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The flu virus, shown here as an illustration, evolves quickly, helping it escape our vaccines and immune systems.
Credit: Bethany Halford/C&EN
Although the Wuhan coronavirus is dominating headlines across the globe, influenza kills hundreds of thousands of people worldwide each year. In the US, millions of people roll up their sleeves annually for a flu shot. But this ritual is confusing for many. Why is it that most vaccines are effective for a lifetime while the flu vaccine is only effective for a year? And why do we sometimes get the flu even when weve gotten the vaccine? The answer is evolution: the flu is constantly evolving to evade our immune systems. In this episode of Stereo Chemistry, scientists who study flu evolution and pandemics explain what makes fighting the flu so difficult.
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The following is the script for the podcast. We have edited the interviews within for length and clarity.
StefanieOlsen: This is the info sheet from the CDC on the flu vaccine. Kind of who should get it, why you should get it, who shouldnt get it, what to expect, whats normal, whats not normal. All that sort of stuff. So Ill give you that for your perusal.
Matt Davenport: Thats Stephanie Olsen. Shes a nurse practitioner at a MinuteClinic in Cambridge, Massachusetts. Thats where C&EN senior correspondent Bethany Halford and her son went to get the flu vaccine back in the fall.
Stefanie Olsen: Are you a righty or a lefty?
Bethanys son: Im a righty.
Stefanie Olsen: OK. Cool. Well use your left arm. Find this big muscle. Here we go: clean, clean, clean. OK. One, two, three. Good job. Done. There you are.
Bethanys son: One tiny sting.
Stephanie Olsen: One tiny sting and done. Good job.
Matt: That didnt seem so bad.
Bethany Halford: It really wasnt bad at all.
Matt: Well hello there, Bethany.
Matt: Thanks so much for bringing your recorder along with you for the flu shot.
Bethany: No problem. Im actually glad I made this recording because I plan to replay it for my son every year just before we go to get our shots. Its a process thats met with no small amount of dread. But the Centers for Disease Control and Prevention recommend that most people get the flu vaccine every year.
Matt: So you and your son went in September. Its now almost February. Lets pretend youre a podcast cohost who has not gotten their flu shot. Is it too late?
Bethany: Well, CDC does recommend getting the flu vaccine by the end of October because it takes a few weeks for your body to create the antibodies that fight the virus. And this year the flu seems to be ramping up early. But doctors say that even now, its not too late to get the vaccine.
And were right in the thick of flu season. During the last flu season in the Northern Hemisphere, from October 2018 to May 2019, as many as 42.9 million people in the US got sick with the flu; 647,000 of those people were hospitalized, and 61,200 died.
Matt: Those numbers are from CDC, and theyre pretty typical for a flu season. So influenza is this huge problem, and its been that way for a long time. And its not going away, right? Unlike other vaccines, the flu shot is something you should get every year. And sometimes that flu shot isnt going to work.
Bethany: And this episode is all about how the flu outfoxes our vaccines and immune systems: through evolution. The flu virus is constantly changing itself to evade our immune systems response. And the virus changes enough each yearsometimes even enough within a single flu seasonthat the vaccine weve created is simply no longer effective.
Matt: So Beth, at the risk of sounding like a chemist right after the Nobel Prize announcement, isnt that a little more biology than chemistry?
Beth: Well, yes. But the evolutionary changes to influenza are really chemical changes. Theyre mutations in the viruss RNA that lead to amino acid changes in the viruss proteins. So there is plenty of chemistry to dig into. Were going to talk to three experts to learn how those changes happen and how studying them could help protect us better in the future. Well also look at what happens at the molecular level when a certain strain of flu becomes a pandemic that spreads quickly across the globe.
And were going to start by talking to a chemist.
Jesse Bloom: Hi, my name is Jesse Bloom.
Bethany: Jesse studies protein evolution at the Fred Hutch Cancer Research Center in Seattle. Hes also affiliated with the University of Washington and the Howard Hughes Medical Institute.
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Jesse Bloom: I actually did my PhD in chemistry, working with Frances Arnold, who studied the directed evolution of proteins.
Matt: Wait. The Frances Arnold?
Bethany: Yes, the Frances Arnold from Caltech who won a share of the 2018 Nobel Prize in Chemistry.
Jesse Bloom: After working with Frances, I remained really interested in protein evolution, but I wanted to study the evolution of proteins in a context with biomedical significance. So my lab now focuses on viral evolution, particularly the evolution of influenza virus. And the reason for that is these viruses evolve their proteins very rapidly.
Bethany: Jesse says there are really two main forms of flu evolution. One is called antigenic drift, and the other is called antigenic shift.
Matt: I like the rhyme scheme.
Bethany: Catchy, right? So lets start with the drift.
Jesse Bloom: Antigenic drift is the much more common form of flu evolution, and that essentially can be thought of as last years strain or a couple years ago strain of human flu evolving to be a little bit different, each year. Our immune systems are actually great at mounting antibody responses that protect us against flu, and theres pretty good evidence that if youre infected with a particular strain of flu, your body will provide very good, long-lasting immunity to that particular strain of flu.
Bethany: So, if our bodies provide long-lasting immunity, Im sure youre wondering why we still have to get a flu shot every year.
Bethany: Heres how Jesse explains it.
Jesse Bloom: The challenge with flu is the virus evolves very rapidly. In particular, the positions on the viral proteins that are recognized by our immune system, primarily by our antibodies, change, and they change enough that after about 5 years, many of those antibodies sort of dont work anymore. So antigenic drift and what typically is responsible for the seasonal influenza outbreaks is the virus that was present last year or the year before changing a little bit so that after about 5 years, its mostly evaded your immune systems memory.
Bethany: Now, I told you this was a chemistry story, so before we go any further, let me give you a picture of what Jesse is talking about. There are two proteins that scientists think are most important with respect to immunitywe create antibodies that bind to these two proteins in order to mount a defense against influenza. The first protein is hemagglutinin, which helps the influenza virus latch on to cells and infect them. The second is neuraminidase, which helps cleave new virus particles away from infected cells so the virus can continue to attack healthy cells. If you think of the flu virus as a sort of blob, hemagglutinin and neuraminidase stick out of that blob like pins in a pin cushion. Scientists name different strains of flu based on which types of hemagglutinin and neuraminidase they have.
Matt: Are those the proteins were referring to when we talk about like H1N1 influenza or H3N2 influenza ?
Bethany: Thats right. Right now, there are three types of flu circulating in humans: H1N1, H3N2, and influenza B.
Jesse Bloom: I mean, they all evolve pretty fast, like, compared to almost anything else we encounter in life. But definitely H3N2 evolves the fastest. H1N1 is sort of in the middle. And influenza B is the slowest, although influenza B is still pretty fast. And this plays outfor instance, influenza B is most known for infecting children because its relatively less good at escaping immunity. Obviously children dont have any immunity at all, if they havent been vaccinated, anyway, to escape. So theyre always going to be susceptible. And then H3N2 is sort of best at infecting older peopleits also good at infecting younger people, but its good at affecting all agesand probably the reason is that H3N2 is evolving the fastest. So it can best get away from that prior immunity.
Matt: So, when he says something is evolving fast, what does that mean on a molecular level?
Bethany: Take H3N2 influenza, for example. The hemagglutinin protein on H3N2 will change three to four of its amino acids every yearan evolution rate that Jesse says is extraordinarily high.
Matt: OK, so I understand why these gradual changesthe antigenic driftmake it so that we have to get the flu vaccine every year. But why dont we need frequent vaccinations for all RNA viruses? Like measles?
Bethany: CDC recommends just two shots for measles as part of whats called the MMR vaccine. It protects you from measles, mumps, and rubella. You get the first shot when youre about a year old, the other when youre about 5 years old. It seems that the parts of the measles virus that the immune system goes afteror makes antibodies forjust dont seem to be changing that much. We know this because before the measles vaccine existed, people who got measles only got it once in their lifetime. And in the 50 or so years since weve had the vaccine, people who get it dont get measles. As Jesse explains, theres no reason measles cant drift like the flu, thats just not what we see. So the thinking is that measles is mutating, but not in a way that helps the virus. Its not as wily as influenza.
Matt: That is super interesting. But . . .
Bethany: How does knowing this help fight the flu?
Bethany (in interview): Can you talk a little bit about how studying flus evolution can help us fight the virus?
Jesse Bloom: So first, the way the flu vaccines are made currently, theres sort of this forecasting problem. We know that the vaccine works better when the vaccine is more similar to the virus that is infecting people. But it takes a while, maybe about 9 months, to really produce enough vaccine to be given to everybody. And because the virus is changing a little bit every year, you have to predict what virus is going to be circulating 9 months in the future. So you basically have to say, How do we think the virus is going to be evolving? And so by understanding the viruss evolution, we can make better decisions about which flu strain should go in the flu vaccine. And when those decisions are better, the vaccine will work better.
Bethany (in studio): Jesse also says that studying evolution helps scientists understand which parts of the flu virus change the least or mutate less frequently. It could be that some of these less-dynamic parts of the flu could become targets for longer-lasting vaccines.
Matt: I can dig it. So whats driving the evolution? Whats making the proteins change?
Bethany: Good question. Lets get another influenza evolution expert to chime in.
Adam Lauring: So Im Adam Lauring. Im an associate professor here at the University of Michigan. I am a physician-scientist, which means I spend part of my time actually doing clinical work in infectious diseases. But most of my time I spend actually running a research lab, in which we study virus evolution, including influenza virus. Evolution is really for me kind of the be all, end all in the problem of influenza. Evolution has immediate and real-world impacts.
Bethany (in interview): When we say flu is evolving, what is actually going on?
Adam Lauring: At its simplest, the flu will mutate, and that means that its making changes in its genome which will lead to changes in its proteins, and those protein changes will make the virus different. And then theres selection. And so viruses that are better at doing what viruses do will take over, and the viruses that are less fit will die away. And so its kind of like you learned when you first learned biology: its survival of the fittest, or the best one wins. And so the virus is mutating all the time, and the ones who are best able to make copies of themselves and spread from person to person are going to become the new viruses and replace the old ones.
Bethany (in studio): Now, flu evolution is a complex process thats influenced by many things. But one thing that helps flu evolve especially fast is that its an RNA virus. That means its genes are stored in ribonucleic acid, or RNA. RNA viruses, in general, evolve faster than viruses that store their genetic information in DNA. Both DNA and RNA viruses have proteins called polymerases, and the job of these proteins is to make copies of the viruss genetic code. DNA polymerases, however, have a built-in proofreading function. They can check their work for mistakes and correct them. RNA polymerases dont do that.
Adam Lauring: Because of this, most RNA viruses have mutation rates or error rates that are about a thousandfold higher than for DNA viruses. That means that an RNA virus can generate mutants way more quickly, and then some of those mutants will confer an advantage to the virus, and that will lead to faster evolution.
Bethany: Adam says that all of the flu viruss proteins can and are evolving but that mutations to the hemagglutinin and neuraminidase proteinsthe Hs and Nsare the ones that matter most.
Adam Lauring: Mutations in those proteins tend to make a bigger difference in terms of whether the virus succeeds or fails, and a major reason is those proteins, theyre on the surface of the virus, and so theyre targeted by the immune system. And so you have antibodies targeting those proteins. So if a virus figures out a way to escape those antibodies, it will do better than its brothers and sisters.
Bethany: So weve been talking a lot about mutation, but Adam also points out that theres a lot more to evolving quickly than just how fast a virus mutates. For instance, the number of people infected could play a role. The example he gave me is the more people infected, the more opportunities the virus has to evolve. Thats because a greater diversity of people would mean a wider variety of immune systems, and the virus would need to generate new or different versions of itself to survive.
Adam Lauring: Broad strokes, flu does evolve quickly but maybe not for the reasons we typically think. And there are probably subtleties yet to be uncovered.
Bethany: To try to uncover some of those subtleties, Adams lab has been collaborating with Arnold Monto and Emily Martin, who are epidemiologists at the University of Michigan School of Public Health. For about 8 years, they have been following 300 or so Michigan families to see what viruses are circulating among them and how their immunity changes over time. The flu virus is part of this sampling. As part of the work, they collect nose and throat swabs anytime someone from one of those families gets sick.
Matt: Oh, wait. Everyone gets swabbed when anyone gets sick?
Bethany: Right. Heres why.
Adam Lauring: Its really kind of a slice of what flu is doing locally, and youre not really biased by only getting sick people or people who tend to go to the doctor.
Bethany: Adams group realized that the collection of samples the epidemiologists had accumulated gave them a great opportunity to see how flu viruses were evolving outside of a laboratory. So they raided the freezer and then did in-depth genetic sequencing of all the influenza viruses they found.
Adam Lauring: The virus makes a lot of mutations. Everybodys flu viruses, their population is actually a little bit different. So I could have the flu and you could have the flu and wed be in the same room, but our flu viruses might be a little bit different if you really looked hard enough. And so what were able to do with our sequencing is really understand those subtle differences in kind of the overall flu mixture that each person has in them.
Bethany: And then they compare, see which versions are actually being transmitted from person to person.
Adam Lauring: And that is really important in understanding evolution, right, because you may generate all sorts of cool viruses inside you. But if they dont make it onto the next person, its kind of a dead end. And that virus could be the most awesome virus there is, but if it doesnt get transmitted, its gone forever. And so what we tried to do is understand exactly how many viruses kind of go across from one person to the next. And we found that its actually a really small number. Its hard for a new virus to kind of make it both within a host and to get on to the next host.
Matt: Thats wild. So, if its hard for a new flu virus to survive within a host and also hard for that virus to make it to the next host, how is that much evolution happening? Why do we still need to get the flu vaccine every year?
Bethany: Adam says its really just a numbers game. Hundreds of millions of people are infected with the flu each year, which gives the virus lots of opportunities to make a successful mutant.
Adam Lauring: One analogy I give is flu viruses are sort of like people playing the slot machines. And so most of the time the virus is losing when you talk about kind of on an individual host or in a household. But if you have a hundred million people playing the slot machines, youre going to hit the jackpot with some frequency.
Matt: I like that analogy. Its kind of empowering. Like humanitys the house and the flus a rube giving us their money.
Bethany: Sure. Just remember, the flus currency isnt money. Its trying to survive, and when it thrives, it makes you sick. So its not like a casino catches fire whenever someone hits the jackpot. And the analogy really works best for antigenic drift. Weve got a whole other type of evolution to talk aboutremember how I said there were two? This second kind leads to pandemics, and well talk about it . . . after the break.
Matt: Hey. Sorry to leave you hanging like that, but dont worry. Theres going to be a silver lining. Were not just going to be like. The flu. Yeah, its brutal. Welp, see you later.
Thats the great thing about covering chemistry. Its that were not just talking about problems, were talking to the people solving them.
In fact, earlier this month, Leigh Krietsch Boerner wrote a phenomenal piece for C&EN about how researchers are examining the effectiveness of flu shots, especially vaccines made using eggs.
Weve got a link to Leighs story in the description, but if you want to inoculate yourself against the possibility of missing more of our great coverage, sign up for our newsletter. Well send a weekly dose of chemistrys biggest goings-on right to your inbox. Head to cenm.ag/newsletter to subscribe.
Matt: So, Bethany, you said there were two main forms of influenza evolution: antigenic drift, which weve been talking about. But there was also, what was that rhyme again?
Bethany: Antigenic shift.
Matt: Right, antigenic shift. Whats that?
Bethany: When the influenza virus undergoes antigenic shift, it experiences a much larger change. It changes so much, in fact, that we usually dont have much of an antibody arsenal built up to fight it.
Matt: And how does it make such a dramatic shift?
Bethany: So, antigenic shift can happen a few different ways. Another way flu is different from measles is that flu doesnt just circulate in people. It also circulates in many other animal species, like pigs and whales and birds.
Bethany: Yeah. But it turns out, the vast majority of influenza strains that exist in the world actually are circulating in wild waterfowl. And sometimes those viruses will jump from birds to people or from birds to pigs to people, for example.
A single animal can also get infected by two different strains of flu from two other animals. Those viruses then swap some of their genetic material to make a new, third strain.
However its happening, when the flu is evolving outside of humans, vaccine makers and our immune systems are largely blind to what these viruses look like. That means if one of these viruses does jump to humans, it could hit us hard. Were talking global pandemic here. Thats because the virus would look very different from anything our immune systems have seen, and we might have little or no ability to recognize the strain or fight it.
Matt: That sounds gnarly. And a little scary.
Bethany: It is. Global flu pandemics occur when a novel influenza virus spreads quickly around the globe.
Matt: Is that why were so concerned when people get infected with flu on chicken farms, for example?
Bethany: Yes. And you may have heard about the recent outbreak that started in Wuhan, China. Thats a coronavirusso, not the flubut its another example of a pathogen that made the jump into people from animals. But theres actually a lot more to becoming a global pandemic than just generating a virus people havent seen before. Lets talk to someone who studies how global influenza pandemics emerge.
Seema Lakdawala: My name is Seema Lakdawala. I am an assistant professor at the University of Pittsburgh in the School of Medicine and the Department of Microbiology and Molecular Genetics.
Bethany: Seema says there are several hurdles a new virus has to overcome before it can become a pandemic
Seema Lakdawala: And the first hurdle is that they have to be able to infect the human host. And so its hard for some viruses that may be emerging in birds to infect the human hosts unless theres access. And so it doesnt happen as readily, but that does happen in many occasions.
Matt: That makes sense, right? Its kind of like what Adam was talking about earlier. How you can have all these cool bugs being made in humans, but if they cant survive, and if they cant make the leap in humans, they really arent a threat.
Bethany: Right. And Seema says the next hurdle, after a virus has made it into a human, is the virus being able to survive in respiratory systems. In humans, the flu is a respiratory infection, but in birds, its gastrointestinal. Influenza virus can move from birds to people through contact with feces or other secretions, butdont worrynot from eating poultry or eggs.
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Podcast: Why do I have to get a flu shot every year? - Chemical & Engineering News