FAO/OIE/WHO Joint Rapid Risk Assessment Human infection with Influenza A(H3N8)

 

#16,765

With COVID variants (BA.2.12.1, BA4, BA.5, etc.) once again on the ascendant in the United State and parts of Europe, a still-unidentified cause of acute hepatitis in hundreds of children around the world, sporadic reports of H5N6 infections in humans in China, and a burgeoning Monkeypox outbreak that already spans several nations, adding a novel H3N8 avian flu virus to the mix feels like piling on. 

But nature doesn't care. 

We looked the initial report in late April (see China: NHC Confirms Human Avian H3N8 Infection In Henan Province), and revisited the topic 10 days ago (see WHO Update & Risk Assessment: Avian Influenza A(H3N8) - China).  

Due to its history of jumping species (see below), H3N8 has been on our watch list for years. 

• First, 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).  
• Second, because about 60 years ago H3N8 jumped unexpectedly to horses, and since the 1970s appears to have supplanted the old equine H7N7 and is now the only equine-specific influenza circulating the globe

• Third, 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).

• Fourth, 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 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. 

All of which makes the jumping of the avian H3N8 to a human - and it causing severe illness in a 4 year-old child - very much worth noting.  

Yesterday the FAO/OIE/WHO published a detailed Rapid Risk Assessment which describes this virus as an avian-origin reassortant - with internal genes from the LPAI H9N2 virus - and a number of distinct mutations, some of which may increase its adaptation to human hosts. 

While the risk of sustained human-to-human transmission is currently considered low, this is another novel virus we need to keep our eye on. 

Preliminary FAO/OIE/WHO Joint Rapid Risk Assessment Human infection with Influenza A(H3N8), China 18 May 2022 

Background 

The Chinese health authority reported an influenza A(H3N8) infection in a 4-year-old boy from Henan Province on 25 April 2022 to the World Health Organization (WHO). No human infection with influenza A(H3N8) virus had been recorded before this case. Genetic analysis of the virus confirmed it is of avian origin. Avian influenza A(H3N8) viruses are commonly found - but not associated with disease - in wild birds [1]; such viruses have also been detected in live poultry markets in Asia [2, 3]. 

Occasionally, A(H3N8) viruses have been associated with disease in dogs [4], horses [5-7], pigs [8], donkeys [9], and most recently seals [10, 11]. However, the genetic composition of A(H3N8) viruses detected in animals to date is different from that detected in the patient. 

Summary of the assessment of current risk to humans posed by A(H3N8) virus 

This is the first reported human infection with avian influenza A(H3N8). The virus detected in the human case is an A(H3N8) avian-origin reassortant that has the PB1, PB2, PA, NP, M, and NS gene segments from Eurasian lineage A(H9N2) poultry viruses. The presence of molecular changes associated with mammalian adaptation in the hemagglutinin (HA) and PB2 warrants close monitoring for other avian-origin reassortant A(H3N8) viruses. 

Further investigation on the source of the virus, contacts of the patient and environmental sampling is being conducted by China’s health authority. While further human infections with A(H3N8) viruses cannot be excluded, the risk is low. The likelihood of sustained human-to-human transmission is also low Based on the limited information obtained to date. FAO, OIE and WHO will re-assess the risk associated with the virus when more information becomes available. 

Understanding of the virus 

The human infection 

The case involved a 4-year-old boy from Henan Province [12]. He developed fever on 5 April 2022, cough and shortness of breath in the following days and was admitted to the hospital in critical condition on 10 April 2022 with severe pneumonia. On 20 April 2022, the National Influenza Center of the Chinese Center for Disease Control and Prevention tested the specimen sent from Henan province and confirmed the sample contained an influenza A(H3N8) virus with all genes being of avian origin. 

No other viruses were detected in the respiratory specimen and blood stream bacterial cultures were negative. The case had exposure to chickens kept at home before onset of disease. Clinical observation and sampling of the patient’s close contacts were conducted and neither infection nor symptoms of illness were found. Preliminary investigations into the source of exposure of this case have yielded A(H3N8)-positive samples from the chicken coops in the patient’s backyard and from live poultry markets in the area. 

Virology 

In the preliminary genetic analysis of the A/Henan/4-14/2022 virus sequence data available in GISAID showed that in the HA, there is an amino acid (AA) mixture at HA position 228 (G/S) that was found in all three sequences submitted to GISAID (two clinical specimens from 10 April and 14 April and the cell culture isolate from the case). HA 228S is conserved in seasonal A(H3N2) viruses; 228G is conserved in avian A(H3) viruses.

In the absence of genetic sequence data from the avian source of the infection, it is unknown if the mutation causing the HA 228G/S  mixture was present in the source or if it emerged during replication in the child.

An increase in the proportion of 228S detected between the samples collected on 10 April and 14 April (from 37% to 64%) suggests the causative mutation occurred during the infection potentially resulting in more efficient binding of the virus hemagglutinin to human cellular receptors. 

As well as this notable HA residue mixture, there are many other differences between this virus and other mammalian A(H3) viruses; most differences were identified in putative antigenic sites indicating that this virus would be antigenically different from other A(H3) viruses detected in mammals (e.g., humans, swine, equines, dogs and marine mammals). 

Phylogenetic relationships of the HA and NA genes to other viruses are shown in Annex 1, A and B, respectively and analyses of internal gene identities to closest BLAST hits in GISAID to assess their origin/lineages and presence of molecular markers of mammalian adaptation and drug resistance are shown in Annex 1, C.

Virus isolation from the A(H3N8)-positive samples collected in the case’s backyard was unsuccessful. Further characterization of A(H3N8)-positive samples from live poultry markets is underway.

 Geographic distribution in animals 

Wild birds form a large gene pool for influenza type A viruses in nature, such that 16 hemagglutinin (HA or H) [13] and 9 neuraminidase (NA or N) subtypes can be found in this reservoir. During the period 2011 to 2019 Low Pathogenic Avian Influenza (LPAI) A(H3N8) detections in animals (mainly in mallards) have been reported to the OIE by Belgium, Czech Republic, Finland and Hungary. This information has been reported through the OIE Voluntary Report on non-OIE listed diseases in wildlife. While influenza A(H3N8) viruses are occurring widely in wild birds, they can also cause outbreaks in equines, canine and other animal species[4-11, 14-16]. However, no genetic similarity was observed between the human case isolate and previously reported animal A(H3N8) viruses.

 Nevertheless, novel reassortant A(H3N8) influenza viruses were isolated from drinking water for ducks on a farm and from wild and domestic birds in China [17-22]. Influenza A(H3N8) was also detected in environmental samples from live poultry markets in China in January 2022, although the genetic compositions of these viruses were different from that detected in this human case. 

Recommended actions

It is recommended that countries, particularly through National Influenza Centers (NICs) and other influenza laboratories associated with the Global Influenza Surveillance and Response System (GISRS), remain vigilant for the possibility of zoonotic infections. All human samples that are confirmed influenza A-positive but negative for the HAs of seasonal viruses and the HAs of any other subtypes that the laboratory tests for (i.e., un-subtypeable viruses), together with any additional information, should be expedited for shipment to a WHO Collaborating Center or H5 Reference Laboratory of GISRS.

Further antigenic characterization of A(H3N8) viruses, notably in relation to similarities with existing Candidate Vaccine Viruses (CVVs), and generation of specific reagents is being prioritized at WHO Collaborating Centers in collaboration with veterinary sector colleagues. Additional data on the prevalence and genetic and antigenic characteristics of A(H3N8) viruses in birds and other animals are of particular importance; see guidance for field research and sampling from FAO [23]. Procedures to reduce human exposure to birds potentially infected birds with avian influenza viruses should be considered and implemented to minimize the risk of zoonotic infections. FAO, OIE WHO and OFFLU are closely working together to monitor the avian influenza situation, including the detection and geographic spread of avian influenza viruses, including A(H3) viruses, and their evolution, and to provide timely updated risk assessments.