Bird Flu: The Next Pandemic?

In the early spring of 1918, the H1N1 Influenza virus began sweeping relentlessly across the globe, tearing through continents with an intensity largely never seen before. By the end of the pandemic, a fifth of the world’s population had been infected and an estimated 50 million people had succumbed to the virus’ grasp, exceeding double the deaths accumulated throughout World War 1. [1] Having emerged in one of the final stages of the war, the virus hitched a ride along soldiers returning to their home countries, vastly exacerbating its spread to essentially every corner of the globe.

Today, as you are reading this, there could be up to 20,000 planes in the air at this very instant [2]. With our increasingly inter-connected, ever-bustling modern world, the emergence of a global pandemic is no longer merely a distant worry, but rather, a very real possibility we must confront. Our bustling modern cities, brimming at their seams, create densely packed populations that facilitate the rapid spread of contagions. Extensive deforestation, be it for agriculture or further urban development, erode the geographic barriers that separate humans and wildlife species. This in turn brings wildlife species in much closer proximity to human dwellings, giving pathogens that previously only existed in wildlife a prime setting to jump to humans. Overwhelming densities of livestock characteristic of our industrial animal farms provide the perfect milieu for the unfettered spread of disease among the livestock we rely on for food. All these components of modern life, fundamental to the functioning of our society today, collude to create the ideal conditions for future pandemics to flourish at an unprecedented scale.

Amidst all this, many of the world's scientists have been on edge specifically with regard to one type of flu in particular: the H5N1 Bird Flu. Over the past few years, it has not been unusual to hear of Avian Influenza outbreaks devastating poultry farms across the world, from the Americas to Asia. With an estimated mortality rate of between 75% and a staggering 100% among infected poultry [3], H5N1 bird flu epidemics in poultry farms could threaten major economic losses for related industries. As for humans, past outbreaks of the H5N1 virus have boasted a rather worrying mortality rate of about 50%, anywhere from 5 to 10 times more than that of the 1918 Flu pandemic that ravaged the world a century ago.[4] Yet, currently, despite the alarming case fatality rate of the H5N1 Bird Flu virus, there has been little evidence of sustained human-to-human transmissions in previous outbreaks, with the consensus being that the risk to the general public is still currently low (most cases of bird flu have occurred due to job-related or recreational exposures to infected animals or contaminated products). [5] So what exactly makes this strain of the flu so deadly compared to its seasonal counterparts? How exactly does it jump from birds to humans? And, of course, how concerned should we be of a potential pandemic?

Influenza Subtypes: What do the H and N mean?

But wait - what exactly do we mean when we refer to a subtype of influenza as H1N1 or H3N2? Firstly, let's look at how Influenza viruses are classified.

Overall, there are 4 main types of Influenza viruses, Types A, B, C and D, based on their core proteins, with types A and B usually being the main culprits responsible for seasonal flu and severe illness. In this case, our H5N1 Avian Influenza belongs to the Type A class of influenza viruses. Yet, even within these classes of the virus lies an even more complicated nomenclature for each strain of the flu, namely “Type/Origin/Strain/Year of Isolation (Subtype)” as seen in the figure below. [6]

Fig 1- The figure above shows an example of how Influenza strains are named [7]

So what do the H and N mean when we mention them in Influenza subtypes? Well, H stands for haemagglutinin and N stands for neuraminidase, both being viral coat glycoproteins (proteins bound to short sugar chains) embedded into the viral envelope.

Haemagglutinin proteins are responsible for allowing viral particles to bind to and enter host cells. Upon entry into a host animal, haemagglutinin binds to sialic acid receptors on the host cell membrane, usually that of respiratory epithelial cells within the respiratory tract. Here, the virus enters the cell via receptor-mediated endocytosis, whereby the virus’s binding onto receptors triggers the invagination of the cell surface membrane. This places the virus into an endocytic vesicle, essentially a little “bubble” in which the virus lies when entering the cell. Hence, this allows the virus to gain entry into the host cell, where it can later take over cellular machinery to produce more viral particles.

Fig 2 - Illustrated life cycle of an average Influenza Virus [8]

Neuraminidase, on the other hand, enables flu viruses to escape and infect other cells. As newly formed flu viruses begin to bud off from the host cell surface membrane, their release is facilitated by neuraminidase. Neuraminidase cleaves sialic acid residues from receptors on the cell surface membrane (to which viral haemagglutinin of new virions may bind), facilitating the release of progeny virions from the infected host cells.

Then, what do the numbers behind H and N indicate, for instance, in H1N1. Well, overall, scientists classify haemagglutinin and neuraminidase glycoproteins based on their structure and properties, with a total of 18 haemagglutinin subtypes and 11 neuraminidase subtypes. [7] Consequently, a subtype like H5N1 possesses type 5 haemagglutinin coat glycoproteins and type 1 neuraminidase coat glycoproteins. These subtypes and the combinations that different flu viruses possess bear immense significance in determining the virus’ characteristics, from its transmissibility (which depends on a balance of haemagglutinin and neuraminidase’s strength and haemagglutinin’s affinity for host cell receptors) to even its virulence and ability to avoid immunity. As such, the different subtypes and hence structures flu viruses bear could ultimately determine their potential as a pandemic-inducing pathogen.

Antigenic Shift: The possibility of Human-Human Transmission

As of now, there has been little evidence of sustained human-to-human transmission of avian influenza, with most infections arising from close contact with infected animals and their contaminated products. In fact, avian influenza has largely been circulating among wild aquatic birds, with animals like domestic poultry, cows and pigs serving as intermediate reservoirs. However, with animals like pigs being susceptible to both avian and human strains of the flu virus, experts have been concerned that such animals could be a prime spot for a novel and transmissible strain of bird flu to appear, one that could cause a devastating pandemic should it jump over to humans. So how exactly could this process occur?

Fig 3 - Genetic Reassortment occurring within the Influenza Virus

Influenza viruses are prone to swapping their genetic information with one another through a process called genetic reassortment. As shown in Fig 3, Influenza viruses have segmented genomes, with each viral capsid or “protein shell” containing 8 RNA segments coding for various viral proteins. When 2 or more different strains or subtypes of the Influenza virus infect the same cell in the same host, new virus particles that eventually form may contain genome segments of different pre-existing strains. As such, new viruses can take on a novel subtype, possessing a different combination of viral proteins from its 2 (or potentially more) parental strains. If this genetic reassortment confers a phenotypic change in the viral coat proteins, that of haemagglutinin and neuraminidase, we call this process antigenic shift, whereby there is a sudden and major change in the virus’ surface antigens (the part of the virus recognised by the host immune system).

Occasionally, such major genetic changes may enable a flu strain to jump from one animal species to another, and with the right luck, evolve to spread from person to person. Eventually, this could cause the production of a highly virulent virus with the potential to ignite a global pandemic.In the case of bird flu, for instance, should an intermediate host like a pig be infected by both avian and human strains of Influenza A, the viruses could infect the same cell to yield a new strain with a mix of genes from the bird strain and the human strain. Given the right recombinations of RNA segments, a novel strain of bird flu could potentially adopt transmissibility similar to that of seasonal flu outbreaks. This could allow a strain that almost no one has immunity against to spread at unprecedented rates from human to human.

Fig 4 - Antigenic Shift vs Antigenic Drift [9]

With Influenza’s tendency to swap genetic information across strains, scientists hence have to develop new vaccines every year to target the specific strains they expect to spread to the greatest extent. Coupled with the high replication rate of the virus and the low fidelity amidst the replication of its genome, surface antigens are also continuously changing their shape, so a vaccine made for last year’s version might not match up with this year’s virus very well. Here, in a process called antigenic drift, the flu virus’ genome gradually accumulates point mutations as the virus's genome, consisting entirely of RNA, is rather unstable. Hence, over time, there is an accumulation of tiny changes to the genome and thus the shape of the virus’ coat proteins encoded by these genes. Through this rather sneaky tactic, the flu virus’ antigenic sites can eventually be altered enough to evade detection by the host immune system, even if the prior strain had previously infected the host. Additionally, vaccines based on the previous year’s flu strains also no longer prove effective for outbreaks involving new flu strains. This forces scientists to ceaselessly update our flu vaccines to better match strains currently circulating in the population to protect against infection.

Bird flu: The Next Pandemic?

For your seasonal flu strains, the virus infects the epithelial cells of the upper respiratory tract, inducing symptoms ranging from body aches, chills, fevers, runny noses, to pneumonia in severe cases. However, one of the reasons bird flu boasts such a high mortality rate, one that towers over its seasonal counterparts, is because it attacks our lower respiratory tract– deep inside our lungs. Additionally,  with the H5N1 subtype being mainly adapted to infecting birds, most humans bear little prior immunity against the bird flu’s antigens. As such, upon infection with a strain of the bird flu, our immune system essentially encounters the bird flu virus as a completely new threat, unlike most seasonal flus we have partial immunity to. Essentially, our immune system has not yet “seen” the virus before and therefore cannot as quickly recognise and neutralise the threat. This gives the virus ample opportunity to replicate further before an effective immune response develops. Hence, the bird flu virus is a particularly virulent pathogen, causing severe and acute respiratory illness in humans.

Yet, despite all these perhaps frightening characteristics of the bird flu, most experts say that for now, the risk to the general public is still quite low. [10] For most historic outbreaks of the bird flu, nearly all infected individuals had been in prior contact with infected animals or their contaminated products. As such, there has been little evidence of sustained and effective transmission of the bird flu between humans, leaving most readers (who I suspect don’t regularly come into contact with animals susceptible to the bird flu) safe to be largely at peace at heart. As part of efforts to further safeguard against bird flu pandemics in livestock (which also reduces the chances of it spreading to humans), there have already been promising trials for mRNA flu vaccines for use in cattle. [11]

Yet, it is undeniably still crucial to emphasise the importance of remaining vigilant of the potential for bird flu to evolve into a pandemic-causing pathogen. In fact, it could be as little as a few mutations (or more specifically, reassortments) away from the capability to transmit from human to human with an exceedingly high virulence. Apart from this, we cannot forget the continued havoc bird flu epidemics can wreak on our dairy and poultry industries, with farms often being forced to cull essentially the entire affected flock following the detection of the avian influenza virus.

Fig 5 - Airport temperature monitoring systems [12]

For most scientists, it has become a question of not if but when the next major threat to human health will appear in the form of a pandemic. Be it from the H5N1 bird flu, or perhaps any other novel sickness, what is key to our survival is surveillance and vigilance. However, from the United States withdrawal from the World Health Organisation to massive funding cuts in key research institutes,  the weakening of global public health coordinations, diminishing of pandemic surveillance networks and the crippling of potentially life-saving research continues to threaten our ability to adapt and properly respond to future pandemics. At any moment, countries across the globe must be willing to coordinate and strive to eliminate the threat, be it culling afflicted livestock or temporarily increasing regulation of movement across their borders (for instance temperature checks in airports). Governments, scientists and health organisations alike must work in close coordination, strengthening surveillance systems, investing in medical research and ensuring rapid responses to emerging outbreaks.

By learning from past pandemics, like that of COVID-19, we can equip ourselves with the foresight to confront the looming threat of bird flu and any other potential pathogen. Only then can we truly safeguard our future generations from the devastating catastrophes a pandemic could wreak, for infectious diseases like bird flu recognise no borders.

References

[1] National Archives and Records Administration. (n.d.). The Influenza Epidemic of 1918. Archives.gov; National Archives and Records Administration. https://www.archives.gov/exhibits/influenza-epidemic/ ‌

[2] Boreadas, J. (2025, June 16). How Many Planes Fly Per Day Around the World? - Eas BCN. Eas BCN. https://easbcn.com/en/how-many-planes-fly-per-day-around-the-world/

[3] Avian Influenza (Bird Flu) Fact Sheet. (2025, March 12). Cornell University College of Veterinary Medicine. https://www.vet.cornell.edu/highly-pathogenic-avian-influenza-bird-flu-resource-center/avian-influenza-bird-flu-fact-sheet ‌

[4] Ministry of Health. (2026). Ministry of Health. https://www.moh.gov.sg/newsroom/bird-flu-danger-have-we-underestimated-risk/

[5] CDC. (2024, June 5). Transmission of Avian Influenza A Viruses Between Animals and People. Avian Influenza (Bird Flu). https://www.cdc.gov/bird-flu/virus-transmission/index.html ‌ ‌

[6] Kit, L. S. (1980). A revision of the system of nomenclature for influenza viruses: a WHO memorandum. PubMed, 58(4), 585–591. https://pubmed.ncbi.nlm.nih.gov/6969132 ‌

[7] CDC. (2024). Types of Influenza Viruses. Influenza (Flu). https://www.cdc.gov/flu/about/viruses-types.html

[8] Influenza Viruses Antiviral Services. (2025, October 10). Creative-Diagnostics.com. https://antiviral.creative-diagnostics.com/influenza-viruses-antiviral-services.html

[9]File:Differences-Between-Antigenic-Shift-and-Antigenic-Drift.webp - Wikimedia Commons. (2021, April 9). Wikimedia.org. https://commons.wikimedia.org/wiki/File:Differences-Between-Antigenic-Shift-and-Antigenic-Drift.webp

[10] Bartels, M. (2025, October 24). Why Bird Flu Is Surging Again—And What It Means for Public Health. Scientific American. https://www.scientificamerican.com/article/why-bird-flu-is-surging-again-and-what-it-means-for-public-health/

[11] Staff, G. B. (2025, May 8). Cutting-Edge mRNA Vaccine Shows Promise Against H5N1 in Dairy Cattle. Global Biodefense. https://globalbiodefense.com/2025/05/08/cutting-edge-mrna-vaccine-shows-promise-against-h5n1-in-dairy-cattle/

[12]Best Practices for Protecting Privacy in the Coronavirus Pandemic. (2020). Freedom House. https://freedomhouse.org/newsletter/keeping-democracy-healthy/best-practices-protecting-privacy-coronavirus-pandemic ‌