High pathogenicity avian influenza in Australia and beyond: could avian influenza cause the next human pandemic?

Background

High pathogenicity avian influenza virus (HPAIV) H5N1 (often referred to as ‘bird flu’) has made world headlines recently with infections recorded for the first time in dairy cows,¹ mice,² cats³ and marine mammals.⁴ This has raised the question: does this virus have the potential to cause the next human pandemic?

Avian influenza viruses are a subset of influenza A viruses that rapidly circulate within shorebirds and waterfowl.⁵ These include low pathogenic and HPAIVs. Mostly, low pathogenic avian influenza viruses (LPAIVs) cause minimal disease within wild birds. However, viruses of the H5 and H7 subtypes can evolve to become HPAIVs by the generation of a multi-basic cleavage site (MBCS) within the hemagglutinin (HA; H5 or H7) protein.⁶ This evolution typically occurs within poultry, and adding a MBCS allows for the dissemination of the virus systemically resulting in high pathogenicity within poultry.⁶

HPAIV H5N1 first spilled over into humans from poultry in 1997 in Hong Kong.⁷ This virus, a precursor to modern-day H5N1 viruses was called A/goose/Guangdong/1/1996 and caused significant concern due to the high mortality rate associated with the outbreak (6 of 18 infected individuals died).⁷ Since 2005, the virus has undergone several neuraminidase (NA) and internal gene reassortments with LPAIVs and other HPAIVs resulting in outbreaks within wild birds across Asia and Europe.⁵ Historically, wild waterfowl carry HPAIV H5N1 with mild symptoms and shed the virus within their faeces, and as a result, have been implicated as a long-distance vector of the virus into Europe and the Americas from Asia.⁵ These events coincide with annual wild bird migratory patterns.⁸

The global situation

The newest variant of HPAIV H5N1 clade 2.3.4.4b was first detected in the Netherlands in late 2020.⁹ This variant quickly circulated throughout Europe and was detected within poultry in Newfoundland and Labrador, Canada, and shortly thereafter, within the United States. The next year, it was introduced to South America.¹⁰ Unfortunately, by late 2022, clade 2.3.4.4b had reached the bottommost tip of South America, posing a serious risk of transmission to Antarctica.¹⁰

HPAIV H5N1 clade 2.3.4.4b, like all HPAIVs, is associated with high morbidity and mortality within poultry,^9,10 and has caused mass poultry die offs across Europe, Africa, Asia and the Americas over the past few years.¹¹ By 2023, it was estimated that this variant had caused the death of 58 million birds in the US alone.¹² Unusually, HPAIV H5N1 2.3.4.4b has also caused die offs of a vast range of wild birds,⁸ even solitary birds such as bald eagles have presented with severe disease.¹³ Several mammalian species including racoons, foxes, dogs and cats, have also been infected, likely by predation or scavenging of infected birds.¹⁴ Within South America, ~50,000 marine mammals, including seals, sea lions and dolphins have been killed by the virus off the coast of Peru, Argentina, Chile and Uruguay.¹⁵ Symptoms were mostly neurological, i.e. seizures, paralysis and stupor; however, respiratory symptoms such as nasal or buccal secretions and dyspnoea were also documented.¹⁵ The infection of marine mammals and birds in South America represents a threat to the unique ecological niche of Antarctica. There have been many outbreaks within elephant and fur seals, and birds including Gentoo penguins, kelp gulls, albatross and skuas within the continent and its islands.¹⁶

In April 2024, the US Department of Agriculture (USDA) confirmed the detection of HPAIV H5N1 clade 2.3.4.4b within a series of dairy herds in several states including Texas, Michigan and Kansas.^1,17 As of July 2024, 171 herds within 13 US states have detected the variant,¹ with reported viral titres within unpasteurised milk between 2 × 10⁵ to 6 × 10⁷ plaque-forming units (PFUs) mL^–1.¹⁸ Notably, pasteurisation inactivates the virus, preventing transmission by milk consumption.¹⁸ Mice and barn cats on these farms have also been infected with the variant likely from consuming unpasteurised milk, with many of these cases in cats proving lethal.² This outbreak represents a new facet of HPAIV H5N1 transmission and pathogenesis, with ongoing implications for the dairy industry, human and animal health.

Human spillover of HPAIV H5N1 clade 2.3.4.4b is very rare – as of June 2024, there have been 15 human cases reported within seven countries (Cambodia, Chile, China, Ecuador, Spain, the US and the UK).¹⁹ However, other HPAIV H5N1 variants have exhibited a high mortality rate – HPAIV H5N1 clade 2.3.4.4b has caused the death of one person in China in 2022.¹⁹ The majority of these human cases were a result of direct exposure to infected poultry, and importantly, no evidence of human-to-human transmission has ever been identified.¹⁹ However, four dairy workers have tested positive for HPAIV H5N1 clade 2.3.4.4b by exposure to infected dairy cows,^1,20 suggesting this variant may be transmitted from mammal-to-mammal without the involvement of an infected wild bird. Most of these cases among dairy workers were mild²⁰; however, it is noted that this number could be an understatement due to the high likelihood of underreporting on dairy farms across America. Symptoms in humans include but are not limited to conjunctivitis, fever, body aches, cough, sore throat and, in severe cases, pneumonia that requires hospitalisation.¹⁹ However, 7 of 15 of these HPAIV H5N1 clade 2.3.4.4b human cases have also been reported as asymptomatic.¹⁹

Avian influenza in Australia

As of June 2024, Australia remains the only continent that has not detected HPAIV H5N1 clade 2.3.4.4b within wild birds, poultry or mammals alike.²¹ This is likely to reflect the fact that most wild bird flyways that circulate within Oceania tend not to intercept with highly endemic regions; however, this may change.²² Many wild birds are diverging from their traditional migration periods and flyway courses as a result of rising temperatures, changing weather patterns and population declines.²³ Within Australia, there have been seven recent detections of HPAIV H7N3 within poultry and duck farms near Meredith, Vic., Australia.²⁴ An additional poultry farm near Terang, Vic., was also confirmed positive for HPAIV H7N9.²⁴ Another six outbreaks of HPAIV H7N8 were reported on poultry farms in New South Wales and two in the Australian Capital Territory.²⁵ These incidents are believed to have occurred by the introduction of H7Nx LPAIV from wild birds, which then evolved to HPAIV once the virus entered the poultry production.²⁶ The Victorian Department of Agriculture, Fisheries and Forestry has performed a detailed risk assessment of HPAIV incursion and an evaluation of the current HPAI surveillance system within wild birds.²⁴ All HPAIV-positive properties have been placed under quarantine and all poultry have been euthanased.²⁴ Australia is currently free of HPAIV H5N1; however, this incursion of H7Nx HPAIV into the poultry industry highlights how avian influenza is an ongoing public health threat to Australia, the poultry industry and native wildlife.

For the first time, a returned Australian traveller from India tested positive for HPAIV H5N1 clade 2.3.2.1a on 22 March 2024.²⁷ The case occurred within a child who is thought to have acquired the virus from consuming undercooked infected poultry, as no interaction with wild birds, poultry or other animals was reported.²⁸ This clade has previously caused human infections in Nepal and India.²⁹ Despite suffering a severe illness, the child made a full recovery and did not transmit the virus.²⁷ This human case and the numerous outbreaks on poultry farms were detected due to Australia’s enhanced surveillance programme,²⁷ which will continue to be an extremely important measure to prioritise as HPAIV H5N1 clade 2.3.4.4b continues to evolve and spread throughout the globe.

HPAIV H5N1: the next human viral pandemic?

Influenza A viruses are considered a significant threat to public health due to their high mutation rate and pandemic potential.³⁰ There have been several past influenza A pandemics in humans, including the 1918 H1N1 ‘Spanish flu,’ the 1957 H2N2 ‘Asian flu,’ the 1968 H3N2 ‘Hong Kong flu’ and the 2009 H1N1 ‘Swine flu’.³¹ Currently, HPAIV H5N1 transmission to humans requires direct, close contact with an infected host, such as wild birds or poultry.³² HPAIV H5N1 can spread by aerosolised droplets and preferentially binds to α-2,3-sialic acids found within the lower respiratory tract of humans.³² As avian influenza viruses begin to become more adapted to the mammalian system, the acquisition of mammalian adaptations by reassortment or antigenic drift may increase the risk of transmission to humans.³⁰ Human-to-human transmission of HPAIV H5N1 has not been confirmed; however, there is some evidence to suggest that sustained mammal-to-mammal transmission has occurred within marine mammals in South America.³³ Sequencing of virus samples obtained from sick and deceased sea lions within these areas demonstrates several key mutations important for mammalian transmission.³³ Some of these include mutations PB20-Q591K and PB2-D701N, both known to increase pathogenicity by enhancing the activity of the polymerase basic 2 (PB2) protein within mammals.³⁴ Bioinformatic analysis and machine learning algorithms must be trained and implemented to evaluate the pandemic potential of HPAIV H5N1 clade 2.3.4.4b as it evolves.

Conclusions

Globally, the HPAIV H5N1 situation will continue to change. The lack of human-to-human transmission of the virus is encouraging. However, we are also witnessing the spread of this virus into previously uninfected continents and species. To better stand prepared against HPAIV H5N1 clade 2.3.4.4b, we must continue to uphold a series of strict biosecurity measures on poultry farms with confirmed cases of HPAIV,³⁵ especially as wild birds migrate back to Australia between August and November 2024.³⁵ If this variant were to be introduced into Australia, it would cause devastation to our unique ecosystem and species diversity.³⁶ Many Australian native birds have never been exposed to this virus before,³⁶ and some birds, including black swans, are known to be highly susceptible to severe disease from avian influenza virus.³⁷ Furthermore, the potential for sustained human-to-human transmission of HPAIV H5N1 clade 2.3.4.4b is still of great concern, especially as mammalian transmission of the virus continues to occur. However, several strategies including enhanced surveillance, stockpiling of antivirals and vaccines and the production of a novel vaccine must be prioritised by governments now to help mitigate the severity of any future pandemic.