The Time is Now: a Call to Contain H9N2 Avian Influenza Viruses

In the past century, we have seen four pandemics caused by human influenza A: H1N1 Spanish influenza (1918–1920), H2N2 Asian influenza (1957–58), H3N2 Hong Kong influenza (1968–69), and H1N1 swine influenza (2009–10).1Brody H Influenza.Nature. 2011; 480: S1-S3Crossref PubMed Scopus (5) Google Scholar Phylogenetic analyses have shown that reassortment of genetic segments from human, animal, or avian influenza viruses is linked to the origin of the four influenza pandemic strains.Since 2013, there have been many novel avian influenza viruses that were identified from humans, including H7N9, H6N1, H10N8, H5N6, H7N4, H10N3, and H5N8 avian influenza viruses (figure). Notably, H7N9 viruses have caused more than 1500 laboratory-confirmed human cases of avian influenza worldwide. In April, 2022, a 4-year-old boy with influenza-like illness was determined to have been infected with a novel H3N8 avian influenza virus in Henan province. Subsequently, H3N8 avian influenza virus caused a second human infection in Hunan province, in May, 2022.3Yang R Sun H Gao F et al.Human infection of avian influenza A H3N8 virus and the viral origins: a descriptive study.Lancet Microbe. 2022; (published online Sept 14.)https://doi.org/10.1016/S2666-5247(22)00192-6Summary Full Text Full Text PDF Google Scholar The continuous emergence of novel avian influenza viruses capable of human infection highlights the increasing pandemic risk that they pose.H9N2 viruses have been reported to be involved in the origin of multiple human-infecting avian influenza viruses, such as H7N9, H10N8, and the recently emerging H3N8 (April, 2022; figure).3Yang R Sun H Gao F et al.Human infection of avian influenza A H3N8 virus and the viral origins: a descriptive study.Lancet Microbe. 2022; (published online Sept 14.)https://doi.org/10.1016/S2666-5247(22)00192-6Summary Full Text Full Text PDF Google Scholar H9N2 viruses have contributed a complete set, or partial internal genes, to the novel human-infecting avian influenza viruses. Poultry that carry H9N2 avian influenza viruses host an optimal environment for viruses of different subtypes to exchange their gene segments with H9N2 avian influenza viruses.4Liu D Shi W Gao GF Poultry carrying H9N2 act as incubators for novel human avian influenza viruses.Lancet. 2014; 383: 869Summary Full Text Full Text PDF PubMed Google Scholar Avian influenza viruses with H9N2-derived internal genes would also probably have an increased ability to infect humans.5Bi Y Chen Q Wang Q et al.Genesis, evolution, and prevalence of H5N6 avian influenza viruses in China.Cell Host Microbe. 2016; 20: 810-821Summary Full Text Full Text PDF PubMed Scopus (202) Google Scholar Therefore, poultry that carry H9N2 avian influenza viruses are viewed as genetic incubators for the origin of novel avian influenza viruses that infect humans.4Liu D Shi W Gao GF Poultry carrying H9N2 act as incubators for novel human avian influenza viruses.Lancet. 2014; 383: 869Summary Full Text Full Text PDF PubMed Google ScholarH9N2 avian influenza viruses show low pathogenicity in birds, and H9N2-infected poultry are often subclinical, presenting with no or very few symptoms; however, avian hosts can shed and transmit the viruses to other clinically vulnerable individuals. Notably, H9N2 avian influenza viruses have been identified in domesticated poultry across China, with stable endemic lineages in commercial chicken flocks.6Gu M Xu L Wang X Liu X Current situation of H9N2 subtype avian influenza in China.Vet Res. 2017; 48: 49Crossref PubMed Scopus (94) Google Scholar Since 2016, H9N2 has also gradually become the dominant avian influenza virus subtype in live poultry markets.7Bi Y Li J Li S et al.Dominant subtype switch in avian influenza viruses during 2016–2019 in China.Nat Commun. 2020; 115909Crossref Scopus (46) Google Scholar More than 100 human cases of H9N2 avian influenza virus have been reported as of July, 2022, including more than 50 cases after the outbreak of COVID-19.2WHOMonthly risk assessment summary.https://www.who.int/teams/global-influenza-programme/avian-influenza/monthly-risk-assessment-summaryDate: 2022Date accessed: June 27, 2022Google Scholar A retrospective seroprevalence study revealed that human infection with H9N2 exceeded 10% in occupationally exposed populations (eg, poultry workers, including wholesale sellers and food delivery workers) in seven regions of China sampled between 2014 and 2016.8Quan C Wang Q Zhang J et al.Avian influenza A viruses among occupationally exposed populations, China, 2014–2016.Emerg Infect Dis. 2019; 25: 2215-2225Crossref PubMed Scopus (22) Google Scholar The majority of circulating H9N2 avian influenza viruses possess an increased propensity to bind to human-type sialic acid receptors.7Bi Y Li J Li S et al.Dominant subtype switch in avian influenza viruses during 2016–2019 in China.Nat Commun. 2020; 115909Crossref Scopus (46) Google Scholar Therefore, the number of human H9N2 cases has likely been greatly underestimated.In fact, at least 60 countries have reported the identification of H9N2 avian influenza viruses in domesticated and wild birds, including most of the countries in Europe and Asia, and several countries from Africa, and North and South America. Notably, H9N2 avian influenza virus has been found in more than 50 species of wild birds and can infect a diverse range of domesticated and wild mammals, including cats, dogs, pigs, pikas, foxes, and raccoon dogs.Several whole inactivated virus (WIV) vaccines have been licensed by the Chinese Ministry of Agriculture and Rural Affairs to prevent H9N2 avian influenza virus infections, with the first vaccine licensed in the early 2000s. Of the vaccines, some are monovalent in nature, with a single representative H9N2 avian influenza virus employed as the vaccine strain. Trivalent and tetravalent prophylactic vaccines are available for H9N2 avian influenza virus, together with vaccine strains for Newcastle disease, infectious bursal disease, and infectious bronchitis, to simplify the immunisation procedure. However, these intensive vaccination programmes have not prevented the national circulation of H9N2 avian influenza viruses. The low efficacy of vaccination and H9N2 avian influenza virus prophylaxis has also been reported frequently in other countries, and the poultry with single vaccination can also be infected and subsequently shed the virus.6Gu M Xu L Wang X Liu X Current situation of H9N2 subtype avian influenza in China.Vet Res. 2017; 48: 49Crossref PubMed Scopus (94) Google Scholar This could at least partly attribute to the constant genetic and antigenic variation of the virus.6Gu M Xu L Wang X Liu X Current situation of H9N2 subtype avian influenza in China.Vet Res. 2017; 48: 49Crossref PubMed Scopus (94) Google Scholar In particular, as a low pathogenic avian influenza virus, the initial infection of H9N2 happens at respiratory or alimentary mucosal surfaces,9Payne S Family Orthomyxoviridae.in: Payne S Viruses. Academic Press, London2017: 197-208Crossref Google Scholar whereas the whole inactivated virus vaccines primarily induce a humoral immune response, which is not able to produce sterilising immunity in immunised chickens.10Kapczynski DR Swayne DE Influenza vaccines for avian species.Curr Top Microbiol Immunol. 2009; 333: 133-152PubMed Google ScholarThe pandemic potential of H9N2 avian influenza viruses is shown by the constant emergence of human-infecting avian influenza viruses with H9N2-derived internal genes; the increased human type receptor-binding capacity; the widespread transmission networks in domesticated poultry and wild birds; and the increasingly expanding host spectrum for the viruses. Now is the time to contain H9N2 in China and worldwide. New, effective strategies against H9N2 avian influenza viruses are urgently required, and we recommend development and licensure of vaccines to induce not only humoral immune responses, but also T-cell responses and mucosal immunity to prevent onward viral transmission. In the past century, we have seen four pandemics caused by human influenza A: H1N1 Spanish influenza (1918–1920), H2N2 Asian influenza (1957–58), H3N2 Hong Kong influenza (1968–69), and H1N1 swine influenza (2009–10).1Brody H Influenza.Nature. 2011; 480: S1-S3Crossref PubMed Scopus (5) Google Scholar Phylogenetic analyses have shown that reassortment of genetic segments from human, animal, or avian influenza viruses is linked to the origin of the four influenza pandemic strains. Since 2013, there have been many novel avian influenza viruses that were identified from humans, including H7N9, H6N1, H10N8, H5N6, H7N4, H10N3, and H5N8 avian influenza viruses (figure). Notably, H7N9 viruses have caused more than 1500 laboratory-confirmed human cases of avian influenza worldwide. In April, 2022, a 4-year-old boy with influenza-like illness was determined to have been infected with a novel H3N8 avian influenza virus in Henan province. Subsequently, H3N8 avian influenza virus caused a second human infection in Hunan province, in May, 2022.3Yang R Sun H Gao F et al.Human infection of avian influenza A H3N8 virus and the viral origins: a descriptive study.Lancet Microbe. 2022; (published online Sept 14.)https://doi.org/10.1016/S2666-5247(22)00192-6Summary Full Text Full Text PDF Google Scholar The continuous emergence of novel avian influenza viruses capable of human infection highlights the increasing pandemic risk that they pose. H9N2 viruses have been reported to be involved in the origin of multiple human-infecting avian influenza viruses, such as H7N9, H10N8, and the recently emerging H3N8 (April, 2022; figure).3Yang R Sun H Gao F et al.Human infection of avian influenza A H3N8 virus and the viral origins: a descriptive study.Lancet Microbe. 2022; (published online Sept 14.)https://doi.org/10.1016/S2666-5247(22)00192-6Summary Full Text Full Text PDF Google Scholar H9N2 viruses have contributed a complete set, or partial internal genes, to the novel human-infecting avian influenza viruses. Poultry that carry H9N2 avian influenza viruses host an optimal environment for viruses of different subtypes to exchange their gene segments with H9N2 avian influenza viruses.4Liu D Shi W Gao GF Poultry carrying H9N2 act as incubators for novel human avian influenza viruses.Lancet. 2014; 383: 869Summary Full Text Full Text PDF PubMed Google Scholar Avian influenza viruses with H9N2-derived internal genes would also probably have an increased ability to infect humans.5Bi Y Chen Q Wang Q et al.Genesis, evolution, and prevalence of H5N6 avian influenza viruses in China.Cell Host Microbe. 2016; 20: 810-821Summary Full Text Full Text PDF PubMed Scopus (202) Google Scholar Therefore, poultry that carry H9N2 avian influenza viruses are viewed as genetic incubators for the origin of novel avian influenza viruses that infect humans.4Liu D Shi W Gao GF Poultry carrying H9N2 act as incubators for novel human avian influenza viruses.Lancet. 2014; 383: 869Summary Full Text Full Text PDF PubMed Google Scholar H9N2 avian influenza viruses show low pathogenicity in birds, and H9N2-infected poultry are often subclinical, presenting with no or very few symptoms; however, avian hosts can shed and transmit the viruses to other clinically vulnerable individuals. Notably, H9N2 avian influenza viruses have been identified in domesticated poultry across China, with stable endemic lineages in commercial chicken flocks.6Gu M Xu L Wang X Liu X Current situation of H9N2 subtype avian influenza in China.Vet Res. 2017; 48: 49Crossref PubMed Scopus (94) Google Scholar Since 2016, H9N2 has also gradually become the dominant avian influenza virus subtype in live poultry markets.7Bi Y Li J Li S et al.Dominant subtype switch in avian influenza viruses during 2016–2019 in China.Nat Commun. 2020; 115909Crossref Scopus (46) Google Scholar More than 100 human cases of H9N2 avian influenza virus have been reported as of July, 2022, including more than 50 cases after the outbreak of COVID-19.2WHOMonthly risk assessment summary.https://www.who.int/teams/global-influenza-programme/avian-influenza/monthly-risk-assessment-summaryDate: 2022Date accessed: June 27, 2022Google Scholar A retrospective seroprevalence study revealed that human infection with H9N2 exceeded 10% in occupationally exposed populations (eg, poultry workers, including wholesale sellers and food delivery workers) in seven regions of China sampled between 2014 and 2016.8Quan C Wang Q Zhang J et al.Avian influenza A viruses among occupationally exposed populations, China, 2014–2016.Emerg Infect Dis. 2019; 25: 2215-2225Crossref PubMed Scopus (22) Google Scholar The majority of circulating H9N2 avian influenza viruses possess an increased propensity to bind to human-type sialic acid receptors.7Bi Y Li J Li S et al.Dominant subtype switch in avian influenza viruses during 2016–2019 in China.Nat Commun. 2020; 115909Crossref Scopus (46) Google Scholar Therefore, the number of human H9N2 cases has likely been greatly underestimated. In fact, at least 60 countries have reported the identification of H9N2 avian influenza viruses in domesticated and wild birds, including most of the countries in Europe and Asia, and several countries from Africa, and North and South America. Notably, H9N2 avian influenza virus has been found in more than 50 species of wild birds and can infect a diverse range of domesticated and wild mammals, including cats, dogs, pigs, pikas, foxes, and raccoon dogs. Several whole inactivated virus (WIV) vaccines have been licensed by the Chinese Ministry of Agriculture and Rural Affairs to prevent H9N2 avian influenza virus infections, with the first vaccine licensed in the early 2000s. Of the vaccines, some are monovalent in nature, with a single representative H9N2 avian influenza virus employed as the vaccine strain. Trivalent and tetravalent prophylactic vaccines are available for H9N2 avian influenza virus, together with vaccine strains for Newcastle disease, infectious bursal disease, and infectious bronchitis, to simplify the immunisation procedure. However, these intensive vaccination programmes have not prevented the national circulation of H9N2 avian influenza viruses. The low efficacy of vaccination and H9N2 avian influenza virus prophylaxis has also been reported frequently in other countries, and the poultry with single vaccination can also be infected and subsequently shed the virus.6Gu M Xu L Wang X Liu X Current situation of H9N2 subtype avian influenza in China.Vet Res. 2017; 48: 49Crossref PubMed Scopus (94) Google Scholar This could at least partly attribute to the constant genetic and antigenic variation of the virus.6Gu M Xu L Wang X Liu X Current situation of H9N2 subtype avian influenza in China.Vet Res. 2017; 48: 49Crossref PubMed Scopus (94) Google Scholar In particular, as a low pathogenic avian influenza virus, the initial infection of H9N2 happens at respiratory or alimentary mucosal surfaces,9Payne S Family Orthomyxoviridae.in: Payne S Viruses. Academic Press, London2017: 197-208Crossref Google Scholar whereas the whole inactivated virus vaccines primarily induce a humoral immune response, which is not able to produce sterilising immunity in immunised chickens.10Kapczynski DR Swayne DE Influenza vaccines for avian species.Curr Top Microbiol Immunol. 2009; 333: 133-152PubMed Google Scholar The pandemic potential of H9N2 avian influenza viruses is shown by the constant emergence of human-infecting avian influenza viruses with H9N2-derived internal genes; the increased human type receptor-binding capacity; the widespread transmission networks in domesticated poultry and wild birds; and the increasingly expanding host spectrum for the viruses. Now is the time to contain H9N2 in China and worldwide. New, effective strategies against H9N2 avian influenza viruses are urgently required, and we recommend development and licensure of vaccines to induce not only humoral immune responses, but also T-cell responses and mucosal immunity to prevent onward viral transmission. WS receives support from the Academic Promotion Programme of Shandong First Medical University (2019QL006). JL receives support from the Programme for Youth Innovation in Universities of Shandong Province (2021KJ064). All other authors declare no competing interests. Editorial note: The Lancet Group takes a neutral position with respect to territorial claims in published maps and institutional affiliations Human infection of avian influenza A H3N8 virus and the viral origins: a descriptive studyThe novel H3N8 virus that caused human infection had originated from chickens, a typical spillover. The virus is a triple reassortment strain with the Eurasian avian H3 gene, North American avian N8 gene, and dynamic internal genes of the H9N2 viruses. The virus already possesses binding ability to human-type receptors, though the risk of the H3N8 virus infection in humans was low, and the cases are rare and sporadic at present. Considering the pandemic potential, comprehensive surveillance of the H3N8 virus in poultry flocks and the environment is imperative, and poultry-to-human transmission should be closely monitored. Full-Text PDF Open Access