Influenza Epidemics and Pandemics PM250

so welcome back to what will be the final video on influenza where we are going to look at influenza as a pathogen capable of causing seasonal epidemics sporadic pandemics and how these two events come about so first and foremost what is an epidemic and what is a pandemic well these terms aren't exclusive to viruses they aren't exclusive to influenza and therefore they can be applied to any type of infectious disease so you might have heard of them before but briefly an epidemic refers to an often but not always sudden increase in the number of cases of a particular disease above what we would typically be expecting for that disease within a certain population or area now a term that is closely related to this is an outbreak which is very similar to an epidemic but is often limited to a smaller geographical location now the definition of a pandemic is an extension of our epidemic definition whereby the disease occurs over a much wider area and usually refers to epidemics of the same disease occurring in multiple countries so as a non-influenza example there was an outbreak of severe acute respiratory syndrome coronavirus 2 in wuhan city which led to an epidemic outbreak of covid19 in china leading to the current global pandemic which is affecting most countries around the world now when talking about influenza in the uk an outbreak would refer to an abrupt increase in the number of influenza cases within a local health board an epidemic refers to the increased number of cases seen in the winter months and a pandemic is where the virus causes widespread disease across many different countries now as i said epidemics can be yearly occurrences but pandemics are rare events and there have only been four recorded pandemics in modern history so the first pandemic commonly referred to as the spanish flu infected a third of the world's population and caused in the region of 50 million deaths and to put that into context the current death toll for covid19 is in the 2 to 3 million range now i guess a key question we need to think about is why does influenza sometimes cause an epidemic and sometimes cause a pandemic and why can it cause both mild and severe diseases now up to this point whilst we learnt that there are four genera of influenza virus within the ortho mix of iridae family we have primarily focused on influenza a as the most common of the four now this raises a very valid question is one influenza a virus the same as another influenza a virus and the short answer is no different influenza a viruses can have different genotypes leading to different phenotypes leading to what we call different subtypes of influenza a now these influenza a subtypes are based on the phenotype of two key surface glycoproteins hemoglutinin or ha or the h protein and neuraminidase or na or the n protein which you should remember from our second video and as we learned in that video these glycoproteins are surface antigens which have various functions that help with the dissemination and disease of the virus but not all hemoglobin and neuraminidase glycoproteins are the same subtle differences in these proteins change them allowing the virus to evade the host immune system cause mild or severe disease and spread with altered efficacy now in the structure video i pointed out that there are 18 different subtypes of hemoglutinin and 11 different subtypes of neuraminidase each with a unique phenotype confirmed by a different genetic sequence on the respective rna segment now the subtypes of those two glycoproteins make up the total antigenic subtype for our influenza a virus meaning there are theoretically 198 different influenza a subtypes out there based on combinations of different hemoglobin and neuraminidase subtypes now a select few subtypes are more common so in general terms h1 h2 and h3 are common hemagglutinin subtypes found in viruses infecting humans and n1 and n2 are common neuraminidase subtypes in viruses infecting humans which therefore means antigenic subtypes of influenza a are more common so if we were to put these into a matrix with different hemagglutinin subtypes running top to bottom and different neuraminidase subtypes running left to right we can get a wide range of different subtypes by mixing different hemagglutinins with different neuraminidases now a minute ago i said some influenza a subtypes are more common than others so h1n1 is a relatively common subtype and referring back to the public health data i mentioned in the first video h1n1 was the prevailing subtype of influenza a in both the 2018 to 2019 flu season and the 2019 season and the 1918 spanish influenza pandemic but are these subtypes the same i.e is influenza a h1n1 in welsh hospitals the same as the spanish influenza h1n1 virus well the short answer and hopefully obvious answer is no the reason why they are different is that the hemoglobin and neurominidase genes only account for two of the total eight rna segments which make up the influenza virus therefore there could be differences in the matrix proteins the m2 ion channels or even the components of the rna-dependent rna polymerase and so the reason why we use subtypes based on the hemoglutinin and neuraminidase proteins is because of their antigenic properties and how our body responds and mounts a response to the presence of these antigens now in most situations we can get away with just using the subtype so h1n1 for describing our influenza a h1n1 virus because as i said before this is an antigenic representation of what our bodies see however the world health organization has come up with a more detailed and robust way to describe influenza viruses now this naming convention dates back to the 1980s and is still used today when referring to specific viral strains and it's based on the type of the virus so if it's influenza a b c or d the geographical location of where the virus was first isolated the strain or lineage number which is based on phylogenetic analysis of its genome the year in which the virus was first isolated and finally the antigen subtype of the virus as we saw on the previous slides so here we have four examples the first is a circulating epidemic strain so if you remember back to what an epidemic is this is what we might call a seasonal strain causing many influenza cases during the winter months and hopefully this h3n2 subtype will ring a bell as it was also listed as a dominant influenza subtype in welsh hospitals in the two reports i asked you to look at the second is a pandemic strain which caused the 2009 swine flu pandemic and it has the h1n1 subtype which is extremely similar to the original 1918 spanish flu which was also h1n1 and based on what we knew at the time with regards to the large numbers of deaths this caused some panic as it wasn't known if this would have the same mortality rate as the previous h1n1 pandemic strain thankfully it only resulted in mild illnesses the next strain originated in hong kong and caused the 1968 hong kong pandemic which had moderate severity now this particular epidemic strain has the same subtype as the current epidemic strain but the disease they cause are very different and this comes back to what i said earlier the hemagglutinin and neuramindase glycoproteins are only part of the influenza genome there are plenty of other sections of the genome that can change resulting in different clinical outcomes and finally our bottom strain originated in japan and gave rise to the 1957 asian influenza pandemic which had extremely severe clinical outcomes associated with high mortality rates and this essentially brings us up to the first observed pandemic strain causing the 1918 spanish influenza pandemic however this has never been directly sequenced it has always used various indirect methods and so the specific designation around this ancient strain is somewhat contested now hopefully from the few strains you can see here the influenza virus has a lot of genetic variation but how does this genetic variation arise how does a virus arrive at a point where it has these different subtypes capable of causing disease of mild moderate or even severe severity well there are two key processes which occur we have genetic drift more commonly referred to as antigenic drift when talking about influenza viruses and we have genetic shift and again this is more commonly referred to as antigenic shift for our influenza viruses and so a key question would be what are these two processes and how do we induce change in the influenza virus well let's start with genetic drift which by definition is the process of naturally accumulating small changes in the genetic code over a time period and we can quite easily visualize this with a simple graph so if we were to look at our influenza virus over time we get small point mutations within the genetic code and every time a point mutation occurs within the genome there is an observable genetic change resulting in a new genetic code as we can see by these jumps in the graph now if we were to compare this back to the original genetic code of the influenza virus there is a measurable difference between the two and we call this difference drift essentially the genetic code has drifted away from its original code through point mutations now these small changes or more precisely point mutations are driven by poor rna proofreading you see the host cells proofreading machinery is tasked with preventing the accumulation of point mutations within a genome but because it belongs to the host cell it is designed to work with dna and because the influenza virus is an rna virus the same proofreading process doesn't happen now another key question might be where do these mutations occur well on a technical level they can occur at any point in the genome leading to genetic drift as i talked about on the previous slide however when it comes to influenza we are more concerned with something known as antigenic drift which is where we get these point mutations in sections of the genome encoding the antigenic glycoproteins hemagglutinin and neuraminidase so that would be segments four and six of the influenza genome now the reason why antigenic drift is so important for the influenza virus is because any modifications in the hemagglutinin and neuraminidase proteins can result in some altered interactions between the influenza virion and the immune system of humans to the point where our bodies may no longer recognize the virus or it may cause a slightly different infection now the process of antigenic drift doesn't happen evenly across the influenza genera alpha beta and gamma influenza viruses so influenza a b and c are listed as being capable of this antigenic drift but when we consider the potential problems antigenic drift could cause in relation to human disease some textbooks and journals will only list influenza a and b as being capable of antigenic drift again this difference comes down to what it can do on a technical level and what we are concerned with when it comes to human disease now one of the biggest effects of antigenic drift is the emergence of seasonal epidemics each year as time passes the genetic code of the influenza virus changes slightly potentially resulting in altered hemoglobin and neuraminidase antigens being presented on the surface of the virus and this presents a few benefits to the virus and problems for the host when it comes to disease progression you see the presentation of different antigens on the surface of the infective agent means our bodies won't recognize the new variant even if they were exposed to the old base variant effectively allowing the virus to evade detection by the host immune system during infection now hopefully from everything mentioned up to this point you can see that antigenic drift is the driving force behind the emergence of new seasonal epidemic strains now this doesn't always happen as you would have seen from public health whales data i talked about in the first video but the possibility of it happening is always there now one of the biggest problems when it comes to antigenic drift and seasonal epidemics is that because we have a new prevailing strain we need to generate a new influenza vaccine each and every year which begs the question how do we know what the prevailing strain is going to be after all vaccines take time to develop and produce well the truth is we don't there is a degree of guesswork by scientists and healthcare professionals when it comes to determining what variant will become the prevailing strain and causative agent of the season epidemic therefore by using models we try to best predict which is most likely early on in the flu cycle so that when it comes to the winter peak those who are at risk have been vaccinated and this has backfired in the past where we got it wrong and predicted it wrong leading to excessive deaths during the winter peak now two final things that need to be pointed out the use of vaccines in this instance forces a selection pressure on the virus whereby if the virus drifts enough so that it doesn't resemble the vaccine strain it can survive and go on to infect other people and if it does there is the potential for it to become the next seasonal epidemic strain now in a very similar way if we were to use antiviral to combat an influenza virus we would be putting a selective pressure on it and antigenic drift can lead to antiviral resistance by inducing subtle changes in its genome changing things like target sites so this whole process of antigenic drift can be completed by a wide range of viruses with rna viruses being more at risk due to poor rna proof reading during the replication process now our next process genetic shift is much less common in terms of the number of viruses capable of undergoing this process and that is because on a very general level it occurs in viral genomes that are segmented as we'll see over the next few slides now from a definition point of view genetic shift is what we would call an abrupt or major change in the genetic code and just like our genetic drift the change confers different properties on the virus and we can quite easily visualize this with a simple graph like we did earlier now just like last time we can see the process of drift occurring however at some point a major change or shift in the genetic code can occur in a single step and we call this genetic shift now the process of genetic shift isn't an extension of genetic drift it is not an accumulation of multiple point mutations at the same time and the reason why this isn't the case is that it would require quite some coordination to have multiple point mutations occur simultaneously but also the genetic code is designed to be more stable than this as we technically don't want lots of mutations occurring at the same time so what is actually happening well there is a reassortment of genetic material from multiple sources and there are two aspects to this point reassortment happens when a segment of influenza virus is switched out for a different segment from another influenza virus so from a genetic change point of view we would have hundreds or thousands of nucleotides being instantaneously swapped and if you remember back to what i said earlier only certain viruses undergo genetic shift because in a general sense only certain viruses have segmented genomes which facilitate this easy switching of genetic information now genetic shift is particularly important for influenza viruses however it is more commonly referred to as antigenic shift and that is because the result of this reassortment event usually results in a major shift in the antigens presented on the surface of the influenza virus and this is especially true when the shift occurs in segments 4 and 6 of the rna genome because these segments encode for the hemoglutinin and neuraminidase glycoproteins which as we all know from our previous videos act as the main antigens now a key question you might be wondering is where do these different segments come from well this links back to our previous statement where we need multiple sources of genetic material and in the case of our influenza virus these different segments come from different viral subtypes infecting the same host cell and if you remember back to our previous video on viral replication within a host cell the eight different segments from our influenza virus are exported from the nucleus and accumulate near the cell membrane ready for export now if the cell is infected with two different subtypes at the same time then there could be two different types of each viral segment within the host cell leading to a mismatch when it's all packaged together with the result being a new variant displaying some properties of each variant now that's quite a bit to take in so let's quickly visualize this let's say a host cell becomes infected not only with a blue influenza virus but a yellow influenza virus at the same time now these two viruses represent different subtypes of influenza so if we were to use the terminology we learned earlier the blue could represent subtype h1n1 and the yellow subtype could represent h2n2 now because both of these viruses are in the host cell at the same time once they enter their genomes make their way to the nucleus at this point multiple copies of the genome are made by the host cell machinery which is then exported from the nucleus to be packaged and released from the host cell now during this packaging process as we learned previously segments of the genome are arranged so that one copy of each ends up in the new virion it's at this point the genetic reassortment can occur and as we can see here segment six from one subtype has been switched for segment six of another subtype and to cut a long story short what we end up with as a result of this reassortment is progeny variants that aren't exact copies of the parental subtypes but are amalgamations of both so on the left we have a new variant subtype designated h1n2 containing the h1 gene of the h1n1 strain and the n2 gene of the h2n2 strain and on the right hand side the virus contains the opposite so the h2 gene of the h2 n2 strain and the n1 gene of the h1n1 strain and as you can see the new variants not only contain the genes but they also could display the phenotypic properties associated with these genes now this only becomes a problem if they confer certain clinical properties now a lot more goes into it but for the sake of argument let's say the h1n1 subtype confers for low infectivity through hemoglobin in subtype h1 and high mortality rate through neuraminidase subtype n1 now the clinical phenotype of this virus would be one that spreads slowly but has severe symptoms requiring medical intervention if we look at the h2n2 subtype this could be the complete opposite conferring high infectivity through hemoglobin and subtype h2 and low mortality rate through neuraminidase subtype n2 now the clinical phenotype of this virus would be one that spreads quickly but has very mild symptoms requiring only bed rest now if we look through our new subtypes h1n2 might have a clinical phenotype of being poorly transmitted with very mild symptoms which doesn't have any clinical concern but h2n1 on the other hand is our nightmare scenario as the clinical presentation of this is a super spreader that leads to severe symptoms and hospitalization and that is basically antigenic shift in influenza and how problematic strains can come about very abruptly but there are a few crucial points we need to pick up on we mentioned earlier that antigenic shift occurs when there are two different virus subtypes infecting the same host cell which is rare but it does happen now because influenza a has many different subtypes and the other influenza viruses don't antigenic shift is only observed in influenza a and as we saw this can lead to some dramatic changes in phenotype as new variants have the potential to become more transmissible more severe or both now it's this process of antigenic shift which is the driving force behind pandemics why well the shift is so sudden so abrupt that the result is a virus which hasn't been encountered yet by human hosts and therefore most people will not have the necessary immunity to this novel virus and this is a key word because novel means new and in terms of infection it could be a completely new subtype to humans and human infection but parts of it might have been observed previously in other organisms now if we cast our minds back to our second video we found that influenza a was the only genus of the ortho mix of iridae family that was capable of infecting both humans and animals and so if we have a human influenza virus and an animal influenza virus in a mixing pot antigenic shift can produce something new that is potential deadly to humans now the animals that can be infected with influenza a range from various birds so typically ducks pigeons and chickens to pigs whales horses and seals but the main animal reservoir or animal host for influenza a viruses are birds leading to avian influenza and pigs leading to swine influenza two terms you might have heard of in the news and whilst only a few subtypes can be seen in human infections mainly those with the h1 h2 h3 n1 and n2 glycoprotein subtypes the vast majority of the other subtypes are found in various bird species now avian influenza can be directly transferred from infected birds or a contaminated environment to humans directly causing an infection not typically seen in humans some scientists call this antigenic shift but it's not really it more precisely represents a zoonotic infection causing an isolated outbreak now avian influenza subtypes can undergo what we actually call antigenic shift as per the definition earlier by infecting an intermediate host and one of the most common hosts seen to facilitate this are pigs now as we learned in the last video human influenza a viruses bind to the terminal cyalic acid receptors linked to the galactose of the receptor protein via an alpha 2 6 glycosidic bond avian influenza a viruses on the other hand have a preference for terminal cyalic acid receptors linked to galactose via an alpha 2 3 glycosidic bond pigs on the other hand well they have both types of receptors and therefore can accept both avian influenza a and human influenza a viruses and when this happens we have the potential for antigenic shift to occur as we saw earlier so within the pig we might have an avian influenza virus and either a swine influenza virus or a human influenza virus this means after reassortment of the genomes we might end up with a new virus capable of infecting humans and causing severe disease in this instance we refer to the pig intermediate as our mixing bowl and that is influenza from the disease it causes to its structure replication cycle and ability to change resulting in both seasonal epidemics and global pandemics but just before we end the video there are two tasks for you to complete as part of your self-directed learning and they both revolve around further characterization of the virus from a genetic point of view and a biochemistry antigenic point of view there will be links on canvas that will take you to information pages on the center for disease control and prevention which i would like you to look at you will need to go through these pages to further enhance your understanding on influenza characterization and i've specifically chosen these websites as the information is relatively easy to understand it's not jargon heavy especially considering how much of the influenza virus we have covered in these videos and with that we come to the end of the video and the end of the video series and the end of our viruses i hope you've enjoyed the content i've tried to make it as easy to understand as possible which has meant some of these videos have gone on but i like to try and explain things fully so that you don't have to go away and find certain other information however where i have asked you to go and find other information please make sure you go and do this as it will really help your understanding and learning about the influenza virus if you do have any comments or questions then please do get in touch via email i'm always happy to answer any questions that you may have maybe i didn't explain something right maybe i was going too quick at some time and you didn't quite catch what i said please email me and i'm always happy to help out where i can take it easy stay safe and keep learning

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