Immune Booster 32: Vaccine protection versus natural infection with Jenna Guthmiller

[00:00:00]From Microbe TV, this is a special episode of Immune [music] and Immune Booster, recorded on January 23rd, 2026.

[00:00:08]I'm Cindy Lifer and you're listening to the podcast about [music] the body's defenders against disease. I'm here at Cornell University in my office for another office interview where we learn more about the scientist behind the science. If you like what we do on these boosters, on Immune in general, or any of the Microbe TV shows, please consider contributing by going to microbe.tv/contribute.

[00:00:34]Today, I'm joined by Jenna Guntmiller from University of Colorado Anschutz Medical Center. Jenna was a speaker this week in our seminar series, so I got to listen to her talk earlier today and I thought it'd be really great to have her on Immune to talk about her career and her work. And we actually talked about her work on Immune >> [gasps] >> number 35, where she published some great work about antibodies to SARS-CoV-2.

[00:01:02]Um, if you want to check that out, go to Immune 35. But I am excited to have her here today because I want to talk a little bit about, you know, how she got into science and also a little bit about the war between viruses and the immune system because her work really works to uncover the immune system how the immune system develops B cells and antibody responses to different insults and how the history of exposure to those insults shapes future responses. And also how the B cell responses at infection sites like the nose might be different. And so her talk today was super exciting and I'm really excited to talk to her today about more of her studies. So, welcome to Immune, Jenna.

[00:01:42]>> Yeah, thank you for having me.

[00:01:43]>> Great. So, can you just start by telling us a little bit about your training, your history, how you got interested in immunology?

[00:01:50]>> Yeah, okay. So, I I am originally from the state of South Dakota, so a small state, not a lot of people there. Um and I grew up on a dairy farm. And I would say that like maybe my foray into immunology was actually from that. Um so when I was a kid on a dairy farm, there would always be these like gallons of yellow milk, I think would be the best way to describe it. And I knew it as colostrum.

[00:02:15]>> Oh. Okay.

[00:02:16]>> And so we would call it like liquid gold, for example, because if you had a sick calf, you just thaw some and give it to them and they would sort of like miraculously recover. And my parents said, "Oh, you know, there's there's um components in there that help sort of boost the immunity of the calf." So I was like, "Oh, that's pretty cool." And then I always really enjoyed the days on the farm when we would vaccinate.

[00:02:37]>> Mhm.

[00:02:38]>> And I that was how I learned about vaccines and how we did this preemptively to protect them against various diseases. And I was like, "Dang, that's pretty cool that we can like do that uh ahead of ahead of time um to, you know, protect them, keep them healthy, and, you know, ultimately keep production, you know, active and welfare animal's well-being." So I I would consider that like my foray into immunology, even though I didn't really understand that that was immunology at the time. Um and then ultimately I went on to do an undergraduate degree, really not, you know, I knew I liked science, I figured I'd go to medical school. Um and I got into my first, you know, lab um microbiology course. I fell in love and I said, "This is for me. Like this is what I want to do." Um and sort of just sought opportunities there, figured out I really liked infectious diseases.

[00:03:26]And went on to to do a PhD um focused on humoral immunity against uh Plasmodium, so malaria.

[00:03:33]>> Oh.

[00:03:34]>> And then I circled back for my postdoc to viruses, cuz ultimately Plasmodium, very interesting bug, but really hard to study, cuz it's got like 5,000 genes. So for my postdoc, I strived to sort of go to a lab where I could really understand specificity. So I chose a virus that has like eight proteins cuz that was much more tractable.

[00:03:55]And um really have grown to love influenza. I think it's a an infinitely fascinating virus for so many reasons.

[00:04:03]Um the evolution of it, the history of it, how it has shaped history. Like I think it's just an infinitely fascinating uh virus. Um and I'm glad to talk more about that as well.

[00:04:16]>> So that was really interesting that you grew up on a dairy farm when you you saw this milk. Did you When did you start to put together that that was immunology?

[00:04:26]And when did you really become more fascinated with immunology? Cuz it sounded like you got were did a lot with um microbiology.

[00:04:35]>> Yeah.

[00:04:35]>> Um from the pathogen side and you did study some Plasmodium as a graduate student. When did you really start thinking more about the immune system and understanding how B cells work and things?

[00:04:45]>> Yeah, no that's that's a great question.

[00:04:47]And actually I'll bring it back to colostrum. So when I was an undergraduate, the the job that I took was at a colostrum factory. So it was a company that was buying colostrum from dairy farms and drying it down into powders or gels.

[00:05:00]And then giving that as a supplement to cows. But then they were also trying to maybe potentially market this as an alternative to to formula. And one thing that I did was just in the quality control lab was measure, you know, various aspects of it. And then I learned, "Hey, there's antibodies in these things." And I was taking immunology at the time and learning more about how the immune system works. And so I was like, "Wait, this thing that this liquid gold from when I was a kid, it's it's actually antibody mediated." So I would say that was sort of when I connected those two things back to each other. And I thought, "Oh, that's that's really cool." But I I did go to graduate school with the intention of probably ending up in either a virology or bacteriology lab. And then I rotated through a lab that was doing, you know, mouse model infection, studying the immune responses from these infections. And I said, "That's for me." I think that I thought that was so cool learning how to do flow cytometry, doing ELISAs, you know, culturing B cells. And you know, sort of the rest is history, I think, from there. And you know, I will probably never touch a T cell intentionally in my life. It'll always be B cells and antibodies cuz I think they're just so interesting.

[00:06:06]>> Do you see my B cells back here?

[00:06:08]>> I love it. I love it.

[00:06:11]>> It's pretty cool. I love those pictures.

[00:06:13]Um so >> [clears throat] >> what is it about B cells that you're enamored by? Like what is what is it that draws you to them to study them?

[00:06:22]>> Yeah, I think there's several things, right? So there's an immense diversity in the repertoire of B cells. We have all of these these B cells that are expressing essentially unique receptors or antibodies, right? And that is super interesting. They can use all the different parts of those variable parts of the antibody to bind to things. They recognize three-dimensional structures, which is also very interesting.

[00:06:46]But I think the most interesting thing about them is that they undergo the process of somatic hypermutation. So they actually mutate themselves to improve their affinity. Name a cell in your body that actually wants to mutate itself to make itself better. Like evolutionarily, that doesn't make a lot of sense. That's how you get >> dangerous.

[00:07:06]>> It's dangerous. Exactly. And I think the fact that B cells have figured out an educated way to do that is one of the coolest things as far as like evolution goes. How did we evolve this process to specifically mutate these genes and not other places, and do it in such a way that we're encouraging cells to feed back on those B cells to select them for higher affinity, you know, recognition of their antigens, for example. I think that whole process is just infinitely fascinating.

[00:07:37]>> And you have what now that you've started your own lab, you got a several different areas of focus. They're all kind of around B cells, but can you tell us a little bit about what it is that you do study in your lab?

[00:07:50]>> Yeah, I would consider sort of like three parts of my lab. One part is very focused on you know, how does pre-existing immunity, so how do prior exposures to influenza viruses shape future responses? Because we know that prior immunity to this virus that evolves famously to get around our immunity, that that prior immunity really dramatically shapes how we respond in the future. And we just we don't really understand the fundamentals behind that. Like why does that prior immunity have such a strong hold on how we can respond in the future? And I think there's negative aspects of that, right? That sort of can restrain us from in how we respond, but there's potentially ways that we can harness that to further improve immunity. So that's sort of one aspect of my lab is understanding that. Another is understanding how we can generate vaccines that do a better job of driving responses against the virus that we want responses against. So since influenza is a virus that likes to mutate, can we sort of harness B cells and preferentially select for B cells that hit conserved protective parts of the virus that seemingly can't evolve to get around humoral immunity cuz it's just too much of a fitness cost. And sort of understanding the factors that that um that limit viral evolution as well. And then I would consider the third part of my lab is understanding immunity in the airways. Because most of the work in you know, I'm guilty of this myself, has really been studying responses in circulation and our serum antibody responses. But of course that's not where flu infects. That's not where we need the antibodies to be to mediate protection. So what does immunity actually look like in our respiratory tracts? And not our lungs, like our actual nasal cavity where that virus is replicating, and our ability to control it there determines whether or not we're going to have we're going to it's going to disseminate into our lungs, or we potentially transmit it, you know, further to the next person. How do we stop it at that site?

[00:09:58]>> That I So, I love this. So, let's dive a little bit more into each of those areas. So, So, first in in 2022, published a publish a published a paper in Nature talking about the first part, the broadly neutralizing antibodies. So, how do we get them?

[00:10:13]>> Mhm.

[00:10:13]>> And some of that was this stalk versus head of HA. Can you say Tell us more about hemagglutinin structure, what it is about the stalk, and what your what you really studied, and what you found from that?

[00:10:27]>> Yeah, sure. So, uh hemagglutinin or HA is uh the main glycoprotein on the surface of influenza viruses. Has immense antigenic varieties, if you will. Um so, we have influenza A, which is just one type of flu. Um for that HA protein, there are 19 known subtypes.

[00:10:48]So, there's a lot of antigenic space in that area. Albeit, you know, we don't get infected with all those subtypes.

[00:10:54]So, it's like that sounds scarier than it really is. But, we do have in circulation um things like H1N1 and H3N2. Those are responsible for seasonal outbreaks.

[00:11:03]And within those even those two viruses, there are multiple clades and subclades that are co-circulating just in humans, let alone in other animals that sort of pose a risk to humans. Um and those What's really remarkable about those viruses is that they're specifically evolving to evade our antibody responses. And most of that evolution is taking place in that HA protein. Um because A, it's the most abundant protein on the surface.

[00:11:28]Um but also, most of neutralizing antibodies target that protein. And so, HA can sort of be divided into two domains. One is this head domain. It's the part that's sort of at the top, part that sticks out. Um that's really where a most of the antibody response is generated against. It's also where we see most of the evolution. Um the head domain also contains what is known as the receptor binding site. So, that's how the virus attaches to its receptor.

[00:11:54]So, functionally very important. So, the virus has been actually very good at sort of mutating itself around that area while still being able to maintain its ability to recognize its receptor, get in, and infect. Um in contrast, there is sort of the second half or the lower half of this protein. It's known as the stock domain or the stem domain. It really depends on who you trained with.

[00:12:16]Do you call it the stock or the stem? I could have debates about that, and I have very strong feelings that it should be called the stock cuz it's kind of stocky.

[00:12:24]She's thick.

[00:12:25]>> [laughter] >> And um the stock domain is important in the viral life cycle because this is where the fusion peptide is. So, influenza is a is an enveloped virus.

[00:12:36]So, in order for it to, you know, get its genome into a cell, it has to fuse its membrane with a host membrane. And most of most viruses that are enveloped have some sort of fusion machinery in order to combine those. And so, when you when you think of the stock domain, um that fusion machinery is quite sensitive. It's got all of these sort of checks and balances to make sure that we're not triggering that fusion too early. And as a result, it's very difficult for the virus to actually mutate in this area because, you know, a mutation could change the pH at which now it triggers that fusion event or um or it could just affect the ability of that fusion peptide to even trigger the the process of sort of piercing through the membranes. And so, this is a very sensitive area um of the virus, and it's very difficult for it to mutate. And therefore, it's much more well conserved um in in the circulation.

[00:13:31]Why don't we generate tons of antibodies against that part if it's so protective?

[00:13:36]>> Yeah, I think this is a great question.

[00:13:38]>> it's so hard for the virus to mutate, right?

[00:13:40]>> Yeah, so influenza so I think the short answer of that is is that it's quite hard for antibodies to even recognize it. So if we think about an antibody, right? This Y-shaped molecule. There potentially two binding sites on that antibody, right? And when you have something like the head that sticks out, HA is also a trimer, right? So there's essentially three repeats.

[00:14:03]>> Yep.

[00:14:04]>> That's the part that's sticking out, you know, the virus is quite decorated.

[00:14:08]There's a lot of HA proteins on the surface.

[00:14:11]An antibody in those two little arms and and thinking more broadly of a B cell that has multiple antibody copies on its surface.

[00:14:18]That it's going to induce a lot more bivalent binding but just more of those B cell receptors and antibodies on the surface are actually going to be able to engage their epitopes, right? Which is we know increases receptor signaling strength, the ability for that B cell to endocytose that and then present it to T cells, right? All positives for that B cell recognizing those head epitopes.

[00:14:39]But if we sort of bring that down to the stock domain because it's quite decorated, it's more difficult to reach those epitopes, right? It just sterically there's stuff in the way.

[00:14:49]In addition to that, the odds that you actually sort of bivalently, so two arms binding to two epitopes, it's it's difficult to actually crosslink those because it's harder to reach. And so just fundamentally B cells against these epitopes are at a competitive disadvantage relative to those against the head domain where it's just easy access, if you will, to those particular epitopes.

[00:15:12]>> So we'd love to be able to do it but it's really hard.

[00:15:15]>> It's yeah, it's really challenging and I think we don't have a firm understanding of how do we overcome those restrictions?

[00:15:22]How do we get B cells that are capable of sort of cross-linking multiple arms of this in order to trigger those responses? And certainly people are working on this. You know, this is not a novel idea that I'm coming up with.

[00:15:33]There's been a lot of work well before my time that has, you know, focused on trying to trigger these responses.

[00:15:40]>> So what did you find? So what what you know, what did you do? What system did you use and and what kind of information did you add?

[00:15:47]>> Yeah, so so when I started my postdoc, you know, there were the group that I joined Patrick Wilson who's actually at your sort of sister campus of Weill Cornell.

[00:15:58]He his group is really fundamentally worked a lot on monoclonal antibodies and getting sort of samples from humans of unique cohorts, making monoclonals, trying to understand how different exposure types, vaccine types shape immune responses. And so I was very fortunate to come into this lab where basically he had freezers of plasmas that I could just make monoclonals and start to interrogate specificity, which was really fun time to sort of like come in because there was a lot that could be done. And he had all of these stock targeting antibodies. And what I realized was is that there's only one there's only one epitope or one sort of site that antibodies were known to bind on the stock domain. But you know, this is a full domain. There's a lot of territory or real estate if you will.

[00:16:42]What what else are antibodies binding to on this stock domain? And so I identified that of all the stock antibodies that he had in the lab, only like 20% were against this one epitope.

[00:16:53]So we have like 80% that we don't know what they're against. Yeah, exactly. So you know, did quite a bit of work trying to understand this and ultimately, you know, just through happenstance in the influenza field, an unrelated Wilson, Ian Wilson, said to us, "Oh, well, you should contact this person Andrew Ward at Scripps to help you understand the structures of these of these antibodies. So, I just gave them three antibodies to start with. Said, "Let's see what these three look like. Let's just give it a shot."

[00:17:24]And what was really remarkable is is that when we got the data back as to where they were binding, they're all targeting the same epitope. And that was like by complete accident that that I just gave them three, let's see what happens, all targeting the same epitopes, which is really quite mind-blowing for me at the time. And what we found was is that they were targeting this epitope at sort of the way bottom part of the HA protein that um has been termed the anchor epitope.

[00:17:49]And part of the reason we named them the anchor epitope is that, if you can imagine, I know this is probably not the grace greatest for audio, but if you can imagine, you know, HA is this protein that is sticking or that, you know, is in a membrane, it's membrane bound.

[00:18:02]These antibodies almost look like they're coming from the bottom, like they're coming from the membrane side to bind to this. And they come at actually an upward angle at this epitope that's at the way bottom of the HA.

[00:18:13]And we find so uh since then uh and what we published, we found over 50 of these antibodies from like over 20 individuals. It's almost every single person that had a stock antibody was targeting that epitope. And so, I think it was just a really under-appreciated site. And there were some technical things that may it had limit the discovery of these antibodies, which I subsequently had to sort of deal with because for a long story short, that, you know, when we make recombinant proteins, not all recombinant proteins are made the same. And because influenza is a trimer, um the trimerization domain that you use to trimerize it can actually impact the ability of these antibodies to bind to it. And so, I had to learn that sort of the hard way cuz I was like, "Oh, these are HA negative here, but HA positive here. Like, what's going on here?" So, I think because most people were using this older trimerization domain that blocked their binding, that it took a long time to actually discover these antibodies.

[00:19:09]>> That's really cool. And I want to emphasize the fact that you kind of downplayed it a little bit, but to get to studying these antibodies, you had to collect these B cells from all these different people and take individual B cells and find the sequence of the antibody and then make a recombinant version of that, express that, and then be testing it in vitro.

[00:19:30]>> Yes.

[00:19:32]>> hundreds of these.

[00:19:33]>> Yeah, hundreds. Yeah.

[00:19:34]>> This is incredible. It's an incredible amount of work.

[00:19:37]>> I absolutely cannot take the credit for all of that though, right? So, one thing about about my post-doc lab was that, you know, he's just been accumulating samples and studies over the years. And while I did contribute to making some new ones, a lot of these were from years before I even got there that, you know, people had made, you know, had identified various things about them and then, you know, either graduated or left for other positions. And I sort of was able to come in and say, "Well, you know, all of these things sort of have features in common. Maybe we should study this a little bit further."

[00:20:09]And that was one other very interesting thing about those antibodies is that they genetically, they're almost all the same.

[00:20:16]So, there were there were sort of two characteristics that we identified with them, which was one residue in the heavy chain of the antibody, and then this NWP motif in the light chain of the antibody. Every single one of those antibodies had it. To the point that I actually went through a separate data set and looked for antibodies with those specific features. It was a little bit more than just those two features with very strict guidelines and made a handful of antibodies and and by handful I mean like 50 different antibodies. And it was all but two didn't bind that epitope.

[00:20:52]And so, it really implied that we as individuals actually make very even though we have all this diversity in our antibody responses, we actually all are mounting very similar responses against this one epitope. So, they're sort of convergent across all these individuals.

[00:21:09]>> That's pretty amazing.

[00:21:10]>> It's very cool.

[00:21:11]>> Yeah, it's very cool.

[00:21:12]Um switching a little bit to to the idea of this pre-existing antibodies, so the other area that you study. So you've also published a couple of papers on this, um and the idea here is that whatever your immune response was first shapes how you can respond later. So can you talk a little bit more about that?

[00:21:30]Um cuz today you you focused a little bit on vaccine versus infection generates different types of antibody responses, which I think is also really cool, and then how that plays into the story.

[00:21:43]>> Yeah, absolutely. So um certainly the exposure route, right? What what are you being exposed to is is certainly going to change how you respond and the specificity of those res- those responses. So I think that infection and vaccination is maybe one of the starkest differences in how we respond, and I always get I always get like a little bit peeved when people are like, "I just want that natural immunity." And I'm just like, "What does that mean?" Like, you know, you're just essentially getting whatever dose of virus that you happen to get, and your immune response is really just uncontrolled in some way, right? Like you have no way to focus in on the parts. You're just making a response against anything that you're exposed to. Our immune system is not that smart. It doesn't know what parts of the virus are protective and not protective. And that's why vaccination is so important cuz we can actually control um what you're receiving to be the things that are going to mediate protection and get rid of those factors or those proteins that will not mediate, you know, antibody-mediated protection.

[00:22:39]And so this is nicely demonstrated by a study we did with infection versus vaccination samples where we found when you get a seasonal flu vaccine, almost the entire response is against the HA protein, right? And that's really the correlate of protection against flu is how well of a response you make against that HA protein. But when we get infected, again, because it's just the virus is replicating all these different viral proteins are being produced, our immune response just makes a response against whatever it sees. And a lot of it as especially as adults, we're just recalling memory from past infections.

[00:23:12]And most of that immune memory that we can recall is going to be against perhaps conserved parts of the virus, but not necessarily protective parts of the virus. So, we know that when people get infected, they make really great responses against the nucleo protein, which is something that encapsulates the genome. Well, this is something inside of the virus that that protein is really only found when, you know, a virus or a virus-infected cell dies and they sort of, >> You know, release a bunch of crap.

[00:23:42]>> Yeah, exactly. Release a bunch of crap.

[00:23:44]That's a great way of describing [laughter] it. And what happens is is you get crappy antibodies cuz they're against things that aren't going to mediate protection. And so, we see that much more readily with infection, whereas vaccination, again, it's just fine-tuning those responses against a protein that we know that humoral immunity humoral immunity mediates protection.

[00:24:04]>> So, so say a little bit more about how that the pre-existing immunity affects the response. So, so part of it is like what types of antibodies you've made, so whether you developed antibodies to the HA or to other things, but what what about the recall of the B cells? So, so they're they're more recognizing more conserved residues, but you have this idea of immune imprinting and you're not the one first one to come up with that, but some of your work gets to that. So, is is it good? Is it bad?

[00:24:38]Like what So, what Why do we have that, do you think, and how is that influencing our responses? Cuz you went into a little bit about like if you were born before here or after this date and you were you got infected first or you got vaccinated first and and and how that influenced how you respond to newer flu infections. So.

[00:25:01]>> I think I think one of the greatest examples of the impacts of like immune imprinting and viral evolution and sort of specificities of immune responses is really focused on this one epitope on the side of the head known as the lateral patch. And this is this is on H1 viruses specifically.

[00:25:18]And this is an epitope that was discovered in the late 2010s. The first paper came out on it. And what what that particular group had observed is that um that antibodies against this epitope, they recognized H1N1 viruses from before 2009 and H1N1 viruses after 2009. Uh subsequently, when I was in my post-doc lab, I had made the discovery that when people were first exposed to the 2009 H1N1 virus, which we had observed that when you're first exposed to that virus, you've essentially very limited pre-existing immunity against that virus, you preferentially recall memory B cells that react with broadly reactive epitopes, so well-conserved epitopes.

[00:26:00]And this lateral patch happened to be one of those. So, people of all ages made a really robust response against that epitope. Okay? And one observation that we made was depending on when you were born, you target that epitope differently.

[00:26:14]So, if you were born between roughly like the mid-1960s and you know, about 1977, you made responses against that epitope were sort of coming from the top. Okay?

[00:26:27]But if you were born in the mid-80s, you made it more against the side. And part of the reason behind that is is that there was a mutation that was acquired in the mid to early 1980s that sort of introduced a glycan right above that epitope that sort of redirected antibodies to come in at like a perpendicular angle. It's really that simple, just from the top or to the side.

[00:26:48]And what we find is is that after the 2009 pandemic, a bunch of people made antibodies against this epitope.

[00:26:56]Um And that was the first real sign of antigenic drift in the 2009 H1N1 virus, is that by about 2013, there's a mutation at within that epitope that really affected those antibodies that were coming from the top, but not the ones that are coming in from the side.

[00:27:15]Okay? And so, what happened was is that all these people born in the mid-1960s until the late 1970s, um they that flu season was bad for that particular age group. And it was sort of like unexplained. Why are all these people in their 40s like not on death's door, but like really sick from H1N1? Like this is just weird. And I will say that I'm in I'm in the second group. I'm in the perpendicular group.

[00:27:40]Um and and that group was was completely fine. And so, it it suggests that, you know, the first H1N1 that you're exposed to, right? You We're going to make these responses either here or here, and that dictated your susceptibility to that particular outbreak. And that's why we saw it in though that particular age cohort of individuals.

[00:28:04]>> Did it surprise you that one epitope would make that much difference? Cuz presumably, you have a polyclonal antibody response, and you should be able to recognize other parts of the molecule that should be somewhat protective.

[00:28:17]>> Yeah.

[00:28:18]>> But clearly, those individuals were much more susceptible.

[00:28:20]>> Yeah, which which is even It's not even just one epitope. It was one residue.

[00:28:24]It's a one residue change that made this big difference. It was also from a lysine to a glutamine. I don't know if you're like an amino acid nerd.

[00:28:32]Pretty semi-close to each other, right? As far as structure goes. So, to have that big of an impact is quite striking, of course.

[00:28:42]Um Um now I forgot what your question was.

[00:28:46]>> Just said Was it surprising that one one amino acid was like one epitope, but one amino acid had such a big difference on your susceptibility to infection given that you have you should generate a polyclonal response with antibodies to multiple different parts of the the HA.

[00:29:02]>> Yeah, but so there's actually been groups that have come back to look at the the serum level against that one particular epitope after the 2009 pandemic. And in that particular group, that was if you mutate that one site, the fold reduction in antibody titers was like four to eightfold. So this was just a really dominant site for some people to generate an antibody response, and that's likely why there was enough immune pressure placed on the virus to drive that mutation. First off, um but secondly, because those individuals made such a concentrated response against that epitope that this this was sufficient for them for that virus to evade their, you know, so, you know, {quote} {unquote} a polyclonal sera, which was maybe more like a ligoclonal really against H1N1 at that point, and that left them susceptible to infection.

[00:29:53]>> So a lot of what you're doing is trying to figure out how all this works to make better vaccines.

[00:29:58]>> Absolutely.

[00:29:59]>> Because I'm assuming that, you know, that that's your driving hope is that you can make better vaccines for people to protect them from infection. So can you tell us a little bit about what you are learning and how you're using that now to to test different vaccine strategies?

[00:30:14]>> Yeah, absolutely. So I think one of the one of the biggest challenges, I mean, we discussed, you know, the bias for responses against the head domain versus the stalk domain and sort of why that is.

[00:30:25]Um and so there's been a lot of efforts to sort of, you know, redirect responses against the stalk domain. And um the one that I was fortunate to be involved with was a phase one clinical trial of a chimeric HA vaccine. And so the idea behind this was is, you know, we as humans have pre-existing immunity against in this case H1N1.

[00:30:47]Um, and we have immunity against that stock domain. Can we figure out a way to just continue to boost those responses?

[00:30:54]And so, the idea was was well, let's take that stock domain from uh H1N1 and then replace the head domain with something of a zoonotic influenza virus.

[00:31:04]So, something we have no pre-existing immunity against. And because we for whatever reason when we have pre-existing immunity, we love to recall memory B cells. That when you give these chimeric HAs with this new head domain, that maybe you can just recall exclusively B cells against that stock domain and just continue to drive responses against that domain. And to make a long story short, that does work.

[00:31:29]You can use that approach um to induce responses against the stock domain. But, I think the challenge that we continue to face is still that head domain. So, what happens is is yes, you boost those stock responses, but to about the same magnitude, you make de novo responses against that head. And if we're thinking about, you know, germinal center reactions where we're trying to get somatic hypermutation, affinity maturation, and we really want those responses to be against the stock domain, those stock B cells are just going to lose because those epitopes are harder to target than those against the head. And we may just be driving affinity maturation on the head or for B cells specific to the head domain and maybe not so much against the stock domain. And I think moving forward, this is something we really need to think about is how do we get rid of these head specific B cells or or out get the stock B cells to outcompete them. And so, I I will say a lot of that work is not me. Um, one some really great work out of the Vaccine Research Center at the NIH has focused on these what are for two stabilized stem constructs where they basically just chop off the head domain. Right? So, now you don't have a head domain, no problem.

[00:32:42]They have shown in in actually phase one clinical trials of that that that also can induce really nice responses against stock domain. But, my concern perhaps there is is that because you've you've cut off the head domain, it's sort of like an artificial exposed surface.

[00:32:57]>> Yeah, which you can also recognize and start making novel responses.

[00:33:02]>> you know, I think it's still to be determined if that's happening, but that would be one that I have. So, it doesn't completely solve the problem, but I think it's a nice it's a nice direction that we're going in as, you know, as a field. And then there's other groups that are trying to, you know, add like glycosylation sites to sort of like silence these particular epitopes with sort of varying results. I think what sort of was realized, and this was a really nice study by Aaron Schmidt's lab at the the Ragon Institute in Boston, where they found that you can try to immuno silence all of these things, but actually antibodies and B cells have can do a pretty remarkable job of especially on the head domain sort of finding those crevices and still mounting a response against those these like little epitopes that they managed to get into because, you know, again, it's trimerized. You can if you can sort of squeeze your way in there, that's still better than the stock domain. So, how can we trick the immune system to do a better job of of targeting the stock domain? I think there's there's a lot of work still that needs to be done on that that effort.

[00:33:58]>> that it's it's also translatable to other viruses that have receptor, you know, binding domains and proteins that are glycoproteins on the surface that are important for binding. COVID is one of them. Spike proteins, you worked on that some. So, um I want to ask you as as we're, you know, winding this up a little bit. That's been really interesting, but a little bit more about you, going back to what is it you love most about being a scientist?

[00:34:27]>> Yeah, I think, you know, it's it's so interesting the science you do as a graduate student, a post-doc, and a PI.

[00:34:34]And I will say that I think it's very like um you know, when you're a PhD student, right? You're running one to two projects, right? Like and you're like the person that's doing all the work, doing all the experiments, you know, getting a lot of help with the thinking, the writing, the communication. And I think that's why a PhD is so important. Post-doc, right?

[00:34:52]You know, you probably I I mean, I had like four projects as a post-doc, right?

[00:34:55]And I'm trying to handle all of these different things. I'm coordinating with people, I'm collaborating with people, and like sort of setting myself up as a PI, right? And now as a as a as a you know, assistant professor running my own research group, what I really love about that is it's just it's I sort I kept expanding and expanding and doing that.

[00:35:12]And now it's I don't hold a pipette anymore, right? Like there's other people that are doing the science, but I get to allow them to grow in those areas as a graduate student teaching them how to think about their projects, how to communicate about their projects, how to drive their projects forward, so that they gain that skill, right? The post-docs, same. Taking multiple projects, coordinating collaborations, gaining that independence. Independence in both your ability to think, but also independence on the approaches you can take. Like sort of facilitating those two things I think is one of the funnest parts of being a PI.

[00:35:48]And then, you know, all these hairbrained ideas that I have I can just give to somebody as a project to sort of figure out. I don't have to physically do the science anymore, which, you know, I think that's always very daunting.

[00:35:57]Like, you want me to do what?

[00:35:59]>> [laughter] >> Do Do they Do they Do they scatter and freak out when you walk in the lab now?

[00:36:03]>> I No, I don't think so. I mean, it's so funny. My lab manager, every time I like walk into the lab, she just has this big smile. She's like, "Hey, I need to stop you about something." And I'm like, "Okay, what's going on?" And no, I think >> Did you catch on to the fact that maybe she's the guard to keep you out of the lab?

[00:36:17]>> I think No, I don't think it's that. But I mean, it's it's generally very good.

[00:36:21]And actually, every time I go into the lab, it's just question after question after question. Be like, "Do you think this is the right time point to be doing this or should I be giving this at this time point or you know, how should I be doing this or what's the best way to set up this experiment?" Like I still get a lot of those questions and I sort of like sitting down with them and discussing it, thinking it through, how can we be most efficient, how can we try to do the most at once? I think I think a lot of graduate training and and as a postdoc it's just, you know, multitasking, which is a skill that takes practice but also guidance.

[00:36:51]>> Yeah.

[00:36:52]>> Right? Cuz you'll probably fail cuz you're trying to do too at once but then you'll eventually figure out, "Oh yeah, I can do all of that at once. I just have to do it this way." Right? So, more experienced people helping others.

[00:37:04]>> I love that. What Was there a time when you thought, "I'm not sure that I belong here, that I should be a scientist" and and how did you push through that?

[00:37:14]>> Yeah, I would say I think there's a lot of challenges um particularly when you're first starting in graduate school, first starting a postdoc and actually I would argue like ending a postdoc as well. Um and I think the biggest things about starting graduate school and postdoc is is that you're you've moved somewhere new. You're starting somewhere new. You're like sort of reestablishing yourself and I think there's a lot of imposter syndrome that goes with that and I think um like my myself, right? Like I don't have a prestigious background, right? Like I grew up on a dairy farm. I went to like a state school that isn't like known for scientific research. I also didn't go anywhere super fancy for graduate school. And you know, and I did go somewhere a little bit more prestigious for my postdoc and you know, I felt at each one of those steps going into graduate school and a postdoc like, "Oh, I don't have the pedigree to be here."

[00:38:09]>> Mhm.

[00:38:10]>> You know?

[00:38:11]Um but I always sort of kept my head down to a degree and just worked hard, read, thought, you know, raised my voice when I thought it was appropriate and people realized like, "Oh, no, that that person actually has something like important to say." And I think, you know, you build that confidence over time, but you just have to realize like you don't you can't have it from day one.

[00:38:32]And understanding that it's okay to be learning and to be growing, and that when you feel comfortable to sort of break out of that shell and get more comfortable.

[00:38:42]That would be one time. And then the second time I would say that's really hard, especially for academia, is um when you're ending your postdoc.

[00:38:50]And so it was sort of when I was a when I was a postdoc, um there was a graduate a student that started like 2 weeks after me.

[00:38:56]>> Mhm.

[00:38:57]>> Right? And so because of that we we kind of bonded. Um I I helped her a lot with her training, and I remember we were both basically finishing up at the same time, and she she always wanted to go into into industry, and I was going into academia.

[00:39:12]I had all these extra years on top of her, and I saw her starting salary, and I saw my starting salary, and hers was higher, despite the fact I had spent more time doing this, I was the one that trained her to do a lot of the things that she was capable of doing, although she was phenomenal, so I can't take I can't take all the credit, obviously, for that. Um and for me I was just like, "What am I doing?" Like, you know, I've been just like scraping by for like 10 years, and it's he's like, "I could be making that much money straight out of graduate school?" But at the end of the day, I'm really happy with my decision to, you know, stay in academia for the reasons I mentioned of training people, to really get to drive science forward as a PI. Um I maybe a weird person, I actually like writing grants, cuz it allows me time to like think about stuff and and, you know, what are the next things that I want to do with this, and and what's known and what's missing, and you're like, "Oh my gosh, I can't believe we don't know that." Like, okay, I'm going to write about that, let's do that. Um and try to figure out how to do that, and I still really enjoy that aspect.

[00:40:09]>> That's awesome. I totally agree with you 100%.

[00:40:12]>> Yeah.

[00:40:12]>> Yeah. So, just very last question, what is one of your non-science guilty pleasures?

[00:40:19]>> One of my non-science guilty pleasures.

[00:40:25]Non-science guilty pleasures. Like what do I like to do outside of science?

[00:40:29]>> Yep.

[00:40:29]>> Um I This is probably makes me sound bad. I love I'm still I'm a millennial. I still love craft beer. So and I live in Denver, right? Which has so much craft beer. Um so I try to go once every 2 weeks to a brewery to like just try some things out. Um my husband also really enjoys craft beer. So that's just like something that we enjoy doing together, trying new beers, supporting local businesses. And yeah, I don't know if that's a guilty pleasure, but um it's probably not the healthiest pleasure.

[00:41:02]>> [laughter] >> No, that's great. So that's a great note to end on. So I really appreciate you taking the time to come and talk with me here at my office today while you were visiting Cornell. This was really fun.

[00:41:15]>> Yeah, thank you for having me.

[00:41:16]>> Great. So that's a special episode of Immune and Immune Booster. You can send questions or comments to [email protected].

[00:41:26]Again, consider supporting Immune um and all the shows of MicrobeTV by going to microbe.tv/contribute.

[00:41:35]Remember, MicrobeTV is a 501c3, so any money you donate is tax deductible and extremely welcome to help support all of the shows that we put out through MicrobeTV.

[00:41:48]I'm Cindy Leifer and I'm at Cornell University and I was joined today by Jenna Gunt Miller from the University of Colorado Anschutz Medical Center. Thank you. [music] >> Yeah, thank you.

[00:41:59]>> Music on Immune is by Titani.

[00:42:02]Thanks for listening to Immune, the podcast that's infectious.

[00:42:07]>> [music] >> I want >> [music] >> I want I want >> [music] >> I want