H5N1 News: European Centre for Disease Prevention and Control (ECDC) Reports Worrisome Mutations Spotted On Circulating H5N1 Avian Flu Virus

H5N1 News: The European Centre for Disease Prevention and Control (ECDC) along with the European Food Safety Authority (EFSA) and the EU reference laboratory (EURL) has released a new report detailing the new worrisome mutations found on the H5N1 Avian Flu virus that is circulating around the world and wreaking extensive havoc by infecting and killing millions of birds, poultry and also many mammals now. Most of these new mutations and genetic occurred in mammal infections.
 


According to the published document, between 3 December 2022 and 1 March 2023 highly pathogenic avian influenza (HPAI) A(H5N1) virus, clade 2.3.4.4b, was reported in Europe in domestic (522) and wild (1,138) birds over 24 countries. An unexpected number of HPAI virus detections in sea birds were observed, mainly in gull species and particularly in black-headed gulls (large mortality events were observed in France, Belgium, the Netherlands, and Italy). The close genetic relationship among viruses collected from black-headed gulls suggests a southward spread of the virus.
 
Moreover, the genetic analyses indicate that the virus persisted in Europe in residential wild birds during and after the summer months.
 
Though the virus retained a preferential binding for avian-like receptors, several mutations associated to increased zoonotic potential were detected. The risk of HPAI virus infection for poultry due to the virus circulating in black-headed gulls and other gull species might increase during the coming months, as breeding bird colonies move inland with possible overlap with poultry production areas.
 
Globally, HPAI A(H5N1) virus continued to spread southward in the Americas, from Mexico to southern Chile. The Peruvian pelican was the most frequently reported infected species with thousands of deaths being reported.
 
The reporting of HPAI A(H5N1) in mammals also continued probably linked to feeding on infected wild birds. In Peru, a mass mortality event of sea lions was observed in January and February 2023.
 
It was reported that since October 2022, six A(H5N1) detections in humans were reported from Cambodia (a family cluster with 2 people, clade 2.3.2.1c), China (2, clade 2.3.4.4b), Ecuador (1, clade 2.3.4.4b), and Vietnam (1, clade 2.3.4.4b), as well as two A(H5N6) human infections from China. The risk of infection with currently circulating avian H5 influenza viruses of clade 2.3.4.4b in Europe is assessed as low for the general population in the EU/EEA, and low to moderate for occupationally or otherwise exposed people.
 
Mutations Identified In A(H5N1) Viruses From Avian Species
 
Detailed molecular analyses of the A(H5N1) viruses circulating in birds in Europe during the 2022– 2023 epidemiological year indicate that these viruses continue to be well-adapted to avian species, as they retain a preferential binding for avian-like receptors. 
 
Numerous mutations previously described in one past study that can cause the following:  i) enhance polymerase activity and replication in mammals or mammalian cells, ii) increase virulence, iii) increase/confer resistance toward antiviral drugs, iv) in vitro increase binding to humantype receptors alpha2,6 -SA, and v) decrease antiviral response in ferrets were observed with a frequency varying for the distinct mutations.
https://pubmed.ncbi.nlm.nih.gov/31428925/
 
However, the real effect of these mutations on the biological characteristics of the viruses is still unknown and further studies are needed to improve existing knowledge.
 
Among the detected mutations, it is worth mentioning the detection of the mutation PB2-E627K, an adaptive marker associated with an increased virulence and replication in mammals, in two A(H5N1) viruses, one collected from a domestic bird in Belgium in December 2022 and one in a wild bird in Sweden in January 2023.
 
Moreover, about 3% of the European viruses belonging to the H5N1 A/Herring_gull/France/22P015977/2022-like genotype show mutations in the NA protein which cause disruption of the second sialic acid binding site (2SBS), a feature typical of human-adapted influenza A viruses.
https://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2023.28.7.2300085
 
Importantly, among the mutations in the HA protein which have been previously demonstrated to increase the binding to human–type receptor, some of them (ie. S137A, S158N, T160A, S128P and R496K) have been identified in the majority of the A(H5N1) viruses circulating in Europe since October 2022, while others (ie. T192I, S159N, Q196R, V214I) have been sporadically observed.
 
Furthermore, all the mutations associated to antiviral resistance were identified only sporadically in the circulating viruses.
 
Genetic Diversity Of A(H5N1) Viruses In Mammals
 
It was reported that since October 2020, complete genome sequences of 57 HPAI A(H5) viruses of clade 2.3.4.4b collected from 12 distinct mammalian species (badger, cat, coati, ferret, fox, lynx, mink, otter, polecat, porpoise and seal) in 13 European countries were generated.
 
The characterized viruses belong to 8 different A(H5N1) and A(H5N8) genotypes previously identified in birds, with most of the viruses (75%) belonging to the two most widespread genotypes in birds in Europe (H5N1 A/Eurasian_Wigeon/Netherlands/1/2020-like, H5N1 A/duck/Saratov/29-02/2021-like).
 
Mutations Identified In A(H5N1) Viruses From Mammals
 
Worryingly, about half of the characterized viruses contain at least one of the adaptive markers associated with an increased virulence and replication in mammals in the PB2 protein (E627K, D701N or T271A).
https://pubmed.ncbi.nlm.nih.gov/31428925/
 
These mutations have never (T271A) or rarely (E627K, D701N) been identified in the HPAI A(H5) viruses of clade 2.3.4.4b collected in birds in Europe since October 2020 (Less than 0.5% of viral sequences from birds).
 
This observation suggests that these mutations with potential public health implications have likely emerged upon transmission to mammals.
 
Furthermore, the viruses collected in October 2022 from a HPAI A(H5N1) outbreak in intensively farmed minks in northwest Spain (Aguero et al., 2023) shows mutations in the NA protein which cause disruption of the second sialic acid binding site (2SBS). This feature is typical of human-adapted influenza A viruses, which may favor the emergence of mutations in the receptor binding site of the HA protein. These same mutations were detected also in seven A(H5N1) viruses from birds.
https://www.eurosurveillance.org/content/10.2807/1560-7917.ES.2023.28.7.2300085
 
Risk To Humans Is Still Low
 
The updated assessment on H5N1 avian influenza reported that although the risk to humans is still low, worrisome signs include the appearance of certain mutations in circulating strains and mass animal mortality events that hint at a greater risk of spread among mammals.
 
The updated assessment was posted today on the ECDC's website. It covers data collected from December 2022 to March 1.
https://www.ecdc.europa.eu/en/publications-data/avian-influenza-overview-december-2022-march-2023
 
The European officials said poultry outbreaks have declined in the region since a peak in November, but, given mass die-offs in gulls in multiple countries due to the virus, poultry outbreaks involving the 2.3.4.4b H5N1 clade could increase in the months ahead.
 
Gulls will be moving inland to breeding colonies that overlap poultry-production areas, the report notes. The 2.3.4.4b H5N1 clade is now circulating on multiple continents.
 
In the full 43-page report, the groups said that, from September to March, virus detections in seabirds were unexpectedly high, especially in gulls, with large morality events seen in France, Belgium, the Netherlands, and Italy. Genetic analysis of viruses from black-headed gulls points to a southward spread of the virus and that it persisted after the summer in resident wild birds.
 
Genetic analysis of the viruses from infected European birds over the winter suggests that H5N1 still binds preferentially to avian receptors.
 
The experts note, however, that some of the viruses from mammals have markers in the PB2 protein associated with increased virulence and replication in mammals….very rarely seen before 2020. They said the changes probably emerged following transmission to animals and possibly have public health implications.
 
The European researchers said most recent H5N1 detections in mammals involve species such as red fox that hunt or scavenge infected birds or dead animals. However, they pointed to three mass mortality events: one involving harbor seals in Maine, an outbreak at a Spanish mink farm, and a die-off in Peruvian sea lions.
 
Importantly, transmission events to and between mammals, serologic evidence of infection in wild boar and pigs, and mutations that would make the virus better adapted to mammals are concerning and need to be closely followed, they warned.
 
The researchers added that more sporadic infections in humans are possible in individuals exposed to sick or dead birds, and the groups put that risk as moderate. The recent severe cases from Asia and South America underscore the risk of unprotected contact with infected birds, they note. The risk of travel-related cases in humans is very low.
 
The ECDC, EFSA and EURL recommend the appropriate use of personal protective equipment when in contact with birds. People exposed to infected birds or mammals should be tested and followed-up, in order to early identify potential transmission cases.
 
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