A high-pathogenic H5N1 subtype of the bird flu (avian influenza) virus has infected farm poultry and wild birds with high mortality on almost every continent. Surprisingly, bird flu has jumped to mammals. Alarmingly, over 800 cases of bird-to-human transmission of the virus have been documented in the past twenty years, with severity of illness ranging from mild to severe, and an overall mortality of 52%. Although rare human-to-human bird flu infections have occurred, there has been no sustained human transmission. Nevertheless, the likelihood of a pandemic in humans appears to be increasing. Vaccines against H5N1 in humans have been developed. Clinical trials are underway into new types of bird flu vaccines for human use based on mRNA technology that has proved successful with Covid-19.
Different subtypes of avian influenza virus have evolved
During a bird flu infection, an antibody response is directed at the viral H and N antigens on the surface of the virus particle. The separate gene segments of the virus that code for the H and N antigens readily undergo mutation and recombination between different viruses from which new virus subtypes and variants evolve. Avian influenza viruses are divided into low- and high-pathogenic subtypes denoted HxNy. Most are in the low-pathogenic group, while the high-pathogenic viruses of most concern include H5N1, H7N7, and H7N9.
Worldwide spread of high-pathogenic bird flu subtypes
Low-pathogenic bird flu has been endemic in waterfowl such as wild ducks, swans, and geese for many decades, accompanied by sporadic outbreaks of high-pathogenic viruses. In 2020, H5N8 caused the death of wild birds which spread the virus to farm poultry in several countries. H5N8 was subsequently replaced by H5N1, a more easily transmissible high-pathogenic subtype. In many countries H5N1 has devastated chickens, ducks, and turkeys on commercial farms, where the poultry usually live in close proximity, requiring the slaughter of millions of birds.
H5N1 spread further to wild birds on almost every continent. Unlike earlier subtypes, H5N1 persisted all year round in migratory bird populations. The virus spread quickly where birds gather in large flocks in their breeding grounds. Bass Rock, lying off the coast of North Berwick in Scotland, is normally the spring breeding ground of a massive colony of up to 150,000 migratory Northern gannets, the largest colony of this majestic sea bird in the world. In 2022, large numbers of gannets succumbed to H5N1, but the colony has since recovered, possibly due in part to a certain level of natural resistance in the population.
While it is impossible to stop the spread of the virus in the wild, surveillance and mitigation strategies can be put in place to contain bird flu outbreaks in farm poultry. This includes the use of protective clothing and making sure wild and farm birds do not interact, for example, by using netting and keeping the poultry indoors as much as possible. Moreover, if the poultry are indoors, the wild birds cannot access their feed. Despite the use of these and other control strategies, the recent unprecedented worldwide epidemic of H5N1 in wild birds and farm poultry has been the worst on record and has had a significant economic impact on food production.
Deadly bird flu jumps to mammals
H5N1 has jumped from farm poultry and wild birds to at least 26 mammalian species including seals, sea lions, mink, raccoons, alpacas, foxes, and dairy cows. Wild birds and mammals continuously interact in nature so there are many opportunities for transmission of the virus to mammals. Foxes scavenge infected bird carcasses. Seals and sea lions pick up the virus by feeding on the carcasses of infected sea birds. Over 600,000 seals and sea lions have succumbed to H5N1 all the way from Eastern Canada to countries in South America.
It was a huge surprise when dairy cows on dozens of farms in the USA were recently found to be infected with H5N1, which is not lethal to these animals. The sick cows appear to have transmitted the virus not only to each other but also to chickens and cats on nearby poultry farms. High titres of the virus were found in cow’s milk, and it has been suggested that transmission among the animals occurs via contaminated milking machinery in crowded milking sheds. We do not know which mutations in H5N1 allow the virus to infect so many diverse mammals, but it makes it more likely that sooner or later it will spread to humans.
Different bird flu subtypes can infect humans
The first fatalities of H5N1 in humans were recorded in Hong Kong in 1997. All were associated with exposure of people to infected poultry. In the past two decades, many sporadic infections of humans with high-pathogenic subtypes have been documented. In China and Laos, 80 cases of bird-to-human transmission of an H5N6 subtype have been reported. Limited outbreaks of H7N3 (64 cases) have occurred in the UK and Canada. H7N9 has caused hundreds of fatalities mainly in Asia.
With hundreds of cases of bird-to-human transmission documented worldwide in recent years and over half of cases proving fatal, there is valid cause for alarm. A few recent cases provide evidence of transmission of H5N1 from infected cows to livestock workers in the USA, which suggests an additional route for bird flu to infect humans is possible and increases the likelihood of sustained human-to-human transmission.
Non-sustained transmission of bird flu among humans
Non-sustained human-to-human transmission of low and high-pathogenic subtypes of bird flu has occurred in several countries, not all of which were associated with farm workers. H7N7, which has been circulating in the Netherlands for several years, was transmitted from an infected individual to three family members. Many isolated cases of non-sustained human-to-human transmission of H5N1 have been reported in Thailand, Pakistan, and Indonesia.
In China, widespread infections of high-pathogenic H7N9 in humans have occurred since 2013. These cases were linked to live poultry markets, backyard domestic poultry, and close family members. Worryingly, a few instances of the spread of H7N9 among related family members and unrelated individuals were recorded in Chinese hospitals during this period.
The fact that human-to-human transmission of H7N7 and H7N9 has occurred in addition to H5N1 increases the probability that a dangerous novel virus might arise through mutation and/or gene recombination between different bird flu subtypes. Even the possibility that the exchange of genes between human and bird flu genomes giving rise to a hybrid virus with pandemic potential must be considered. There is a worrying precedent for this. Although controversial, evidence has been presented that the Spanish flu pandemic of 1918 which killed over 50mn people, was caused by a human H1N1 subtype with its origins in both human and bird flu viruses.
Can vaccination protect humans from bird flu?
Vaccines designed to protect humans from H5N1 were manufactured in 2007-2008 by CSL Seqirus, GSK, and Sanofi Pasteur, but were hardly used. These earlier vaccines may not be effective against future H5N1 variants and subtypes such as H7N7 and H7N9. Because of the serious risk of a pandemic in humans, the European Commission has purchased 665,000 bird flu vaccine doses from CSL Seqirus with the option of a further 40 million doses over the next four years. This newly manufactured vaccine is made by cultivating the virus in live chicken eggs, a cumbersome but reliable method. In addition to chicken eggs, CSL Seqirus has now created an H5N1 vaccine employing mammalian cell culture technology already in use for manufacturing seasonal human influenza virus vaccines.
The UK government has decided to order tens of thousands of vaccines for use against bird flu in humans. A contract to supply the vaccines was put out to tender in June 2024 by the Health Security Agency, the objective being to stockpile the vaccines in the event of a sustained outbreak of H5N1 bird flu in humans. The vaccines are expected to be ready for use in December 2024.
In 2023, Moderna started phase one clinical trials of mRNA vaccines designed to be effective against current H5 and H7 viruses employing mRNA technology that has proved successful against Covid-19. These mRNA vaccines can be modified, tested, and manufactured quickly if a new H5 or H7 vaccine-resistant variant were to arise. Effective vaccines will be essential as sustained human-to-human transmission of avian influenza viruses looks increasingly likely, but we cannot predict when or whether it will happen.
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