Written by Klara Martinovic. Revised by: Maria Ines Berrojo Romeyro Mascarenhas and Georgia-Vasiliki Gkountana

This week’s scientific corner continues the story of the Influenza A virus, giving an overview of pandemics caused by the Influenza A virus and explaining why these pandemics can occur.

First outbreak of influenza H1N1 caused the Spanish flu in 1918. It was one of the largest pandemics in the history of human population with around 50 million deaths. In the second half of the twentieth century, two more pandemics occurred. The first was in 1957. It was an outbreak of the Asian flu (H2N2) which caused 1-2 million deaths, while the Hong Kong influenza (H3N2) began in 1968 and caused upwards of 2 million deaths. The twenty-first century saw its first pandemic in 2009 caused by the new H1N1 subtype, commonly known as the Swine flu which originated in Mexico. It caused over half a million deaths and H1N1 virus is still circulating today together with H3N2 subtype from the Hong Kong pandemic; both of these are considered to be remnants from their respective pandemics. However, considering the characteristics of Influenza viruses, we can freely predict that such pandemics will occur again in the future, maybe even more often than before.

One of the reasons why the Influenza virus can potentially cause pandemics is because it is a Zoonosis (infectious disease caused by pathogen transferred from non-human animals to humans). The main natural reservoir of IAV are wild birds which can carry IAVs with 16 HA types and 9 NA types. Even though these different types of surface glycoproteins represent an enormous source for new viruses, only 3 viruses have caused infection in humans so far. However, the constant interchange of viruses from animals to different animals and humans presents potential danger. Infection of humans almost always goes via pigs or via poultry, due to the receptors to which influenza virus binds to. In birds, the receptor is an α2,3-linked sialic acid, while the receptor on human cells is an α2,6-linked sialic acid. However, a pig has both linkages of sialic acid receptors and it can be infected with both bird and human viruses, and when that occurs simultaneously, viruses can reassort in a pig.

Reassortment and recombination are major mutations that are called the antigenic shift because segmented genomes of influenza viruses can form new subtypes and, all of a sudden, the surface glycoproteins are not recognizable by the host’s immune response and antibodies. Another way of changing genetic material in influenza viruses is the antigenic drift, which occurs when a virus slowly changes due to the accumulation of point mutations in surface glycoproteins which are then again not recognized by existing antibodies. These point mutations occur often because of low fidelity of viral RNA dependent RNA polymerase which makes a lot of mistakes and has no proofreading mechanism. For this reason, a person has to be vaccinated every year again in order to have correct antibodies for protection from new Influenza mutants.

Now that we know what reassortment is, we can follow the mutations in influenza A viruses throughout history; after the first outbreak of influenza H1N1 in 1918, this virus reassorted with an avian H2N2 virus in pigs and a new H2N2 virus emerged and caused the Asian flu pandemic in humans. The next crucial event of reassortment in pigs was with an avian H3 virus resulting in the new H3N2 virus subtype which caused the Hong Kong flu and also outcompeted the Asian flu virus. The last known reassortment event occurred as a series of reassortments, resulting in the development of the then-new H1N1 subtype, which caused the Swine flu and outcompeted the original H1N1 subtype that had caused the Spanish flu.

Another threat are the Highly pathogenic avian influenza viruses (HPAIV) A like the H5N1 subtype. They are strict zoonoses, almost always spread by poultry, and so far, spread only from animals to humans causing sporadic human infections. They cause high mortality in poultry, and even though they are not widely spread, H5N1 caused severe respiratory illness in infected humans. Considering the influenza virus’ ability to reassort and quickly change its genome content with the possibility to gain the ability to infect people, there is reason to fear that these HPAI viruses could start spreading among humans, and potentially cause new pandemics with outcomes worse than the ones that the H1, H2 and H3 pandemics have had.

Note: this paper is largely based on a lecture given by professor Patrik Ellström and researcher Mahmoud N. Naguib from Uppsala University.

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