Avian ‘Bird’ Flu – Undue media panic or genuine concern for pandemic potential requiring global preparedness action?

In 1996, highly pathogenic avian influenza (HPAI) A(H5N1) virus was first isolated from a domestic goose in Guangdong province, China.[1Chen H.L. H5N1 avian influenza in China.Sci China Ser C-Life Sci. 2009; 52: 419-427https://doi.org/10.1007/s11427-009-0068-6Crossref PubMed Scopus (69) Google Scholar] Since then, it has been identified in other poultries and wild birds with spillover into humans in over 60 countries, including United States of America (US), United Kingdom and Canada. In May 1997, the first human case of A(H5N1) virus infection and an outbreak of a total of 18 cases and 6 deaths in Hong Kong were documented.[2Katz J.M. Lim W. Bridges C.B. Rowe T. Hu-Primmer J. Lu X. et al.Antibody response in individuals infected with avian influenza A (H5N1) viruses and detection of anti-H5 antibody among household and social contacts.J Infect Dis. 1999; 180: 1763-1770https://doi.org/10.1086/315137WHOCrossref PubMed Scopus (0) Google Scholar] The high mortality rate was very concerning and attracted significant media attention and the disease was dubbed "bird flu". Five years later, two human cases with a history of travel to southern China were reported in February 2003 in Hong Kong.[3Guan Y. Poon L.L. Cheung C.Y. Ellis T.M. Lim W. Lipatov A.S. et al.H5N1 influenza: a protean pandemic threat.Proc Natl Acad Sci U S A. 2004; 101: 8156-8161https://doi.org/10.1073/pnas.0402443101Crossref PubMed Scopus (373) Google Scholar] First human infection reported in 2005 in China,[4Yu H. Shu Y. Hu S. Zhang H. Gao Z. Chen H. et al.The first confirmed human case of avian influenza A (H5N1) in Mainland China.Lancet. 2006; 367: 84https://doi.org/10.1016/S0140-6736(05)67894-4Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar] A(H5N1) continued to spread and human cases with high mortality were reported from Asia (Southeast and West) and subsequently Africa.[5Lai S. Qin Y. Cowling B.J. Ren X. Wardrop N.A. Gilbert M. Tsang T.K. et al.Global epidemiology of avian influenza A H5N1 virus infection in humans, 1997-2015: a systematic review of individual case data.Lancet Infect Dis. 2016; 16: e108-e118https://doi.org/10.1016/S1473-3099(16)00153-5Abstract Full Text Full Text PDF PubMed Scopus (189) Google Scholar] Since the global incidence of human A(H5N1) cases has remained at low level, public health authorities' attention was diverted to other emerging and re-emerging zoonoses such as Ebola, Lassa fever in West Africa, MERS in Saudi Arabia, variant swine 'pig' influenza A(H3N2) in the US, novel avian influenza A(H7N9) in China, and other avian influenza A(H5) subtypes in Asia, Europe and North America. From January 1, 2003 to April 1, 2024, 889 human cases of HPAI A(H5N1) and 463 deaths (CFR, 52%) were reported from 23 countries worldwide.[6World Health Organization . Disease Outbreak News. Avian influenza A(H5N1) – United States of America. 9 April 2024 . Geveva:WHO, 2024 https://www.who.int/emergencies/disease-outbreak-news/item/2024-DON512Google Scholar] While A(H5N1) currently does not transmit easily from human to human, its ability to cause severe illness, the high mortality rate, its potential to mutate to more contagious variants, the ongoing circulation in poultry and wild birds as well as the continuing reports of human cases is of concern for pandemic potential and critical for preparedness. The current outbreak of the Eurasian origin HPAI A(H5N1), clade 2.3.4.4b began in 2020 and has proven its unique ability to infect many mammalian species. Outbreaks in mammals have been attributed to their close proximity to avian reservoirs or consumption of infected prey in scavenging species. While most outbreaks in free-ranging wildlife have remained small, some outbreaks such as those in seals and sea lions have devastated local populations.7Ulloa M. Fernández A. Ariyama N. Colom-Rivero A. Rivera C. Nuñez P. et al.Mass mortality event in South American sea lions (Otaria flavescens) correlated to highly pathogenic avian influenza (HPAI) H5N1 outbreak in Chile.Vet Q. 2023; 43: 1-10https://doi.org/10.1080/01652176.2023.2265173Crossref PubMed Scopus (7) Google Scholar, 8Plaza P.I. Gamarra-Toledo V. Rodríguez Euguí J. Rosciano N. Lambertucci S.A. Pacific and Atlantic sea lion mortality caused by highly pathogenic Avian Influenza A(H5N1) in South America.Travel Med Infect Dis. 2024; 59102712https://doi.org/10.1016/j.tmaid.2024.102712Crossref PubMed Scopus (0) Google Scholar, 9Puryear W. Sawatzki K. Hill N. Foss A. Stone J.J. Doughty L. et al.Highly pathogenic avian influenza A(H5N1) virus outbreak in New England seals, United States.Emerg Infect Dis. 2023; 29: 786-791https://doi.org/10.3201/eid2904.221538Crossref PubMed Scopus (38) Google Scholar In April 2022, the first human case of HPAI A(H5N1) infection in US was reported in Colorado, in a person who was involved in the culling of poultry with presumptive A(H5N1) infection.[10Centers for Disease Control and Prevention . Press release: Highly pathogenic avian influenza A (H5N1) virus infection reported in a person in the U.S. 1 April 2024 . Atlana:CDC,2024. 〈https://www.cdc.gov/media/releases/2024/p0401-avian-flu.html〉Google Scholar] In March 2024, A(H5N1) was detected in dairy cows from 16 herds in six different states in the US. On April 1, 2024 Texas public health authorities reported to the US CDC, the country's second human case of A(H5N1) infection in a person who had a history of exposure to dairy cows presumed to be infected with the A(H5N1) virus.[6World Health Organization . Disease Outbreak News. Avian influenza A(H5N1) – United States of America. 9 April 2024 . Geveva:WHO, 2024 https://www.who.int/emergencies/disease-outbreak-news/item/2024-DON512Google Scholar] This first report of a cow-to-human spread of "bird flu" has created widespread media coverage and fear of an impending epidemic. While the US public health authorities have reassured the public that the safety risk to cattle, meat, and pasteurized milk is very low, concerns about potential impacts on prices and the livelihoods of farmers have however arisen. Nevertheless, the CDC has issued recommendations to avoid consumption of raw or undercooked food or related uncooked food products, such as unpasteurized (raw) milk or raw cheese, from animals with suspected or confirmed infection with HPAI A(H5N1) virus. Genetic sequencing has shown only minor mutations in the virus isolated from the cases.[11Centers for Disease Control and Prevention . Technical Update: Summary analysis of genetic sequences of highly pathogenic avian influenza A(H5N1) viruses in Texas. Atlanta:CDC, 2024 . 〈https://www.cdc.gov/flu/avianflu/spotlights/2023-2024/h5n1-analysis-texas.htm〉Google Scholar] According to WHO the virus seems not to have acquired mutations that may facilitate transmission among humans and the estimated public health risk is considered to be low for the general population, and low to moderate for occupationally exposed persons.[6World Health Organization . Disease Outbreak News. Avian influenza A(H5N1) – United States of America. 9 April 2024 . Geveva:WHO, 2024 https://www.who.int/emergencies/disease-outbreak-news/item/2024-DON512Google Scholar] The report of the US human case brings forth several important issues including the question of whether this signals a global pandemic in the making? Foremost, how has transmission in cows and from cow to human occurred? Infected cows show symptoms such as decreased lactation, anorexia, lethargy, fever and dehydration, raising concerns of an increased risk of H5N1 viruses becoming better adapted to mammals with enhanced potential to spilling over to humans and other livestock.[12World Organization for Animal Health . High pathogenicity avian influenza in cattle. 5 April 2024 . Paris:WOAH, 2024. 〈https://www.woah.org/en/high-pathogenicity-avian-influenza-in-cattle/〉Google Scholar] It has been suggested that A(H5N1) might not be spreading among cows through the air.[13Kozlov M. , Mallapaty S. Bird flu outbreak in US cows: why scientists are concerned. Nature 2024 ; 〈https://www.nature.com/articles/d41586-024-01036-1〉Google Scholar] The current thought is that the virus has spread via the use of contaminated milking equipment between infected and uninfected cows.[14Cohen J. Bird flu may be spreading in cows via milking and herd transport. Science 2024; April 24 〈https://www.science.org/content/article/bird-flu-may-be-spreading-cows-milking-and-herd-transport〉Google Scholar] How a virus that causes respiratory tract disease ends up in cow udders, and is detectable in milk, and whether other organs are infected is important to elucidate. No infection in beef cattle has been detected yet, but this could be due to sub-clinical or mild symptoms and lack of active surveillance. Another question is how to prevent further spread from dairy farms. Taking reference from experiences with controlling HPAI associated with poultry, the strategies include culling of the entire herd, while vaccination is another option. Improving on farm biosecurity and establishing surveillance programs will be critical, including steps to protect personnel involved in the culling, by vaccination and antiviral prophylaxis. HPAI had previously led to the culling of hundreds of millions of poultry around the globe in the past years and local outbreaks have been contained in this manner. However A(H5) is largely carried by migrating birds and continues to spread to new regions and new mammalian hosts including cats, tigers, seals, dolphins, goats and polar bears, constantly mutating and hence possibly increasing risk of spillover to humans.15Jang S.G. Kim Y.I. Casel M.A.B. Choi J.H. Gil J.R. Rollon R. et al.HA N193D substitution in the HPAI H5N1 virus alters receptor binding affinity and enhances virulence in mammalian hosts.Emerg Microbes Infect. 2024; 132302854https://doi.org/10.1080/22221751.2024.2302854Crossref PubMed Scopus (0) Google Scholar, 16Huang P. Sun L. Li J. Wu Q. Rezaei N. Jiang S. et al.Potential cross-species transmission of highly pathogenic avian influenza H5 subtype (HPAI H5) viruses to humans calls for the development of H5-specific and universal influenza vaccines.Cell Discov. 2023; 9: 58https://doi.org/10.1038/s41421-023-00571-xCrossref PubMed Scopus (7) Google Scholar Also, there has been a number of outbreaks on a mink farm in Spain in autumn 2022 [17Agüero M. Monne I. Sánchez A. Zecchin B. Fusaro A. Ruano M.J. et al.Highly pathogenic avian influenza A(H5N1) virus infection in farmed minks, Spain, October 2022.Euro Surveill. 2023; 282300001https://doi.org/10.2807/1560-7917.ES.2023.28.3.2300001Crossref Scopus (79) Google Scholar] and in 2023 multiple outbreaks on fur farms in Finland.[18Lindh E. Lounela H. Ikonen N. Kantala T. Savolainen-Kopra C. Kauppinen A. et al.Highly pathogenic avian influenza A(H5N1) virus infection on multiple fur farms in the South and Central Ostrobothnia regions of Finland, July 2023.Euro Surveill. 2023; 282300400https://doi.org/10.2807/1560-7917.ES.2023.28.31.2300400Crossref Scopus (18) Google Scholar] So far, limited number of human cases have occurred after close contacts with infected wild birds or poultry, while the latest US case was the first that followed exposure to mammal; importantly, little human-to-human transmission has been observed. The European Food Safety Agency (EFSA) warned of a large-scale avian influenza pandemic if the virus becomes transmissible among people given that the human population has no immunity against the A(H5N1) virus and herd immunity is absent.[19European Food Safety Authority (EFSA); European Centre for Disease Prevention and Control (ECDC) Adlhoch C. Alm E. Enkirch T. Lamb F. Melidou A. Willgert K. Marangon S. Monne I. Stegeman J.A. Delacourt R. Baldinelli F. Broglia A. Drivers for a pandemic due to avian influenza and options for One Health mitigation measures.EFSA J. 2024; 22e8735https://doi.org/10.2903/j.efsa.2024.8735Crossref Scopus (0) Google Scholar] As a respiratory infection, transmission in human would require a shift in the preferred receptor on the cell surface from sialic acid alpha 2,3 found deep in the human lungs to the 2,6 receptor found in the human upper respiratory tract.[20Nicholls J.M. Chan R.W. Russell R.J. Air G.M. Peiris J.S. Evolving complexities of influenza virus and its receptors.Trends Microbiol. 2008; 16 (Apr): 149-157https://doi.org/10.1016/j.tim.2008.01.008Abstract Full Text Full Text PDF PubMed Scopus (172) Google Scholar] However, the US patient who was exposed to dairy cattle had presented with conjunctivitis as the only symptom, and mucosal transmission may have occurred. It is possible, however, that more human cases, sub-clinical, mild cases might have remained undetected and further investigation is needed, including serology studies of exposed humans. A pertinent question is whether H5N1 vaccines based on the current circulating clade 2.3.4.4b should be developed and stockpiled, and also if dairy workers should be vaccinated using the human H5N1 vaccine stockpile? Currently only a limited stockpile of vaccines targeting early strains of H5N1 are available, and more specific vaccines for birds,[21European Food Safety Authority (EFSA) . Vaccination of poultry against highly pathogenic avian influenza – Available vaccines and vaccination strategies (10 October 2023). EU:EFSA, 2023. 〈https://www.efsa.europa.eu/en/news/vaccination-poultry-against-highly-pathogenic-avian-influenza-available-vaccines-and〉Google Scholar] animals and humans need to be developed since the threat of ongoing mutations and more human-to-human transmission is ever present. For cattle, no H5N1 vaccines exists. It is possible to develop a new cattle vaccine by modifying the ones based on the swine vaccine which is already used. On the other hand, poultry vaccines are used in China, with some successes.[22Swayne D.E. Spackman E. Pantin-Jackwood M. Success factors for avian influenza vaccine use in poultry and potential impact at the wild bird-agricultural interface.Ecohealth. 2014; 11: 94-108https://doi.org/10.1007/s10393-013-0861-3Crossref PubMed Scopus (61) Google Scholar] Concerns about international trade restrictions limited the adoption of vaccination in poultry industry in many countries. Vaccinating birds is potentially concerning, due to the possibility of continued transmission of silent infections and the risk of breakthrough transmission leading to vaccine resistance.[23Islam A. Munro S. Hassan M.M. Epstein J.H. Klaassen M. The role of vaccination and environmental factors on outbreaks of high pathogenicity avian influenza H5N1 in Bangladesh.One Health. 2023; 17100655https://doi.org/10.1016/j.onehlt.2023.100655Crossref Scopus (3) Google Scholar] Nevertheless, vaccination as a strategy has been recently endorsed as compatible with the pursuit of safe trade by the World Assembly of World Organization for Animal Health (WOAH) national delegates.[24Capps B. Lederman Z. One Health, Vaccines and Ebola: The opportunities for shared benefits.J Agric Environ Ethics. 2015; 28: 1011-1032https://doi.org/10.1007/s10806-015-9574-7Crossref Scopus (25) Google Scholar] Current prevention and control programs rely on reactive surveillance, notifications, isolating farms or other places of captivity, and culling of infected birds and those in close contact. This policy may not be effective as it has missed early 2024 outbreaks heralded by dead cats on the farm.[13Kozlov M. , Mallapaty S. Bird flu outbreak in US cows: why scientists are concerned. Nature 2024 ; 〈https://www.nature.com/articles/d41586-024-01036-1〉Google Scholar] The mechanisms have not taken into account the influences of climate and environment change as drivers of zoonotic diseases outbreaks. At this time there are a lot of uncertainties. Scaling up of the production of human vaccines against the new A(H5N1) variants seems imperative, primarily to protect high-risk individuals such as farm workers against infection, but also for stockpiling, and secondly to increase preparedness should the virus evolve to sustained human-to-human transmission. Culling of poultry has so far not resulted in controlling the zoonotic pandemic (enzootic) of A(H5N1); perhaps a shift towards prevention instead, by the vaccination of farm animals and farm workers needs to be considered. Limiting exposure to and spread of avian influenza will require more comprehensive 'One Health' measures to mitigate risk of adaptation and spread from current bird reservoirs to mammals and humans,19European Food Safety Authority (EFSA); European Centre for Disease Prevention and Control (ECDC) Adlhoch C. Alm E. Enkirch T. Lamb F. Melidou A. Willgert K. Marangon S. Monne I. Stegeman J.A. Delacourt R. Baldinelli F. Broglia A. Drivers for a pandemic due to avian influenza and options for One Health mitigation measures.EFSA J. 2024; 22e8735https://doi.org/10.2903/j.efsa.2024.8735Crossref Scopus (0) Google Scholar, 25Franklin S.I. Can One Health fight H5N1 avian influenza?.Lancet Planet Health. 2023 Jun; 7 (PMID: 37286240.): e442-e443https://doi.org/10.1016/S2542-5196(23)00086-4Abstract Full Text Full Text PDF PubMed Scopus (1) Google Scholar embracing the concept of shared risks and benefits. Extrinsic drivers that require investigation are wildlife and human activities, farming practices and the use of natural resources, climatic and environmental factors. They need to be addressed urgently through enhancing surveillance, and ensuring access to rapid diagnostics. Can new rapid diagnostic tests be manufactured quickly and distributed to all those involved in domestic animal husbandry? Effective engagement between veterinarian and human health virologists, epidemiologists and professionals of other expertise is important, so as to strengthen animal health programs, and the reduction of wildlife contact with domestic animals, especially at poultry and animal farms. More proactive surveillance for HPAI needs to be put in place alongside current proactive detection and surveillance programs. The scale of the A(H5N1) pandemic in wild and domestic birds is enormous, and the spillover in mammals is a concern.[26Venkatesan P. Avian influenza spillover into mammals.Lancet Microbe. 2023; 4e492https://doi.org/10.1016/S2666-5247(23)00173-8Abstract Full Text Full Text PDF Google Scholar] The recent incident of A(H5N1) in dairy cattle and the human infection is a wake-up call for action. Since 2020, A(H5N1) has caused over 50 million bird deaths worldwide, many migrating from Europe to the Middle East contracting the virus from domestic poultry. The hundreds of dead or dying sea lions in Peru indicate that the virus may be adapting for mammal-to-mammal transmission. The problem may even be related to climate changes, as migration of birds may be affected by drought, rising temperatures, increasing sea levels.[27Wille M. Atkinson R. Barr I.G. Burgoyne C. Bond A.L. Boyle D. et al.Long-distance avian migrants fail to bring 2.3.4.4b HPAI H5N1 into Australia for a second year in a row.Influenza Other Respir Viruses. 2024; 18e13281https://doi.org/10.1111/irv.13281Crossref Scopus (0) Google Scholar] The potential for a leap to become a human pathogen that may lead to a pandemic must be monitored carefully. Given the evolving epidemiology of the A(H5N1) virus, and the obvious shared risk for domestic animals, wildlife and pandemic potential for humans worldwide, it is urgent to apply the notion of a 'shared benefit' approach, grounded in One Health,[24Capps B. Lederman Z. One Health, Vaccines and Ebola: The opportunities for shared benefits.J Agric Environ Ethics. 2015; 28: 1011-1032https://doi.org/10.1007/s10806-015-9574-7Crossref Scopus (25) Google Scholar] for enhancing preparedness and achieving effective control. Striking the right balance between the existing pandemic in birds with the pandemic potential for humans is the essence. Based on an inter-species immunity protection that could only be attained through mass vaccination of poultry with no further hesitancy, it is a real test case for the quadripartite organizations – FAO (Food and Agriculture Organization), UNEP (United Nations Environment Programme), WHO and WOAH. Eskild Petersen and Lone Simonsen acknowledge financial support for the PandemiX Center, from the Danish National Research Foundation (grant No. DNRF170). Professor Sir Ali Zumla acknowledges support from the Pan-African Network for Rapid Response, Research and Preparedness for Emerging and Re-Emerging Infections (PANDORA-ID-NET) funded by the EU-EDCTP2 - EU Horizon 2020 Framework Programme. He is in receipt of a UK NIHR Senior Investigator Award. He is also a Mahathir Science Award and EU-EDCTP Pascoal Mocumbi Prize Laureate.