three individuals that were born in the 1950s and 1960s. Furthermore, neither seasonal H3N2 vaccination in China (38) nor in the US (Figure 2B) were able to generate antibodies that cross-reacted against H3N8 IAV strains. 

However, non-neutralizing immunity from prior H3N2 infection could protect from clinical disease, viral load, and susceptibility to infection. Therefore, the overall risk of current zoonotic H3N8 is moderate to low in the face of prior seasonal H3N2 immunity.

However, continued H3N8 spillover events into marine mammals have been documented, including seals (9), and provide an opportunity for the virus to evolve and escape the protection conferred by prior H3 immunity. The three spillover events of H3N8 were a result of exposure to live poultry, reinforcing the importance of surveillance of the natural reservoirs in migratory waterbirds for avian influenza virus, which have the potential to intersect and result in incursions of H3N8 influenza virus into poultry.

        (Continue . .  )

Avian H3N8 is another in a growing list of partially-adapted, but not-quite-ready-for-Prime-Time, novel flu viruses. 

While it is always a long-shot for a novel flu virus to adapt well enough to spark a pandemic, it has already happened at least 3 times in my lifetime.  

• 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 55 years later.
• In 2009, a triple-reassortant swine H1N1 virus emerged, sparking a relatively mild pandemic, that nonetheless heavily impacted younger adults and children.

Which is why we continue to track these obscure viral threats, because it will undoubtedly happen again.