Vaxart, Inc. (VXRT) Earnings Call Transcript & Summary

Good afternoon, and welcome to the Vaxart KOL panel on an oral tablet vaccine, the best global solution to COVID-19 and norovirus. [Operator Instructions] As a reminder, this conference is being recorded, and a replay will be made available on the Vaxart website following the event. I'd now like to turn the call over to Andrei Floroiu, President and Chief Executive Officer of Vaxart. Please go ahead, sir.

Tara, thank you so much for the introduction. We are so excited to be here today, particularly since I just learned that there are 600 of you attending this event, and that's extraordinary. 600 of you are attending this event despite lots of recent positive data from other COVID-19 vaccine manufacturers. And I think I know why, because you know that an oral room temperature-stable tablet can really be transformative, not only for the COVID-19 pandemic, but more broadly, for the vaccine industry. Also, I think that you understand that the more COVID-19 vaccines work, the more likely it is that our vaccine will also work because, after all, we are all going after the same antigens, more or less. And I think you also understand that a -- to start, refrigerated injectable needle vaccine will not be enough to defeat this pandemic globally. So it should be no secret that we believe that our oral room temperature-stable COVID-19 vaccine is the most elegant, the most practicable global solution to the COVID-19 pandemic. And today, for the first time, we'll be talking about our first human clinical data from our COVID-19 Phase I program. So that should be pretty exciting. Also, we'll be talking about norovirus and our norovirus program for 2 reasons. The norovirus program is our second most important near-term value creating opportunity. And it's also a significant unmet need. But also, we believe that if you see more signs of activity against more viruses, we started the year showing the world that our pill protects us well against flu as the leading injectable vaccine. Now we're going to show you signs of activity against norovirus. So the more you see that our platform works against more viruses, probably your confidence in our COVID-19 vaccine will increase. And with that, I'd like you to turn over to Dr. Jan Vinje, from the Center of Disease Control. Dr. Vinje, take it from here.

Thank you very much. Greetings, everybody, from Atlanta, Georgia. I will present an overview on the status of the burden of disease of noroviruses. I'll also provide some information on the strains that are causing that disease. And I will then give an overview on the status of several vaccines that are in clinical trials including the Vaxart vaccine. You can go to the next slide. So I provide here an overview on what I will be talking about, give you an overview of what norovirus is, the clinical symptoms, and then summarize what we know about the clinical and economic burden of norovirus disease. Tell a little bit about the virology, about the strains, how many strains there are, a vaccine needs to protect against. I will summarize some of the surveillance system that we have in place for norovirus, both in the U.S. as well as globally. And then I will finalize with an overview on the status of a norovirus vaccine development. So on the next slide, just to summarize the clinical symptoms of norovirus gastroenteritis. It is a virus that has a very short incubation time between 12 and 48 hours. And what is very typical, is an acute onset of vomiting and diarrhea. The diarrhea is usually watery and nonbloody, that's compared to bacterial enteritis. Most people here on the call, probably will recover from a norovirus, although if you have experienced it yourself, then you still remember that because it's a pretty nasty couple of days. However, there are a substantial number of people that seek medical attention and some people require hospitalization and fluid therapy. And I will show you later on, there is also a substantial number of people that die because of norovirus gastroenteritis. So it is primarily in the elderly, but also in the young. So both age spectra are most affected by this disease. But is not very unusual for a viral infection. There are also a lot of asymptomatic infections. And that's important if you think about foodborne diseases where people are in the food industry and they could contaminate food even if they're asymptomatic. So there's always a portion of the level of asymptomatic setting of these viruses. And then in the next slide, I present a study where we look at the community of norovirus incidents, and that was conducted in 2 Kaiser Permanente member populations, 1 of the East Coast here in the U.S. and 1 on the West Coast. What you clearly see on this slide is that the highest burden of disease is clearly in the young children. And then you see like a -- it's kind of a u-shaped -- and you see that as it increases towards the more elderly state. But this is just the sporadic cases. If you look at outbreaks, what we do here -- follow here in the U.S., coordinated by CDC here, you see that most outbreaks of acute gastroenteritis are caused by noroviruses. So it's a major cause of outbreaks. And in sporadic cases, you see that the highest burden here is in a young children. And on the next slide, so looking more further into the severe cases. You see on the left in blue, you see there that the ED visits, emergency department visits, that is where most of the burden is for the young children, again, younger than 5 years of age. And then if you look at the severe outcome on the right, you see most of the severe outcome is in the elderly, older than 65 years of age. And on the next slide, it's a summary of all the data that we have collected in different segments. We usually present that as the disease permit, as is here on the top is the number of estimated deaths in the United States, up to 800. You see a staggering number of hospitalizations, about -- up to 70,000. 400,000 emergency department visits. And then you can go all the way down. The estimate is about 20 million norovirus diseases per year in the U.S. And since there is not immediate protection, the estimate is that during your lifetime, you will experience about 5 -- on average, 5 norovirus illnesses. In the next slide, when we look at the global disease burden, and this is some data that is gathered in a couple of years ago by the WHO Foodborne Disease Burden Epidemiology Reference Group, and that also found that norovirus was the #1 cause of foodborne illness worldwide. That is for most people, a little bit -- it's kind of an expected, most folks think about Salmonella and E. coli. But just the sheer numbers of norovirus is leading to this -- to the top status of the cause of foodborne illness worldwide. Other numbers that I would like to show is also the financial burden. As the most recent estimates is about $16 million in health care and health system cost and productivity losses. And again, if you look globally, it's primarily the young children where the most severe outcomes like death is about 200,000 deaths in -- primarily in young children. On the next slide. This is kind of the overview. I'm a virologist. So I always have to show the cool virology with the genome organization. It's an RNA virus. And what is most important just for an understanding, if you've never heard about norovirus, that it is not like, for example, coronavirus, it doesn't have spikes, it doesn't have an envelope. And that means that outside the human host, for example, on surfaces, it is pretty hardy, it can survive on, for example, door knobs for at least for a couple of hours. And in some cases, we have data up to a couple of days. So it is a very hardy virus, and it's difficult to disinfect. Mostly chlorine is the only known way, how you can disinfect properly norovirus on surfaces. So that has to do with the fact that how this virus is composed of not having an envelope. So on the next slide, I show you a graphic representation of how many different genetic clusters there are. And so you see on the top, you see in Genogroup II, GII, and that's up to 23 different genotypes, they all can cause the same type of disease. There's no difference in the disease outcome. And you see in GI on the lower part, also in a green balloon, those are 9 different genotypes. So all this together, causing about 95%, 99% of all disease. Thank you. So that means that a vaccine against noroviruses need to protect against all these different strains. And most of the formulations include a representative of both the Genogroup I and the Genogroup II noroviruses, that will protect against like 95%, 99% of all the different viruses that we are aware of that are circulating. The next slide. This is one of the surveillance networks that we're using. We have been operating for at least the last 10 years. This is an outbreak surveillance platform in the United States, we call it CaliciNet because norovirus is part of the caliciviruses as a family, a virus family. And in green, you see the states where state health departments and local health departments are able to, A, test a virus, but also perform typing. All these data is being uploaded to a central database. So we have overview on the different trends over the different years, which strains are causing the disease. The states here in blue, we cover them with what we call outbreak support centers. If, for example, the state of Washington is covered by Oregon as far as for typing viruses that have been causing outbreaks of -- norovirus outbreaks in the state of Washington. So we have a national picture, and we were able to have a complete coverage in that way of all the 50 states. And on the next slide, you can see if you compare these different strains that I mentioned before, all these many different strains while you see here in blue, you see 4 different pie charts. The only piece of information that I'd like to relay is the colors in this sense. So hopefully, you're not colorblind, most people are not for blue. You see in blue, it's about 50% in all these different seasons are caused by a single genotype, G24. That's the most important causing the most illnesses here in the U.S. in outbreaks. But you can also see that every year, the other colors of those pies are changing. So we have -- every year, we have G24 noroviruses, but we also have another genotype. So the importance of this is that if you need to prevent these diseases, you need to find protection against all of these different genotypes. And hopefully, by cross protection, we're able to achieve that. The next slide, please. So we also started a global pediatric norovirus network. I told you that the highest disease burden is in young children, younger than 5 years of age. And this network that I'm showing here in green, the countries that are participating, is of children that have norovirus disease that are hospitalized. So the more severe cases and we are tracking that, we're tracking it in the Southern Hemisphere as well as in the Northern Hemisphere. And so we can really have a good view of which strains are causing disease in young children. And we found some initial data that shows that strains that are causing disease in children are slightly different than are causing disease in adults. So again, it provides excellent information as far as for which strains a future norovirus vaccine is to protect against. In the next slide, you see a visualization of this global norovirus -- pediatric norovirus network. You see the pie charts and for the participants, they can zoom in on these pie charts and see the different distribution of the different strains and the different colors are presenting that. So initial overview, you can see there are different colors in the different countries that is reflecting a little bit of bias, but some countries are uploading more data than others. But again, this is just the initial pilot phase, and we would like to have more coverage also, for example, in Africa, to get a better global and more comprehensive picture. But we are very excited about this new network. It works really well. And it's almost giving us an information in real time. The next slide, please. So if you think about prevention by vaccination. So we know about the disease burden. It's about 80% of all cases of acute gastroenteritis, diarrhea and vomiting globally. I showed you in the pyramids that about 21 million cases are being recorded in the U.S., 70,000 hospitalizations. And overall, we look at all the outbreaks of acute gastroenteritis, about 50% and more are caused by this virus. The risk groups are the elderly, most outbreaks occur in long-term care facilities. But also, as I showed you, young children are of high risk of hospitalization because of norovirus. And then in particular, in other parts of the world, it is the leading cause of death because of acute gastroenteritis. So what we also know is the natural history of disease. Also important, we know that some people are able to shed the virus for a prolonged period of time, sometimes young children up to 4 weeks. I showed you something about the virus strains. The Genogroup I and Genogroup II and the predominant strains like G24. And I also mentioned that maybe in children, some strains are -- some -- the formulation needs to be a little bit different because some strains are more seen in children compared to adults. And then the most important part is, again, immunity. We know a little bit about the correlation of protection. And we also know that the duration of natural immunity is not life long. We don't know if a vaccine is able to protect for a prolonged period of time. Maybe for a couple of years, that's what we anticipate. And then also, we hope that cross protection between the different strains can be achieved. The approach that most vaccine development have established is the use of virus-like particles. So they are safe, they don't contain any nucleic acid, and they have a robust -- they generate a robust immune response. They are immunogenic. And the next slide. So this is an overview of the vaccines that are currently in clinical trials. And on the top, we have a vaccine that is in Phase II -- Phase IIb that just finalized that. It's from Takeda Pharmaceuticals. And then also you see Vaxart has this -- the oral pill, they have completed the Phase Ib, and it looked very promising. Good data for this -- for that study have been published in a peer review literature. So there are [ 2 1 ] clinical trials. And then -- yes, on the next slide, thank you. So of course, there are always challenges. And so those challenges are listed here, some of the more important one. Which strains, which genotypes need to be included. I mentioned the G24, but I also mentioned that maybe in -- for children, you need to have cross protection against G2 -- another viral strain, the G23, in this case. But we are aware of this global surveillance system that we have now up and running. And the key question is, there's need to be updated to keep up with the viral evolution. And that is something that we currently are trying to research by having multiple years of data. And following the same trends, the same groups in the different countries for over a couple of years. So that's a key question: Is a vaccine able to show cross protection against multiple different genetically different viral strains. Another question is, is the role of prior infectious history. I think all the people on this call probably have been exposed to norovirus, maybe asymptomatic, maybe symptomatic. And so is one immunization enough to get enough of an immune response to protect you against noroviruses? Obviously, in young infants, that is probably a different regime. It probably needs to have a second dose. But we don't know, and that's, I think, also very interesting to look into is the duration of protection. I mentioned that the formulation can be different for children and versus adults, so any vaccine is -- a company is able to change that and have a manufacturing in place to swap out some genotypes for other genotypes, different strains that will be -- probably would be very favorable. And there is another aspect that I haven't really mentioned and that's that some people are genetically susceptible against norovirus. So that's an important issue when you study and you do your Phase III trials to look at the efficacy of your vaccine. So that's the summary. And the next slide is -- I would like to thank you, and I hope to be able to answer some questions you may have. So thank you very much for your attention.

I'm not sure if I'm on. Tara, am I on?

Yes, you're on.

Yes. Thank you so much, Jan. And now I'd like to turn it over to Dr. Marion Pepper from the Department of Immunology at the University of Washington Medical School. And Dr. Pepper will be talking about COVID-19.

Thank you very much, and thank you for having me. So thank you so much for having me. My name is Marion Pepper. And I'm an associate professor in the Department of Immunology at the University of Washington. And my lab there has been studying how immune memory forms to both allergens and infectious diseases for the past decade. And so when the pandemic and SARS-CoV-2 pandemic emerged, we really rapidly pivoted to see what we could understand about how immune memory forms to COVID-19, and how this might inform vaccine trials and vaccine design. I want to say that we need to disclose that the honorarium that I've been given for this talk is being donated to the University of Washington Department of Immunology. They are part of this. So let's get started. So just to make sure that everyone's on the same page because immunologists often talk about their research in terms that people can't understand. So I'm just going to give a broad overview of the immune system and why it's so difficult to actually mount a strong immune response in the time necessary to control a disease or an infectious pathogen. So basically, every single pathogen that your body recognizes, you need to have a cell that can recognize pieces of it. So every single B cell or T cell in your body, which are cells of the adaptive immune system, have these unique receptors that allow them to bind distinct pieces of a pathogen. Yes. So this receptor, for example, can recognize a piece of 1 pathogen, whereas this pink receptor over here can recognize a piece of a different pathogen. Because of that, the human embody has to have billions of these T cells and B cells that circulate throughout your body surveying for pieces of infectious diseases. And this means that you have to have a lot of different T cells and B cells that express unique receptors. What that also means, however, is that you only can have a few of any 1 individual cell that can recognize a piece of a pathogen. And the reason why that works is that if you encounter a pathogen, if that B cell or T cell sees its antigen or its protein of interest that it can bind to in this sort of lock in key model that you can see here, that activates the B cell. And so that cell will then go through this process of differentiation and gain of function such that an immune response will form over about 5 to 7 days. Now, of course, at the same time, you've been infected by a virus. So that also means that the virus is being given the same amount of time to proliferate and to infect more cells and to replicate itself. But once the immune system gets going, it's very good at controlling the virus. So what you can see is this viral load that we call this red line here will go down once the immune system is fully engaged and can secrete all of these different proteins and effector molecules, including antibodies that will kill the virus and prevent infection. So once the infection is controlled, you can't constantly have this inflammatory state. So the immune system actually begins to decline. And about 90% of those cells that you've expanded to control the virus will die. And what that leaves is about 10% of the cells remaining that we call immune memory cells. And these are both B cells and T cells. And these B cells and T cells have retained characteristics of that differentiation period during the first 5 to 7 days. They also migrate to different tissues, to different immune sites, so that if you see a virus again, you now mount an immune response within hours in what previously took 5 to 7 days. And what that means is there isn't the time for the virus to replicate and cause disease in the same way that it did in that first initial encounter with the pathogen. So what my lab studies is, is this idea of immune memory and how do we create good immune memory by vaccination, such that we can get immune memory cells that have the right functional output to the right tissue sites where they can then control the pathogen so there is no disease. And we decided to first try to figure out the most basic question that we had in February, which is, okay, we know that there are a lot of different ways that this disease is presenting. About 80% studies in China showed that about 80% of individuals who had the disease were presenting with what we call mild disease. So maybe a slight fever, some costs, sometimes a loss of sense of smell, but they weren't being hospitalized. And because this was the majority of people, we decided to really look at what types of immune cells could we find that could be protective against the virus. Now keep in mind on that slide that I showed you previously, when the immune system declines, it's not only the cells that decline during that stabilization phase when immune memory forms, it's also their products. So one of the things that's important to recognize there was a lot of indication that antibody levels were declining at the beginning of this pandemic. And people were really worried about that. But to us, what that meant was the immune system was actually undergoing this very normal contraction that it should undergo, and you weren't going to actually see as much antibody circulating as you did at the early points during that acute infection. So what we wanted to see is using some novel techniques that we developed in my lab is, could we actually find the cells of the immune memory and study them to learn what they look like and if they persisted throughout infection. And so there are a couple of ways to do this. Some of these cells are circulating through the blood, and we can see them, other cells are not. So one of the cell types that we were really interested in are these long-lived plasma cells. Unfortunately, they go to the blood -- I'm sorry, they go to the bone marrow. So all we can detect from these long-lived plasma cells, which are cells that secrete lots and lots of antibody that can prevent infection. All we can detect there is antibody and use that as a surrogate. However, there are other cells that come out of the same tissues of the immune response that are called memory B cells. These memory B cells express receptors on their surface so that if they ever see that pathogen again, they can very quickly differentiate into a cell that secretes loads and loads of antibodies it within days. So we can actually find these cells in the blood and study their persistence and what types of antibodies they're making. There are also very -- 2 subsets of T cells, and I won't go into a ton of detail here. There are CD4 T cells. Some of these cells help the memory B cells, while others make their own effector proteins themselves that kill the virus directly, as well as the presence of memory CD8 T cells, which are also called cytotoxic T cells or killer T cells because they'll recognize an infected cell directly and kill it directly. So we decided to look for all of these components of immune memory circulating through the blood of individuals who recovered from mild COVID-19. All of these individuals had a PCR positive test in late February, and we had not seen them for about a month until after that PCR positive test. So they had resolved disease. And when we actually looked at their blood, we could see that their blood cells and the frequency of blood cells that they had actually looked no different than in a normal healthy control. Our healthy controls consisted of individuals who had never tested positive for SARS-CoV-2. And we also tested their serum antibody levels and compared those to serum that we had acquired from pre 2019 that we called historical negatives when there was no SARS-CoV-2. So we knew that these were truly negative. And this is a story that's impressed itself that should be online next week. So what we first started to look for is any hallmarks that we could find of these long-lived plasma cells. And by that, I mean, what did the antibody titers look like in the blood at this time point? And what we could see -- blue in all of these graphs I'm going to show you represents the healthy controls, and red represents those that have undergone COVID-19. Visit 1 means the 1-month time point, visit 3 means the 3-month time point. And when you look at these data, I want you to remember that when I drew that graph of the immune response, there's an inflection point where after that immune response declined by 90%, and it's retained at this pretty stable level for, hopefully, the rest of your life. So we were intentionally looking at that time point when we thought there was an inflection point to show that immune memory had formed and that immune memory, we predicted would last for long periods of time. So if you look at the antibody levels, we looked for both RBD-specific antibodies as well as spike-specific. Spike is the protein that sticks out of the coronavirus. The RBD portion is the portion of the spike that's critical for binding to the ACE2 receptor on the epithelial cells when it's infecting. So antibodies that are against this RBD portion can actually block that interaction and prevent infection. So we looked for anti-RBD antibodies. What we could see at the earliest time point is that there were high levels of IgG, IgM and IgA that were still present 1 month out after infection. When we looked at the 3-month time point, the IgG levels had been retained but the IgM levels and the IgA levels had gone down. And this was really interesting to us because it suggested that we probably had some bone marrow resident long-lived plasma cells making these IgG antibodies that the memory cells for both the IgM memory B cells and the IgA memory B cells, weren't actively making antibodies but could be in the tissues, which we couldn't actually look for at that time point. And we'll have to see if those antibody levels go back up upon reexposure. So what we could also look for is if the antibodies in the serum were capable of blocking infection. And we could do that both by examining the interaction between this RBD portion of the spike protein and the ACE2 on the epithelial cells. And you can see that in this assay here, this is the percent of inhibition or blocking of that interaction between this spike protein and the ACE2 receptor. And what we could see is that at both time points, there was good inhibition of the interaction between the RBD and the ACE2 proteins. And that's just summarized here. We didn't see similar serum levels in the individuals who had never had CoV-2, suggesting that this is definitely a memory response that we're looking at. So we could also take the serum from the individuals at the 2 time points and actually go into our Biosafety Level 3 suite in our lab, with Mike Gill's at the University of Washington, and look for the ability of the antibodies in the serum and in the plasma to actually block infection with the direct virus. And so basically, what we're doing is we're providing virus and epithelial cells and then adding our antibody and seeing if our antibody can inhibit the ability of the virus to infect. And you can see here that the inhibition was really good at the first time point, and that lasted at the second time point. And if we actually compared the amount of neutralization of the virus to the percent of inhibition that I showed you above, those 2 factors were correlated, again suggesting that binding to this RBD portion of the virus is really important for preventing infection. So the way that a B cell gets activated is that a B cell will see it's cognate antigen, so the thing that it's specific for in the special area of your lymph nodes in your spleen. It will get activated and rapidly migrate to this site where it can get cues from the CD4 T cells. Those 2 cells interact, and these B cells can actually switch out their antigen receptors so that they still bind the same thing, but they express different isotypes, like the IgG and the IgA. And that's called class switch recombination. The next thing that happens is some of those B cells will go into this very much talked about part of the immune response called the germinal center. And there, during that germinal center response, those B cells can pick up mutations that allow them to be able to bind a broader diversity of proteins. They gain lots of mutations in their B-cell receptor which diversifies the B-cell receptor and allows them to bind any escape mutants or any types of proteins that the original B-cell receptor wasn't able to bind. What's great about this is the outcome are these memory B cells and long-lived plasma cells that can then produce these antibodies that I've already talked about for the long-lived plasma cells, but also retain these circulating populations of memory B cells that hopefully now will be able to even recognize more proteins from the virus than it did before. Now these all get tested during this process. So only those cells that can really bind to proteins from the virus, make it out of this germinal center response. So we know that cells that look like they've gone through this memory B cell response are going to be high-quality cells that are able to quickly bind the viral antigen and get reactivated. So we set up a system to look for these memory B cells and to see if they were in the blood circulating as we hypothesized they might be. And we did this by setting up a system where we made what we call tetramers, just meaning that there are 4 of these spikes, that are bound to a brightly colored flora, a brightly colored phycoerythrin molecule, which just is a big fluorescent label in the middle of this molecule here. And what this does is it basically creates a substrate that's labeled with this fluorescent dye, so that if a B cell binds that specific reagent, we can isolate that B cell and study it. And we did this by making both tetramers that expressed just the RBD protein portion of the spike protein and the spike itself. Because B cells are so good -- I just told you, you needed to have a B cell that combined every single type of reagent -- every single type of protein or pathogen that it could encounter, there are also B cells that combined to other aspects of our reagent. So we also developed this decoy reagent, which has all the same components of our tetramer, but in a relevant protein and an additional flora for us. So we can saturate all of the cells first with this decoy reagent, get anything that's going to bind our reagent as opposed to just this little bit of protein on the end and then come in with our tetramer. And so the way that we do this is that we stain ourselves -- in this experiment, it's blood cells, with the decoy reagent first. We then come in with our B cell tetramer after that. Because I've told you these cells are so rare, their frequency is about 1 in 100,000 cells that we survey. We also use a magnetic bead enrichment protocol that we developed, where we use antibody-coated beads. And the antibodies are against that fluorescent tag in the middle. We can then take that entire sample that now consists of magnetic beads bound to reagent, bound to cells, run it over a magnetized column, and then allude from the column, the cells that we actually are interested in because they'll be enriched in that population due to the magnetic interactions between the beads and the magnet. And so what that looks like, if we look at this on flow cytometer, which is a machine that allows us to look at individual cells as they're going across lasers, is we can look for cells -- each one of these little dots is a cell. We can look at cells that are binding our reagents specifically. And that's shown on the x-axis here, this RBD tetramer cells. And this gate here that you can see is identifying the cells that actually bind our tetramer. But you can also see all these cells that would have been caught up in that decoy binding component of the population. So it's really important that we gated those out to find these really rare cells. In people who have had SARS-CoV-2, we could find increased numbers of RBD-specific cells. It was slightly increased at the first visit and even more increased by the second visit. And you can see this based on the number of dots in these boxes in the CoV-2 individuals on the bottom row, down on the left-hand side. And we could not only just count how many cells are there, but we can really look in-depth at what those characteristics of those cells are. And I'm not going to go into a lot of detail here, but just know that the cells in the upper right quadrant of these boxes are cells that have been associated with strong antiviral responses and good memory responses. And you can see if you compare the healthy controls across the top versus the CoV-2 positive individuals across the bottom, that there's a far greater frequency of these cells in the people who have undergone mild disease, suggesting that they have memory cells that are specific for the virus. And what was great about this is, again, we saw that not only was there an increase at the first visit, which was pretty small, but there was a much bigger increase at the second visit, suggesting that these germinal centers that I told you about previously, were continuously pumping out these memory B cells into the blood that we were picking up over time. We did a lot of characterization of these cells to look at what types of memory B cells there were. The predominant frequency of these memory B cells was IgG, but there's still IgA cells here. We saw fewer of these IgA cells at visit 2 than visit 1, suggesting to us that they may have gone into the tissues, into the mucosal sites where they like to reside. But we also see some IgM and IgD. But the predominant population in the blood by both frequency and number where these IgG class switch memory B cells that increased over time. So we found, overall and what we can say is that in individuals who undergo mild COVID-19, they form persistent functional IgG memory B cells. And I'm not going to go into a lot of detail here. But what we did to really show that these were very, very potent memory B cells that could protect individuals, is we actually singly sorted each one of these cells. Each one of these lines is a B cell receptor that has been sorted from an individual cell and then expressed as an antibody. So we could actually test whether the antibodies that these cells secrete would actually be protective. And what you can see here, the green is a control antibody here. The blue antibody is the one antibody that didn't bind our protein of interest. All of our other antibodies that we generated from the B cell receptors of these memory B cells, all bind the RBD protein. And about 50% of those inhibited RBD interactions with ACE2, showing that they can neutralize. We've gone on to show that these can also neutralize in those assays and the BSL3 with virus and epithelial cells. So we now have a broad array of neutralizing monoclonal antibodies that we're testing in different assays. Okay. So we're going to speed this up a little bit just to say that we now know that memory B cells are capable of binding -- the RBD binding the SARS-CoV-2. And they're also, if we express them as antibodies, are capable of neutralizing virus. We went on to show that memory CD4 T cells are also formed in individuals who've had disease. This -- both was found for these B cell helping subsets called the T follicular helper cells, and the effector cells that produce the cytokines. And this is just summarized one more time here, showing that these memory CD4 T cells express all of the molecules that they would need to reactivate memory B cells. And they also expressed interferon gamma and IL-17, which are cytokines that can help to defeat the virus. We confirmed that these really were memory cells by actually sorting on memory cell populations and restimulating those sorted memory cell populations with pieces of the virus, in this case, the spike. And on the bottom right-hand plots, where the red squares are, you can see that there are large populations of proliferating cells that were derived from sorted memory cells only in the individuals that had CoV-2 before and not in the healthy controls. And that's just shown here. So this is just the summary of all the different immune parameters that we have seen and that we've looked at. Across the left-hand side of this graph are the healthy controls, across the right-hand side of this graph are the individuals who underwent CoV-2 and had mild disease. Red means higher, blue means lower across almost every parameter that we looked at. We could see higher specific -- SARS CoV-2-specific immune responses and individuals that had mild disease, which was really good news. It was saying this immune response looked normal, and it looks like memory cells that would last for long periods of time and have functions associated with antiviral immunity were being formed. Now this is one cohort. We don't know how long this is going to last. We also don't know if this is going to happen in everybody who's had more severe disease, which could disrupt some of these immune responses. And we're still learning now, I think, to this day, whether people were protected in a paper online that showed up at Bioarchive this week, and was written about New York Times, said that they found the exact same thing 3 months later. So these cells that we found have really persisted out to a 6-month time point and 8-month time point. And so we think this is really good news. So with that, I just want to thank the people who helped us with this, the University of Washington, this involved an enormous collaboration between multiple labs. Seattle Children's did a lot of the sequencing of our B cell receptors for us. This was work done by Lauren Rodda, who is a postdoc in the lab, and Jason Netland, a Research Scientist at The Benaroya Research Institute contributed to these studies, as well as our funders through the NIH and Burroughs Wellcome Fund and Emergent Ventures. So with that, I'd like to thank you for listening.

Thank you, Dr. Pepper, for the presentation. And now I'd like to turn it over to Dr. Sean Tucker, who is the founder of Vaxart; and our Chief Scientific Officer. And I think he's going to walk you through both our norovirus program as well as our COVID program and talk about some of the clinical data that is coming out of our Phase II COVID-19 vaccine program. Sean?

Great. I hope everyone can hear me. Certainly, we're going to talk a little bit about what Vaxart is doing right now. I'm going to start a little bit by talking about our norovirus program and, actually, in some ways, the way that we're exploring norovirus, how it's translated to how we're looking at COVID-19 as well. So with that, I'm going to ask for the next slide. And Jan already got into this in some detail about the fact that norovirus is essentially a pretty big indication from the standpoint of the number of people that are infected each year. The main thing I want to point out is that through work by Bruce Lee and others, it seems that there's like something around the order of $10.6 billion cost of the U.S. health care system annually for norovirus infections or due to norovirus infections. And if you go to the next slide, I think one of the things that we had sort of figured out or other people have figured out, essentially is that, really, there's essentially probably about a $3 billion U.S. market. And as Jan pointed out before, most of the -- most severely affected are the very young. They're the kids 0 to 40 years of age as well as the adults that are 65 and older. So those are the main targets. It's not the cruise ship people, but it's certainly on the both ends of the age spectrum are the main targets, and it's a pretty large market. Next slide. So Marion did a really good job about talking about memory responses. And again, since everyone's stuck at home and learning about immunity, how the immune system works, I probably don't need to spend much time on this. But essentially, I adopted this from -- something from Immunize BC just to make sure it's clear. But the main thing is, of course, the vaccines work by recognizing a component as being foreign. When they start mounting an immune response, we consider that to be the effector response. That's the serum antibodies. For instance, it's the initial response that you get. And as Marion talked about before, what happens as those effective responses decrease, but then you have a memory response. That allows you to basically to recognize something that comes in the future and to respond much faster the next time. And again, from the standpoint of what we understand, a lot of times what we really focus on is the effector response because it's a lot easier just to measure serum antibodies. And -- but as Marion pointed out, again, from the standpoint of giving long-term protection, the memory response may actually be much more important. But it's definitely more difficult to study. And certainly, Marion has done some fantastic work for sort of understanding novel ways to sort of go after these rare sales. With that, the next slide. Again, Vaxart is sort of a little bit different from the standpoint of how we're basically approaching vaccines. One of the things that we wanted to do is build a vaccine platform that could come to you rather than having you go out and get a shot somewhere and wait in line and deal with all the hassles. So what we found is, again, the best way to do that would become something like room-temperature stable tablets. There's no devices. It's pretty easy to figure out how to swallow a tablet. And obviously, this is a lot easier to distribute. The other thing, of course, is that we had to come up with ways to essentially make this technology work. And we took advantage of the way the intestinal system works in the intestine. And what we found out is that if you take a nonreplicating adenovirus and you put it into the intestine, first off, you can bypass any antivector immune responses. But the other thing is that we found is that it's pretty much ignored. It's sort of another protein down at the intestine or food. And what we figured out is if you expressed a double-stranded RNA adjuvant basically, it's a localized sort of approach for the danger signal, then you would actually get an immune response, not against the vector, but essentially more focused toward the transient or whatever you express, and the way we have this set up is we can set in any sort of antigen of choice that we want, whether that's a COVID or a norovirus gene and move forward very quickly into the clinic. Next slide. So right now, this platform has been tested in a variety of different indications. Again, it's exactly the same backbone. We're approximately 500 subjects to date, give or take a few. And what I could tell you about this, obviously, we've tested everything in adults, in tablets or capsules, and the safety profile is really benign. It's really a favorable profile. We've tested in a head-to-head comparison of our vaccine for flu versus leading injectable vaccine and show we saw a really nice response in efficacy that was equivalent or better than what was -- had been done from the needle standpoint. One of the other things I want to point out, and I think this is very important is that when you inject a vaccine, you get a very strong serum antibody response. And that's important for a lot of indications. But from mucosal standpoint, it may be more important or it could be very important to get not just a serum antibodies response but systemic T cells and mucosal T cells and B cells. And I think that's the thing that I would like to point out about the platform is that this works a little differently. This is more like natural infection at a mucosal site where you get the broadness of the immune response. Next slide. Jan talked about a lot of the challenges actually that are in for norovirus in terms of what vaccine development. And I can't address all of them in this discussion, but I'm going to address a couple of them. The first is that one of the things is that with a mucosal vaccine, you get not just a systemic IgG response, but you get a mucosal secretary IgA response. And that's kind of the first line of defense at the epithelial layer, whether it's in the respiratory system or in the intestine. And that -- those antibodies, the key thing is they can block infection at the site, so you can have reduction of infection. They actually block infections to the point where you have less shedding and less transmission, which could be very important as well. The other thing is that secretory IgA can be much more potent in terms of being able to neutralize virus, and it could be much more cross-reactive than an IgG response. And again, from the standpoint of being able to address an enteric virus in the intestinal -- in the intestine, secretory IgA is certainly the first line of defense, and it may be much more cross-reactive than an IgG response in the serum. Next slide, so our last study that we did in norovirus was basically to do a bivalent study to compare with monovalent tablet versus a bivalent tablets with both GI and GII.4 strains. And just ask the question whether you have a similar response with the bivalent compared to the monovalent for each of the different genotypes. And again, this is from the standpoint of just showing that there's no interference. One of the main ways we wanted to look at this is we basically counted the antibody-secreting cells to noravirus or norovirus VP1. And again, the reason why we think we wanted to do this is we know that IgA ASC has correlated very strong protection in other enteric pathogen studies as well as our own influenza vaccine study, that was one of the more important correlated protection for us. And what you can clearly see is that both -- is that bivalent produces very strong responses in the subjects that we're getting these [indiscernible] plots, and there's no real difference between the monovalent and the bivalence. So this vaccine seems to be very robust and create something that's not going to be -- it's not interfered with having 2 different strains. Next slide. One of the things we wanted to know is basically is like how strong the response do we get, and obviously, we knew that natural infection could create at least short-term immunity, and we wanted to compare our vaccine approach in terms of how it compared to infection. And one of the ways we do these things -- one of them is to look by flow cytometry at very early time points. This is from day 7 or day 8 post-vaccination. And what you can appreciate whether we use the infection on the bottom or vaccination with our vaccine at the top, our plasmablast response is pretty similar to natural infection. And again -- and the other thing is that the cells that are actually elicited have an up-regulation in the mucosal homing receptor a4ß7, as shown here. And again, the IgG and IgA ratios were pretty similar. From our standpoint, this looks at least we're in the same order of magnitude, again, using this early flow cytometry data. Next slide. So one of the things that Marion discussed was the fact that studying memory cells can be very tricky and especially because they disappear over time. And certainly, when you have memory cells that are going to mucosa, it's not easy to go and find those cells in people because no one wants you to really cut pieces of the intestine or your epithelial layer of the lungs out to go and measure it. So one of the things we did is we looked at basically by essentially looking by flow cytometry early time points gating on the mucosal homing receptor. And they're just asking the question what was -- what's going on with those cells. And what we could see is, first off, there seem to be much more IgA than other isotypes, at least on the surface. And if we look at with the CD27 versus CD19, it did seem to be that there was both effector and memory cell populations. And again, this wasn't a clear indication of antigen specificity. So we wanted to go and explore this a little bit more carefully. Next slide. So we've stimulated the B cells from the peripheral blood. And what we found is what Marion had pointed out before is that it goes through a cycle of expansion and contraction. And one of the things we figured out is that there is definitely a big boost in both IgG and IgA memory responses against VP1 on Norovirus. And in fact, those magnitudes are similar to what was reported from infection. So again, we're making a very strong memory response similar to what happens in natural infection. What was very interesting too is that it seems like the IgA responses were disappearing much more quickly from the purple blood. And again, because of the mucosal homing receptor that we saw on those cells, we think that most of these are basically in the tissues. So from going forward, one of the things, again, we're making a memory response, but we also want to look to see if we're making an effector response at the site of infection, which would be the intestine. And if you go to the next slide, here, we're looking at the fecal IgA response. And again, when you take a fecal sample from people, it's not exactly the most clean and pristine material to work with. But what you can greatly appreciate is either low dose or high dose, there's an increase in the fecal IgA response, and it seems to be durable up through 6 months. So again, an effector response we know is there, and we know -- we believe that the mucosal memory response is going to the tissues as well. Next slide. So just to summarize our norovirus experience, we saw a strong induction of antigen-specific B cells. There was no interference between the 2 different strains. We had some memory cell induction, both IgA and IgG. There seem to be some migration of the memory cells out of the blood, at least they were disappearing quite rapidly, but they do have mucosal homing receptor on their surface. And we did see a mucosal IgA response at the intestine, and just to be clear, we have now restarted the norovirus program after potentially putting on hold while we're focusing on COVID, and we'll have more guidance for what we're going to do next soon. Next slide. Now let me switch gears again, and we're going to talk again about COVID. Now obviously, COVID is a significant health problem, a vaccine solution seems to be possible. Again, actually, there's a couple of vaccines out there that now are -- have shown efficacy interim time points, and we think that's great. Obviously, one of the key things about these vaccines is they're looking at infection at very early time points vaccination when their antibody titers are really high. So it may be that the contributions from the effector response are basically making it really potent now. But obviously, as the antibody titers wane, it may go down. Obviously, we hope that memory responses will be important as well. We think that there's still a good market for a second-generation vaccine, and if you have to releast in the world, there's several limitations for the rollout of a needle-based solution. You need a qualified health care to administer it. Many of the leading vaccines are kept frozen, even minus 80 degrees, which is really difficult. And again, we're all supposed to sequester and avoid contact to this cost. And making the real goal of the vaccine is to make long-lasting herd immunity in the population, and these things make it a challenge. We also want to point out that mucosal immunity may have some definite advantages. Obviously, local immune responses may do a better job of blocking an actual infection. We know that subjects with gastrointestinal symptoms seem to shed virus longer. And we know that mucosal T and B cells could be able to inhibit shedding much more readily than a systemic response. And we think that this will also impact the rate of transmission, and we plan on studying this in preclinical models. Keep in mind that mucosal immunity isn't really induced by injected vaccine. So we go to the next slide and talk a little bit about what our goal was. And our goal was to make a candidate that could induce robust antibody and T cell responses, both systemically as well as mucosally. We made several candidates early on, and we selected the candidates that made the highest serum and lung-neutralizing antibody responses. We obviously are now evaluating these things in parallel, actually in humans and in animal efficacy studies. And our plan is to move to a Phase II study in the regional of the world with COVID infection is really high next. Keep in mind, one of the things that is going on is that every candidate, right, so far has been using the S protein, a spike protein, and it's a really good target because it is basically on the surface and is where the virus binds to the target cell through S2. But obviously, S protein is much more variable. And so one of the things we decided to do early on was basically add something that was much more conserved to try to drive T cell responses against that more conserved protein. And so we put in N as well into our vaccine candidate. Next slide. This is just briefly showing a little schematic of what the virus looks like. Obviously, S is on the surface and N is an internal protein. Next slide. So keep in mind, what we found is that we did a lot of work in terms of understanding the structure of the S. We evaluated very truncated versions versus full-length S, and we found the full-length S seem to be right or better antibody response. And in particular, it seemed to do really well from the standpoint of making a better neutralizing antibody response in the lungs, which we think is, again, pretty important from the standpoint of making mucosal vaccine. Next slide. We are currently getting -- or we just finished the study recently where we actually tested the antibody -- or our -- vaccine ability of our vaccine, given orally in hamsters to protect against infection. And here just shows the antibody titers grow quite readily whether you deliver our vaccine orally or intranasally, they're about the same. And it's about 10^4, 10^5 pre-challenge. And then after challenge, obviously, the no-vaccine group can actually boost as well. So again, we're making a very strong antibody response. If you go to the next slide, one of the key things, the take-home points is that by oral immunization, we saw -- what we saw is like a four to fivefold order of magnitude decrease in the viral loads and the lungs post-challenge. And again, it looked equivalent from the standpoint of intranasal delivery. So again, the vaccine was proven to be efficacious when we're looking at the ability to protect against this -- in a hamster model is -- very severe challenge model. Next slide. So let me tell you a little bit about our Phase I design. What we have done is we basically have the sentinel group, which was basically 5 subjects, and then we waited and then went ahead with -- after a safety review to go ahead and do 2 different new cohorts, which basically were at low dose and high dose. And the key point from the standpoint of a Phase 1 is to understand the safety. And again, this is -- and we decided to go with open-label because of all of our experience before with the platform. And the other thing we wanted to do, in the sentinel subject alone, was actually evaluate 2 doses to provide guidance in sort of going forward. And so right now, we're basically at day 15, and we've been able to look at early time points from the standpoint of the immunogenicity due to PDMC samples and our understanding from prior work what's really important from looking at the immune response. If you go to the next slide, what I can show you is these are the solicited symptoms post-vaccination. And what you can see is that realistically, this is a very benign vaccine. I mean, it looks -- there's no fevers. It's much -- it's not very severe. There's no real complaints of malaise and fatigue, which has happened in a lot of other sort of COVID vaccines that have been very potent. So I think from that standpoint, we're in good shape. There's been no severe adverse events or any adverse events of special interest to date as well. Next slide. In terms of immune responses, and again, we were able to work with the sentinel subjects and had 4 samples that were basically repaired that we could see to pre and post-immunization. And what we could tell you from the standpoint -- and again, this is preliminary data, is that we do see expansion of the plasmablast population. We do see the B cells that will eventually be -- make vaccine-specific responses. And those plasmablast look equivalent to what we've seen before. We have seen increased antibody-secreting cell responses between day 0 and day 8. That's been great. And one of the things that's been interesting, of course, is the T cell side of things. There's definitely a heavy bias toward Th1 versus Th2. We're making gamma, not IL-4 and IL-13, which is no surprise given the sort of platform approach with the adjuvant plus the vector. One of the things we've seen is the S protein-specific responses have expanded in all subjects tested to date, and we've seen a majority of expansion in N responses as well. What was particularly interesting for me was that the CD8 responses have been particularly robust and polyfunctional in nature. And I think that from the standpoint of what's been reported for COVID vaccines has been more focused on the CD4 response. So certainly, the cytotoxic T cell is important. And let me share with you a couple of flow cytometry plots from that study. Next slide. Here, we're looking at the plasmablast populations. And again, because we only have early time points, this is day 8 post-immunization. But what you can see is there's substantial population expansion to the plasmablast as we gate on the the IgD negative 20 -- CD27 B cells. And again, post-immunization, you see this is market population of plasmablast, and if you gate on that and ask the question about ß7 versus IgA, the key thing I want to take home is that there's an up-regulation of the ß7 or the mucosal homing receptor. So that was really important. Next slide. And as alluded to before, I think this -- for me, what was very striking was the fact that we saw an increase in the CD8 T cell responses post-immunization. What was interesting is there was actually a background. There was actually people that respond essentially day 1 in terms of having a gamma interferon response to the S protein peptide library. And after immunization, that responds quite a bit. So again, from our standpoint, preliminary data from the standpoint of the COVID trial looks pretty promising, and we're very excited about it. Next slide. With that, just to summarize where we are, obviously, we've made -- clinical candidates been selected based on mucosal responses. It's proven efficacious in a hamster challenge study. Our Phase I trial is enrolled. We are now in the middle of like day 15, well-tolerated safety profile so far based on solicit adverse events, and we do see early signs of immune activation. And again, since we only have early time points in the sentinels, to keep that with a grain south. But certainly, it looks consistent with what we've seen before in clinical studies. And with that, let me just -- next slide, just thank. Obviously, I'm just the spokesmodel, but there's a lot of people that have worked on this, and I particularly wanted to put stress on the people in research, clinical and our collaborators that worked on the preclinical side of things. And I would be remised if I didn't thank the people in manufacturing and quality control that have done a fantastic job of making this vaccine go really quick. I think we went from gene to vaccine in something on the order of 7, 8 months, and that's sort of our internal record, and we're pretty proud of it. With that, I'll turn it back over to the moderator, Tara.

[Operator Instructions]

So Tara, can I recognize Mayank from B. Riley?

I think Mayank is still on mute, yes.

Can you hear me now?

Yes, we can hear you.

Excellent. So maybe just going into reverse order, maybe I can start with you, Sean. Can you just give us an idea on how you're thinking about -- you have the 2-dose vaccine here. As you think about the immunogenicity data that's evolving, again, I understand very early data PBMC data. So how does this inform your thinking as you think about the immunogenicity data? And specifically, both in the systemic immunity but also mucosal immunity, could you just talk about that?

Sure. I mean, obviously, the -- one of the points that we wanted to do with the Phase I trial is to really evaluate sort of high dose versus low dose and hopefully provide some guidance when we're doing the Phase II study about whether on the dose-ranging that we should do. Obviously, with 1 dose versus 2 doses, there is certainly -- from my standpoint, scientifically, we want to know if there's a big difference from the standpoint of 1 versus 2, particularly on things like neutralizing antibodies in circulation, I would think, or T cell responses. And I know that there's a lot of interest in basically coming up with a 1-dose vaccine solution. And certainly, we are looking at 1 high versus 1 low in our Phase I. But I'm going to say as a scientist, I'd like to see that the data guides the next steps.

Great. And maybe one follow-up for Dr. Pepper. So in your clinical study, there was some pre-vaccination, CD8 T cell response. So I'm just curious, Dr Pepper, could you comment on this phenomena of cross-reactivity, maybe exposure of previous coronaviruses that might be contributing to the memory B cell response. Any -- and importantly, as we think of this moving forward, what are the things we should focus on as we think about durability of immunity of vaccines, be it of any form?

Yes. Sure, I'd be happy to comment on those. We definitely saw, similar to what Sean showed in his data, CD8 T cells that could respond to the spike protein that were in individuals who had not had SARS-CoV-2. So there was clearly some cross-reactivity. We still don't know -- and cross-reactivity has also been shown for CD4 T cells as well. We still don't know whether those cross-reactive cells can contribute to protection or not. So I think the jury is still out on whether they're high-enough affinity and whether they actually get activated appropriately to be beneficial. But I think there's good reason to think that maybe they will. We also saw cross-reactive memory B cells, and they were lower affinity. They didn't do quite as much, but they may contribute as well to the overall response. So yet to find out, and we'll hopefully see some results of TCR sequencing that will allow us to be able to answer that question more thoroughly. As far as durability, I think we know that the mild infection is inducing durable protection. So I think it's encouraging to see that the Vaxart tablet isn't inducing massive inflammation. I think that's a nice parallel to have, but we'll, again, have to see what that does.

Great. And final question for Dr. Jan. It would be helpful. I think you mentioned there was also the Takeda vaccine systemic approach. So could you just talk in context of what that experience was? And what maybe Sean talked about the data that was generated with the bivalent vaccine in terms of both immunogenicity and safety?

Yes. So far, the data from the Takeda vaccine is also bivalent vaccine and it's 1 of 2 components. Safety looks very good. The efficacy is at least what they published the data is it's -- I think they didn't reach their endpoint. So they had to reassess their endpoints. That's at least what in the published literature is. So -- but they still found a -- and that was very encouraging. They found cross-reactivity because they did a study in the military, the U.S. military, where there was an outbreak with a different strain than was in the vaccine, and they found significant protection. So I think that made them decide to move on into Phase III trials.

Excellent. Okay. Going to the next person, Charles Duncan from Cantor. Can you unmute his line?

Okay. Super. Can you folks hear me?

Yes.

Okay, great. Andrei and Sean, thanks for hosting this call. Very helpful. And thank you to the KOLs for sharing your perspectives. I had just a couple of questions for you, really for Dr pepper and for Dr. Vinjé. I'm wondering -- and sorry if I didn't pronounce your name correctly. I'm wondering, kind of like the last set of questions, when you think about what you've seen out of the 2 RNA vaccines in terms of 7-day immunogenicity, I'm wondering how you think that looks in terms of, say, measuring 7-week or 7-month protection against disease. I understand that the immune system should work, and so it should reduce. But if you're a consumer of these products in the future, what would you like to see out of them to really use them either with your patients or with yourselves and family?

Well, I can start. I think it's really encouraging to see that immunogenicity data. And as you said, the immune response should work. We would expect a 90% contraction and hopefully, immune memory from those responses. I think, clearly, the protection data and the efficacy seems to suggest that, that's what's happening. But I think more studies actually analyzing the cells that form are going to need to be done at later time points, unfortunately, to say anything definitive about that.

Dr. Vinjé, a perspective on that.

Yes. So most people think about elderly and think about nurses working in hospitals where some of these outbreaks are pretty devastating. So I think an oral pill would immediately, as Sean indicated, would boost up the local immune response. And I think that is -- I would -- we have been discussing here, my colleagues, I think I can depending on the price, but it's just having an oral pill every season because, yes, norovirus is primarily seasonal in the winter season. So before, right now, to take a pill to be protected, have a boost of your immune local immune response, I think that is -- with the data that I've seen, is very reasonable to expect.

Okay. And maybe I could follow-up with a question that's more specific to Vaxart and the technology platform, which is, in my view, intriguing. If you think about the effectiveness of an oral vaccine program, is that effectiveness simply driven by compliance in the sheer numbers of patients that we can assume would be interested in taking the oral vaccine? Or is it driven by a nuance in terms of the technology and how the candidate is engineered. It seems like the company has some differences in terms of its approach, not only including the spike protein, but also the N protein. And so I'm wondering what is driving your interest in the oral vaccine technology, compliance or design?

Yes. I think that both of them can contribute quite a bit, obviously, because the end result is you want to get herd immunity up everywhere in the world so that we can start traveling and living normally. And certainly on the compliance standpoint, I think it's -- I think we all appreciate that if the oral vaccine works as well or even a slightly less well than they inject it, it should do a much better job of being distributed throughout the world. From my standpoint, since I'm a geeky scientist, I like the fact that one of the things that we do that's a little bit different is that -- and this is -- comes straight from our flu vaccine study where we did a challenge study in humans. But we didn't wait -- we didn't just challenge them 1 month after the vaccine when the titers were at the maximum in the serum, we waited for 3 months and then actually challenged and then -- and again, the data suggests that ours is as good and maybe even better from the standpoint of protecting its shedding. And I think that -- I think one of the technical advantages of having this vaccine is that you're going to be able to put memory cells and effector cells in a place that's more mucosally oriented. And that may make a difference long term. I love the fact that Pfizer vaccine and the Moderna vaccine are showing 90% efficacy. But probably, a lot of that's driven by the fact that serum titers are right now through the roof and your effector mechanisms may be really contributing a lot more than any of the memory. That would be my bias, but I don't know what -- maybe Marion has a different interpretation, but that's kind of how I see.

Yes. I think it's really elegant to actually try to get the right immune memory cells to the right tissue to protect. And I think this approach does that in a way that an intramuscular injection can't do. So in my mind, it's getting the right immune memory cells to their tissues where they can actually protect. And I think that's really elegant.

Very good. Last question, then I'll hop back in the queue, and I appreciate you taking all my questions, is relative to COVID-19 right now and the potential for the future. I guess I'm wondering if you think there's a risk or a need for an annual immunization program and, therefore, getting back to something the company alluded to, say, the viability of a second-generation approach?

Yes. I'll answer first and then Marion may pipe in, but my read from the -- at least from some of the data that was coming out from the Kissler paper and others suggest that natural immunity may last only something on the order of 41 weeks. Now it may be that, that's with a different coronavirus. And it may be that the -- the memory responses from these corona vaccines could do better than that maybe every few years or maybe longer, but we just don't know until you do the study. But our bias has always been based on the -- some of the data is that we've got a plan for 1-year annual vaccines. And if it turns out, you can wait longer, I think everybody would be pretty stoked about it. So Marion, do you have any more?

No. I mean, this is the problem with studying a recently emerged pandemic as we only know how long the immunity lasts from when it emerged. So we know so far, so good. And it looks like it should persist for several years, but we'll have to find out. We'll have to learn.

I'll -- let's see, I'd like to recognize Yasmeen Rahimi. Can you open the line for her?

Paul on for Yasmeen. Congrats again on all the progress and all the data today. Really excited to see it. I was just wondering to start, Andrei and Sean. Can you actually just walk us through -- so we saw a really nice a4ß7 integrin signals and the flow cytometry data. I was wondering if you could kind of help us understand going from gut mucosal targeting to some other mucosal immune organisms, like how that -- how this data kind of implies -- or looks going forward?