It is 60 years since the iconic Alfred Hitchcock movie “The Birds” was released, based on the true events of a mass bird attack in California. Today, the avian influenza A virus has created its own drama.
Reports of human infections have been sporadic, but the circulation of the highly pathogenic avian influenza (HPAI) virus has been rising in avian species and mammals such as red foxes, seals, and minks.
Thankfully, human avian influenza infection rates remain low and are mainly confined to those who have been in direct contact with sick or dead birds that harbor the disease. In fact, the spread has led to the mass culling of poultry. The concern is not the number of reported human infections but the potential for the avian influenza virus (AIV) to further mutate, allowing for human-to-human transmission and the start of another pandemic.
There are four types of influenza virus; A, B, C, and D. AIV, nicknamed ‘bird flu,’ is a highly contagious type A virus that spreads between wild aquatic birds. causing severe respiratory disease. Once confined to Asia, type A has appeared in Africa, Europe, and North America, and has recently spread southwards from Mexico to southern Chile. Mammals that feed on wild birds are also being infected, which resulted in a mass mortality event of 3,487 South American sea lions in Peru in early 2023.1
AIV has many subtypes based on two proteins, hemagglutinin (HA) and neuraminidase (NA). For example, the H5N1 virus has a HA 5 protein and a NA 1 protein.2 Viral modification can occur by antigen drift, where small mutations arise due to the influence of the host, or by antigen shift, where genetic reassortment occurs to create new HA or NA subtypes, leaving a human host without any immunological defense against the new strain of the virus due to lack of previous exposure.3
H5N1, H5N6, H5N8, H6N1, H7N2, H7N3, H7N7, H7N9, H9N2, H10N7, and H10N8 are all known to infect humans. While mild symptoms are associated with H6N1, H7N2, H7N3, and H7N7 subtypes, H5N1 and H7N9 can cause severe symptoms in humans, leading to a high mortality rate.3 The viral strains that originate from animal hosts with new HA or NA subtypes are most likely to impact pandemic risk. These novel strains can spread quickly through the human population due to a lack of immunity.4
The current clade (the original virus and its descendants) of the H5N1 virus is known as 2.3.4.4b. Cases of H5N1 2.3.4.4b have been reported from Chile, China, England, Ecuador, Spain, and the U.S., with one reported fatality in China.5 The most recent AIV H5 infection was identified in two poultry workers in England in May 2023. Importantly, no human-to-human transmission has been reported in any of these cases.6
H7N9 is a potential pandemic AIV as it is widespread in poultry markets, can overcome host barriers, pre-existing neutralizing antibodies are absent, has a gene reassortment with H9N2, and adapts to a human host. H5N1 and H7N9 are of greatest concern due to their high mortality rates.7 The U.S. Center for Disease Control and Prevention (CDC) currently places the pandemic risk of H5N1 clade 2.3.4.4b virus as moderate, and H7N9 as moderate-high.8
Human disease can occur after contact with infected bird droppings, saliva, or contaminated food and water; hence poultry workers are at higher risk of infection than the general population. The onset of symptoms after initial infection usually appears after three to five days. For H5N1 infection, human incubation is between two and five days but can be as long as 17 days.3 Symptoms of avian influenza include headache, sore muscles, cough or shortness of breath, and an extremely high temperature. Other symptoms may include diarrhea, nausea, chest pain, conjunctivitis, and nasal hemorrhage.7 In severe cases, it can lead to encephalitis, pneumonia, multi-organ failure, and acute respiratory distress syndrome (ARDS), as the lungs of those infected experience diffuse alveolar destruction and bleeding. High viral loads, lymphopenia, and elevated levels of cytokines have all been associated with fatal outcomes in H5N1-infected individuals.3
Treatments include antiviral medication such as Tamiflu (oseltamivir), Rabivab (peramivir), and Relenza (zanamivir), which are aimed at reducing the severity of symptoms, preventing complications, and improving the chances of survival. All drugs are NA inhibitors and are most effective when taken early in infections. However, the best defense against the influenza virus remains vaccination.7
In 1918, the subtype H1N1 caused the Spanish Flu pandemic, resulting in millions of deaths worldwide. This was followed by the Asian Flu pandemic in 1957 (H2N2), the China Flu pandemic in 1968 (H3N2), and the H1N1 ‘swine flu’ global pandemic in 2009.3 H5N1 is currently the most problematic strain of the flu virus. First identified in 1959, it remained undetected until 1996 when the virus was found in geese in southern China and Hong Kong. In 1997, 18 people became infected with H5N1 resulting in six deaths; the virus did not reemerge again in humans until 2003.9 The highly pathogenic strain H7N9 was first identified in humans in China in 2013, and the country experienced several waves of infection up to 2017. Cases identified outside of China were found to be in people who had traveled from the country.4
During the severe pandemic of 1918, over 500 million people (about one-third of the world’s population at the time) became infected with H1N1, and between fifty to hundred million people were reported to have died. The 1968 H3N2 pandemic was reported to have killed 0.03% of the world’s population, but by the 2009 H1N1 pandemic, just 0.001% to 0.007% of the global population died during the first 12 months. Still, this accounted for an estimated 700 million to 1.4 billion human infections and 151,700 – 575,400 deaths, a mortality rate between 0.02% and 0.04%.3, 10
AIV subtypes H5N1 and H7N9 are of most concern as they can cause severe symptoms in humans, leading to a high mortality rate. Globally, as of 2 June 2023, there have been 876 human infections with H5N1, including 458 deaths reported in 23 countries since 2004, a mortality rate of 52.2%, while H7N9 has caused 1,567 human infections and 615 deaths, a mortality rate of 39%. 4, 6
H5N6 has been reported in China and Laos, causing 84 human infections and 29 subsequent deaths, a mortality rate of 35%.1 H9N2, first identified in humans in 1998, is a low pathogenic AIV and therefore differs in virulence from H5N1 and H7N9. As it is not a notifiable infection, only 124 human infections and one death have been recorded.6
Since the 2009 "swine flu" pandemic, the influenza A H1N1 virus circulates seasonally, causing multiple infections, hospitalizations, and deaths. The CDC estimates that in the U.S., from 2009 to 2018 there were over 100 million infections, of which fewer than 1% of individuals were hospitalized. There were a reported 75,000 deaths, a mortality rate of 0.075%. 11
One of the ways to combat a pandemic is through mass population immunity. Immunity can occur either through natural infection or vaccination. Creating vaccines is a long and arduous process, but as there are already approved influenza vaccines, adapting them to new strains typically only takes around 6 months.4
The development of messenger ribonucleic acid (mRNA) vaccines is not new, but they came to the forefront during the COVID-19 pandemic when they were rapidly approved in response to the SARS-CoV-2 viral outbreak in humans. mRNA vaccines have many advantages, particularly as part of a pandemic response, as they can be manufactured quickly and are highly scalable.
In 2016, The European Medicines Agency (EMA) granted conditional marketing approval for the pandemic influenza vaccine H5N1 AstraZeneca, meaning that it was approved in the interests of public health based on less comprehensive data than normally required, as the medicine addressed an unmet medical need.12 The US Food and Drug Administration (FDA) has also licensed the use of two H5N1 influenza virus vaccines.13
In 1982, the WHO established a global influenza surveillance network, known as the Global Influenza Surveillance and Response System (GISRS). It was set up to prepare, monitor, alert for, and respond to influenza outbreaks. It subsequently developed the ‘Tool for Influenza Pandemic Risk Assessment’ (TIPRA) in 2016 to estimate the risk of a pandemic from novel influenza strains.1
The CDC also has a risk assessment tool for pandemic potential posed by influenza A viruses, known as the Influenza Risk Assessment Tool (IRAT).8 Both the WHO and CDC models take into consideration features such as viral transmission in animal models, population immunity, the severity of disease, infection rates in humans and animals, genomic make-up of the virus, and the geographic spread of disease in risk assessment.
| Dot | Influenza Virus | Emergence Score | Impact Score | Risk Assessment Year |
|---|---|---|---|---|
| A | A(H1N1) [A/swl ne/Shandong/1 207/2016] | 7.5 | 6.9 | Jul-20 |
| B | A(H3N2) variant [A/Ohio/1 3/201 7] | 6.6 | 5.8 | Jul-19 |
| C | A(H7N9) [A/Hong Kong/1 25/201 7] | 6.5 | 7.5 | May-17 |
| D | A(H7N9) [A/Shanghai/02/2013] | 6.4 | 7.2 | Apr-16 |
| E | A(H9N2) Y280 lineage [A/Anhui- Lujiang/1 3/201 8] | 6.2 | 5.9 | Jul-19 |
| F | A(H3N2) variant [A/lndiana/08/201 1 ] | 6 | 4.5 | Dec-12 |
| G | A(H1N2) variant [A/Cahfornla/62/2018 | 5.8 | 5.7 | Jul-19 |
| H | A(H9N2) G1 lineage [A/Bangladesh/0994/201 1] | 5.6 | 5.4 | Feb-14 |
| I | A(H5N6) clade 2.3 4 4b [A/Slchuan/06681 /2021 ] | 5.3 | 6.3 | Oct-21 |
| J | A(H5N1) Ciado 1 [A/Vlctnam/1 203/2004] | 5.2 | 6.6 | Nov-11 |
| K | A(H5N6) [A/Yunnan/14S64/201 5) - like | 5 | 6.6 | Apr-16 |
| L | A(H7N7) [A/Netherlands/21 0/2003] | 4.6 | 5.8 | Jun-12 |
| M | A(H5N8) clade 2.3 4 4b [A/Astrakhan/321 2/2020] | 4.6 | 5.2 | Mar-21 |
| N | A(H5N 1 ) clade 2.3 4 4b [A/Amerlcan wigeon/South Carolina/AHOI 05145/20211 | 4.4 | 5.1 | Mar-22 |
| O | A(H10N8) [A/Jiangxi Donghu/346/201 3) | 4.3 | 6 | Feb-14 |
| P | A(H5N8) [A/gyrfalcon/Washington/41088/2014] | 4.2 | 4.6 | Mar-15 |
| Q | A(H5N2) [A/Northern pintail/Washington/40064/2014] | 3.8 | 4.1 | Mar-15 |
| R | A(H3N2) [A/canlne/lllénols/1 2101 /201 5] | 3.7 | 3.7 | Jun-16 |
| S | A(H5N1 ) [A/Amerlcan green-winged teal/Washington/1057050/2014] | 3.6 | 4.1 | Mar-15 |
| T | A(H7N8) [A/turkey/Indiana/1 573-2/2016] | 3.4 | 3.0 | Jul-17 |
| U | A(H7NO) [A/chlcken/Tennessee/1 7-007431 - 3/2017] | 3.1 | 3.5 | Oct-17 |
| V | A(H7NO) [A/chlcken/Tennessee/1 7-007147- 2/2017] | 2.8 | 3.5 | Oct-1 7 |
| W | A(H1N1) [A/duck/New York/1 006] | 2.3 | 2.4 | Nov-1 1 |
With the avian influenza virus now circulating among multiple animal species, there is an increased chance of AIV mutating and becoming more infectious in humans. At present, human infections with AIVs tend to be a direct result of handling infected poultry and not because of human-to-human transmission. However, AIV has pandemic potential due to the emergence of new viral subtypes including H5N1 and H7N9, both of which have a high mortality rate. As the virus continues to spread in birds and animals, more human infections can be expected. As it has not yet adapted to allow for sustained human-to-human transmission, the likelihood of an avian influenza pandemic is presently very low.
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