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Time Stamps

  • 03:08 The history of the influenza virus
  • 08:27  What does the influenza vaccine target?
  • 13:29 Chickens, and bugs, and mammalian cells, oh my! How the vaccine is made.
  • 14:05 What to do about egg allergies.
  • 16:08  Vaccine effectiveness and herd immunity.
  • 17:50 Waning immunity and other debates

Show Notes

  • The infamous flu pandemic of 1918 sadly led to at least 25 million deaths and triggered research into influenza and the creation of a vaccine.
    • What we now know of as “the flu” was first thought to be a bacterial infection due to Haemophilus influenzae, which is where the virus got its name.
  • Influenza has at least 3 species that infect humans (A, B, and C), but only A and B have been known to cause significant disease.
    • Flu A is the most prevalent worldwide (on average around 75% of cases) and possibly more virulent, although new data challenges this.
    • Flu B has cause localized epidemics in parts of Africa and South America.
  • Influenza naming conventions require the flu species, where it was isolated, the strain number, and finally, the year. For example: Influenza A/California/04/2009.
    • Influenza A is further separated into various serotypes differentiated by how antibodies respond to their hemagglutinin and neuraminidase proteins.
    • For example, the “Swine Flu” pandemic of 2009 was due to Influenza A/California/04/2009 (H1N1), hence the nickname “H1N1.”
  • The flu vaccine specifically targets the hemagglutinin protein, whereas anti-virals used to treat the flu target the neuraminidase protein.
    • Hemagglutinin is an envelope protein that allows the virus to enter cells.
    • Neuroaminidase is an envelope protein that allows the virus to leave cells after replicating in them.
  • The vaccine formulation changes every year to match the viruses latest mutations. These mutations are caused by antigenic drift and antigenic shift.
    • The strains are recommended by the WHO and a US group called the VRBPAC based on trends they see from epidemiology and genetic data.
  • There are 3 ways to produce the inactivated flu vaccine:  the age-old chicken egg culture, the newer mammalian cell culture, or the recombinant method (which uses insect cells).
    • But, the first flu vaccines were created using ferrets! They have a uniquely strong immunogenicity against viral antigens and are still used to test vaccine effectiveness today.
    • Most vaccines today are made using the chicken egg method, although new methods are gaining popularity.
    • Of note, the CDC recently changed its guidelines to specify that patients with an egg allergy can get any vaccine. While patients who had a hive reaction to eggs previously required monitoring for >30 mins after getting the vaccine, the new guidelines now reserve this caution only for patients with an anaphylactic allergy only.
  • There is also an activated (but attenuated, aka not very strong) flu vaccine that is delivered nasally. As with other live vaccines, it should not be used in pregnant or immunocompromised patients.
  • The flu vaccine can be trivalent or quadrivalent, meaning it contains 3 or 4 strains.
  • Vaccine effectiveness must be measured retrospectively and is typically around 40%.
  • Current frontiers in flu research include:


Flu Part 1:

In part 1 of our flu series, we explore the history and present day understanding of the flu, just in time for flu season!

S: Medically, 1918 started off like many others before it.

J: The New England Journal kicked off the year with a treatise on the differential diagnosis of chronic cough, which they called pulmonary tuberculosis.

S: From the article: “Someone has said that every cough of two months’ duration is due to tuberculosis. This is, of course, absurd.”

J: If only we could write like that now.

S: It goes on to mention that cases of what they called “chronic influenza bronchiectasis” were wrongly diagnosed as TB. Interestingly, it’s because sputum from those patients often yielded influenza bacilli.

J: Wait influenza bacilli? Influenza is a virus, not a bacteria!

S: Yeah… and that threw me off too. This is the age when germ theory (aka bacteria) is just taking off, so the modern understanding of viruses isn’t really there.

J: It turns out they were actually talking about the bacteria we now know as “Haemophilus influenzae.”

S: Which at the time they thought caused influenza, hence the name. 

J: So we reviewed a lot of old journal editions from 1918 to 1919, expecting to find sensationalized headlines about the 1918 Flu Pandemic.

S: But found these instead. For example, the health benefits of “Horseflesh as food

J: Or articles from World War I about new diagnoses like “War psycho-neurosis” and “Organic lesions in shell shock

S: Presumably forerunners of PTSD.

J: We didn’t find much of what we now know of as the deadliest flu pandemic in modern history. Why is that steve?

S: Maybe because they were probably distracted by World War I. It was kind of a big deal I hear.

J: Well, they would eventually get there, right?

S: By June and July, they start to report on the flu outbreaks. But due to limited understanding by that point, tens of millions of people had already died.

J: Fortunately, since then we’ve gotten a lot better at preventing and treating the flu.

S: It’s no surprise that we’re discussing this as the flu season itself starts  to heat up. 

J: Cases of flu are already on the rise in the US.

S: So let’s try to stay ahead of things and explore the A, B, Cs of influenza.


J: Welcome to Mind the gap, I’m Janine Knudsen 

S: And I’m Steve Liu

J: We’d like to thank Dr. Aditya Shah, Chief Infectious Disease fellow at the Mayo Clinic and Dr. Denise McCulloch, Infectious Disease fellow at the University of Washington for peer reviewing this episode.

S: During today’s episode, we’re going to jump right into our modern thinking about influenza and how influenza prevention was developed.

J: Namely, we’ll start with a little more history and, well, how it’s named.

S: Followed by a deep dive into flu vaccines.

J: Answering questions like, how is the vaccine actually made?

S: And how do we select what strains go into the vaccine each year.

J: From there we’ll discuss how effective the vaccine really is.

S: Including this idea of herd immunity

J: And lastly we’ll discuss some concerns about the vaccine like waning immunity and vaccine contraindications.

To jump back into our historical play by play, when did they first pick up on the fact that an epidemic was underway in 1918?

S: The flu epidemic actually hit in three distinct waves. The first occurred at the tail-end of what we now call the flu season, in March of 1918.

J: Ah, so that’s why by midsummer, after the first wave, there’s still no mention of the epidemic in any major journal.

S: Until July 1918, the Lancet first notes an ongoing epidemic of respiratory illnesses.

J: They wondered, quote, “Is the present widely spread epidemic one of influenza or is it something new?” They were confused because they were unable to isolate that Haemophilus influenzae bacilli that at the time was the most commonly thought cause of influenza.

S: They described the disease:

J: “The most striking symptoms are: sudden onset with chills, severe headache with pain… in limbs and general malaise… the maximum temperature was 103 to 104… Many cases develop a cough, harsh in nature with thick sputum.”

S: Sound familiar to anyone who’s ever had the flu?

J: Gives me the chills just thinking about it. Well, first, they didn’t think it was that serious. But then articles began to note that in some patients, delirium and death occurred within 24 hours.

S: By October 1918, the second wave had already struck. The Boston Medical and Surgical Journal, now the New England Journal, noted the spread of the influenza epidemic through Boston and the East Coast. They also noted a typical death rate at the time, but rapid spread.

J: A week later they noted that the epidemic was “still maintaining unprecedented strength” and drastic measures were being taken. The New York State Health Commissioner printed posters noting that it was “unlawful to cough or sneeze without turning the face away from others and covering the nose and mouth with a handkerchief.

S: How amazing is that

J: Yeah, the numbers are pretty sobering. At this point in October, in Massachusetts alone over 150,000 people got sick in just two weeks, and five thousand died.

S: By November they noted that the epidemic was really starting to wane locally but had spread throughout the US into the West.

J: The reality is that this second wave of flu smoldered, catching fire in some regions for the next month.

S: So what did they do about this? First, they began urging people to get vaccinated.

J: But the problem is that they still thought they were dealing with H. influenzae or another bacteria… so they were using the wrong vaccine.

S: So they got pretty desperate. Still, other treatments advocated for included spraying people with formalin, giving antistreptococcal serum to others, or – get this – giving alcohol to the ill.

J: Always a good choice.

S: The public remained confused – some thought the disease was a form of malaria.

J: Doctors were misled by culture data, and debated intensely in multiple journals about whether the infection was caused by H. flu, or instead staphylococcus – now we know that these may have been secondary infections.

S: By the time the third influenza wave finished crashing over the world, estimates ranged that between 20 and 50 million people had died.

J: That’s pretty horrific. So why hasn’t it happened again?

S: Well, the 1918 virus was special, it had a w-shaped mortality curve.  

J: Wait Steve, what’s a “w-shaped” mortality curve?

S: Most of the time when we talk about the flu we talk about people dying young and dying old. And that looks like U on the graph. During these specific outbreaks, young adults died giving it a weird peak in the middle, kind of like a “w”.

J: Ok, backing up, when did they realize it was a virus, not a bacteria?

S: That will actually come two decades later in 1933.

J: That’s crazy… and it took a few more years to realize that there were multiple species of influenza.

S: And there are actually 3 that cause influenza in humans.

J: I bet you didn’t know that Influenza C exists.

S: More trivia for my nerdy cocktail parties!

J: Now we’re going to talk about naming conventions and the creation of the influenza vaccine!

S: Influenza A is the most common species and has caused the most pandemics in the world. Influenza B is less common and usually only causes regional epidemics.

J: For example, last year (2018-2019) 95% of all influenza viruses detected were Flu A. But that was particularly extreme – on average influenza B makes up around 25% of cases.

S: In addition, it also tends to vary by region. Last year, despite its overall low prevalence, Flu B was actually more common in certain regions of the world, particularly parts of Africa and South America.

J: It’s also still unclear whether flu B is less dangerous than flu A. It causes fewer deaths, but that could be due to its lower prevalence, not actually lower virulence. New data coming from ICUs is calling this into question – see our show notes for more.

S: But across the board people recognize that Flu C is the mildest and also the rarest.

J: Ok, now that we’ve established which flu species we *actually* care about,.

S: Flu C is not clinically relevant.

J: Remind me how to name them? How do we tell strains apart?

S: Glad you asked – let’s go over naming conventions: You start with your species – like A/B/C – followed by where it was isolated, the strain number, and the year.

J: So let’s give an example: the infamous 2009 pandemic strain was officially called Influenza A/California/04/2009.

S: Wait, why do we call that one H1N1?

J: Ok, so for Influenza A, it’s additionally divided into serotypes sorted by how our antibodies react to hemagglutinin and neuraminidase molecules.

S: Ahh, the Hs and Ns. Just as a note, for Influenza B and C we don’t use these serotypes.

J: No, they don’t. As a refresher, the hemagglutinin protein allows influenza to bind and enter cells and the neuraminidase protein helps the virion leave to infect other cells.

S: Virion?

J: Let me use my fancy words, Steve.

S: Hemagglutinin is important because it’s the target of the flu vaccine.

J: That makes sense – after all that’s how viruses get into the cell!

S: And as it turns out, neuraminidase is also as important. That’s what is targeted by inhibitors like oseltamavir, peramivir, and zanamivir – the drugs we now use to treat influenza.

J: Side note – we’re really fortunate that resistance to these neuraminidase inhibitors is rare, although we are seeing a few cases.

S: So, for influenza A, the Hs and Ns really matter. Hence the name H1/N1 for the 2009 strain.

J: Another important fact about that strain, we keep seeing it every year. So ever since 2009, its been a part of the flu vaccine.

S: Its shadow grows darker…

J: It’s legacy lives on… okay, moving on… let’s talk more about what goes into these flu vaccines.

S: First, a little more history – the first flu vaccines were created using ferrets! It turns out that of all creatures, they have a uniquely strong immunogenicity against viral antigens.

J: Well I never would have guessed that…

S: In fact, even to this day, ferret serum is used to test whether or not a particular vaccine will be effective.

J: But to culture viruses, a breakthrough in the 1940s led to the use of chicken eggs.

S: Ferrets and chickens, who would’ve thought.

J: This in turn allowed for the development of a bivalent influenza A vaccine.

S: Now we have trivalent and quadrivalent vaccines, that include – you guessed it – 3 or 4 strains.

J: The trivalent vaccines covers 2 major flu A viruses – the H1/N2-like virus and a common H3N2 virus – along with 1 flu B virus.

S: The quadrivalent vaccine adds another flu B strain.

J: But is it better?

S: Well, in some ways it doesn’t matter because more than 80% of vaccines on the market are quadrivalent.

J: But what do the studies say? Does that extra flu B strain really help us? Especially if it’s not that common?

S: Well some studies argue that it’s more effective, but it’s largely based off of projected data

J: Ok well for now, the guidelines from the CDC still say that you can get either vaccine, and that as long as you get one of them you don’t need to go the extra mile to get the quadrivalent one.

S: Ok, we’ve established trivalent and quadrivalent… just get the vaccine it doesn’t really matter. So, let’s start answer another important question: how do we decide what strains of the flu go into it every year?

J: Well, for starters, it’s important to note that unlike other vaccines like Hepatitis B or Measles, we need a new flu vaccine every year and that’s because the virus has a high rate of mutation.

S: Yes, because of antigenic drift and antigenic shift, we’re exposed to new viral strains nearly every year.

J: As a quick reminder – drifts are small changes that occur over time. Shifts are big changes that usually happen when an infection has an animal reservoir. Like the H1N1 swine flu epidemic.

S: The WHO Global Influenza Surveillance and Response System or GISRS uses 142 influenza centers to monitor shifting influenza trends around the world.

J: At the end of every flu season the WHO publishes a recommendation for the following year’s vaccine.

S: And fun fact – this happens every 6 months, not a year because the flu seasons are both the northern and southern hemispheres. For world travelers, you have to get a southern flu vaccine.

J: It’s also actually only finalized in March in the US when the annual Vaccines and Related Biological Products Advisory Committee meets. This year was the 155th one!

S: What they are actively trying to figure out is which viruses can help generate an immune response against the majority of circulating viruses.  

J: Ok, so we have our flu strain recommendations. From there, it still takes months to make the vaccine.

S: They’re going to release all those trivalent and quadrivalent vaccines on the market.

J: And remember, you can get either one as long as you get the vaccine

S: So, who can’t get the vaccine Janine?

J: From the WHO: “There are no contraindications to the use of these vaccines in age groups greater than 6 months.

S: To start, the only kind of contraindications is anaphylaxis, but you can still get it as long as you’re being monitored.

J: That said, not all brands are approved for younger children. Furthermore, if it’s your child’s first go around with the flu vaccine, the CDC recommends two doses in their first season.

S: Remember the vaccine typically takes about two weeks to kick in, so if you’re listening to this now and haven’t gotten it, go get it!

J: Now we recognize we’ve mentioned a few different subtypes of vaccines.

S: So what are the different types… manufacturers produce inactivated viral products vaccine via one of three ways… via chicken eggs, mammalian cells or recombinant vaccines.

J: Oh! So that’s why when I go to order the flu vaccine in my EHR, I have so many options to choose from – Fluzone, Flucelvax, Flublok – am I even saying those correctly?

S: Exactly. In all cases the general idea is the same – we infect a cell, mostly egg cells, with a “candidate virus,” then the virus can replicate.

J: Then everything is killed to inactivate it and the hemagglutinin antigen is purified from the inactivated virus’s antigen soup and made into a vaccine.

S: So chicken eggs were the original way to make the vaccine, but there is a downside.

J: And it’s not the egg allergy! The CDC guidelines state that anyone can get the egg-based vaccine because the rates of anaphylaxis are so super low – 1.31 in a million.

S: They just advise caution in patients with a severe egg allergy (we’re talking anaphylaxis, not just hives) – those folks should be monitored closely when they get the vaccine.

J: Ok, so the main issue now with the egg-based vaccine is that it relies on a good egg supply. 

S: Which may not be available in the case of pandemics when millions if not billions of vaccines are needed quickly…

J: That’s why scientists have come up with new ways to make the vaccine, like mammalian cells and recombinant flu vaccine. 

S: If you care, these are brand-names like Flucelvax and Flublok.

J: So mammalian cells are intuitive, but what’s the recombinant virus method?

S: For that, Janine, we use insect cells.

J: Gross.

S: The hemagglutinin gene from the flu virus is mixed with a different virus that grows well in insect cells

J: This sounds like such crazy science fiction, I mean isn’t this how Frankenstein was created?!

S: Stop spreading fear. You will only probably become Frankenstien if you get one of these. Inside the insect cells, just like the eggs and other mammalian cells, the virus replicates, makes a bunch of hemagglutinin and providing substrate for the vaccine.

J: For the chicken fans out there: the recombinant flu vaccines definitely does not involve any chickens.

S: But it is bug juice.

J: In a manner of speaking, remember these are insect cells, not actual insects.

S: So, we’ve gone over how to make the vaccine. Manufacturers use these methods to make something to the tune of nearly 170 million vaccines in the US each year.

J: And most of them are still made using the egg method.

S: So many scrambled eggs lost.

J: The great chicken egg massacre.

S: For a good cause! But that actually doesn’t seem like enough. Aren’t there almost 330 million people in the US?

J: Well unfortunately not everyone gets vaccinated, but remember technically not everyone has to. Remember…. herd immunity.

S: Oh, you’re right. The general idea is if enough people are vaccinated, the flu is less likely to spread?

J: That’s a little too simplistic. Our listeners can handle the details! Herd immunity is calculated using a simple formula that compares how transmissible the infection is to how effective the vaccine is.

S: Some people are more likely to transmit the infection – like soldiers who were packed into tight quarters in 1918, or healthcare workers today – we’re kind of like a horrible gold mine for flu to spread.

J: So that’s transmission. The second part of herd immunity is vaccine effectiveness.

S: And to answer that, we have to know how good we are at predicting what strains to put into the vaccine each year.

J: To quote Dr. Nancy J Cox, formally of the WHO and CDC: “What I would say is that the methods that have been developed thus far can predict the past. They have not been able to predict the future.”

S: Keep that in mind for when we talk about how good or how bad the vaccine is every year.

J: So what we care about is not vaccine efficacy, aka how something performs in the lab under ideal circumstances, but effectiveness – how it performs in the real world.

S: To measure this, the CDC looks at how many people who got the vaccine also got the flu.

J: But to make it easy on us don’t require flu cases to be confirmed via test, like a viral swab. It’s ok for people to just have influenza-like illness, with a fever and respiratory symptoms.

S: So some of those cases could actually have been caused by other viruses, which the flu vaccine does not protect against.

J: Which means that this measure of effectiveness probably underestimates how well the flu vaccine works.

S: Effectiveness in flu vaccination has ranged as low as 10% in the 2004-2005 season to as high as 60% in 2010.

J: But generally ranges fall in the mid-40%s.

S: That said, things get murkier in certain populations. For example, there has been a long-time there has been a concern about waning immunity in the elderly.

J: Yeah, in general flu immunity may wane even within 1 season, like after 7-8 months, but it may be even faster in the elderly.

S: From the VRBPAC meeting, those are the folks that select the flu vaccine in the US, “There is a growing body of literature on waning immunity… that may be more pronounced among older adults than among younger people… it may be more common with H3s than with H1s…”

J: While the experts agree that this probably happens, they don’t agree on what to do about it.

S: Some folks have advocated for the high dose influenza vaccine.

J: But to be clear there is a study from 2014, published in the NEJM, showing an improvement in serological markers of immunity. The high dose vaccine’s impact on actual clinical outcomes, like visits to the ED, hospitalizations and pneumonia was minimal.

S: A Lancet study from 2017 was similar and showed very slight improvement in hospitalization rates.

J: Well, one thing we can all get behind is something the NIH is working on – universal flu vaccine, that immunizes against every strain of the flu and doesn’t need to be repeated every year.

S: A flu vaccine that protects you for life? This might sound like science fiction again…

J: Like the zombie insect cells

S: It is based in sound science and worth reading about on the NIH website!

J: If they can make it happen we may never see a flu pandemic again!

S: Ok, now we’re getting ahead of ourselves. Let’s save the rest of the fun for our next episode, where we’ll talk about flu diagnosis and treatment.

J: To wrap up, let’s cover key points from today’s episode:

S: First, we went over the history of the flu, and how they used to think it was caused by the Haemophilus influenzaE bacillus, hence the name.

J: Next we went over flu nomenclature, including the 3 main flu species – A, B, and C – and the H and N serotypes that are specific to the Flu A virus.

S: Then we jumped into vaccines, which target the hemagglutinin protein on the outside of the flu virus that allows it to enter cells.

J: Compared to the neuraminidase protein that helps it leave cells to attack new ones – that’s what drugs that are used to treat the flu infection target.

S: The inactivated flu vaccine can be created in 1 of 3 ways: the age-old chicken egg culture, the newer mammalian cell culture, or the fancy recombinant method using insect cells.

J: It’s important to note that now the CDC says all are safe for people to use even if they have an egg allergy.

S: Then there’s the live flu vaccine – only available as a nasal spray – that should not be used in pregnant or immunocompromised patients. But I guess it’s good for people who really hate shots?

J: We also reviewed that each flu vaccines contains 3-4 strains – but most in the US are now quadrivalent.

S: The combo of strains in the vaccine changes mostly every year because the flu vaccine mutates quickly through antigenic drift and shift.

J: The strains are recommended by the WHO and a US group called the VRBPAC based on trends they see from epidemiology and genetic data.

S: Vaccine effectiveness is measured retrospectively, and is typically around 40%, which is probably an underestimate based on how they measure it.

J: But thanks to herd immunity, as long as a majority of people get the vaccine, we’ll generally be protected.

S: Except for the elderly, who may have waning immunity over the course of a flu season – we haven’t quite figured out what to do about that yet.

J: And finally, at some point, hopefully in our lifetimes, they’ll come up with a universal flu vaccine so all this yearly vaccination business won’t be necessary.

S: So whose ready for the next episode!

J: So we know that we went kind of quickly through the data and arguably not as in depth as some might like. So as always we want to encourage you to check out the data too, take a look at the links below at so you can take the time to judge it for yourself and sound smart on rounds.

S: Super smart, super smart!

After all, this is a podcast talking about those gaps in our knowledge. So if you really want to feel confident on the data, take the time to pick it apart yourself. And if there are any other topics you’d like to hear discussed, please let us know.

I’m Steve Liu and I’m Janine Knudsen and remember mind the gap! Thanks for listening. Janine and I are assistant professors in the department of general internal medicine at NYU. Opinions in this podcast, our own and do not represent the opinions of NYU or other affiliated institutions. Please don’t use this podcast for medical advice, but instead consult with your healthcare provider.


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