Dr. Matthew Memoli — A Better Shot Against the Flu

>> Diego (narration): Well folks, it’s that time of year again, when Halloween decorations retreat to boxes in the attic and tag in Thanksgiving and holiday ornaments.

[Light music with bells and string]

Gravy boats replace buckets of candy, hanging cobwebs turn into twinkling string lights and witches’ hats slouch down into merrier shapes.

[Santa’s “Ho, Ho, Ho”]

It’s a time to celebrate time-honored traditions with your nearest and dearest, and I’d hope that among those traditions is getting the annual flu shot. It may be the season for giving, but the last thing you want to do is give sweet Aunt Marleen a runny nose and a 102-degree fever.

[Sniffling and coughing sound effects]

You should, however, give yourself a better chance against the strains of the influenza virus that are predicted to circulate this year.

Like all vaccines, the flu vaccine gives your body the opportunity to develop antibodies against the virus in the event that you’re faced with a natural infection. These antibodies recognize specific parts of the virus, known as antigens, and trigger the immune system to neutralize the threat. But sometimes, the antigen your body trains to fight, is not similar enough to the particular strain of the virus it encounters in the real world. This mismatch allows the virus to fly under the radar and spread undetected. And other times, the vaccine works well for some people, but doesn’t provide protection for others like the elderly, small children, or individuals with chronic disease.

These are problems scientists are now contending with with the COVID-19 vaccines. But they’re nothing new for influenza. For years, many scientists have focused on developing a universal flu vaccine—that is, one that can protect against all, if not most, strains of influenza. Dr. Matthew Memoli is one of these scientists. As the director of the Clinical Studies Unit in the IRP’s Laboratory of Infectious Disease at the National Institute of Allergy and Infectious Disease, or NIAID, Dr. Memoli works to understand how the flu attacks the body and is devising new ways to stop that attack from the start. In fact, he is gearing up to launch a phase I clinical trial with a vaccine candidate that could offer better protection from more strains and for more people, than what’s currently available.

In talking with Dr. Memoli, he told me why influenza is so difficult to pin down, and how his new trial could bring us closer to a more broadly protecting vaccine.

>> Diego (interview): I don't think it would be an exaggeration to say that the world is abuzz with vaccine talk. The COVID-19 vaccines have been top-of-mind for a better part of two years now. And the flu season is just around the corner, so I figured we could start by discussing how the vaccines for SARS-CoV-2 and influenza are similar and how they differ.

>> Dr. Memoli: Yeah, so there are both similarities and differences between the sets of vaccines. So, let's talk about some of the similarities first. The similarities are that they both target a major protein antigen of the virus. Current influenza vaccines—the quadrivalent intramuscular vaccine that most of us get every year—targets the hemagglutinin protein and a particular portion of the hemagglutinin protein that we call the head of that protein. And that stimulates your immune response, and you develop systemic antibodies against that HA head. The SARS-CoV-2 vaccines that we're currently using are designed to stimulate an immune response of a similar nature to the spike protein; and in particular, a region of the spike protein called the RBD or receptor-binding domain. And so, in a way, they're very similar and they both take what I call a single antigen strategy. And the goal is to take this major antigen and try to generate a very high level of systemic antibodies in your blood that hopefully are going to get to the right places in order to prevent you either from getting infected or prevent you from having a more severe infection. And so that's the similarity and sort of how they work. But some of the differences related to how they work is that currently, the influenza vaccines that we use are primarily made up of protein antigen.

>> Diego (interview): Right.

>> Dr. Memoli: In that we take a flu virus and we essentially chop it up into pieces and we focus mainly on making sure that we have enough of the HA protein present in the vaccine so you're really getting a good dose of HA protein. With two of the three SARS-CoV-2 vaccines that are being used in the United States, we're not administering protein. We're administering mRNA, messenger RNA, that codes for that protein. So that's a little bit different. And the reason that that's significant is that when I give you the influenza vaccine, I'm giving you an absolute known quantity of the protein. When I'm giving you the mRNA vaccines, I'm giving you mRNA and then relying on your body to make the protein. And that may be a little bit different depending on who you are and how you respond to the vaccine. In terms of the J&J vaccine, that is a little bit different in that you are having protein delivered through the vector that they're using. So it's a little bit more like the flu vaccine, although not exactly the same.

>> Diego (interview): Well, from an outsider's perspective, just to revisit the idea of the mRNA platform, it seems that the mRNA platform has great promise for all sorts of like infectious diseases because it is based around the genetic information and uses the body's own mechanisms to get the right conformation, like you said, of the mock viral protein. It almost seems like you just have to switch out the cassette, if you will, to get the right target that you're looking to produce. In theory, could the mRNA platform work for flu and has it been attempted?

>> Dr. Memoli: So yeah. So it could. You know, we've gotten excited about mRNA. It's sort of the latest hot thing and we have these trends and that's great. It's fine, it's a good technology. It's good that we have it. However, you know, ultimately, you're still relying on the same basic principle. You're relying on an antigen, a protein, being delivered in appropriate amounts to stimulate an immune response at the right place that's going to prevent infection. Whether or not I give you HA protein or I give you an mRNA that encodes for that HA protein, is only going to be as good as the antigen, the protein that I'm actually delivering to you. So, in other words, if I delivered to you a 2007 H1 protein in an mRNA vaccine, well, that's not going to protect you from the post-2009 H1N1 virus because it's a mismatch. So whether that was mRNA or protein, it makes absolutely no difference. It's not the right antigen.

>> Diego (interview): Right.

>> Dr. Memoli: So mRNA, it's just another way of delivering antigen and, you know, we can debate what's better protein or mRNA. You know, do you really know the dose of mRNA that people are getting? There's a lot of issues, and there's problems with both, and there's things you can discuss. But the reality is, the thing we really need to be focused on is what are the appropriate antigens to be delivering? How do we deliver them to induce the best immune response that's going to protect the most people?

>> Diego (interview): Right. On the topic of delivering the appropriate antigens, coronavirus and influenza have something else in common—that is, the proliferation of different strains. COVID has the delta strain we’ve gotten overly familiar with in the last several months. And you mentioned that the strain of the vaccine in the flu vaccine has to match the one that is in circulation that year for optimal protection. Do you know roughly how many strains of influenza there are and how that variability affects the vaccine development process?

>> Dr. Memoli: Yeah, so there's enormous numbers of strains of influenza. So first, you have to identify what is the hemagglutinin type and the neuraminidase type subtype. We have various subtypes that we name based on their HA and NA. And then, there are different strains within those subtypes. So I was just talking about that a second ago in that two H1N1s don't necessarily mean they're identical enough that you can just assume that if you’re vaccinated against one, you're protected against the other. And that's exactly what happened in 2009 in that we had the emergence of a new strain of H1N1 that was different than the H1N1 that had circulated the prior two, three years, and was able to cause a mild pandemic. And the only reason it caused the mild pandemic was because the HA itself was similar enough to classical H1N1s from say, the 1940s, the 1930s, the 1920s that older people were protected at that time because they had natural immunity to those viruses. But younger people who had never seen those classical H1N1s were not protected.

One of the big differences between influenza and coronavirus is that influenza A is a segmented genome. It has eight segments. And so those segments of RNA can recombine. And you won't just find one set of eight genes making up one virus. You'll find four or five HAs, two or three NAs, six or seven PB1s, PB2s. In other words, all different versions of the genes that could come together at any time to give you a new strain. So, it's almost like a Lego set, right? As long as you get eight of the individual pieces, it could be a blue one, a green one, a red one, an orange one, right, all coming together.

>> Diego (interview): Right, so it’s a matter of combinations. Flu has a lot of options or possibilities when assembling itself, so it makes sense that the number of variations will be higher. But what about coronavirus?

>> Dr. Memoli: Coronavirus also has strains but it's less flexible in that it has a single piece of RNA as its genome so it doesn't have that same level of recombination that flu can have. What it does have though, is that it's an RNA virus. And so, it makes errors as it replicates and it can develop mutations. And we've seen that, that's what the variants are all about. And so it can change. But it can't change to the level that flu can change.

>> Diego (interview): Got you. And is that ability to change so much and like you were saying that variability, is that why it causes different responses in different groups of people, particularly those in older age groups?

>> Dr. Memoli: Yeah, it's part of the reason why for flu because how you respond to flu is a complex interplay between your age, your genetics, your environment and your previous exposure to flu viruses and flu vaccines. So as I was saying, if you were a person who was 50 years old or older in 2009, you seem to be protected from severe disease and death during that pandemic because as a child, you were exposed to classical H1N1 viruses, had natural immunity throughout your life that protected you. Whereas if you were born in 1995, you were not protected in 2009 because you did not have that exposure when you were young. And the same thing has happened at other times in other pandemics, in that we clearly see that the viruses that you're exposed to earlier on in your life when you're younger, especially naturally infected with, has a particular effect on how you respond to future viruses depending on what they are. And so hopefully you're lucky in a pandemic and you have something that protects you. But that's not always the case, of course.

We've also seen that sometimes, the first exposure you have to a particular virus could affect how you respond immunogenically to future vaccines. There's this concept called original antigenic sin, where if say you were infected with a particular H3N2 strain as one of the first viruses you ever saw in your life. And then 10, 15 years later, we tried to vaccinate you against a newer H3N2 strain that was similar but different enough that it, you know, had some antigenic differences. Sometimes people have a preferential response from this new vaccine, but it stimulates their memory to that old virus. And so that original antigentic sin actually almost impedes you from developing stronger immunity to the newer virus that's contained in the vaccine because it's a more dominant response, because it's the one your body remembers the best. And so, there certainly is an element of what happens now can affect you in the future.

>> Diego (interview): yeah, that's interesting. I would have thought that if you’ve gotten the flu vaccine every year and you’ve done so for the last ten years, that that would contain enough variability to protect you against most subtypes.

>> Dr. Memoli: Well, the flu vaccines we have right now for influenza A, only contain H1 and H3. That's it. So, you're getting H3 and H1 and you're getting flu B in your flu vaccine. And the reason that's the case is because those are the two subtypes that circulate in humans right now. And we found that when those vaccines mismatch, we have an increase in disease and severity. What we've ended up with is that we have a vaccine that is about 10 to 60% effective depending on the match of our vaccine to the currently circulating strain. So we're not doing that great, because even in the best conditions our flu vaccine is only about a coin flip efficacy, right? 50/50. And what we found in studies that I've done is that even if you have good antibody levels against the HA, it may protect you from shedding the virus and potentially spreading the virus. But it does not necessarily protect you from getting sick and developing symptoms and disease from the virus. It's very interesting because for a respiratory virus, like flu or coronavirus –those viruses infect at the mucosal level. They infect you in your nose and your throat, maybe in your lungs. And so, in order to have that protection to be present, you need to have very high levels of antibody in your blood. And you can't maintain high levels of antibody in your blood forever against everything you've ever been vaccinated against or seen as an infection otherwise, you would have sludge for blood, right? All that protein would be present in your blood.

So over time from the flu vaccines and what we're seeing now from the SARS-CoV-2 vaccines is that those antibody titers begin to decrease. They, what we'd call, wane over time. This may have something to do with the fact that we're giving a systemic vaccine for a mucosal respiratory disease. We've found, and there's a bit of research on this, that the mucosal immune system is compartmentalized from the systemic. Meaning you could have a very strong memory at the systemic level, but not necessarily have that same strong immune response at the mucosal level and vice versa. So the body's not going to respond right away to that infection and so you're able to be infected. It's not until the body really says, "Hey, I'm sick," that that systemic immunity sort of kicks in. So, we have to start thinking more, I believe, about the mucosal immune system and how we can stimulate that. And a good example of this is I've taken individuals, challenged them with my H1N1 challenge virus. So I've given them flu. They've gotten sick. They've had an immune response. Many of them have good antibody titers against the virus. A year later or even sometimes less, I've given them the same virus and I've been able to reinfect them. So, it shows you that you can still be reinfected with the same virus.

So, there's a lot we need to understand about immunity to these respiratory viruses. And I think one of the keys is getting a better handle on this mucosal immunity and how it works and how we can use it to better protection from vaccines.

>> Diego (interview): Well, now that you bring up the topic of getting better protection from vaccines, I know that NIAID is working to develop a universal flu vaccine. Is that something that you're involved with?

>> Dr. Memoli: Yes, very much so.

>> Diego (interview): Can you tell me how that universal vaccine would differ from what we get year to year at a local pharmacy?

>> Dr. Memoli: Yeah. So right now, you go and you get your yearly flu vaccine. And as I said, right now, we get 10 to 60% effectiveness depending on the year. And I tell patients it's sort of like wearing a seatbelt. You get in the car, you put your seatbelt on every time you get in the car, right? You have to do it over and over again. And if you get into an accident, sometimes it doesn't matter whether you have the seatbelt or not. The accident wasn't that bad, it wouldn't have mattered either way, right? And that's true with flu sometimes. Then many times, you may get into a worse accident and the seatbelt helps you, right? You don't go through the windshield.

>> Diego (interview): Yeah.

>> Dr. Memoli: You know, it saves your life. There are some instances, maybe more rare, where the seatbelt doesn't matter, right? The car's crushed, it flips over. There's nothing the seatbelt could do about it. And then there's a rare circumstance where having the seatbelt on could be detrimental, right? Car goes off a bridge into the water, you're trapped in the car, you can't get out of the seatbelt, right, something rare like that. So that's kind of how I describe the flu vaccine. Because that's really what it is. Most of the time it probably doesn't make a difference. Much of the time, it saves you. And then, there's some circumstances where it could be detrimental or it's not going to make a difference. You're up the creek, right?

So what we want to do is we want to try to do better than that. And ideally, what we want is we want to have a vaccine that hopefully you wouldn't have to get every year. Maybe you would get it a few times in your life. So now, instead of having a seatbelt you have much safer cars, right?

>> Diego (interview): Yeah, that’s a very interesting way to put it.

>> Dr. Memoli: And then, we want that vaccine to contain the proper antigens and be delivered in the proper way to deliver a broad-based immune response that is going to give you at least some protection, no matter what flu pops up. So it'll work against any variant of the H3N2 and the H1N1 that's currently circulating. It would protect you if all of a sudden there was a new pandemic with H2N2, H6, H5, H10, whatever could pop up. And it would protect you even if you had a zoonotic exposure, say you were working in a poultry market and you had a high path H10 exposure, right? So that's what we're trying to do. And I add an additional factor to universal vaccine in that I don't want it to just be universal in terms of protecting against all different viruses. I also want it to be broad enough and universal enough that it can protect as many different types of people as possible. So I want to be able to protect the old, the young, the sick, people who are on immunomodulating drugs, people who are immunosuppressed, people who are, you know, genetically susceptible to certain kinds of viruses. I want to try to find vaccines that offer as many of those people protection as possible.

>> Diego (interview): Right. And what would qualify -- so once -- if and when it is achieved, what qualifies a vaccine as universal?

>> Dr. Memoli: Well, you know, I think we use this word universal which maybe is a little bit too strong a word. It's probably better to say broadly protective or more broadly protective, something that just gives you much more coverage than what we currently have. Now, hopefully, we will get to a point where it absolutely covers everything imaginable. But I think right now, we would be really happy if it was just a lot better than what we have.

>> Diego (interview): Yeah.

>> Dr. Memoli: And it may be an incremental process. Maybe you only have to get it every five years, maybe it shows that it can protect against a bunch of major subtypes that we worry about right now. Maybe it's an intranasal vaccine that's much easier to administer. And people don't have to get needles, because there's lots of people who don't like needles. Or maybe it works much better preventing death in the elderly and in children. You know, we have 30, 40, sometimes 50,000 deaths in the US from flu every year. You know, we get excited about pandemics but when you start adding up all those deaths over numbers of years, it's a whopping number of people that have died of flu even in the last 10 years. And that includes children. We oftentimes have anywhere from 300 to 1,000 children die of flu every year in the United States depending on the year. So, if we can improve upon that and start limiting those numbers more, that's a big success as well. So, there's no perfect definition, there's no absolute qualification for what is a universal vaccine. I think we just need to see improvement.

>> Diego (interview): Got you. So, what has made the development of this uni—not universal, but broadly-protecting—vaccine so tricky? Are the hurdles mostly biological? Is it something -- like, do you envision a different sort of mechanism for this type of vaccine?

>> Dr. Memoli: Yeah. So, there's a couple of things. One is that variability we were talking about earlier, right? Trying to find the right antigens that can protect and limit flu's ability to evade immunity is challenging because flu, as I've said before, has such an unbelievable ability to recombine, mutate, and change and it's unpredictable. In fact, some people say it's predictably unpredictable. And so that’s one of the major biologic hurdles. The other major biologic hurdle is, as I said to you earlier, you're dealing with a respiratory infection that you can be infected with multiple times. So even a natural infection doesn't induce fully 100% protective immunity. It induces good immunity but it's not 100% protective. So we have to do better than nature. Usually when we make vaccines, we're just trying to do as well as nature. But with this, we're trying to do better than nature. So that's a tall order for scientists.

Now, having said all that, the other hurdle I think is there's sort of a conceptual hurdle about vaccines that I think we have to move past. This is my personal opinion having worked in this area for 17 years now; most companies and most researchers, what they do is they develop a platform for vaccination. So like we talked about before, mRNA is a platform, adenovirus vectors like the J&J vaccine is a platform, nanoparticles are a platform. And then, they try to fit that platform onto different diseases to try to use it. And that's fine. It's great to have platforms. But they're putting I think more effort into developing the plattform and less effort into truly understanding the disease itself and figuring out what are the best antigens that we need to deliver. You can have the absolute best vaccine platform in the world but without the right antigens, it will make no difference. And so what I think we have to get back to is studying the disease itself, understanding the pathogenesis, identifying the true effectors of protection, and then trying to incorporate that information into our vaccine development. And then, the platforms can come along and help us. But I think we're doing it backwards.

The reason why I think this is important is we seem to be limited to this single antigen approach. Everyone takes their platform and they try to find a magic bullet antigen that will protect against all flu viruses, but those strategies have failed now time and time again. And what I think they need to do is start looking the data we have about flu and pathogenesis immunity and say, "Hey, how can we deliver not one antigen but multiple antigens that stimulate multiple types of immune responses; B cell responses to different subtypes, T cell responses to different portions of the virus, mucosal immunity, systemic immunity, and kind of take all of this and get it into one vaccine?" And if we could bring a lot of those components together, I think we have a better chance at making a universal vaccine. And so I've been working on a vaccine with Jeff Taubenberger's lab, who's also in LID that tries to do something like what I'm talking about. In fact, we're getting ready to start a phase I trial with our first vaccine. And essentially the idea is to deliver multiple antigens in a way that stimulates a lot of different immune responses in order to generate very broad-based responses that can protect people.

>> Diego (interview): Sure. Can you tell me more about how you made this vaccine?

>> Dr. Memoli: Yeah, sure. So, the vaccine is a vaccine that's made from four low-path avian viruses. So avian influenza viruses come in sort of two flavors, high-pathogenesis and low-pathogenic avian viruses and the ones that you typically hear about in the news are the highly pathogenic avian influenza viruses. Those are viruses that make birds very sick, particularly, animals like chickens, for example. You hear about, "Oh, there was an H5N1 in a poultry farm in China, and they have to cull all the birds." And occasionally, one of those viruses maybe jumps into a human at a poultry factory or something. There are other avian influenza viruses that can circulate within species of birds, but they don't really make the bird sick. We call these low pathogenic avian influenza viruses. So, what we did was, in particular, Jeff did this, he identified four lowly pathogenic avian influenza viruses that genetically are precursors to currently circulating viruses. And so they're sort of earlier on the phylogenetic tree of flu. And the idea is that these sort of precursor viruses would stimulate immune responses that could protect against most downstream influenza viruses, whether they be avian, human adaptive, mammalian adaptive, what have you. And so what we did was we took these four viruses, and we took the whole of the virus and inactivated it. So we didn't take the proteins, we didn't make mRNA, we didn't stick the HAs on some platform. We took the entirety of the virus—all of it—we inactivated using a chemical that we call BPL which kills the virus and we're delivering these viruses as a cocktail of four viruses in a vaccine. And we're going to do it both intranasally and intramuscularly, we're testing both. Our hope is that the intranasal is going to be safe because we think that's going to be the optimal way to deliver this. However, it could end up being a combination in the future of intranasal and intramuscular, depending. But we've seen very good protection in animals against every single virus we throw at it even over a long period of time, especially the intranasal has been able to protect animals, even after a year after vaccination. So it really looks quite good. We're very excited. But we won't know until we get this thing into humans, how it's going to go, right? We need to see how it's tolerated, the safety. Do we get immune responses? You know, we see great results in animals but that doesn't mean anything until you show it in humans.

>> Diego (interview): Yeah.

>> Dr. Memoli: So that's where we're heading. So, we're really excited about this. I mean, it really, really, really, really, I think hits all the high points of what we're trying to do with the vaccine. So, I really hope we see good results as we as we move into people.

>> Diego (interview): Well, before I let you go, the clinical studies unit isn't solely focused on influenza. Can you talk about the other projects that are going on there?

>> Dr. Memoli: Yeah. So, you know, over the past 17 years, we've been primarily focused on respiratory viruses and in particular, over the past 10 or 11 has been helping to develop healthy volunteer human challenge studies with influenza—

>> Diego (interview): And what does that entail specifically? I’m not sure I know the difference between human challenge trials versus like a regular clinical trial.

>> Dr. Memoli: Yeah. So, I mean, they are a type of clinical trial but they're fairly unusual. So our trials are trials where we take healthy young people, let's say, between 18 and 50, 18 to 45, people who are completely healthy. We screen them meticulously to make sure they don't have underlying comorbidities that would put them at risk. We actually bring them into the clinical center. We isolate them and we give them a live wild-type influenza virus on purpose in order to make them sick.

>> Diego (interview): Ohh.

>> Dr. Memoli: And we do this in order to do various things. In some cases, we're trying to study the disease, the pathogenesis and the immune responses. In some cases, we do it to evaluate a product. So for example, we've done studies where we've administered a vaccine and then two months later people come in and get challenged to see if the vaccine protects them. We also did a study where we administered the challenge virus and then 48 hours later, we treated them with an IV infusion of antibody to see if that would prevent or abrogate the infection. And so we've done phase II efficacy trials in these studies to try to better understand how they work. And the beauty of these studies and the reason we do them is that with a disease like flu, by the time you identify somebody is sick, they've usually been sick for a few days. Usually, people don't show up to the doctor until they've had a fever or they've been sick for longer than they expect. By that time, a lot of the immunological action, and the genes being turned on and off and everything that's going to happen, has already happened. And what predicts how you're going to fare a lot of times happens in that first 24 to 48 hours. Well, in a natural history study where you just go to a hospital or doctor's office and look for people with flu, you miss all of that. So it's only in a challenge study where you catch all of that action. And we've had an amazing success with seeing this. To give you a good example of this, we've found that within the first 24 hours of someone being exposed to flu, so this is long before they have any kind of symptom, we can identify patterns of genes being turned on and turned off that actually predict how sick someone's going to get and how long they're going to shed virus for, how long they're going to be potentially infectious.

>> Diego (interview): Wow.

>> Dr. Memoli: So it shows you that all of this action that's happening in that first 24 hours is really important. And so trying to get to the bottom of that and understanding it could actually be one of the keys to unlocking how we protect people from these viruses. But it also could be used over time with enough research to generate tests, let's say, that are point of care that you could have in a hospital, right? Where you could test someone very early on after they've been diagnosed with flu and identify, "Hey, is this someone we need to treat? Is this someone we need to keep in the hospital for observation? Or is this somebody we can send home?" We have a lot of work to do to get to that point but there's a lot of possibilities from this kind of work. And so the challenge studies offer you a very unique opportunity to do this. Now, they are very unusual. There aren't that many people that do these kinds of studies which, as you can imagine, it's not easiest thing to do. You know, you have to be very careful, and you have to have the right kind of facility, and you have to know what you're doing. But they can be very useful with the right diseases.

>> Diego (interview): Yeah, well hopefully all your work and with the help from all those selfless volunteers, you’ll able to prepare for or even prevent another pandemic.

>> Dr. Memoli: Well, that's what we hope.

>> Diego (narration): Although there is room for improvement, the flu vaccine is still the best way to protect yourself and others from illness. The vaccine is estimated to prevent millions of medical visits and thousands of deaths each year. So in the words of Dr. Memoli, put on that seatbelt, roll up those sleeves and arm yourself against the flu.