Avian Flu Diary: WHO: Influenza at the Human-Animal Interface Report - Identifies New H5 Clade 2.3.2.1e Infections in Cambodia & Vietnam

#18,475

We've a recent WHO Influenza at the human-animal interface update which contains a bit of a surprise, as it reports two recent H5N1 infections with clade 2.3.2.1e viruses. Until very recently, this clade has flown pretty low beneath the radar.

Two years ago the WHO described clade 2.3.2.1e as:

Clade 2.3.2.1e viruses were detected in Timor-Leste. The HAs of these viruses were most closely related to viruses previously detected in Indonesia. There are no CVVs representative of this HA clade and the viruses from Timor-Leste reacted poorly with post-infection ferret antisera raised against clade 2.3.2.1a and 2.3.2.1c CVVs. No human infections have been associated with viruses of this clade and the extent of their circulation is uncertain.

Clade ~~2.3.4.4x~~ 2.3.2.1x virus detections go back nearly 20 years, and are now divided into 6 subclades (a-f). A 2023 study, Evolution and biological characterization of H5N1 influenza viruses bearing the clade 2.3.2.1 hemagglutinin gene describes their geographic range.

The viruses bearing the clade 2.3.2.1a HA gene were mainly detected in South Asia and Southeast Asia;
the viruses bearing the clade 2.3.2.1b HA genes were mainly detected in China;
the viruses bearing the clade 2.3.2.1c HA genes were mainly detected in Southeast Asia;
the viruses bearing the clade 2.3.2.1d HA genes were mainly detected in China;
the viruses bearing the clade 2.3.2.1e HA genes were mainly detected in Japan and Korea;
and the viruses bearing the clade 2.3.2.1f HA genes were mainly detected in Africa and China

For the past two years we've been following spillovers of H5N1 clade 2.3.2.1c - mostly in children - in Cambodia.

This new report from the WHO reclassifies the last case as clade 2.3.2.1e, and preliminary testing suggests that the recent case in Vietnam is also clade 2.3.2.1e. Previously, in the March 2025 report, the WHO reported a clade 2.3.2.1e case in a boy from Cambodia.

Sequence analysis of the HA gene revealed the virus belongs to clade 2.3.2.1e (previously classified as clade 2.3.2.1c)7 , and is similar to viruses circulating among birds, including poultry, and detected in human cases since late 2023 in Cambodia.

First the link, summary and some excerpts from the latest WHO report.

Influenza at the human-animal interface

Summary and risk assessment, from 20 March to 22 April 2025

• New human cases : From 20 March to 22 April 2025, based on reporting date, the detection of influenza A(H5N1) in four humans and influenza A(H9N2) virus in three humans were reported officially.

• Circulation of influenza viruses with zoonotic potential in animals: High pathogenicity avian influenza (HPAI) events in poultry and non-poultry continue to be reported to the World Organisation for Animal Health (WOAH).3 The Food and Agriculture Organization of the United Nations (FAO) also provides a global update on avian influenza viruses with pandemic potential.4

• Risk assessment : Sustained human to human transmission has not been reported from these events. Based on information available at the time of the risk assessment, the overall public health risk from currently known influenza viruses circulating at the human-animal interface has not changed remains low. The occurrence of sustained human-to-human transmission of these viruses is currently considered unlikely. Although human infections with viruses of animal origin are infrequent, they are not unexpected at the human-animal interface.

• IHR compliance: All human infections caused by a new influenza subtype are required to be reported under the International Health Regulations (IHR, 2005).6 This includes any influenza A virus that has demonstrated the capacity to infect a human and its haemagglutinin (HA) gene (or protein) is not a mutated form of those, i.e. A(H1) or A(H3), circulating widely in the human population. Information from these notifications is critical to inform risk assessments for influenza at the human-animal interface.

(EXCERPT)

A(H5N1), Cambodia

On 23 March 2025, Cambodia notified WHO of a human case of influenza A(H5N1) in a 3-year-old boy from Kratie Province. On 18 March, he developed symptoms and was seen at a local private clinic. On 21 March, he was admitted to hospital in critical condition. Upper respiratory specimens collected on 22 March tested positive for influenza A(H5N1) by reverse transcription-polymerase chain reaction (RT-PCR) at the National Institute of Public Health of Cambodia. The results were confirmed by the Institut Pasteur du Cambodge (IPC) on 23 March. The patient died on 23 March.

Sequence analysis of the haemagglutinin (HA) gene revealed the virus belongs to A(H5) clade 2.3.2.1e (previously classified as clade 2.3.2.1c) and is similar to viruses circulating in poultry in Cambodia in 2025.

Early investigations revealed that several chickens died at the boy’s house between 16 and 17 March and were used in meal preparation. The boy played near the area where the chickens died at his house. The Cambodian Communicable Disease and Control Department (CDC), Ministry of Health (MoH), and local Rapid Response Team (RRT) established enhanced surveillance and conducted further investigations. As of 25 March 2025, upper respiratory specimens collected from all contacts tested negative for influenza A(H5N1). Samples from local poultry were collected, and test results are pending. This case is the third human infection with influenza A(H5N1) reported in Cambodia in 2025.

(SNIP)

A(H5N1), Viet Nam

On 22 April 2025, Viet Nam notified WHO of a laboratory-confirmed human infection with an avian influenza A(H5N1) virus in child in Tay Ninh Province. The case developed fever, headache, and vomiting on 11 April 2025 and was seen at a hospital on the same day. On 13 April, the case was admitted to a tertiary children’s hospital in Ho Chi Minh City (HCMC) and was diagnosed with encephalitis. As of 21 April 2025, the patient was showing clinical improvement.

On 13 and 16 April, cerebrospinal fluid (CSF) samples were collected. On 16 April, testing indicated possible A(H5N1) virus detection and treatment with antivirals was initiated. On 17 April, nasopharyngeal (NP) swabs were collected and sent to the Oxford University Clinical Research Unit (OUCRU) of the Hospital of Tropical Diseases in HCMC, together with the CSF sample collected on 13 April, for RT-PCR testing. On the same day, the hospital also sent NP swabs and the CSF sample collected on 16 April to the Pasteur Institute (PI) in HCMC for RT-PCR testing. The CSF sample tested positive for influenza A(H5N1), while the NP sample tested negative for influenza A(H5N1) at both laboratories. Genomic sequencing conducted by the OUCRU indicated the virus belongs to the H5 HA clade 2.3.2.1e. The genomic sequencing results from PI HCM were pending at the time of reporting.

Buried fairly deep in another report issued last month (see Updated joint FAO/WHO/WOAH Public Health Assessment of Recent Influenza A(H5) Virus Events in Animals and People) are several brief mentions of clade 2.3.2.1e.

On page 3 (of 14) the report states:

Domestic and wild felids have been reported infected with influenza A(H5) virus belonging to other clades as well. In 2024, avian influenza outbreaks were reported in captive wild felines in two zoos in southern Viet Nam. These led to the death of at least 47 tigers, three lions and a leopard, and were confirmed to be caused by clade 2.3.2.1e A(H5N1) viruses, previously classified as a 2.3.2.1c clade A(H5) viruses.29,30

and

Other A(H5) virus clades such as 2.3.2.1e and 2.3.2.1a continue to circulate and evolve in poultry in geographically restricted regions.

On page 4 it states:

Two human cases of clade 2.3.2.1e38 A(H5N1) virus infection were reported from Cambodia since the last update of December 2024. Both cases were fatal and had exposure to sick or dead backyard poultry.

And on page 5:

The majority of the clade 2.3.2.1e viruses characterized antigenically reacted well to ferret antisera raised against the existing and CVV proposed in September 2024.

The phrase ` previously classified as a 2.3.2.1c clade A(H5)' appears several times in these reports, which hints at the difficulties in differentiating between closely aligned subclades. Since influenza A viruses are highly mutable - new subclades are occasionally added or better defined - meaning viruses previously cited as belonging to one subclade may shift to another.