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Skip to 0 minutes and 14 seconds In this short video, we’re going to look at avian influenza, commonly referred to as bird flu. The very mention of the phrase bird flu is likely to raise alarm. And there is no doubt that bird flu in humans is a very serious disease indeed. But what most people don’t realise is that bird flu is in fact around us all the time. So we shouldn’t really worry so much. Bird flu is everywhere because influenza itself is a fundamentally avian disease. Birds are what we call its “reservoir hosts”. And other species that suffer from it– and some suffer a lot– like humans, pigs, and horses. We’re only temporary receptacles of the virus.

Skip to 0 minutes and 57 seconds Now, the word “temporary” requires a bit more explanation in this context. Humans have had seasonal H3N2 circulating in us since the 1968 pandemic. And 51% of the world’s current population weren’t born until after 1968. So for most of us, this temporary seasonal flu has been a permanent fixture. Nevertheless, in terms of the total history of flu, this is a short period of time. In bird flu, there are 16 subtypes of haemagglutinin and 9 subtypes of neuraminidase, which makes 144 different possible subtype combinations from H1N1 to H16N9. Of these 144, 129 have been seen at some point somewhere in the past in birds. A mere two human subtypes, H1N1 and H3N2, are very insignificant indeed in comparison.

Skip to 1 minute and 58 seconds The sheer variety of bird flu also emphasises another important point. Reassortment must be common in birds. The only way that a new subtype can be generated is by the mixing up that occurs in double infections. That doesn’t necessarily imply that double infection with two subtypes is happening all the time in birds. But it must be common enough. Otherwise, we wouldn’t see so many of the 144 potential combinations in reality. Our H3N2 seasonal flu is a product of one such reassortment event. Some unfortunate individual must have had a combined infection with an H2N2 seasonal flu and an avian H3 strain, thus launching the H3N2 pandemic in 1968.

Skip to 2 minutes and 45 seconds Likewise, back in 1957, another unfortunate person must have contracted an avian H2N2 along with the seasonal flu of the day, which would have been H1N1. Reassortment in humans, therefore, can be disastrous, causing new subtypes to emerge that carry enough human adapted segments to be easily transmitted in humans, but also with enough avian influenza segments to be virulent in humans. So let’s construct the origins of the 1957 H2N2 pandemic in a little more detail. At some point in early 1957 or the year before, somebody was unlucky enough to catch two kinds of flu simultaneously. One of those flus was the ordinary seasonal flu of the day, the H1N1 descendant of the 1918 pandemic. The other one was an H2N2 bird flu.

Skip to 3 minutes and 38 seconds We don’t know who this person was, or if they survived. The chances are that they didn’t. But what happened inside them gave birth to the 1957 pandemic strain. H2N2 bird flu, like all bird flus, was probably very hard for humans to contract, but once contracted, would be very severe. In the cells of that unfortunate victim, the genome segments of H1N1 seasonal flu and bird H2N2 circulated together. When the time came for the new flu virus particles to be assembled, segments were mixed up. And probably many weird and wonderful combinations were produced, most of them non-functional.

Skip to 4 minutes and 18 seconds But one of those combinations had just the right set of genome ingredients– the internal proteins of seasonal H1N1 and the surface proteins, the H and N, of H2N2 bird flu. This meant that it was well adapted for replication in human hosts, better than bird flu itself, but had surface proteins against which those human hosts had no immunity. This was the perfect recipe for a new pandemic strain. Essentially, the same reassortment process is thought to have occurred in 1968. The seasonal H2N2 of the day and the bird H3 flu ended up in one unfortunate individual. That time, the resulting reassorted strain retained the N2 of the seasonal strain, but incorporated the H3 of the bird flu strain. The result was H3N2.

Skip to 5 minutes and 8 seconds Reassortment brought us another pandemic influenza in 2009. Unlike the reassortment events that gave rise to the 1957 and 1968 pandemics, this one did not involve a human seasonal strain and a bird flu strain, but in fact, two strains of swine flu, one from North America and one from Eurasia. The North American parent strain was itself known to be the product of at least three previous reassortment events and was referred to as triple reassortant swine flu. The resulting quadruple reassortant, therefore, had segments from two varieties of pig flu, bird flu, and even one segment from a human flu.

Skip to 5 minutes and 48 seconds Aside from showing just how complicated things can get, it was remarkable that the product was transmissible between humans when neither parental strains had been. So, what are the potential reassortment events of the future? What are the potential new pandemic strains in humans? In order to answer that, we need to look at what current bird flu strains infect humans. As I record this in late 2015, H7N9 bird flu is currently causing some concern in China. From its first appearance in March 2013, there have been 677 confirmed cases, of which 275 had died. That’s a mortality rate of 41%.

Skip to 6 minutes and 31 seconds The most famous bird flu of all, though, is H5N1, which has caused 844 confirmed cases in humans since 2003, of which 449 have died. That’s a mortality rate of 53%, a bit higher than H7N9. From 2003 to 2009, the worst affected country for H5N1 was Indonesia. But in the succeeding six years, Egypt has become the epicentre. Rather smaller numbers of cases have been spotted of other bird flus in humans, such as H5N6 and H7N7. So if we were to speculate about what the next pandemic flu subtype might be, a fair guess might be H1N9 or H7N1 or H3N9 and so on. But of course, we don’t really know.

Skip to 7 minutes and 23 seconds And the most important lesson of the 2009 H1N1 pandemic is that pandemic strains don’t need to have avian flu involved at all, necessarily. Pig flu strains have pandemic potential too. But, back to the birds themselves. Not all species of birds seem to be equally susceptible, or perhaps, equally exposed to bird flu. It’s difficult to be precise about numbers because we aren’t monitoring all bird species all the time. And that’s what we call an ascertainment bias. An ascertainment bias is when you’re collecting data from a limited sample set and then drawing wrong conclusions about the world as a whole, based on that limited sample.

Skip to 8 minutes and 5 seconds We can say, for instance, that the common teal, a species of small duck found across Northern Eurasia and which overwinters in North Africa and Southeast Asia, has been found to harbour at least 21 different subtypes of bird flu. At the other extreme, birds such as the Canada goose, the black-necked and great crested grebes, and the merganser have only ever tested positive for H5N1. There may be ascertainment bias at work here, or it may be that teals really are super reservoirs for bird flu. It’s possible that ascertainment bias also operates geographically. For instance, here in the UK, since the year 2000, we’ve only had bird flu in our farm poultry population very sporadically.

Skip to 8 minutes and 48 seconds And as a result, there hasn’t been much organised testing of wild bird populations. However, 2014-2015 has seen three farm outbreaks of bird flu in the UK, rather more than is common or economically comfortable. So interest in wild bird flu in Britain might well grow. By contrast, in Europe, bird flu has had a rather greater problem in agriculture. And hence, we have a wider effort to seek out its origins. As a result, 69 subtypes of bird flu have been spotted in European wild birds since 2000. For farmers, their main consideration is to keep bird flu out of their poultry stocks. So far in Europe, we’ve largely succeeded.

Skip to 9 minutes and 28 seconds But in the USA in 2015, there has been a very damaging outbreak of H5N2. Farms across 20 US states have been affected and the United States Department of Agriculture ordered the killing of over 45 million birds as a consequence. So far despite this, we haven’t had any infections of H5N2 in humans, which illustrates two facts. Firstly, that bird flu is difficult for humans to catch, as we’ve already said. And secondly, in an advanced country such as the USA, farmers are aware of the protective measures that are needed to protect their workers, and they can afford to implement those measures.

Skip to 10 minutes and 6 seconds The real danger from bird flu probably doesn’t come from infection of farmers involved in high-profile agricultural outbreaks such as the 2015 H5N2 outbreak in the USA because any farm workers who develop suspicious symptoms will be immediately quarantined and tested. The greatest long-term danger is probably from a small outbreak in a poor country, where the reassortment event between bird flu and human seasonal flu could occur. And the new subtype starts spreading within humans before the world’s medical authorities were aware of it. And this is why the World Health Organization monitors bird flu so carefully.

Bird Flu

While you watch this video on bird flu, think about how it has affected you personally. Perhaps you live in the USA and were aware of the serious poultry outbreak in early 2015. Did eggs become more expensive? Did your local stores run out of eggs at any point? Perhaps you’ve worked on a poultry farm and can describe the precautions taken against bird flu. In the next step we’ll be asking you to share your experiences.

Influenza is a fundamentally avian disease - meaning that most of the flu viruses currently in the world are inside bird hosts. Also the overwhelming proportion of the variation in influenza virus - its subtypes, of which there are nearly 150 - are found in birds. Just two of those subtypes, H1N1 and H3N2, are found in humans with any kind of regularity. The exception is when a human catches a bird flu strain.

Bird flu is important for several reasons. Most obviously, it can cause havoc in the poultry industry. That doesn’t just include chickens, turkeys, ducks and other things that may end up in our ovens, but also eggs, without which the baking industry would collapse too. Another reason for watching bird flu carefully is that it is very dangerous to humans, although fortunately very rare.

But the third, and arguably most important, reason is that bird flu strains appear to be crucial elements in the creation of new pandemic strains in humans.

2009 was the first flu pandemic to occur in the “age of molecular biology” meaning the first to occur at a time when we have the scientific knowledge and skills to carefully explore its origins, and follow the molecular evolution of the pandemic as it happens. 1977’s Russian Flu occurred just before the age of molecular biology really got going, and the three other pandemics of the 20th century well before we had any tools to analyse their origins.

Our conclusions about the origins of previous pandemics are therefore retrospective, meaning that scientists have had to reconstruct what might have happened by performing genome sequencing on old samples where available. In the previous activity, a phylogenetic analysis was demonstrated, and performing these on all segments of a flu strain can tease out its origins.

We know that 2009’s pandemic flu strain was in fact nothing to do with bird flu. Its immediate origins were in two pig flu strains, so “swine flu” was a fairly appropriate nickname. However, its deeper origins were considerably more complicated, and if we go back far enough into the complex chain of reassortment events that produced it, we can find some segments of bird flu origin.

The reassortment history, as best we can reconstruct it, for the 2009 swine flu is very complex indeed. It’s actually fairly likely that the same is the case for the 1957 and 1968 pandemics, but we can only make deductions based on what material remains to us for sequencing. For instance, although we think that there must have been an avian H3 strain as one parent of the 1968 H3N2 pandemic strain, we don’t know what its N subtype was - the N that ended up in the H3N2 strain was the N2 from the previous H2N2 seasonal flu.

Influenza is complex. That’s one of the reasons it is so fascinating - but also so dangerous. The links below provide some further reading.

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This video is from the free online course:

Influenza: How the Flu Spreads and Evolves

Lancaster University