Terminology
Influenza viruses are named after the Latin word "Influentia", meaning “influence”. There are four types of influenza viruses: A, B, C and D. During "flu season" several influenza A and B viruses are spreading. Only influenza A viruses are known to cause pandemics, health emergencies on a global scale. Influenza viruses possess three membrane proteins, the hemagglutinin (HA), the neuraminidase (NA), and the matrix protein M2. The membrane is the surface of the virus and is the part visible to the immune system. The 16 major antigenic variants of HA and 9 of NA are used for classification. The currently most relevant influenza virus subtype has variant 5 of HA and variant 1 of NA, therefore the subtype is named H5N1. This classification is biologically relevant because antibodies generally don't cross-react to different subtypes. This is why scientists try to create antibodies with a broader range of subtypes and the seasonal influenza vaccine is a mix of 3 or 4 different vaccines. The CDC provides more details on the terminology. This overview shows how HA is used for classification and the recent variants of H5N1, H5N6, and H5N8 are closely related.
Mutations
Influenza viruses have segmented RNA genomes, consisting of eight segments. The eight segments are PB2, PB1, PA, NP, HA, NA, M, and NS. Influenza viruses tend to mutate rapidly, changing single nucleotides. This is called "genetic drift". But their true superpower is that they can swap entire segments, resulting in sudden and drastic changes. This is called "genetic shift". A lethal H5N1 virus could one day swap segments with one of the many influenza viruses well adopted to spreading between humans. This could suddenly start a very deadly outbreak, or even a pandemic. One example of reassortment is the virus infecting cows.
>> Mutations
History
The first influenza pandemic that is scientific consent was in 1580, followed by 1729, 1781, 1830, 1898, H1N1 in 1918, H2N2 in 1957, H3N2 in 1968, and H1N1 in 2009. According to this source this resulted in 40-50 million deaths in 1918-1920, 1-2 million deaths in 1957-1958, 0.5 million to 2 million deaths in 1968-1970 and around 0.5 million deaths in 2009. The 1830 pandemic was comparable with the 1918 pandemic in terms of severity (C. W. Potter, A history of influenza), although population growth and rapid societal development make those comparisons difficult. While a pandemic of similar severity would theoretically result in around 250 million deaths today, this raises for example the question to what extend people in 1918-1920 died from co-infections that would be more easily treatable today. The 2009 H1N1 swine flu pandemic had a similar impact as the yearly influenza season, with several hundred thousand deaths and around 1 billion infections worldwide.
It is tempting to think that modern influenza pandemics may have to look similar to the 2009 H1N1 swine flu pandemic. But history clearly indicates that influenza viruses can become very lethal, regardless of old age, aftereffects of war like malnutrition, co-infections or any other explanations.
The extremely high H5N1 case fatality rate may actually be in the double-digits and the nightmare may become reality. The history of a potential bird flu pandemic has already begun with Covid-19, the politicization of public health measures and general pandemic fatigue.
If we take this history into account, it becomes clear that the medical consequences may be overshadowed by even worse disruptions of our complex, interconnected society. Reading "The Story of Influenza" is highly recommended to understand the social context of a severe pandemic.
Questions and Answers
What is happening?
The avian influenza virus H5N1 has mutated and is spreading worldwide, killing millions of animals, mostly birds. This is called a panzootic. H5N1 was first discovered in Hong Kong in 1996. The new variant H5N1 clade 2.3.4.4b was discovered in Europe in 2020 and has since then spread around the world. H5N1 has already reached all continents except Australia and is spreading throughout all seasons. This is unprecedented.
What is the risk?
The risk is adaptation to mammals, leading to sustained mammal-to-mammal transmission and ultimately sustained human-to-human transmission, causing a pandemic. This pandemic bird flu would likely be as transmissible as other influenza viruses, but very lethal with a case fatality rate in the double-digits.
What needs to happen for the virus to be cause a pandemic?
Birds and mammals have different receptors in their airways. But the difference is gradual and some animals like minks have a more even distribution of both receptors in the same part of their airways. The virus needs to change its' preference from birds to mammals. For this some mutations are necessary. Those mutations could occur in farms with a lot of mammals in a small space, especially fur farms or hog farms. The virus could also evolve in cats, which often come into contact with both birds and humans. There are many interactions between mammals and infected birds and each of them could cause a pandemic.
Has there been human-to-human transmission?
Probably yes, but transmission was not even close to sustained. Genetic analysis and serologic tests both confirm a low transmission potential. Furthermore, there are many uncertainties regarding human-to-human transmission. There are various cases of likely human-to-human transmission.
Has there been mammal-to-mammal transmission?
Probably yes, very likely between minks on fur farms. Mammal-to-mammal transmission between seals and sea lions is also very likely, although contamination with birds feces is also relevant. Of course mammal-to-mammal transmission happened in laboratory experiments. A special case is bird flu in cows, because transmission seems to be caused by contaminated milk and milking equipment.
Does the seasonal influenza vaccination prevent bird flu infections?
"Seasonal flu vaccination will not prevent infection with bird flu viruses but can reduce the risk of getting sick with human and bird flu viruses at the same time."
Are there antiviral drugs to treat bird flu?
Yes, there are antiviral drugs, but they could be better.
Are there vaccines to prevent bird flu?
Yes, there are vaccines, but it is uncertain how well they would work.
Are there stockpiles of antiviral drugs and vaccines?
Yes. The USA has stockpiled around 200 million doses of antiviral drugs and vaccines for around 20 million people. The strategy is to protect healthcare workers and critical infrastructure first. There are various agreements and stand-by production capabilities. CSL would for example deliver 150 million doses within 6 months. The situation in developing countries would be a lot worse.
What medical countermeasures are in development?
Long-lasting antibodies may improve both treatment and prevention. mRNA vaccines will improve efficacy and production process of vaccines.
What can be done to prevent a bird flu infection?
With less than 1.000 documented H5N1 cases, the personal risk for an average person is currently minimal. Pets are at risk from contact with wild birds. A pandemic bird flu would probably be as transmissible as the seasonal influenza, far less than Covid-19. Buying masks would drastically reduce the infection risk in case of a pandemic.
What other influenza viruses are considered especially dangerous?
Double-digit case fatality rates also occur with H5N6 and H7N9. The risk assessment tool IRAT of the CDC puts an emphasis on existing adaptation to humans. This explains the high ranking of seasonal influenza components H1N1 and H3N2. H7N9 is ranked third with about twice as many documented human infections as H5N1 and a case fatality rate of 39%. A H3N8 virus with concerning mutations has recently been documented.