#Genetic and #antigenic characteristics of #zoonotic #influenza A viruses and development of candidate #vaccine viruses for #pandemic preparedness {WHO, March 28 '25}

February 2025 

The development of influenza candidate vaccine viruses (CVVs),  coordinated by WHO, remains an essential component of the overall global  strategy for influenza pandemic preparedness. Selection and development of  CVVs are the first steps towards timely vaccine production and do not imply a  recommendation for initiating manufacture. National authorities may consider the  use of 1 or more of these CVVs for pilot lot vaccine production, clinical trials and  other pandemic preparedness purposes based on their assessment of public health  risk and need. Zoonotic influenza viruses continue to be identified  and evolve both antigenically and genetically, leading to the need for additional  CVVs for pandemic preparedness purposes. Changes in the antigenic and genetic  characteristics of these viruses relative to existing CVVs and their potential risks  to public health justify the need to develop new CVVs. This document summarizes  the antigenic and genetic characteristics of recent zoonotic influenza viruses and  related viruses circulating in animals1 that are relevant to CVV updates.  Institutions interested in receiving these CVVs should contact WHO at gisrs-whohq@who.int or the institutions listed in announcements published on the WHO website.{2}

Influenza A(H5) 

Since their emergence in 1997, high pathogenicity avian influenza (HPAI) A(H5)  viruses of the A/goose/Guangdong/1/96 haemagglutinin (HA) lineage  have become enzootic in many countries, have infected wild birds  and continue to cause outbreaks in poultry and sporadic human and  other mammalian infections across a wide geographic area. In the United  States of America (USA), an outbreak of HPAI A(H5N1) in dairy cattle has been  reported since March 2024 with 2 additional introductions from wild birds  detected in February 2025. A(H5) HA gene segments have paired with a  variety of neuraminidase (NA) subtypes (N1, N2, N3, N4, N5, N6, N8 or N9).  These viruses have diversified genetically and antigenically, leading to the need  for multiple CVVs. This summary provides updates on the characterization of  A/goose/Guangdong/1/96-lineage A(H5) viruses and the status of the  development of influenza A(H5) CVVs. 

Influenza A(H5) activity from 24 September 2024  to 24 February 2025 

Since 2003, 16 A(H5), 7 A(H5N8), 93 A(H5N6) and 956 A(H5N1) human  infections or detections have been reported. Since 24 September 2024, 60  human infections with A/goose/Guangdong/1/96-lineage viruses have been  reported to WHO. A/goose/Guangdong/1/96-lineage A(H5) viruses have been  detected in both domestic and wild birds with spillover to mammals in many  countries, and sustained circulation in dairy cattle in the USA (...). The  nomenclature for phylogenetic relationships among the HA genes of  A/goose/Guangdong/1/96-lineage A(H5) viruses is defined in consultation with  representatives of WHO, the Food and Agriculture Organization of the United  Nations (FAO), the World Organisation for Animal Health (WOAH) and academic  institutions.{3} There has been a recent update to this nomenclature to reflect  the genetic diversification of the A(H5) viruses, particularly clade 2.3.2.1c, to add  2.3.2.1d, e, f, and g.{4} Where relevant, updated clade nomenclatures have been  adopted in this report. 

Genetic and antigenic characteristics  of influenza A(H5) viruses 

Sixty new human infections or detections with  A/goose/Guangdong/1/96-lineage viruses were reported. Most infected individuals had recent exposure to  birds or dairy cattle. One fatal human infection with a clade 2.3.2.1e A(H5N1)  virus was identified in Cambodia in this period. The HA of the virus recovered  from this individual, A/Cambodia/KSH250004/2025, had 2 amino acid  substitutions relative to the A/Cambodia/ SVH240441/2024 CVV and antigenic  data are pending. One human A(H5) infection from Viet Nam was detected;  no genetic or antigenic data were available for this case. One A(H5N1) virus  detection was reported in the United Kingdom of Great Britain  and Northern Ireland in an individual with recent exposure to infected commercial  poultry. This virus was confirmed as belonging to clade 2.3.4.4b and was  genetically and antigenically similar to existing clade 2.3.4.4b CVVs. One case of  clade 2.3.4.4b virus infection was detected in Canada in a severely ill  individual that ultimately recovered. Although a source of exposure was not  identified, the virus was genetically related to other clade 2.3.4.4b viruses  detected in wild birds and poultry in the region. The HA of the virus had 4 amino  acid substitutions relative to the  A/Astrakhan/3212/2020 CVV. Antigenic analysis  showed the virus reacted well to post-infection ferret antisera raised against the  A/Astrakhan/3212/2020,  A/American Wigeon/South Carolina/22-000345-001/2021, A/chicken/Ghana/AVL-763_21VIR7050-39/2021 and  A/Ezo red  fox/Hokkaido/1/2022 CVVs (Table 2). Fifty-six clade 2.3.4.4b A(H5) human  infections were identified in the USA. All but 2 cases reported exposure to dairy  cattle or poultry in backyard or commercial settings, and most reported mild  illness. One case where underlying comorbidities were present was hospitalized  with pneumonia but recovered. A second case, with prolonged, unprotected  exposure to infected birds in a backyard setting developed severe respiratory  disease leading to a fatal outcome. The HAs of viruses detected in human cases in  the USA and Canada were genetically similar to viruses detected in either dairy  cattle or birds (...) and had between 1 and 6 amino acid substitutions  relative to existing clade 2.3.4.4b CVVs. Most of the viruses tested antigenically  reacted well with ferret antisera raised to the clade 2.3.4.4b CVVs (...). A(H5)  viruses from birds and non-human mammals belonged to the following clades:  Clade 2.3.2.1a viruses were detected in poultry in Bangladesh and in wild birds  and poultry in India. Detections in captive tigers, a captive leopard, and domestic cats were also reported in India. The circulation of clade 2.3.2.1a  viruses in these countries has continued despite the introduction of clade 2.3.4.4b  viruses. The viruses from Bangladesh had HAs genetically similar to those of  viruses detected previously and reacted well with post-infection ferret antisera  raised against the A/duck/Bangladesh/19097/2013 CVV. The HA of viruses  detected in India were genetically related to A/Victoria/149/2024, a virus isolated  from a traveller returning to Australia from India{5} (...). No antigenic data are  available for the viruses collected in India; however, many of the HA amino acid  substitutions they contained were shared  with A/Victoria/149/2024, which  reacted poorly with post-infection ferret antisera raised against available CVVs  (...). Clade 2.3.2.1e viruses were detected in poultry in Cambodia, Lao People’s  Democratic Republic, and Viet Nam and in captive tigers and a captive leopard in  Viet Nam. The HAs of these viruses were similar to viruses detected in previous  periods in the region. Viruses from Lao People’s Democratic Republic and Viet Nam  were characterized antigenically. The viruses from Lao People’s Democratic  Republic reacted well with post-infection ferret antisera raised against  A/Vietnam/KhanhHoaRV1-005/2024, a A/Cambodia/SVH240441/2024-like virus  that is under development as a CVV. The viruses from Viet Nam reacted better  with post-infection ferret antisera raised against the  A/duck/Vietnam/NCVD1584/2012 CVV. Clade 2.3.2.1g HA sequences from  viruses circulating in multiple islands of the Republic of Indonesia in the previous  reporting period were analysed. Currently, there is no CVV proposed for  this clade. These viruses accumulated many amino acid substitutions when  compared to the sequences of CVVs of closely related clades previously classified  as clade 2.3.2.1c (...). No antigenic data were available from recently detected  viruses and will require further monitoring. Clade 2.3.4.4b viruses were  detected in birds in many countries, areas and territories in Africa, Antarctica, Asia, Europe, North America and South America. A(H5N1) viruses have  continued to circulate in birds in most regions; A(H5N6) viruses have been  detected in Eastern Asia; A(H5N5) viruses have been detected in Europe and North America; and A(H5N9) viruses were detected in poultry in the USA.  Infections in wild and captive mammals have continued to be reported, as well as  the ongoing outbreak in dairy cattle with subsequent spread to poultry, peri- domestic birds, and mammals in the USA. During this period, 2 additional  spillovers from wild birds to dairy cattle were reported in the USA. Since March  2024, the ongoing dairy cattle outbreak has spread to over 970 herds in 17  states. The majority of HAs from the characterized 2.3.4.4b viruses had less than  10 amino acid substitutions compared to the 2.3.4.4b CVVs, and most tested  viruses from dairy cattle reacted well to at least 1 of the post-infection ferret  antisera raised against the 2.3.4.4b CVVs. Ongoing circulation of virus in wild  birds in North America resulted in numerous outbreaks in commercial and  backyard poultry in the USA and Canada. Viruses tested reacted well with post- infection ferret antisera raised against at least 1 of the 2.3.4.4b CVVs (Table 2).  A(H5N6) and A(H5N1) viruses identified in China had only 3-7 HA amino  acid substitutions compared to 2.3.4.4b CVVs. Most viruses tested reacted well  with post-infection ferret antisera raised to viruses related to the current CVVs,  albeit with some A(H5N6) viruses showing reduced reactivity. Viruses detected in  wild birds and/or poultry in multiple countries in Europe and Asia reacted well with  post-infection ferret antisera raised to at least 1 of the available CVVs.  Several viruses identified in poultry in Egypt showed reduced reactivity to post- infection antisera raised to CVVs and require further monitoring. Clade 2.3.4.4h A(H5N6) viruses were detected in poultry in Fujian and Guangdong provinces of China. Detections of 2.3.4.4h viruses have been infrequent over recent years  but have been noted in the last 2 reporting periods, including 2 human infections  reported in 2024. The A(H5N6) viruses had accumulated up to 14 HA amino acid  substitutions relative to available CVVs and reacted poorly to post-infection ferret  antiserum raised against a surrogate of the A/Guangdong/18SF020/2018 CVV.  Similarly, 1 of the 2 human cases detected in 2024 reacted poorly to post- infection ferret antiserum raised against the A/Guangdong/18SF020/2018 CVV, the other reacted well, likely due to a single HA amino acid substitution (...). 

Influenza A(H5) candidate vaccine viruses 

Based on current genetic, antigenic and epidemiologic data, new CVVs that are antigenically like A/Victoria/149/2024 (clade 2.3.2.1a) and A/Fujian/2/2024  (clade 2.3.4.4h) are proposed. The available and pending A(H5) CVVs are listed in  Table 5. 

Influenza A(H9N2) 

Influenza A(H9N2) viruses are enzootic in poultry in many parts of Africa, Asia and the Middle East with the majority of viruses belonging to either the B  or G HA lineage.{6} Since the late 1990s, when the first human infection was  identified, sporadic detections of A(H9N2) viruses in humans and pigs have been  reported, with associated mild disease in most human cases and no evidence for  sustained human-to-human transmission. 

Influenza A(H9N2) activity from 24 September 2024 to 24 February 2025 

Sixteen A(H9N2) human infections have been identified in China, 1 of which  had an illness onset date in the previous reporting period. Twelve of the infections  were in individuals under the aged <10 years and all infected individuals  recovered. 

Genetic and antigenic characteristics of influenza A(H9N2) viruses 

The HAs of the 11 human viruses that were sequenced belonged to the B4.7  clade. Ten of these viruses had HAs that clustered phylogenetically, having  at most 10 amino acid substitutions relative to A/Anhui-Tianjiaan/11086/2022,  from which a CVV is being developed. The other virus had a genetically distinct HA  that was more similar to the A/Anhui-Lujiang/39/2018 CVV with 12 amino  acid substitutions relative to this CVV. All of the human viruses tested antigenically  reacted well to post-infection ferret antisera raised to A/Anhui-Tianjiaan/11086/2022 or A/Anhui-Lujiang/39/2018. A(H9N2) viruses from birds  belonged to the following clades: Clade B4.5 viruses were detected in Republic of  Indonesia, although from samples collected in the previous period, and from Viet  Nam. The HAs of the viruses from Republic of Indonesia had at least 19 amino  acid substitutions compared to available CVVs. No viruses were available for  antigenic characterization. The viruses from Viet Nam, despite having  accumulated over 20 HA amino acid substitutions, reacted well to post-infection  ferret antiserum raised against the A/chicken/Hong Kong/G9/1997 CVV. Clade  B4.7 viruses continued to predominate in poultry in China, and similar viruses  were detected in poultry in Cambodia, Lao People’s Democratic Republic, and Viet  Nam. Viruses from this clade continued to diversify genetically but reacted well  with post-infection ferret antiserum raised against the A/Anhui-Lujiang/39/2018- like CVV. Clade G5.6 viruses were detected in poultry in Egypt. Despite the  accumulation of up to 24 HA amino acid substitutions relative to the  A/Oman/2747/2019 CVV, post-infection ferret antiserum raised against this CVV  reacted well with the viruses from Egypt. Clade G5.7 viruses were detected in  Bangladesh and in a sample from India collected in the previous reporting period.  The HAs of recent viruses fell into phylogenetically distinct clusters differentiated  by country. The recent viruses from Bangladesh reacted well with post-infection  ferret antisera raised against the A/Oman/2747/2019 and  A/Bangladesh/0994/2011 CVVs. The virus from India was not available for  characterisation. 

Influenza A(H9N2) candidate vaccine viruses 

Based on the available antigenic, genetic and epidemiologic data, no new  CVVs are proposed. The available and pending A(H9N2) CVVs are listed in Table  6. 

Influenza A(H10) 

A(H10) viruses are frequently detected in birds in many regions of the world  and are considered endemic in poultry in China, with rare human infections  reported. Prior to this reporting period, 3 A(H10N3), 1 A(H10N5), 4 A(H10N7) and  3 A(H10N8) human infections were detected in China and A(H10N7) viruses  were detected in individuals with conjunctivitis or mild upper respiratory tract  symptoms in Australia (n=2) and Egypt (n=2). 

Influenza A(H10) activity from  24 September 2024  to 24 February 2025 

An A(H10N3) virus infection was identified in China in an adult with severe  illness who recovered. Antigenic and genetic characteristics  of influenza A(H10N3)  viruses The HA of the human virus was similar to those of the  A(H10N3) viruses previously detected in humans in China, but distinct from that  of a previously identified A(H10N5) human virus in China, in 2024. The internal  gene segments of the A(H10N3) virus were most similar to those of A(H9N2)  viruses circulating in chickens in China and its HA had 13 amino acid substitutions  compared to A/Jiangsu/428/2021, from which a CVV has been proposed. Antigenic data are pending. A(H10N7) viruses have been identified in poultry in Cambodia. The HAs of these viruses were most closely related to sequences of  A(H10) viruses detected in wild birds in East Asia, Southeast Asia and North  America and related to A(H10N3) viruses detected in humans in China. However,  the internal genes of the A(H10N7) viruses detected in Cambodia were unrelated  to the internal genes of the A(H10N3) viruses from humans in China. 

Influenza  A(H10N3) candidate vaccine viruses 

Based on the available genetic and epidemiologic data, no new CVVs are proposed. The pending A(H10N3) CVV is listed in Table 7. 

Influenza A(H1)v{7} 

Influenza A(H1) viruses are enzootic in swine populations in most regions  of the world. The genetic and antigenic characteristics of the viruses circulating in  different regions are diverse. Viruses isolated from human infections with swine  influenza A(H1) viruses are designated as A(H1) variant ((H1)v) viruses and have  been previously detected in the Americas, Asia and Europe. 

Influenza A(H1)v  activity from 24 September 2024  to 24 February 2025 

Multiple clades of A(H1) viruses were detected in swine populations globally  with 1 A(H1N1)v virus infection detected in China and 1 A(H1N2)v virus infection  detected in the USA (...). Genetic and antigenic characteristics of influenza A(H1)v  viruses The virus from the A(H1N2)v case detected in the USA belonged  to clade 1B.2.1 which is known to circulate in swine in the USA. The virus from the  case detected in China was a clade 1C.2.3 virus. Antigenic analysis of the  viruses from these cases were not performed because viruses could not be  recovered from the samples. Influenza A(H1)v candidate vaccine viruses Based on  the available antigenic, genetic and epidemiologic data, no new A(H1)v CVVs  are proposed. The available and pending A(H1)v CVVs are listed in Table 9.

Influenza A(H3N2)v 

Influenza A(H3N2) viruses with diverse genetic and antigenic characteristics are enzootic in swine populations in most regions of the world.  Human infections with influenza A(H3N2)v viruses originating from swine have  been previously documented in Asia, Australia, Europe and the Americas.  

Influenza A(H3N2)v activity from 24 September 2024 to 24 February 2025

A(H3N2) viruses were detected in swine in Canada and the USA (...). No  cases of infection with A(H3N2) v viruses were detected in this reporting period. 

Acknowledgements 

Acknowledgement goes to the WHO Global Influenza Surveillance and Response System (GISRS) which provides the mechanism for detection and monitoring of zoonotic influenza viruses. We thank the National Influenza Centres (NICs) of GISRS who contributed information, clinical specimens and viruses, and associated data; WHO collaborating centres of GISRS for their in-depth characterization and analysis of viruses and preparation of CVVs; and the U.S. Centers for Disease Control and Prevention, the U.S. Food and Drug Administration/Center for Biologics Evaluation and Research, WHO Essential Regulatory Laboratories of GISRS and WHO H5 Reference Laboratories for their complementary analyses and preparation of CVVs. We acknowledge the WOAH/FAO Network of Expertise on Animal Influenza (OFFLU) laboratories for their in-depth characterization and comprehensive analysis of viruses and other national institutions for contributing information and viruses. We also acknowledge the GISAID Global Data Science Initiative for the EpiFluTM database, and other sequence databases which were used to share gene sequences and associated information. 

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{1} For information relevant to other notifiable influenza virus infections in animals refer to https://wahis.woah.org/#/home 

{2} See https://www.who.int/teams/global-influenza-programme/vaccines/who-recommendations/zoonotic-influenza-viruses-and-candidate-vaccine-viruses 3 See https://onlinelibrary.wiley.com/doi/10.1111/irv.12324 4 See https://pubmed.ncbi.nlm.nih.gov/39829835/ 

{5} See No. 43, 2024, pp.–621-640.

{6} See https://wwwnc.cdc.gov/eid/article/30/8/23-1176_article 

{7} Standardization of terminology for the influenza virus variants infecting humans: Update https://cdn.who.int/media/docs/default-source/influenza/global-influenza-surveillance-and-response-system/nomenclature/standardization_of_terminology_influenza_virus_variants_update.pdf?sfvrsn=d201f1d5_6

Source: World Health Organization, https://iris.who.int/bitstream/handle/10665/380900/WER10013-14-eng-fre.pdf

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