Greetings, welcome to the Vaxart Norovirus KOL Event webcast. All participants may submit questions at any time by using the Q&A icon at the bottom of your screen. A question and answer session will follow management's opening remarks. As a reminder, this conference is being recorded. I would now like to turn the webcast over to your host, Brant Biehn, Senior Vice President, Business Operations. Good day, and welcome to today's call. Joining us from Vaxart are Andrei Floroiu, our Chief Executive Officer, Dr. Sean Tucker, our Senior Vice President and Chief Scientific Officer, and Dr. James F. Cummings, Chief Medical Officer. We're also very pleased to be joined by the prominent norovirus disease experts, Dr. Jan Vinjé, who's the head of the National Calicivirus Laboratory at the CDC, and Sarah M. Bartsch, who's the Project Director at Public Health Informatics, Computational, and Operations Research at the Research Foundation of the City University of New York. Before we get started, I would like to remind everyone that during this conference call, Vaxart may make forward-looking statements, including statements about the company's financial results, financial guidance, its future business strategies and operations, and its product development and regulatory progress, including statements about its ongoing or planned clinical trials. Actual results could differ materially from those discussed in these forward-looking statements due to a number of important factors, including uncertainty inherent in the clinical development and regulatory process and other risks described in the Risk Factors section of Vaxart's most recently filed annual report on Form 10-K and other periodic reports filed with the SEC. Vaxart undertakes no obligation to update any forward-looking statements after the date of this call. I'll now turn the call over to Dr. Jan Vinjé from the CDC. Jan. Thank you, Brant. Hello, everybody. What I would like to do today is in a brief presentation, give you some data that support the need for a norovirus vaccine. Next slide, please. Simply overview what I'm going to present. Will tell you a little bit about the clinical disease. I'll leave the economic burden for the next speaker, Dr. Sarah Bartsch. Tell a little bit about the virology, the different strains that are causing norovirus disease. I will briefly highlight the surveillance networks that we are leading, both in the U.S. as well as global. I will finalize with the status of the norovirus vaccine developments. Next slide, please. You probably all have heard about norovirus, even if you haven't taken a cruise ship, a cruise on a cruise ship. It is usually relatively mild. Incubation periods are for maybe between 12 and 48 hours. It's a very typical clinical symptoms with acute onset of vomiting and diarrhea. Most people recover, but there is a significant number that seek medical attention, and some require hospitalization and fluid therapy, and more severe illness is reported, and deaths are being reported even in the U.S., primarily in elderly and those people with underlying diseases. Next slide, please. This slide gives you an overview of some of the studies that we did in collaboration with Kaiser Permanente about a decade ago, but it showed clearly where the highest burden is. These are two Kaiser Permanente sites. In red bars, the Northwest, and in green, the Mid-Atlantic, and in blue is kind of summarizing both data. You can clearly see that the highest burden of norovirus disease is in young children. Next slide, please. If you look at severity, you see here on the left with the blue bars, the youngest age group from zero to four years of age, where most of the hospitalizations and emergency department visits occur. The deaths are primarily in the US associated with the elderly, you see that the right side of the red bars. Next slide, please. If you look at several studies over the last couple of years, we were able to assess and describe the burden, the disease burden in the United States. This pyramid on the left shows you, starting at the top, the number of estimated deaths, 800. There's a lifetime risk of one in 5,000. Hospitalizations are not an insignificant number of around 70,000 every year. The emergency department visits, you see it listed there, 414,000 a year. Outpatient patients, 1.7. The overall burden of all diseases is estimated to be around 20 million every year. Next slide, please. If you look at the global disease burden, there are some several studies by the WHO have been conducted. From those studies, it's clearly that norovirus is the number one frequent cause of foodborne illness worldwide. It is just the vast numbers. Most people have heard about Salmonella, about E. coli, but if you look at the total number as foodborne illnesses and you look at the pathogen that has been identified, the norovirus is the number one. If you look at the total burden of norovirus disease, it's not only foodborne, but also, the person to person, you see the numbers listed there. It is an enormous amount of burden, globally as well. In most countries, in middle and lower income countries, the highest burden, again, is with the children under five years of age. Next slide, please. We talk about the virus. Briefly, showing you what the virus is, and we all know a little more about viruses and genome organization since COVID. norovirus is also an RNA virus. It's a single strand of RNA virus. It's relatively simple, and it has a second open reading frame here on the top, ORF2, that codes for the structural protein. 90 dimers of the proteins are forming the viral particle. That's where the epitopes are, that's where we decipher the different strains. Next slide, please. There are many different types, and you see here this so-called genetic classifications. It's in 10 different genogroups. The green balloons you see on the left is the Genogroup II. Genogroup II viruses are the most prevalent viruses, with GII.4 causing at least 50% of all the outbreaks in the U.S. You also see GI there in the lower right corner. Those are the two genogroups, they comprise about at least 20 different types that cause disease in humans, most disease in humans. There are these other viruses. They are sometimes seen in humans, but they play a minor role in the total disease burden. The overall message is focus should be on the Genogroup I and the Genogroup II viruses that are depicted here with these two larger green balloons. Next slide, please. The typing of these viruses is sequence-based, and so what we're doing is having developed a typing tool. This is an online typing tool that everybody can use, and people can easily sequence based on the standards and the reference sequences that are here available. We have a standardized nomenclature for the typing to occur based on both the capsid gene, which is defining the viral strain, as well as a non-structural gene to provide us little bit more information on the virus. Next slide, please. In the U.S., we are coordinating at CDC several different surveillance platforms, and I've listed it here. That is looking at outbreaks. NORS is an epi surveillance for all enteric disease outbreaks, where we collect data on setting transmission modes, exposures, and disease outcomes. CaliciNet is a surveillance network that looks more at the laboratory-based surveillance. Looking at sequence-based typing of the outbreak-associated specimens. We are able to identify new strains by using this network. We have endemic disease. One of the most important one is looking at norovirus in young children, medically attended children. That's New Vaccine Surveillance Network that conducts active prospective population-based surveillance of acute gastroenteritis at hospitals and emergency departments. SUPERNOVA is a project in the VA hospitals, that's looking at norovirus burden of disease in adults. The next slide, please. This is an example of the coverage of CaliciNet. In green are the states that the state health laboratory is certified to upload the sequences for the norovirus outbreaks to the national database in here in Atlanta. You see that there are a lot of green states. The other, the blue states that have they are not certified, but the way how we organize it to get a national picture is to have those states, if they do have outbreaks, to submit their samples to a neighboring state. There are the CaliciNet outbreak support centers with the blue stars. We here at CDC, we are charged to investigate cruise ship outbreaks. Next slide, please. Looking at what kind of strains are circulating in these outbreaks over the years, you can see here clearly, five years of data. You see is, there's a seasonality. Most outbreaks occur between November and May of each years. We also can clearly see that in 2020 there is almost no outbreaks. That's the COVID year. You see also that after the COVID, that norovirus is back. Now the most recent data is showing us that, the activity is back to where it was, pre-COVID. The colors indicates the different strains, and I think the only take-home message is there are many different strains, but the major component of what is causing norovirus disease, at least in outbreaks, is GII.4, GII.4 viruses, and they are listed here in green on all these bars. Next slide, please. The question was a couple of years ago, okay, this GII.4, which you see on the left pie in the blue, 48% are listed, about 50% of all the outbreaks. It's the same true if we look at sporadic cases in young children, and that's the pie on the right. You see that blue is significantly less, and there is a light green bar there. That's another genotype that we find more frequently in children. That's where a pediatric vaccine, for example, that is an important one to consider as far as for protection against the that particular strain. Next slide, please. I think this is supposed to be a map. I don't think it's visible here, but this is a global pediatric norovirus surveillance network. We are participating with about 16 different countries. These countries all have the same protocol, standardized protocol that we developed at CDC. It's really a harmonized, standardized lab typing, lab testing, and typing protocol. This is primarily for uploading the typing data to a national database, and hopefully, that's visible on the next slide. Yes. We have a publicly available NoroSurv.org. NoroSurv stands for norovirus surveillance, everybody can access this and look at the data here, which have been uploaded by these 16 different countries. Next slide, please. This is an example of what this the power of these surveillance networks. What you see here is different years, different norovirus years. You see these bars, they are moving. That means there is a different trends in different years, which is the most important virus causing disease in young children. This continuing surveillance gives us over the years, a nice indication which strains are causing the majority of disease of medically attended norovirus in young children below five years of age. The different colors are the different strains here. Next slide, please. As far as for the currently available norovirus vaccine candidates, you can see on the left the preclinical. The first top three are virus-like particle based. There is a recombinant adenovirus vaccines are being developed. The ones that are in clinical trials is Vaxart. Vaxart is in phase II. It's an oral pill, a trial in healthy adults. And HilleVax is also working on a bivalent, a similar bivalent vaccine where there is a one G1 component, genotype 1 norovirus, and a GII.4, as I mentioned before, is one of the most important viruses you would like to protect against. Next slide, please. This is basically summary when you think about prevention by vaccination. Disease burden, we have all the data. At least, we continue to do surveillance and to see if there's any differences. As I mentioned, about 20, 21 million here on this slide, illnesses annually in the U.S. About 70,000 hospitalizations. The risk groups. The risk groups we know it's young children, as I mentioned before, but also the elderly that are usually having underlying diseases, long-term care residents, but also food handlers, because norovirus is an important food-borne disease. Travelers, as well as the military. We know about the natural history of disease. The virus sometimes may be shed more than four weeks. The viral strains, I mentioned G one and G two, the major groups, and including the predominant strain, the GII.4. Maybe for the pediatric vaccine, maybe a different strain needs to be included or at least needs to be shown that this vaccine is effective against. Immunity is still not completely understood. There is not enough information right now about, for example, cross protection between the different strains. The way how the vaccine can be made is, I've mentioned that on the previous slide, virus-like particles or adenovirus vectors are very effective in producing vaccines. Next slide, please. Of course, there are challenges, and I mentioned several of them. I've listed here is not a complete exhaustive list, but I just wanted to highlight it here. Which genotypes strains to include. I think both vaccines in clinical trial are using, I think, the right approach for now. The GII.4 is important one. You would also like to protect against the genotype I virus, the GI. We don't know exactly the level of cross protection. We also are currently not completely sure about the frequency of updating the formulation of the vaccine, because we don't know exactly where the viral evolution of this virus will lead to. Is the virus able to protect against multiple genotypes? What about the role of prior infection history? Probably a pediatric vaccine, you probably will need to have multiple shots or a pill. If you're adult, you may be able to do with a single shot and get your protection higher up. Duration of protection, we think it's probably at least a couple of years, but again, there's not enough information on that particular level. I'd like to go to the final slides, and basically thank you for your attendance, and I will be happy to answer any questions that you may have. Thanks very much. Thank you, Jan. That's a great overview of the disease. We will have questions at the end, of course, at the end of the call. I'm going to turn over now to Sarah Bartsch to talk about the economic impact. Sara, I'll leave it to you. I'm gonna apologize, my dog is barking. I'm so sorry. We can have the occasional bark. That's fine. It never fails. I apologize. I'm Sarah M. Bartsch, and I'm going to be speaking about the potential impact of norovirus vaccine, specifically in the United States. If you could advance to the next slide, please. Quick overview. I wanna talk about the global burden of disease and then do a deeper dive into the burden in the United States, and then what this means for a vaccine. Next slide, please. We previously published a computational model to estimate the global burden of norovirus. This model estimated the economic burden for 233 countries and areas, stratified by WHO region and globally. We also looked at the cost to the healthcare system and societal, which includes productivity losses and direct medical costs, so it's the overall cost to society. Next slide, please. We found that globally, norovirus costs $60 billion each year, and that $23 billion actually occurred in the WHO region of the Americas. The graph on the right side here shows the estimated median cost per symptomatic norovirus case by WHO region. You can see that productivity losses, so people missing school and missing work, not able to perform their daily functions or have the same quality of life on a day when they're ill, represented 84%-99% of total costs, this varied by region. It's also important to note that the high income countries generated 62% of the global health system costs, despite having a similar incidence as low and middle income countries. Next slide, please. I wanna do a deeper dive into the burden specifically within the United States. In this study, we delineated norovirus's burden by different groups and different segments because understanding this burden helps to determine where we can target efforts to kind of reduce the burden of disease. Next slide. This slide summarizes the pathway for a particular norovirus case running through the model. At a high level, a person going through the model can be symptomatic or not. They can seek care, ambulatory care, be hospitalized. They could die. People can miss work or school for different durations, and every time something happens to a person within the model, they accrue costs and health effects. Next slide, please. The results from the model show that the cost per illness is actually higher for older adults. The graph here shows on the y-axis the different age groups, and the x-axis is the cost per symptomatic case. The total bar represents the total medical cost or total cost from societal perspective. The shades are the breakdown. It's the direct medical cost in orange, that's the cost of seeking healthcare, being hospitalized. Productivity losses are again missing your day-to-day. What we can see is that the cost composition varies by age. For example, 6.4% of total costs were direct medical costs for 18-44-year-olds. This increases for those who are older. They were 23.6% for those 65 years and older. On average, any given norovirus case within the US will result in $464 in total costs. Next slide, please. Each year, norovirus outbreaks cost a median of $173.5 million. These costs vary slightly each year depending on the number of outbreaks, cases, and outbreak settings. However, each year the cost due to outbreaks in long-term care facilities by far outweighed the cost of outbreaks in other settings combined. Productivity losses represented 95% of total outbreaks. Each of the plots here just show the different types of settings and how they vary by the different transmission modes, but I won't go into details. Next slide, please. This plot breaks down the total cost of norovirus in the community and how it varies with incidence. On the y-axis, we have the annual cost in $billions, and the x-axis is the incidence in the community reported per 1,000 cases. Each line represents a different type of cost, where the brown line is the direct medical costs and the three above it, represent productivity losses, assuming different types of mortality rates. In general, the take-home from this graph is that productivity losses represent 90%-91% of the total annual cost to society. They far outweigh direct medical costs. Next slide, please. The vast majority of norovirus's burden is actually from cases in the community. The community cases generated 90% to 99%, sorry, of the annual economic burden. This burden then pushes the total cost of norovirus into the billions. On the Y-axis here, again, we have total cost to society, and X-axis is again incidence in the community. The orange line shows the total cost of outbreaks, and the teal line is the community cases. The dashed line is the total for the entire period. Assuming the current incidence in the U.S. that Jan had mentioned, which is 6.89 per 100,000 or per 1,000, norovirus would actually cost $10.6 billion, with the community cases representing $10.4 billion annually. Next slide, please. If you can go back one. This slide just demonstrates how the burden is distributed across the United States. You can see that the cost per person is relatively similar across the regions. However, a substantial proportion of the burden resides in the South because that's where they have 49% of all the cases. The burden in the South reaches about $4 billion each year. Next slide. What does this mean for a vaccine? Understanding economics prior to licensure and development can help guide development of vaccines. It's important to understand the burden and the potential market for the vaccines. To this end, we did a review on the understanding of the economic burden and status of vaccine development for a lot of different diseases. While there is literature growing here, there's a lot of gaps. Next slide. As I mentioned, understanding these economics prior to licensure and development can help avoid a number of obstacles. These types of analyses can help develop target product profiles to help overcome these challenges before something reaches the market. For example, there's a lot of vaccines that have challenges. For example, the RotaShield was too big, didn't fit in supply chain. The LYMErix was a great vaccine, but it didn't have a clear target population. FluMist cost too much. These were more examples of push technology, where things were developed without really considering what the field needed. For vaccine development, we really need more of a pull technology, doing that research and building a product that actually fits what is needed. Therefore, we want to develop target product profiles that can help how the different vaccine characteristics, and they can have that complex impact on adoption and distribution can impact their challenges and avoid challenges post-licensure. Next slide, please. Vaccines and diseases reside in complex systems. Vaccines have different presentations and biological properties. You've got distribution that have different complex systems and how you get that out there, how you're administering vaccines. You have people that reside in complex systems. There's education, infrastructure, economics, all of these different things. It's very important to understand how all the different processes and mechanisms will connect together to make a vaccine that is going to be the most impactful. Mathematical and computational modeling can help us better understand and address these complex problems by representing all or most of these components and relationships and processes within the model. Next slide, please. To this end, we developed a computational model representing the different segments of the population, norovirus spread, and its clinical and economic outcomes to look at the potential value of vaccine, specifically vaccinating children under five due to their role in transmission and adults 65 years and older due to their high disease burden. Next slide. This is a high-level overview of the transmission and vaccination model. Essentially, there are seven different states that any given person in the population can be in on any given day. We represented vaccination, and that would actually impact a person's probability or chance of having and developing symptomatic infection. You can go to the next slide, please. Our model showed that vaccinating children under five could avert a relative 8%-72% of illnesses in the community, and vaccinating adults 65 years and older could avert 2%-29% of illnesses. This range averted depends on the coverage, which we varied from 10%-80%, as well as the efficacy of the vaccine varying from 25%-75%. For example, when vaccinating 10% of children under five, we could avert 3.7 million norovirus illnesses and 1,321 deaths in the US, assuming a vaccine efficacy of 50%. This further increases to 14.9 million illnesses and 2,600 deaths with an 80% coverage. Next slide, please. These figures map out the vaccination cost and coverage combinations at which vaccination is cost-effective and cost savings from the societal perspective. This includes all of the direct medical costs and productivity losses that a person can occur. On the Y-axis here you have the cost per vaccination. The X-axis is the vaccination coverage. Each of the shaded regions shows where the different combinations would be not cost-effective for the gray, cost-effective, which is the orange and the teal, and then cost savings, which is the green. The different panels show different vaccine efficacies with the 50% on the left and 75% on the right. What our modeling showed is that vaccinating children under 5 could be cost-effective for vaccination costs up to $1,600, and actually cost savings for vaccination costs up to $1,300. That is with a 10% coverage and a 75% efficacy. As you can see from these graphs, the cost thresholds increase with vaccine efficacy and they decrease with vaccination coverage. Again, these are from the societal perspective, and we found that the thresholds are lower from the third-party payer perspective. The vaccine can cost up to $325 to be cost-effective and $90 to be cost savings. There's a 50% vaccine efficacy from the third-party payer. Next slide, please. These show similar plots but for adults, older adults, and they could be cost-effective for vaccination costs up to $165, cost savings up to $100. As you can see, the thresholds are lower for vaccinating older adults. Thresholds are lower for lower efficacies and higher coverages. For example, the vaccine would be cost-effective up to $95 with a 50% efficacy and a 45% coverage. Next slide, please. In summary, each year noroviruses cost society $10.6 billion based on the current incidence. About 90% of those total costs are due to productivity losses. Most of these costs are due from cases in the community versus outbreaks. A vaccine could provide substantial health benefits. Even with a 25% efficacy, 10% coverage, vaccination could decrease symptomatic cases by a relative 7.7% and save at least $8,000. The vaccine could be cost-effective and even provide cost savings under many conditions. For example, it could be cost-effective up to $165 - $1,600, but that cost threshold varies with age since they depend on factors such as the cost per case, the norovirus risk, and how they transmit in the community. Thank you very much, and I apologize again for my dog. Sarah, thank you very much. I guess the dog had no comment, so it was a clear, comprehensive view of the economics, so thank you for that. Yes. Now we'll pass it over to Dr. Sean Tucker, our founder and our Chief Scientific Officer. Sean, take it away. Great. Thank you very much. Next slide. Sarah and Jan did a very good job about describing this norovirus indication. James and I are gonna tell you a little about the Vaxart solution. I wanna tell you that one of the things that we have been trying to develop at Vaxart is an oral vaccine platform. From the standpoint of going from one indication to the next or changing strains, having a platform is really critical. There has been some critical issues that we had to solve in terms of being able to create a vaccine platform. You know, replicating vaccines don't work very well all around the world. The protein you deliver to the intestine could be treated like food and preexisting immunity to your adenovirus or whatever vector you're using could hinder that. What we found is using a non-replicating vector delivered with a double-stranded RNA adjuvant and put in with through the intestine, avoids all the issues of preexisting immunity. It creates an antigen-specific response, and you don't get a response against the vector. This has really solved a lot of the issues that have happened with oral vaccines in trying to make platforms. Of course, we wanted to deliver into something that's very easy to use, and we have room temperature stable tablets. Next slide. Let me tell you a little bit about some of the advantages of actually having an oral vaccine. Obviously, if it's temperature stable, it could be shipped anywhere out the world without having a cold chain. It's self-administered, it could be rapidly deployed in a pandemic or stockpiled for that matter. James is gonna tell you a lot about the safety of this indication, but you know, certainly to date it's been well tolerated and there's no, of course, injection site, so there's definitely no pain. One of the key things about this is immunogenicity. Again, one of the things that we're doing is basically delivering something to mucosal surface, and we think that's gonna be very important. I'll explain that in the next few slides. Also what we've seen is we've seen durable serum responses in terms of our vaccines given to humans. Next slide. One of the key aspects of basically creating a mucosal vaccine is you get antibodies at a mucosal surface, and the most important of those isotypes is called IgA and particularly dimeric IgA. Let me explain a little bit more. When people are still asking, again, Jan had mentioned this before, is we don't really know what leads to protection against norovirus, certainly from the standpoint of challenge studies, giving people norovirus and asking questions about what their immunity looked like before the challenge or what happens during it. People have noticed that two different things have popped up on the IgA side of things. Rapid induction about mucosal IgA is correlated protection or in the serum IgA response. We do know from other indications that are oral, such as the oral polio vaccine, that creating what is called alpha-4 beta-7, basically mucosal homing IgA antigen specific B cells, was important from the standpoint of protecting against shedding in those studies. We also know, and one of the things that we were very attracted to, is the fact that the mucosal responses make these IgA antibodies. We do know that these seem to be, and literature says that these things could be much more cross-reactive. If there's strain variations, IgA is much able to tolerate these things because it doesn't just work by direct blocking the virus attaching to cell, that's called neutralization. It can work by immune exclusion. We do know that in head-to-head studies between IgG, this is the blood sort of antibody that happens or most common in the blood, versus monomeric IgA or it is dimeric IgA, that the dimeric IgA is much more neutralizing and potent, and it tends to be much more cross-reactive. Again, one of the things I want to point out is that people are used to telling you know, hey, you stick, you know, something in your arm, you pull out the blood, and that tells you out how your immune system is gonna misbehave against your pathogen. I'm gonna tell you that, you know, injected vaccines and mucosal vaccines can have completely different correlates of protection, and I'm gonna illustrate that in the next study. Next slide. A few years back, we did a study that was sponsored by BARDA and basically asked the question, how does your oral tablet vaccine this against flu compare to the market-leading injected vaccine called Fluzone? What we did is we gave either people or our oral tablets or injected with the commercial vaccine, waited 90 days, gave everybody flu, and just counted how many people got infected or sick. What we found is that both vaccines were able to protect against infection and actually did quite well compared to placebo. One of the things we found is that our vaccine had a different correlate. For the injected vaccine, making neutralizing antibody responses called HAI was very critical, and you need very high levels to get a good level of protection. What we found is if you made a mucosal homing B cell, antigen-specific, so against flu, of IgA class, and you made a few of those, that was equivalent to get the same sort of protection against Fluzone. I think that's really important, again, is that we create a mucosal vaccine, and the cells that home to the mucosa are very important for providing that protection. Next slide. The model essentially works like this. We deliver our oral tablet vaccine that is swallowed. It breaks up into the intestine. Our vaccine gets into the epithelial cells of the intestine. It makes that antigen that we're interested in. What happens is that creates, turns naive B cells into activated B cells. They differentiate. They have the mucosal homing marker, and a lot of them, alpha-4 beta-7, and they're of course IgA class. Again, B cells are the ones that actually provide the protection in the norovirus gastrointestinal tract, or at least we think this could be very critical. Again, those IgA B cells come to the mucosa, back to the mucosa. They secrete this IgA dimer, which can block the interaction of that virus or certainly exclude it from the epithelial layer. Next slide. Jan already talked about the fact that, you know, norovirus is generally a pretty simple, you know, vector. It has three open reading frames. Open reading frame number two essentially encodes the VP1, which is what leads to attachment to the carbohydrates. What we're doing is basically, in our vaccine, is we're expressing in a transgene this VP1 in order to create immune responses. Again, the idea is you block the ability of that virus to reach epithelial cells or in the intestine, get it immune excluded away from those surfaces. This is what our vaccine looks like. Next slide. Well, James is gonna tell you a lot about the details of the clinical path, but let me tell you a little thing that we found in terms of basically making immune responses that matter. You know, again, as I pointed out before, in many different oral vaccines or mucosal vaccines, making these alpha-4 beta-7 B cells are really critical from the standpoint of protection. What we found is that when we went from day one in humans, again, to looking at day seven, you could see a large number of these B cells, up to 27% of them basically were alpha-4 beta-7 marked. Again, most of those cells were of IgA class. Again, in norovirus, we think will lead to protection. Next slide. My summary is essentially we are developing an oral vaccine platform. Platforms are very attractive because you can move rapidly from one indication to the next. Obviously, there are several logistical advantages of giving out pills for vaccines rather than injection. A key benefit of this oral approach is that we are able to make a response at the wet surface, the mucosa, where norovirus invades. Platforms have been tricky to develop. We have solved some of the major technical issues by the way that we've constructed our vaccine. Again, one of the things I want to hallmark is that, you know, our vaccines may have a different correlate of protection. We think that mucosal homing, antigen-specific IgA B cells may be important for this indication, 'cause certainly they've been very important for other mucosal indications like oral poliovirus as well as our flu study. We are developing a norovirus vaccine that expresses the main surface protein VP1 in intestinal cells. As Jan Vinjé mentioned, we're using a bivalent approach in terms of our product. Both G1 and G2 are being addressed. With that, I will turn things over to James to talk about the clinical path. Thanks a lot, Sean. Hi, I'm James Cummings, and I'm the Chief Medical Officer here at Vaxart. Next slide. I'll just start by doing a quick review of all the studies we've completed specifically on norovirus. You can see there's quite a few. From this list, I'll hone in on our 101 study, our 103 study, and our 104 study, looking at both the GI.1 monovalent as well as GII.4 and GI.1, GII.4 bivalent vaccines. Next slide. This is our Phase I double-blind placebo-controlled 101 study, the first one off the books. What we are trying to do here is take a look at two different dosages of a monovalent vaccine of GI.1, a low and a high dose, comparing that to placebo in 66 healthy adult volunteers. Next slide. This vaccine trial is fairly important because it was our first foray into the human vaccine of norovirus, and what we found and demonstrated was that we had a dose-dependent response in the antigen specific IgG and IgA ASC responses, those responses that Sean highlighted just previously in his presentation. If you look on the left of this presentation, there's the low and high dose of IgG, and on the right is the low and the high dose of IgA. Those vaccines are in orange. The placebo is in black. Again, we see a dose-dependent response in both IgG and IgA of ASCs on day seven. Next slide. This is another look at the presentation of immune responses, but here we're looking at the mucosal immune response. What we're seeing is not necessarily a dose-dependent response early on, certainly looks like there is a little later, but looking at fecal IgAs, we show that we demonstrate a fecal IgA response with this vaccine, out, you know, quite a number of days in terms of the high dose, and low dose of that vaccine out to day 180. Now, a little later in this presentation, I'll go over, you know, another way to look at the mucosal immune responses that we're heralding in our current vaccine studies that are ongoing. Next slide. Sean went over a little bit about the plasmablast and mucosal homing B cells in his presentation. This, I think, is a very descriptive slide showing what happens when one is vaccinated with our vaccine and comparing that to what happens with natural infection, what happens after natural infection. You can see the plasmablast response is very similar. The mucosal homing B cells, very similar. Again, the IgA and IgG plasmablasts parallel each other, both on the top from our vaccine presentation, as well as looking what happens after natural infection. We feel we're on the right course here. Next slide. This is another way of looking at those plasmablasts, breaking them down specifically to IgA and IgG. If you'll look, the purple indicators are for vaccines and the light blues are for those of natural infection. You can see our IgA and IgG after vaccination might actually look a little bit better than they do for natural infection, but show a similar incline. Sean has already gone over some of, I think, the more similar data that suggests that these are important potentially in protection. Next slide. On the 103 study, and that's the second study on that large list I showed, we wanted to take a look at both monovalent demonstrations of our vaccine from a G1.1 and a G2.4 strain presentation. That's something Jan mentioned, that the G2.4 right now is the most prevalent in terms of causing disease annually. G1.1 is another strain that causes disease in, predominantly in humans. We want to take a look at what happens when we give these two vaccine strains together. We took a look at this in again, 25, 35 people in monovalence and then an additional 30 in bivalence, comparing that to placebo. Next slide. When we take a look at the IgA responses on day eight, I'll take a look at this chart. The placebos, again, on G1.1 and G2.4, they're fairly low, and you would expect that from receiving placebo. On the monovalent G1.1, the next section over, you'll see an increase in the G1.1 or orange, compared to the purple. In the monovalent G2.4, you'll see an increase in the purple compared to the orange. All right? That's because it's a GII.4 vaccine. In the bivalent vaccine, what we demonstrate is no interference. The responses for GI.1 and GII.4 are essentially equivalent to what we saw in a monovalent presentation. We've demonstrated no evidence of interference. That's important because we're looking at this point in this study at a bivalent vaccine. Next slide. Now to the 104 study. This is very intriguing as a vaccinologist. What we were very interested in, as Jan had mentioned, and Sarah, I think in her presentation of the targeted populations of interest, and we wanted to see how our vaccine would work in an older population. So we looked at low, medium, and high doses in subjects aged 55 to 80 years of age. This is giving, you know, dosages that are similar to what we've used in our younger population of 18 to 45. Next slide. Here we see on the left the IgA ASCs by age. We've opened them up so you can see there was no clumping of age grouping at one end or the other to the spectrum. 55 to 65 years of age grouping was very similar to the presentation of the 66 to 80-year-old groups in both the low, medium, and high doses of vaccine. Again, we're seeing a dose response. When you look over to the right-hand side of this slide, you'll notice that we remark on the one-on-one study that I previously described. That was in 18-49-year-olds, comparing that ASC response for IgA at day seven to those of the older population. Again, they're similar, same such responses. This is without increasing the antigen load, without adding some novel adjuvants, et cetera, without increasing dosage. We didn't see any evidence of immunosenescence in these populations. From a vaccinology standpoint, it's very intriguing, and I think that's one of the benefits of this platform. Next slide. We're looking at sustained serum IgA antibody responses. If you look on the left, we look at the fold change, and clearly, the high dose appears to be the winner, to the AU/mL, we look on the right-hand side. Again, we're seeing a sustained response greater than 200 days. Next slide. In this slide, we'll look at the IgG antibody responses. Again, we see the high dose, having the highest fold change. The AUs per mL may look like the medium dose is a little better, but it actually depends on the start point. I would say the fold change is really where to take a look at on this slide, the responses. Again, we've chosen that high dose. Next slide. BT 50, you know, BT 50, looking at how we maintain a response, that's going out, again, over 200 days. Again, by presentation, it would appear that the high dose gives the most robust response to BT 50 and again, a sustained response, out 210 days. Very encouraging. Next slide. You know, I mentioned briefly when we talked about the NVV-101 study, when we were first getting into this, looking at fecal IgA as a demonstration that we're having a mucosal immune response in the area of activity, which is in the gut. A fecal IgA is somewhat difficult testing to perform and, you know, something that's a bit easier to achieve but also very interesting, is giving an oral vaccine and then measuring a mucosal response on a different mucosal surface in the nose. What we're demonstrating here is that we have a nasal IgA response to G1.1 in the nose after giving an oral tablet vaccine that has impact on the gut. When we look at this demonstration, we're seeing a sustained response, and the best response is from the high dose. Next slide. That's where we were, and here's where we are and where we're going, right? Right now, we have a phase II double-blinded norovirus challenge. We have a phase II double-blinded dose confirmation study. Those studies are both in progress. I'll talk a little bit at the end about a phase I double-blinded study where we'll give products to lactating mothers who are breastfeeding, and a strategy that we feel could prove important in protecting some of our most vulnerable population. Next slide. For the norovirus challenge study, the mechanics are pretty straightforward. It's a placebo-controlled, so either you receive placebo or you receive vaccine. 28 days after being immunized, 29 days, we enroll you in a norovirus challenge where we've already performed a very clear titration study, knowing how much virus does it take to get a certain percentage of folks infected and symptomatic with acute gastroenteritis from norovirus. After you have those amounts known, you take your vaccinees and your placebo controls and enroll them in this challenge model, which is, again, very safe and well documented, to take a look at what is the infection rate and the acute gastroenteritis rate of folks placebo versus vaccinated subjects. Looking at viral shedding and looking at the immune parameters, potentially determining one that could be a correlative protection. Next slide. Our 202 study or our dose confirmation study is a phase II study looking at healthy adults and taking a look at two different dosages. Either a low dose, which is a total dose of 1e11. Two different doses or two different strains, 5e10 or a high dose, two different strains of 1e10, which is or to the 11, which ends up being 2e11 total dose, and comparing that to placebo controls. This, we are in the ongoing stages of this study. We're looking at the safety and the immunogenicity of the bivalent dosing of G1.1 and G2.4. As I mentioned on previous slides, our safety profile for the entire platform really has been fairly safe and well-tolerated. We're also trying to look at what dose would lead to safely proceed to a phase II study. We're looking at solicited adverse events, we're looking at unsolicited adverse events up to 28 days post dosage, as well as the immunologic endpoints that you can see there, both IgA, IgG, and then BT50 titers. Next slide. Finally, just to comment on our study, the 108 norovirus study, which is a study where we are testing our vaccine in moms, who are now lactating and breastfeeding their children. The idea in this, again, a very vulnerable segment of the population, is that we would immunize the mothers, that they might give their infants protection through their breast milk. We're looking at the presence of norovirus specific IgA in the breast milk, and then we're looking at the infant stools for presence of that same such norovirus specific IgA. That is planned to start this year, and more to follow on that particular study, but very excited as we look at our entrance into potentially covering a segment of the pediatric population. Next slide. Just to sort of recap some of the clinical highlights. What I've shown through the last several slides is that our norovirus vaccine induces a broad immune response, both from a mucosal standpoint as well as from a serum standpoint. The immune responses, the rates are above 90% for our high dose of our vaccine. These responses were durable, and they lasted over 200 days. The vaccine responses can be boosted after a year, and the bivalent vaccine showed no interference between the two strains. Immune responses that we induced in the elderly, aged 55 to 80 by definition for that study, were similar to those in young adults aged 18 to 49. As I mentioned, we have a relatively clean safety profile. It's been well-tolerated in all our clinical trials to date. With that, I think I'll turn it back to you, Brant. Thank you, James and Sean, for an excellent review. Now we'll have Andrei, our CEO, come in and talk about the market opportunity and disease burden. Andrei, I turn it over to you. Thank you, Brant. I think we're running a little bit behind. I'll try to be relatively quick here. What I would like to do is bring together what you've heard from our experts, our guest experts, as well as from my colleagues, Sean and James. Basically give you an overview of why we're so excited about the norovirus program as well as why we decided to recently prioritize this program. That's basically for two key reasons. One is clinical, and the other one is economics. We are developing an enterically delivered mucosal vaccine against an enteric mucosal infection. With norovirus, we've had six clinical trials enrolling almost 350 subjects. It's a pretty well-defined program already. What's encouraging here, in terms of what we see the probability of success here is that the immune responses across these trials, as my colleagues already touched on, have been strong, have been broad, both mucosal and serum, long-lasting, similar to natural infection and also similar in elderly and young adults. Equally important is the economic opportunity here that our experts touched on, which is, you know, $10 billion disease burden in the U.S. alone, $60 billion globally, a significant unmet need with no approved vaccine. As I'll cover shortly, our approach gives us the ability to maximize the value of this opportunity by using different pediatric and adult formulations. Next page, please. We've used this slide before showing the $10 billion disease burden. What I'd like to do now is give you a better sense of how this number, which may appear big, particularly as norovirus is not a widely understood or widely known disease. I'll try to give you a sense of how this opportunity can translate into a significant actual commercial opportunity for vaccine. We talked about the fact that there are over 20 million cases in the U.S. alone every year, and they have different severity levels up to including almost 1,000 deaths per year. The biggest portion of this market opportunity comes from the lost productivity. And that's due to 15% of kids under the age of five getting infected annually, as well as almost 8% of elderly. I'm not gonna go into detail into these numbers, but just wanted to read them quickly. The next slide, please. In order to be able to translate the opportunity into how it can impact the value of our program, it's important to note that norovirus affects, there are two segments affected by norovirus, kids under the age of 5 and older adults. About 20 million are kids and a lot more adult, elderly adults, sorry for that. The economics of each of these segments are very different. The price targets for kids under the age of 5 can be as high as $500. Per course versus $75 for elderly adults. What's similar though is that we believe that the prospect of ACIP recommendation is high in both segments. The penetration in both of them could be relatively high, and I'll cover that. The conclusion here is that 2/3 of the opportunity is in kids under the age of five and 1/3 in older adults. Okay. Now how do you translate this opportunity into actual commercial value, if you want? Well, let's start first with, you know, how difficult is it to access this target population. One of the nice things about norovirus is that the seasonality of norovirus is very, you know, is very similar to that of flu. What that means is that you could vaccinate against norovirus at the same time you vaccinate against flu. That's a huge advantage because you don't need to bring people in for vaccination just to give them a norovirus vaccine. You can vaccinate them at the same time they come to take the flu vaccine. What's also encouraging here is that the two key segments have very high vaccination rates against flu. Lots of these people come in to get their flu vaccines, and you could see how you could also vaccinate a lot of them at the same time with a norovirus vaccine. Next page, please. Another issue or potential issue that one could have is can people pay for this, right? As we covered before, we believe that there is a very high chance that a norovirus vaccine will get ACIP recommendation, particularly for the two important segments here, which are the kids under the age of five and adults over the age of 65. What does that mean? Well, that means that a lot of the vaccine for these two key populations is gonna be covered by government insurance programs. For kids under the age of five, that is Vaccine for Children, and we estimated about 60% of the vaccine will be covered by that. For those over the age of 65 is Medicare. In these two key segments, most people wouldn't need to worry about how they would pay for a norovirus vaccine, which is, again, something you wanna see. Next page, please. One thing that we wanted to do here is give you some reference points as to how other vaccines have done. Again, people look at norovirus, they haven't... You don't have a vaccine for norovirus, so it's difficult to benchmark, right? That's why we looked at other vaccines. One of them is the pneumococcal vaccine. Here, the pediatric population is one-fifth of the population for norovirus. Again, we are talking about here the segments that have received ACIP recommendations. Just 4 million kids for pneumococcal versus 20 for norovirus. The elderly populations are actually quite similar. For pneumococcal, that resulted in $3.7 billion of sales globally, $2.4 billion of which... 2.4, this is billion, not million. $2.4 billion in sales in the U.S. The ACIP recommendation on price is kind of in the same ballpark as those that we expect for norovirus. From this data point alone, you could see how you could believe that the norovirus sales should be significantly higher than those for pneumococcal, given that the key pediatric population is five times larger. Next page, please. Another interesting vaccine to look at is the rotavirus vaccine. This is just recommended for kids, 4 million annually. That's enough for $1.5 billion in sales globally and $700 million in the US. If you go to norovirus, the market for kids alone is five times larger. And actually the price that we believe you could target here with the pediatric vaccine is also two times bigger than that for rotavirus. You could be able to justify a 10 times larger market for norovirus vaccine than for a rotavirus vaccine. The next page, please. An interesting case is that of Zostavax, much more recent vaccine targeting the elderly population, those over the age of 65 in particular. This has generated $3.7 billion globally and $2.4 billion in the U.S., with a pricing of just above $200 million. Again, you can use this parallel to estimate the elderly opportunity here for norovirus that, you know, suggesting that that alone should be in the billions of dollars. Next page, please. Okay. An important aspect of our norovirus program is the fact that younger kids and infants don't take tablets. For older kids and adults, our formulation is the oral tablet that we've used in the other programs. However, for kids under the age of five. We are developing these micro tabs, which is something that you can put into a jam or other foods that they take because little kids, they don't take oral tablets. For even younger infants below the age of one or so, we are exploring vaccinating their mothers and immunizing the kids through their mother's milk. We've announced a co-funded study with the Gates Foundation previously, and that is expected to start this year. Next page. Why are these two formulations important from a commercial perspective? Because having two different formulations is almost like having two different products, so you can price differentiate for each of these segments, something you wouldn't be able to do with an injectable. This is very important for norovirus because the pharmacoeconomic value is much, much higher for the pediatric market than for the older adults. That's why the pediatric opportunity represents two-thirds of the total opportunity, even though the number of kids is actually one-third of the target population here. With our program, we'll have two different formulations, micro tabs for little kids and oral tablets for adults, and they will be priced differently, thus allowing us to maximize the overall economics of the program. Next page, please. Before we only talked about the categories here that we believe are gonna receive ACIP recommendation. I'd like to note that there are lots of other segments where we believe that norovirus vaccination could be very important that we haven't touched on and that add up to another 90 million people annually, right? This is, you know, in addition to the over $10 billion market opportunity that we've highlighted. Next page, please. In summary, our norovirus program is addressing a very large commercial opportunity with very compelling clinical data generated so far. We touched on all these points. Again, this is a $10 billion market, significant unmet need with no approved vaccine. I'd like to stop here for a second. I have a four-year-old daughter, the last thing I'd like her to do is to have to get another annual injected vaccine. We believe that even if there would be another norovirus vaccine, that's likely to be an injectable. In that case, we feel very comfortable that an oral tablet vaccine or an oral micro tablet vaccine would compete quite well in that situation. Again, right now there are no other approved, no approved norovirus vaccines. I think that's that concludes my section. Brant, I guess back to you. Excellent. Now we'll take questions. I believe we have them queued. Thank you. Ladies and gentlemen, we'll now start our question and answer session. If you'd like to ask a question via phone, please press star one on your telephone keypad. To remove yourself from the queue, press star two on your telephone keypad. To submit your questions via the webcast, simply type them in the ask a question field on your screen. Our first question comes from Charles Duncan with Cantor. Please state your question. Hey, yeah, hopefully you can hear me. Good afternoon. Andrei and team, great presentation today. Lots of information. I had a couple of questions probably for James with regard to the ongoing clinical studies. I guess with the double blind challenge study, I'm wondering, I think that was 201, the acute gastroenteritis rate, what efficacy would you look for in terms of response rate that you would think is interesting? Then is there any way to measure durability on that study? Because it seems to me that both response rate as well as durability could be really, you know, useful to achieving the target product profile that you're setting out with your vaccine. Thanks. Thanks for the question, Charles. It is a double blind challenge, so we won't know until we get to the end and unblind what we're actually looking at in terms of the response rate. I'd hope to see, you know, a decrease in acute gastroenteritis related to norovirus infection compared to placebo, somewhere around 40% ±. In terms of the durability of response, you know, we're taking a look at what the impact is on folks 28 days after they've been immunized, right? What we're also collecting on these folks is looking at immunomarkers to try and decipher what that correlative protection may be. I think that will be very helpful in determining a correlative protection when we look at some of our other studies that have longitudinal samples going out, you know, almost a year. I think that. Yeah. Part of that, durability of protection, would be extrapolated by a correlative immunity until we get to the phase III study. Okay. That's a great segue to the second question that I had, which is in terms of studies needed for licensure, I guess I'm wondering what could you anticipate in terms of sizing or timing for those next steps? Sure. I think, you know, it's whatever the FDA would like to see for here in the United States. Having some dialogues in an ongoing way with the agency, certainly after our challenge study, discussing, you know, the likelihood of a correlate protection being used as a surrogate. At the end of our phase II meeting with the FDA, which could be, you know, next year, we would look at getting feedback from the agency to determine what the size and shape of that phase III could be. I will say that, based on some interactions with the FDA in more general terms, having a correlative protection that can then be viewed as a surrogate of protection could go a long way in terms of compressing the timeframe of that phase III and decreasing the numbers dramatically. We'll have to wait and see to get official guidance from the agency. That's certainly the information that they've put out there in recent time. Okay. Very helpful. Charles. Thanks for taking the question. Yeah. Yeah. Charles. Yes, I'd like to add something to what James said. I know you understand this point, but a challenge study is much more aggressive than what you would see in the community, right? If you expect to see, let's say, 40% to 50% protection into a challenge study, that could easily translate into much higher levels of protection out there in the community, you know, 70%, 80%. We've seen examples of that. I just want people to understand that our expectations, if you wanna call them, though I don't know that we have expectations, again, we are blindly. What we see could happen in a challenge study is totally not what you'd expect to happen in nature, right? Challenge studies are really meant to allow you to study a smaller number of subjects, and you just bombard them with a lot of, lot more virus than they would be exposed to, naturally. Yeah, I get that. I mean, it's not only more aggressive, it's just like an acute efficacy, and you know that the patient was exposed or a person was exposed to the virus versus more of a population study, which is likely going to be needed. Correct. for the, registration, right? I can see other responses. Yeah. to that end, Charles, and to that end, it doesn't take a whole lot of virus to cause disease, right? I think the point, and Andre, if I'm, if I wasn't clear. Sure. Sure. I think the point of this is our challenge study is aggressive, right? Right. It's meant to be, so we get to the bottom of what the signal looks like. I don't wanna put the cart before the horse. I'll tell you what, we're paying for the whole seat, but we're only using the edge as we wait for the end of this challenge study to look at what the outcomes are. I think that gives us an indication of what that correlate of immunity could be, and then what we're going to see in our phase III. Hopefully, I was clear with that. Yeah. I assume that challenge study will read out sometime yet in the second half of this year. Yeah. We said third quarter. Okay. Then one last question, Andre. You caused me to have another one, and that is ex-US. It would seem to me to be a big problem here in the States. What about elsewhere? Would you seek a partner for ex-US development? Well, I think, first of all, ex-US, the opportunity is significant. A lot of that is in developed countries, so countries that are relatively easier to address by, you know, biopharma players. Look, we are a small biotech company. We think that a larger partner would be able to increase the value that we could create here, particularly ex-US, so obviously would consider ex-US partnerships. You know, as you may appreciate, Charles Duncan, one thing I think is important is there aren't that many mid to late stage vaccine assets, right? What we've seen at JP Morgan this year is that so many of the vaccine players like us focused on COVID for a couple of years or more. They ignored developing a pipeline. We actually started a norovirus program almost three years ago. But many companies, even larger than us, focused just on COVID. Now you have companies that have a commercial infrastructure, but they have no pipeline. The interest into an asset such as ours is quite significant. Maybe to that point, the oral vaccine platform you have tested in influenza and COVID, I guess your thought from a technical perspective, you believe that there may be broader utility of your approach in other infectious disease, correct? Yeah. Yes. I was saying. Yeah. We've shown that, and I'd like my colleagues to jump in if they feel like. We've shown that you can protect against flu with an oral pill, and now we hope to show that you can protect against norovirus. I don't know if that addresses your question. Yeah. Yeah. Got it. Thanks for taking the questions. Very informative presentation. I appreciate it. Okay. Thank you, Charles. Operator, next question comes. Thank you. Our next question comes from Roger Song with Jefferies. Please state your question. Great. Thanks for the very good kind of presentation from two KOLs and the company, thanks for taking the questions. A couple from us. The first one is maybe to the KOL. In terms of the virology and epidemiology, do you see the norovirus tend to mutate or generate new variants? The reason ask behind that is the company is saying maybe we can do annual vaccine like a flu, but we know flu is changing strain every year. What do you think about the, you know, potential annual virus vaccine for norovirus? What the composition of the virus, norovirus, will be in the vaccine? Thank you. Jan, I think that one is presented to you. Yes. I can address this question. I think we have seen the GII.4 over the last decade causing the majority of infections. Although a little bit further ago, we saw like a, like for flu, we saw occasionally after two or three years, a change in the GII.4, which is a new variant, compare that with Omicron or, you know, with SARS-CoV-2. We haven't seen that lately, that's the importance of what I presented, having these surveillance systems in place, not only in the U.S., but also see what's circulating in globally. I don't think an annual renewal is currently really necessary, but I think we need to make sure that we were very and we still very keen on seeing what was happening after COVID, because that is something that has never has occurred before. What does that do? We have seen some other viruses causing changes in seasonality. For example, RSV is a good example quite recently. Things are happening, and I think we were not back to kind of pre-COVID as far as for what we know, as far as for the prevalence of the different viral pathogens. Got it. Yeah, that's really helpful. In terms of the correlate, the potential correlate between the immune response and the efficacy for the oral norovirus vaccine, maybe KOL or Jan, you can give us some kind of your hypothesis or expectation, what kind of correlate you will expect to see from the oral vaccine? Maybe co-company can chime in as well, so, based on to date pre-clinical and the clinical data. Appreciate it. Jan, I think he wanted you to ask first about your prediction of correlate of efficacy for norovirus vaccine. I think you shared that on one of your slides. Yeah. I think it's still. I'm a little bit reluctant to get into too much hypotheticals. I think what we have seen in the different studies so far performed, that it is not completely clear where this correlate will end up. I think Sean made some interesting, and also James, as far as for where we think it is leading. I think the general consensus is exactly where Vaxart is currently looking at. I think one part that was not necessarily addressed, which I think is important, is the secretor status. Meaning that we know that most secretor positive individuals are susceptible to infection. That's in a Caucasian population is about 80%. I think a careful selection as far as for your study design of selecting those individuals that are secretor positives will at least prevent you from drawing maybe not completely correct conclusions as far as for these correlates. Got it. Do we wanna have Sean or James add on here as well? I, yeah, I think Jan, you know, gave us the, you know, what's going on in right now in the field. People are still trying to figure it out. I mean, you know, people have done challenge studies and looked for, you know, new markers and had some basis at least to have some suggestions of what happens. You know, we think that, of course, given the history of oral vaccines and mucosal, that we kind of know a little bit about what might be protective, and those are the kind of things we're looking at in the challenge study. Again, data will speak. You know, we'll have readout this year and, you know, we'll be able to say, "Yes, we have a correlate," or, "We can't find one because we're not measuring the right thing." My expectation is we'll find something, and we'll be able to use it. Thank you. Roger, back to you. Awesome. I think that's it from us. Appreciate it. Our next question comes from Mayank Mamtani with B. Riley Securities. Please state your question. Thanks for taking our questions and appreciate the level of detail here. Maybe just at the higher level first, I, you know, appreciate some of the analog markets, Andre, that you went through. In terms of focus on elderly and kids, it does look like pneumococcal vaccine market looks like a, you know, very nice analog where there are different products, you know, for different populations. Are there any parallels with development path, licensure also that, you know, any of these different analogs that you looked at kind of make sense? Are you able to comment on that? James, do you want to take this? I just, Mayank, hi. You know, what I showed there, as you appreciate, was strictly from a commercial perspective, just to show that look, vaccines that address mass markets just tend to be very big sells, right? That's a point that I think most of us familiar with the vaccine industry will find true. I'll let James speak to the development path for different segments. Fine. In terms of, for the taking a look at sort of two different to three different communities, and if this answers your question, super. Trying to protect those children who are on the one end of the spectrum, both to protect them from disease but also to protect the families from spreading that disease, I think is very important. As I've mentioned with our immunization strategy for lactating moms, protecting that far end of the spectrum, the most vulnerable, is very important to us. By taking a look at the other areas of the pediatric population, we would begin with looking at tableted versus our micro tablets that can be mixed in with applesauce or a slurry or something for children who can't take a tablet or a pill vaccine. This would be from ages seven or eight down to dose, de-escalating down to six months of age. That's a strategy to cover that particular portion of the population that becomes ill themselves, but certainly, serves as an amplifier of infection across the families. Looking at the older population, and I've already, I think, given some data from our 104 study, that's a very vulnerable population. It's interesting, the economic burden on that population is not just from the disease itself, but when someone has physiologically been in very precarious balance, it doesn't take much to tip that person over and have other comorbidities complicating their medical presentation and potentially adding a great deal of cost burden. Protecting that area of the population is very important to us as well, and that's another portion of the strategy. Lastly, looking at the space in between. Certainly, we've talked about the two major components, I think, of distribution for disease, both from a financial impact as well as a disease burden impact. When we look at healthcare workers, food service workers, daycare and long-term health facilities, hospital facilities, etc., I think there's applicability of this vaccine for people throughout the age spectrum. Again, I think that the areas of increased focus are towards either end. That's very helpful. Thank you. Then on the couple of quick technical questions. Sean, could you clarify, looking at IgA from a lens of alpha-4 beta-7 positive versus negative B cells? Also how this particular correlate might be unique to your platform, you know, relative to injectables, for instance. Then in terms of your challenge dose, that you're using in the ongoing monovalent study versus, you know, what you may consider for the bivalent challenge study in the future, do you have any sort of expectations that, you know, you'll stay at the same dose level for the virus that is being used for challenge? Or you may even look to be more aggressive? Thanks for taking our questions. Yeah. Let me first address the question about the alpha-4 beta-7 versus the non-alpha-4 beta-7. From the standpoint of our flu study, and again, this is a study we did in humans, we know that that alpha-4 beta-7 population was very important from the standpoint of, you know, you make the B cells, they need to get to the right place, and having those markers would get them to the right place. They go to the mucosa. We are pretty confident about that, and that was pretty clear in the flu study. Your second question was about the dose in the challenge study. I think, did you mean the challenge dose or did you mean the vaccine dose? Yeah, the challenge dose. Let me take that. Yeah, that's- Let me take that. I'll let James take that. You know, anytime we do a challenge study, we do a titration study beforehand to determine what the optimum infectious dose would be for that particular strain or lot of strain of virus for that particular disease. It would depend on what the titration study for a follow on challenge could be, right? And that's regardless of whether it's a bivalent immunization or a monovalent immunization. As we've shown, we don't show any interference within our strains of vaccine, it would just depend on what particular strain one might look at. Does that answer your question? That does. Thanks for taking our questions. Great. Thank you. I'll now hand the floor over to Brant Biehn to take some questions from our webcast audience. Yes, thanks very much. We are out of time, and I wanna thank the attendees very much. I'll grab a couple of questions here that are seem to be burning questions amongst a number of attendees, and then we'll close. The first one, Jan, this one's gonna come to you, and then I'll let Sean tag on after. The question is, why do you think there's currently no approved vaccine for norovirus? What has made this virus difficult to create a vaccine for, especially given what we had seen with COVID-19? Jan, you first. Yeah. Yeah, it's a good question. I think one of the key reasons that the research in the field on norovirus has moved relatively slowly compared to other viruses. Key of the reasons is we have not like a robust cell culture system. Unlike other viruses that you can grow easily in a cell culture, that is not... Possible. I think that's one of the main reasons that's. Then the virus-like particles became available, and I think we have seen with the human papillomavirus, that's a very safe vaccine. I think that's one of the reasons from, you know, if you think about where are we coming from, the discovery of the virus and how long it took to be able to get the right tools to study the virus, look at the genetic diversity. Of course, you cannot compare it with SARS-CoV-2 because the amount of funding that was available for that virus. Thanks, Jan. Sean, did you want to add? I would agree. I would agree with Jan Vinjé that certainly being able to culture the virus was a big problem. You know, obviously, you know, Jan Vinjé and other people have done some really good work lately about being able to culture. I also wanna point out that there's no good animal model, so you can't really replicate, you know, and explore things in a very rigorous manner before you get to humans. I think that's also been a big issue. Excellent. Thank you both. The next one, this will be mainly James, and then get Andrei potentially to add in after. Well, and you know what? Let's go to Sarah first, actually, 'cause Sarah's done a lot of work in this area. Sarah, given that the highest risk groups are primarily children and the elderly, is there a need for a vaccine for the rest of the population? I'll go Sarah first, then James. I think that is a good question. I think, as Andrei pointed out in his presentation and others have pointed out, there are other, key target populations and segments of the population that could benefit. You've got military, you've got travelers, healthcare workers, everyone is at risk for norovirus, so I think that it would be a matter of weighing their risk and the potential benefits of vaccinating them. I do think there are other potential target groups. Fantastic. James, do you wanna come in there or... I'm in lockstep with Sarah on that one. Clearly, we have the two largest portions of the population at both ends of the age spectrum, all of those food groups that Sarah already hit and have been covered, I think military, healthcare workers, long-term care facilities, food service workers, teachers, et cetera, daycare workers, these are all potentially targets of possibility for decreasing transmission of disease as well. Fantastic. I think we'll go to Sean with it first and then see if somebody else, anybody else wants to come in. Sean, the question is, how important is mucosal immunity to this specific virus? Sean. Well, we don't know for sure if it's gonna be absolutely fundamentally critical or, you know, or just important. I think the data would suggest that it could be very important. You know, again, we're doing this challenge study, and we'll figure out, you know, if there's a mucosal correlate. My expectation is that our vaccine will provide mucosal responses that will be protective. Fantastic. We are running out of time, and I apologize to everybody that we're gone over, but there are a few of these questions. I think the last one we'll do, James, probably this is mainly in the clinical area. It really is, the question is, what differentiates your oral pill norovirus candidate from the primary competitor? Of course, that's the HilleVax injectable vaccine. I'll hand that over to you, James. Well, I think first of all, it's that our vaccine is oral, right? There's none of the issues with logistics in terms of distributing this vaccine. There's no needle pain or etcetera, as Sean has mentioned, but also that it can be distributed far easily without the requirement of medical direct personnel in terms of pushing a plunger on a syringe. The medical waste is much smaller. I think there's a lot of logistical benefits to this particular vaccine. Also, looking at our vaccine demonstrating a mucosal response. I think Sean's already underscored what could be an important feature, and we'll see coming up. I think those are the two of the biggest pieces in terms of looking at our vaccine. Now, our vaccine, again, shows no interference. I can't say that for others in terms of cross-strain, delivery, doing a bivalent to our other approach. Those are, I think, the main discriminators of our approach to this particular problem. Excellent. Thank you so much. I really want to thank all of the attendees today for your patience and your focus and attention on our presentation. I especially want to thank Jan and Sarah for their incredible great job of telling us about the disease and the economic impact thereof, and of course, my team as well. Thank you all. I'll turn it back now to the operator. Thank you. With that, we conclude today's conference. All parties may disconnect. Have a great day.