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Half of the 52 known human infections with the avian H5N6 virus - which first emerged in 2014 in Sichuan Province - have occured over the last 12 months (see map above), and all but one of those (in Laos) occurred in China.
Of particular concern, most of these recent cases have been reported over the summer, a time of year when avian flu is usually at its nadir, raising concerns for this winter. While we've not heard of any new cases since November 1st, China often belatedly reports on cases.
Although we've seen no evidence that this virus has adapted well enough to humans to spread in an efficient or sustained manner, in recent weeks we've seen a flurry of reports from our own CDC, China's CDC, and the UK Health Security agency addressing this recent surge in human infections with avian H5N6, including:
UKHSA Issues Additional Guidance On Recognizing and Treating Novel Avian Influenza
UK HSA Risk Assessment On HPAI H5N6
CDC Monitoring HPAI H5N6 In China
China CCDC Weekly: Genetic Characterization of Two Human A (H5N6) Viruses — Guangxi , China, 2021
CCDC Weekly: Outbreak Report - Five Independent Cases of Human Infection With HPAI H5N6 — Sichuan Province
Roughly half of the known infections with H5N6 have proved fatal, suggesting this is a particularly deadly virus in humans, and since we've not seen any reports of outbreaks in poultry in China for months, it is likely spreading stealthily in vaccinated poultry.
With the potential for the spread of this virus via migratory birds beyond Southeast Asia, and the recent surge in human infections, yesterday the World Health Organization published their own risk assessment.
First, their brief summary, followed a by a link, and excerpts from, the full RRA.Overview
Highly pathogenic avian influenza (HPAI) A(H5N6) viruses belonging to the 2.3.4.4b haemagglutinin (HA) genetic lineage have spread in birds in China and some neighboring countries. There have been 26 A(H5N6) human infections reported in 2021, of those 20 with illness onset dates after 21 June 2021. While the zoonotic threat remains elevated due to spread of the viruses in birds, based on evidence available so far, the overall pandemic risk is considered not significantly changed in comparison to previous years.
Assessment of risk associated with highly pathogenic avianinfluenza A(H5N6) virus
19 November 2021
Background
Highly pathogenic avian influenza (HPAI) A(H5N6) viruses belonging to the 2.3.4.4b haemagglutinin (HA) genetic lineage have spread in birds in China and some neighboring countries. There have been 26 A(H5N6) human infections reported in 2021, of those 20 with illness onset dates after 21 June 2021.
Summary of the assessment of current risk to humans posed by HPAI A(H5N6) virus
The rise in numbers of reported human cases of A(H5N6) infection may reflect the spread of these viruses in poultry and an increased diagnostic capacity and awareness for respiratory illness etiology amongst human health systems in China and likely elsewhere. The increased sensitivity of diagnostic systems is a direct outcome from the response to the COVID-19 pandemic. With continued circulation of the virus in birds, human infections will continue.
It is unclear if the A(H5N6) viruses have enhanced intrinsic zoonotic potential. Although genetic markers known to be associated with mammalian adaptation have been identified sporadically in individual cases following infection, these changes were not consistently present in environmental or poultry viruses and likely reflect intra-host mutations. While the zoonotic threat remains elevated due to spread of the viruses in birds, based on evidence available so far, the overall pandemic risk is considered not significantly changed in comparison to previous years. Minimizing the risk to humans largely depends on decreasing virus circulation in poultry, reducing the amount of virus in environments at the animal-human interface (i.e., live bird markets and farms) and mitigating exposure to potentially infected birds.
Understanding of the virus
Human infections
Twenty-six human infections with highly pathogenic avian influenza A(H5N6) viruses have been reported to WHO in accordance with the International Health Regulation in 2021 (two cases had illness onset dates in 2020). Of the 26 reported cases, 25 by China and 1 by Lao People’s Democratic Republic (PDR), 10 were reported as fatal with three individuals still hospitalized at the time of writing. Cases were reported from 6 provinces and 1 municipality in China (5 in Sichuan, 6 in Guangxi, 6 in Hunan, 1 in Anhui, 3 in Chongqing, 3 in Guangdong, 1 in Guizhou) and occurred mainly in adults with a median age of 55 years. The greatest number of cases (6) were reported during August. The single case reported by Lao PDR was in a child <18 years of age. Almost all confirmed cases reported exposure to poultry. Two cases reported in China in Page 2 of 3 August 2021 were in a husband and wife, both of whom reported poultry exposure. Although common exposure to poultry is the most likely cause, human to human transmission cannot be excluded.
Geographic distribution in animals
The A(H5N6) viruses belong to a group of viruses, falling within HA clade 2.3.4.4b, that have gradually become more prevalent in birds in China and neighboring countries over the past year. These 2.3.4.4b viruses have been paired with multiple neuraminidase (NA) gene segments. The A(H5N6) viruses have been found on environmental surfaces in live poultry markets in China although the true extent of their circulation in birds is unclear. Viruses with similar hemagglutinins (e.g., A(H5N8) and A(H5N1)) have been found in birds throughout Europe and in some countries of Africa and Asia. They have been associated with human infections in the Russian Federation and Nigeria.
Virology
All viruses sequenced from human cases in China with illness onset in 2021 were HPAI A(H5N6) viruses and belonged to HA genetic clade 2.3.4.4b. Genetic sequencing of viruses from 11 cases indicated all gene segments to be derived from wild bird lineages, with some gene segments related to previously identified HPAI A(H5N1) and A(H5N8) viruses. Amino acid residues associated with mammalian adaptation were detected in the PB2 genes (E627K and D701D/N) of 2 viruses and 1 virus had an HA1 substitution of Q226L (H3 numbering), which is associated with increased human cell receptor binding. These molecular markers were not consistently identified in viruses collected from environmental surfaces or poultry indicating that these amino acid substitutions occurred sporadically during human infection.
Candidate vaccine viruses
A(H5N6) and A(H5N8) subtype candidate vaccine viruses (CVV) have been developed. This includes a recommended A(H5N8) clade 2.3.4.4b CVV made from A/Astrakhan/3212/2020. The HA of this virus is closely related to the 2021 A(H5N6) human viruses with at most 4 amino acid differences. Antigenic characterization of these and related viruses will be needed to confirm the predicted cross-reactivity of antisera raised against the CVV and the potential impact of a mismatched NA between N8 and N6 viruses. Antiviral susceptibility No genetic markers known to be associated with reduced susceptibility to clinically relevant antiviral drugs, including those targeting neuraminidase or polymerase, were identified in the recent A(H5N6) viruses causing zoonoses.
Recommended actions
It is recommended that countries, particularly National Influenza Centers and other influenza laboratories associated with the Global Influenza Surveillance and Response System (GISRS), remain vigilant for the possibility of zoonotic infections. All unsubtypable influenza-positive samples should be expedited for shipment to a WHO Collaborating Center or H5 Reference Laboratory of GISRS. Further antigenic characterization of A(H5N6) viruses, notably in relation to similarities with existing 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(H5N6) viruses in birds and other animals are of particular importance. Mitigation steps to reduce human exposure to potentially infected birds should be considered to reduce risk of additional zoonotic infections.
WHO will continue to work closely with FAO, OIE and OFFLU to monitor the avian influenza situation and A(H5) virus evolution and provide timely updated risk assessments.
On November 2nd, the CDC announced that - in view of this increased activity - they would undertake a new risk assessment of H5N6. In an IRAT summary of their last analysis (below), they ranked its pandemic potential as moderate.
H5N6: [A/Yunnan/14564/2015 (H5N6-like)]
Between January 2014 and May 2019, there have been 23 human cases of H5N6 highly pathogenic avian influenza reported and 14 of the cases were fatal. Avian outbreaks of this virus were first reported from China in 2013. Subsequently, avian outbreaks have been reported in several countries through 2019.
Summary: The summary average risk score for the virus to achieve sustained human-to-human transmission was in the moderate range (less than 6).The average summary risk score for the virus to significantly impact on public health if it were to achieve sustained human-to-human transmission fell in the moderate range (less than 7).
