H9N2 avian influenza viruses: challenges and the way forward

We read with interest the work of Yuhai Bi and colleagues1Yang 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; 3: e824-e834Summary Full Text Full Text PDF PubMed Scopus (26) Google Scholar and Rengui Yang and colleagues,2Bi Y Li J Shi W The time is now: a call to contain H9N2 avian influenza viruses.Lancet Microbe. 2022; 3: e804-e805Summary Full Text Full Text PDF PubMed Scopus (7) Google Scholar published in The Lancet Microbe, describing that H9N2 avian influenza viruses were the origin of multiple human-infecting H7N9 and H10N8 avian influenza viruses,1Yang 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; 3: e824-e834Summary Full Text Full Text PDF PubMed Scopus (26) Google Scholar and the origin of the recently emerged H3N8 avian influenza virus.2Bi Y Li J Shi W The time is now: a call to contain H9N2 avian influenza viruses.Lancet Microbe. 2022; 3: e804-e805Summary Full Text Full Text PDF PubMed Scopus (7) Google Scholar Over the past several decades, H9N2 viruses have been isolated worldwide from wild and domestic avian species. The broad prevalence of H9N2 viruses in birds naturally increases the risk of transmission to mammals, especially humans. Although H9N2 viruses are of low pathogenicity to birds, and have only sporadically infected humans with mild or asymptomatic cases, they have continued to contribute to zoonotic spillover events by providing gene materials for the reassortment of novel influenza variants. During our routine influenza surveillance in poultry farms and live poultry markets of mainland China from 2019 to 2020, 22 H9N2 viruses were isolated from chicken populations in seven provinces of China (appendix p 3). Phylogenetic analysis suggested that the haemagglutinin genes of these H9N2 viruses did not cluster together, and formed three independent branches (appendix p 9), indicating that the genomes of these H9N2 viruses evolved recently. We used a hemagglutinin-inhibition assay with antigens of these H9N2 viruses, along with specific chicken antiserum of eight H9N2 viruses, and found that these H9N2 viruses formed three novel antigenic groups (appendix p 2, 10). This finding suggests that H9N2 antigenic variants have emerged in recent years. We also evaluated the protective efficacy of the bivalent HN/SD vaccine candidate (appendix pp 1–2) in chickens against the challenges of H9N2 viruses. Unexpectedly, the H9N2 vaccine could not provide effective protection for chickens against challenge with these H9N2 viruses (appendix pp 5–8), highlighting the urgent need for the analysis of H9N2 viruses. Differing from highly pathogenic H5 and H7 subtype avian influenza viruses, H9N2 viruses have not been a priority for the disease control agencies in many countries. In China, the introduction of a bivalent H5–H7 vaccine successfully prevented chicken infection with H7N9 viruses, and thus avoided (and nearly eliminated) human infections.3Shi J Deng G Ma S et al.Rapid evolution of H7N9 highly pathogenic viruses that emerged in China in 2017.Cell Host Microbe. 2018; 24: 558-568Summary Full Text Full Text PDF PubMed Scopus (165) Google Scholar However, H9N2 has gradually become the dominant avian influenza virus subtype in live poultry markets in China since 2016,4Bi Y Li J Li S et al.Dominant subtype switch in avian influenza viruses during 2016–2019 in China.Nat Commun. 2020; 115909Crossref Scopus (71) Google Scholar which has resulted in the constant emergence of novel human-infecting avian influenza viruses (eg, H10N3 and H3N8) with the donors of H9N2 in China during a 2-year period. The inactivated whole virus vaccines have been used to control H9N2 avian influenza virus infection in poultry for more than 20 years.5Dong J Zhou Y Pu J Liu L Status and challenges for vaccination against avian H9N2 influenza virus in China.Life. 2022; 121326Crossref Scopus (5) Google Scholar Unlike the effective protection of chickens immunised with H5/H7 vaccines, H9N2-inactivated vaccine could not prevent the immunised chicken flocks from reinfection with viruses and shedding viruses, despite high antibody titres of immunised chickens.5Dong J Zhou Y Pu J Liu L Status and challenges for vaccination against avian H9N2 influenza virus in China.Life. 2022; 121326Crossref Scopus (5) Google Scholar In our study, continued antigenic drift of H9N2 viruses had resulted in the poor protective efficacy in immunised chickens; however, there were other factors, including T-cell responses and mucosal immunity, which might have affected the protective efficacy of immunised chickens.2Bi Y Li J Shi W The time is now: a call to contain H9N2 avian influenza viruses.Lancet Microbe. 2022; 3: e804-e805Summary Full Text Full Text PDF PubMed Scopus (7) Google Scholar Particularly, several novel immune escape mutations in haemagglutinin proteins were also identified. Therefore, the antigenic mutations of H9N2 viruses should also be taken into consideration when choosing the vaccine strains. The pandemic potential of H9N2 viruses is shown by the constant emergence of human-infecting influenza viruses with the internal genes of H9N2,2Bi Y Li J Shi W The time is now: a call to contain H9N2 avian influenza viruses.Lancet Microbe. 2022; 3: e804-e805Summary Full Text Full Text PDF PubMed Scopus (7) Google Scholar demonstrating that stopping the generation of novel human-infecting avian influenza viruses at their origin is urgently needed. We strongly advise that more attention be given to the prevention and control of H9N2 viruses, not only to enhance the ongoing H9N2 surveillance of birds and high-density at-risk human populations, but also to develop universal H9N2 vaccines. We declare no competing interests. We acknowledge the authors, originating and submitting laboratories of the sequences from the Global Initiative on Sharing All Influenza Data (GISAID)'s EpiFlu Database on which this research is based. All submitters of data can be contacted directly through the GISAID website (www.gisaid.org). This Correspondence was supported by National Natural Science Foundation of China (grant numbers 31830097 and 31672586), and Young Scholars of Yangtze River Scholar Professor Program (2019 WQ). JZ, ML, and WQ planned and conceptualised the laboratory work, and wrote the Correspondence. JZ and LH conducted the virus isolation from samples, antigenic analysis, animal experiments, and sequenced the genomes. ML and WQ provided the funding. Download .pdf (1.72 MB) Help with pdf files Supplementary appendix