Good morning, and welcome to the Gritstone bio Data Update. At this time, all attendees are in a listen-only mode. A question- and- answer session will follow the formal presentations. If you'd like to submit a question, you may do so by using the Q&A text box at the bottom of the webcast player or by emailing your questions to questions@lifesciadvisors.com. As a reminder, this call is being recorded and a replay will be made available on the Gritstone bio website following the conclusion of the event. I'd now like to turn the call over to Dr. Andrew Allen, Co-founder, President, and Chief Executive Officer of Gritstone bio. Please go ahead, Andrew. Thank you, Tara. Good morning, everybody. Welcome to our webinar this morning. We'll be giving you an update from our COVID-19 self-amplifying mRNA vaccine program, which we refer to as CORAL, and you'll be seeing some new data today. also giving an overview of self-amplifying mRNA or SAM, as I'll refer to it, and its potential differentiation from mRNA vaccines as applied to infectious disease vaccinology. Let's have the first slide, please. Of course, you're all aware we are a public company, and I'll be making some forward-looking statements. If we can advance the slides, please. Thank you. Forward-looking statements will be made, and our most recent public quarterly earnings are on file with the SEC from the second quarter. Next slide, please. Today's agenda. I'll give a brief overview and then I'll hand over to Karin, our Head of R&D, who'll describe self-amplifying mRNA in some detail, and again, illustrating points of potential differentiation from mRNA. We'll then have Professor Andy Ustianowski, PI of our CORAL-Boost study, describing new data from CORAL-Boost, and then Professor Shabir Madhi from South Africa, presenting new data from the CORAL-CEPI study, which is a large study in previously unvaccinated subjects. We've not been able to share data from this program publicly before, so this is the first time you'll see anything from CORAL-CEPI, and we're obviously very excited about that. It'll be our pleasure to invite Professor Larry Corey, who is a renowned figure in the field of vaccinology and virology, to set context for the data that you'll be seeing in advance and help us all understand how perhaps SAM may fit into the vaccine landscape. Let's move to some opening remarks. Next slide, please. As you're all aware, Gritstone has developed two synergistic platforms that we've applied now in two discrete therapeutic areas. First, infectious disease and then oncology. Can I have our next slide, please? Thank you. The first technology is identification of T cell targets. As many of you know, T cells are critical cells of the immune system that recognize not whole proteins, but short protein fragments or peptides displayed on the surface of target cells. They kill cells through recognition of those short peptide targets displayed by variable HLA molecules, which makes it rather complex to identify which fragments of an abnormal cell are going to be the actual T cell targets. This identification is key if you're thinking about vaccines, of course, and we developed the EDGE platform, a machine learning-based platform, to identify targets on the surface of abnormal cells, either tumor cells which have mutations or virally infected cells. This is technology number one. Of course, having identified the targets, you then need to administer them to humans in a potent vaccine vector. We've developed two different vectors. One is used to generate primarily CD8 T cells in the oncology business, and this is the use of an adenovirus. We also use SAM, self-amplifying mRNA, which is capable of generating T cells, but also very good antibody responses, and this is the platform that we've applied exclusively now to infectious diseases. You'll be seeing data today primarily on SAM. Before we turn to that, a moment on oncology. May I have the next slide, please. It's been a very busy week for neoantigens. As you know, Merck paid Moderna $250 million about 10 days ago to take up an option to the development of a personalized neoantigen vaccine in the context of adjuvant melanoma. More recently, Roche picked up an asset for KRAS-directed immunotherapy, somewhat analogous to our SLATE programs. Gritstone has itself recently published our phase I/II data from our first individualized neoantigen vaccine program, or GRANITE, and those data were published in the, in Nature Medicine in August. The focus, I think, is returning to neoantigens and of course, Gritstone is a leader in this field. Next slide, please. Within this field, we have two programs. We have the individualized program or GRANITE, as published in Nature Medicine, and we have key data coming later next year from this program. This is a randomized phase II data. We also have the off-the-shelf or SLATE program, which is currently focused on KRAS mutations, which is one of the commonest forms of shared neoantigen. Next slide, please. The specific study that we're running with GRANITE is a randomized phase II/III study that's been discussed with the FDA, and we're expecting preliminary data from the randomized phase II component, which is open label, around a year or so from now. This will be run in 80 subjects with a primary endpoint of molecular response or ctDNA decline. This is being run in patients with metastatic microsatellite stable colorectal cancer, and this is in newly diagnosed subjects or first-line patients. A much healthier population than we've studied here. The two where immune responses, of course, are expected to be stronger. Next slide, please. We're running this study because we've observed a clear signal in the phase I/II study in advanced disease of molecular response, meaning ctDNA decline, often mirrored by things like CA 19-9 or CEA decline in around half of the subjects treated, even in the advanced disease setting. Excitingly, those subjects who had molecular responses appear to have extended overall survival when compared to those who did not have molecular response. You see those data on this slide. In third-line colorectal cancer, where we've been treating patients with the two, median survival is six-seven months, and that's what we observe in the subjects who did not have molecular response. In those who were fortunate enough to have molecular response, meaning their ctDNA declined from baseline, you can see that overall survival appears to be meaningfully extended. The one death that you observed there, sadly, was in a patient who died from sepsis related to a tube change. This was not a cancer progression death. We've also seen a similar signal. Next slide, please. In the SLATE program, here we're looking at lung cancer subjects treated with our KRAS-specific neoantigen vaccine. Again, here, around 40% of subjects in very advanced disease. These are all patients who progressed on prior checkpoint inhibitor. You can see that molecular response was associated with an apparent extension of median overall survival. Again, you can see that these are very sick subjects we're treating. Those who do not have molecular response have a median survival of just over four months. Again, with active vaccines, it's clearly desirable to move to a fitter population who are gonna have more time to mount an active immune response to our vaccine. Oncology is obviously important to us. There's more to come. It's gonna be an exciting year next year. Let's turn to infectious disease, the topic of today. Next slide, please. I won't describe SAM in detail, that's Karin's job this morning. I will note that we were the first to put sam RNA and lipid nanoparticles into humans. And obviously we've gained quite a lot of experience about how to iterate and learn from human data to keep improving the vectors. And you'll see the fruits of those labors today. We have extensive experience now with INDs or their equivalent and different trials for seven different products in oncology and infectious disease across four continents. Next slide, please. It's important, of course, as we think about infectious disease, to have partners. We've demonstrated an ability to drive both pharmaceutical company partnerships with our Gilead partnership around HIV cure, and partnerships with some of the very important governmental entities that are key for the space of infectious disease. With SARS-CoV-2, we've forged relationships with CEPI, with the NIH, the Gates Foundation, and we have a collaboration with the La Jolla Institute for Immunology. Beyond SARS-CoV-2, we've got relationships with Gates Foundation again for human papillomavirus and a very interesting therapeutic vaccine concept, and some research efforts in the preclinical space around influenza with some academic centers. Next slide, please. Our overall pipeline, of course, therefore spans both infectious disease and oncology. We won't be talking about the oncology piece today. In infectious disease. Can I have the next slide, please? You'll see that we have the CORAL program, and you'll be hearing more about that today. Of course, we won't be talking about any of our other infectious disease assets today. The HIV program, as many of you know, is not our news to share. That obviously belongs to Gilead. That study is in phase I. Finally, as we're gonna focus on COVID today, that's where these data come from. I think it's notable that Professor Peter Marks, Head of CBER, next slide, please, had some comments made in the last few days with regards to vaccines against COVID. Obviously he's reacting to the data that we're all seeing. Professor Corey will address these today. Peter Marks is concerned, obviously, about the reliance upon the first generation vaccines, which appear to be providing limited clinical protection. Can we keep moving the slides forward, please? Can we fix this? This is very slow slide advance. Thank you. As you can see, the remarks from Dr. Marks here, I'll draw your attention to the middle one. We need to look at other types of vaccines. There are those out there that might provide more durable immunity. As Karin will cover, durable and variant-proof immunity remain key unmet needs in the COVID space. Of course, that's also true beyond COVID in spaces like influenza. This is where SAM may have an important role to play. Finally, next slide, please. The focus today will be on two of the studies in our CORAL program. Today, we'll not be talking about the CORAL-NIH study that's being sponsored and run by the NIH, and obviously they'll release those data in due course. Today we'll be focusing on CORAL-BOOST, a boost study in subjects previously vaccinated, and on CORAL-CEPI, which is in vaccine-naïve subjects. That's our agenda for today, and let me now have great pleasure handing over to my long-term colleague and friend, Karin Jooss, who's our Head of R&D, who will describe to you SAM. Karin, over to you. Thank you very much, Andrew, and good morning, everyone. My name is Karin Jooss, and I'm Head of R&D at Gritstone, and I will be giving a short introduction into self-amplifying RNA and its use as a novel vaccine platform. Next slide, please. I will be making forward-looking statements. Next slide, please. In Nature Medicine, Professor Dan Barouch describes the importance of antibodies and T cells in disease. The adaptive immunity includes two complementary arms of the immune system, the humoral and the cellular immunity. Humoral immunity to SARS-CoV-2 includes antibodies that bind to the spike protein and neutralizes the incoming virus. Whereas cellular immunity includes CD8 T cells, which provide long-term immunological memory and directly eliminate virally infected cells. For acute viral infections, including SARS-CoV-2, it is likely that neutralizing antibodies are critical for blocking acquisition of infection. Whereas a combination of humoral and cellular immune responses most likely controls viral replication after the infection occurs and prevents progression to severe disease, hospitalization, and death. In the context of waning neutralizing antibodies or emergence of new variants of concerns that largely escape neutralization, cellular immunity may be particularly important for long-term protection against severe disease. Next slide, please. Shown here is a schematic of the role of neutralizing antibodies and T cells during a viral infection. As I just mentioned, incoming virus on the left-hand side is being neutralized by neutralizing antibodies. In the context of waning antibodies, free virus can infect epithelial cells of the lung, and once the virus is inside those cells, it is not accessible to these neutralizing antibodies, and in the absence of T cells, starts replicating and spreading, leading to severe disease, shown on the left graph. However, in the presence of CD8 T cells, which are the second pillar of defense, the T cells will recognize and eliminate virally infected cells, controlling virus spread and severity of disease. Next slide, please. A key unmet needs for vaccines against respiratory virus are durable immunity and breadth involving both arms of the immune system, as I just mentioned. Currently, neutralizing antibodies wane quickly within several months post-vaccination with the mRNA SARS-CoV-2 vaccines requiring frequent boost vaccinations. In future, we would like to try durable immunity that enable less frequent boost, likely annually or even less frequent. Concerning the breadth, approved SARS-CoV-2 vaccines focus on the spike antigen only which leads to immune escape with some variants of concern that mutate in the regions where the neutralizing antibodies bind. Driving broad humoral and cellular immunity to spike and highly conserved viral sequences outside of spike are anticipated to provide broad protection against emerging variants of concern. Next slide, please. This figure from the review article by Professor Barouch shows the COVID-19 breakthrough rates from April 2021 to May 2022 for persons who received the Pfizer-Moderna mRNA vaccines in the U.S., and data taken from the Centers for Disease Control and Prevention, the CDC, and the graph clearly demonstrates that vaccine effectiveness wanes over time against emerging variants of concerns, most notably in January 2022 with the emergence of the Omicron virus. Next slide, please. A cornerstone solution to current vaccine limitations for the infectious disease is the samRNA vaccine platform, which replicates post-vaccination, thereby leading to long-term antigen expression, driving durable immunity, and is potentially therefore dose sparing, as well as the chimeric antigen cassette delivering Spike, as well as highly conserved viral gene sequences outside of Spike to drive broad humoral and cellular immunity. Next slide, please. Shown here are the basic structure of RNA-based vaccines. In the center, the RNA, which can be conventional, circular, or self-amplifying RNA, is the core of the vaccine that delivers the antigens of interest. Surrounding the RNA, the delivery vehicle consists of lipid nanoparticles, which is used to formulate the RNA core and highly essential for cellular uptake and release of the RNA within the cells from the endosomes. Next slide, please. Comparing mRNA and self-amplifying RNA. mRNA, once released within the cells, start expressing antigen of interest. The injected amount of mRNA is actually the maximum vaccine dose the personal patient receives. In contrast, samRNA, once released within the cell, starts replicating, expressing large quantities of the antigen within the cell, and the extended antigen expression is believed to drive the durable cellular and humoral immune responses of high magnitude. samRNA, therefore, offers potential dose-sparing opportunity for an infectious disease vaccine. Next slide, please. The structure. Here's the side-by-side structure of samRNA and mRNA vaccines. The basic structure looks similar with its cap, UTRs, which are the hairpin loops, and the antigen cassette. samRNA, in addition, contains a replicase complex here in blue, which is the motor of this vaccine platform, driving amplification of the RNA, as I just described a minute ago. Next slide, please. Shown here is the durability of antigen expression from a mRNA vaccine platform expressing luciferase in mice. Antigen expression increases from day two to day seven due to the replication most likely, and remains positive for several weeks. In contrast, the half-life of mRNA vaccines has been described to be around 18 - 22 hours, so distinctly different from antigen expression duration. Next slide, please. As Professor Ustianowski will describe in more detail in a minute, we do find highly durable neutralizing antibody titers in our subjects in our CORAL-BOOST study in the U.K. with one mRNA boost vaccination post the primary series of ChAdOx1, as shown here in the right graph, which compares favorably to the neutralizing antibody kinetics observed with the mRNA-based vaccines, as shown on the left. Next slide, please. As mentioned before, Gritstone uses here on the right-hand side, highly conserved gene sequences from viral genes in addition to cell surface antigens as, for example, Spike, to generate chimeric antigen cassettes and drive broad humoral and cellular immune responses. Next slide, please. This is an example of how we define and select T cell epitopes within nucleocapsid. The predicted epitopes selected by our proprietary neural network are in blue and validated T cell epitopes from Alex Sette's work, for which we have a license, as shown in green. We select sequences with epitope hotspots to generate our chimeric vaccine cassettes, including full-length Spike. Next slide, please. These are examples of chimeric immunogen cassettes from our COVID vaccine work at Gritstone delivering full-length Spike. One of these constructs or vaccines also has full-length nucleocapsid, and the TCEs are the T cell epitope hotspots that we select from highly conserved viral genes. Next slide, please. Besides observing durable neutralizing antibody responses in our CORAL-BOOST study, we are also measuring durable T cell responses up to day 180 post the samRNA boost vaccination against Spike here on the left-hand side, and then the T cell epitope sequences on the right-hand side. Next slide, please. Gritstone's versatile mRNA vaccine can be administered either as separate vaccines, as shown here on the very left, co-injected, which means we injected in one syringe, as shown in the middle, or as a co-formulation of multiple vaccines, here shown on the right, to drive broad immune responses, for example, for a pan-respiratory vaccine approach. Next slide, please. In summary, the same RNA vaccine platform is designed to tackle the challenges of the first-generation infectious disease vaccines. Long-term antigen expression is most likely driving the durable immune responses currently observed in our early clinical studies. With this, I would like to pass the microphone to Professor Ustianowski, who is our investigator leading the CORAL-Boost study, and he will describe the initial data from the CORAL-Boost study, ongoing in the U.K. Thank you very much for your attention. Data on the CORAL-BOOST GO-009 study, looking at a self-amplifying mRNA as a vaccine against SARS-CoV-2 in adults. I'm Andy Ustianowski. I'm a consultant in infectious diseases and a clinical researcher based in Manchester in the U.K., and chief investigator on this study, but I've had other roles. I've been the national clinical lead in the U.K. for our COVID vaccine research program. This is the vaccine, and importantly, it contains two elements. It contains the spike protein, and the particular strain chosen is the Wuhan or the original wild type strain of virus. But there's also the TCE5 segment. This is T cell epitopes against non-spike proteins, ORF3a, nucleocapsid, and membrane protein. This is the design of the study. There are several cohorts. I want to focus first on cohort one and cohort two. Both were healthy adults over the age of 60 who'd been primed with the Oxford-AstraZeneca vaccine at least four months prior to enrollment. The difference between the two cohorts is 10 mcgs or 30 mcgs of the samRNA vaccine. These particular individuals could then receive an optional second dose of samRNA vaccine. We have Cohorts 3, and we have Cohorts 4. These individuals received 10 mcg and then a repeat dose 28 days later on. The difference between the two is some of them were primed beforehand with the adenovirus vector vaccines and others with the mRNA vaccine. The immunology data is from the first dosing in Cohorts 1 and 2. The reactogenicity and safety data is the entirety of Cohorts 1, 2, 3, and 4. This is the demographics. You can see the duration between the last dose of the primary series and the first dose of SAM was around six months in most groups. The ages are shown, as well as the female percentage, which varies, but the numbers are quite small. The BMI was fairly standard, and we have positive anti-N specific serology mentioned here. This is a marker of natural infection or natural exposure to SARS-CoV-2. It was an exclusion criteria for Cohorts 1 and 2, but people were allowed into Cohorts 3 and 4 if they had no symptoms consistent with SARS-CoV-2 for 112 days prior to enrollment. Let's start off with the safety and reactogenicity. On the left, you can see the local adverse events, and on the right, the systemic adverse events. Each pair of columns on the left is 10 mcgs, and on the right is the 30-mcg dosing. The first thing to say is these adverse events, rates, and severities are consistent with what we'd expect with such a vaccination. I would say numerically, it does appear that the 30-mcg dose gives you slightly more severe solicited local adverse events and perhaps numerically more systemic adverse events. The question, though, is: What about the second dose? Do people get more or less reactogenicity on the second dose? This data shows that individuals got less severe reactogenicity on their second dosing. Now, let's look at the immunology data. If we look at the 10 mcg dosing, if we look at the panel on the left, we can see that day one, prior to their SAM dosing, their neutralizing antibodies against the wild type variant were actually very low. There was a very significant boosting within 29 days of receiving the SAM vaccine. Though we have to be careful about cross-study comparisons, on the right-hand side, it's shown a similar group of individuals from the COV-BOOST study and the impact of having a booster with the two different commercially available mRNA vaccines. If anything, it's comparable. That's against the wild type variant. What about the other variants? Well, the panel on the left is exactly what I've shown you on the previous slide. If we think about Beta, Delta, and Omicron variants, however, we can see the other panels. The first point is that prior to receiving SAM, the large proportion of individuals had no significant neutralizing antibodies against these variants. After the SAM dosing, at day 29, all of them had a very significant incremental increase in their neutralizing antibody responses. Neutralizing antibodies aren't the only assay we can do in terms of antibodies. We can look at total binding antibodies. Antibodies work in other ways, not just by neutralizing. Here we see the data on that total IgG against spike. For wild type, Beta, Delta, and Omicron, we can see a significant increment between predosing and 29 days post-dosing. What about the two different doses, the 10 mcg versus the 30 mcg? Well, here we've got data about total binding antibodies at the top and neutralizing antibodies at the bottom. To me, and I hope to you, the levels are comparable between the dosings. Taking that into account with the slightly increased reactogenicity shown with the 30 mcg dose, the 10 mcg dose was pursued in the further cohorts in this particular study. Now, a really important factor is the persistence of these antibodies, and we're used to seeing the antibody levels drop over the period of weeks to months after vaccination and after boosting. If you remember the previous slides I showed, which was after AstraZeneca/Oxford priming, a lot of individuals had negligible significant neutralizing antibodies against some of the variants of concern. In our study post-SAM, however, you can see persistence of these neutralizing antibody levels up until at least day 180. If we break it down to total IgG or neutralizing antibodies against the different variants, you can see the same pattern that these serological responses are persistent over the 180 days. What about T cell responses? We have the T cell epitopes. If we look at spike first on the left-hand side. T cell responses against spike were present at baseline in this study, but people had been vaccinated with the AstraZeneca vaccine, which contains spike. I hope you can see that there was a boosting of this T cell response against spike that actually increased over the period of 180 days. If we look at the non-spike epitopes and proteins that were included, while most individuals would not have been exposed to them in the past, and therefore this is almost a priming. Again, we can see significant increases in the level of the T cell responses, particularly at the 180 day. Those T cell responses were against all the constituents of this vaccine, nucleocapsid, membrane, and ORF3a. In this slide, we're looking at the breadth of the spike and the TCE specific T-cell responses in these adults over 60. If we look at the pie charts on the right, the first one is at baseline, the middle one at day eight, and the right-hand one at day 29. Spike at the top, the other T-cell epitopes at the bottom. I hope you can see an increase in the darker blue and purple colors, which implies that over time, over the eight days and over the 29 days, there's been an increase in the breadth of the T-cell response against these particular epitopes. In conclusion, this is the first clinical trial to assess the safety and immunogenicity of a SAM SARS-CoV-2 vaccine candidate in healthy adults over the age of 60. Both the 10-mcg and 30-mcg doses of SAM had a good safety profile and were well tolerated, with only mild and moderate solicited adverse events. I didn't show the data, but these adverse events were very transient in nature. Both neutralizing and binding IgG spike antibodies were substantially boosted. The neutralizing antibodies translated across the variants of concern studied and importantly, were persistent up to the 180-day stage. This particular vaccine boosted and broadened the spike-specific T cell responses and also primed the T cell responses to the non-spike viral epitopes included in the vaccine. I'd like to thank the clinical trial participants and their families, the investigational sites, and Gritstone bio. Thank you. Great. Thank you, Andy. That was very helpful. Now I'd like to invite Professor Shabir Madhi, who's Dean of the Faculty of Health Sciences and Professor of Vaccinology at the University of the Witwatersrand in Johannesburg, South Africa, also a member of the WHO Strategic Advisory Group of Experts on Immunization, to present data from the CORAL-CEPI study. Thank you. Hi. Good day. My name is Shabir Madhi. I'm from the University of the Witwatersrand in Johannesburg, South Africa. I'm going to be presenting provisional results of a phase I study which evaluated the self-amplifying RNA COVID-19 vaccine, which contains the spike protein as well as other protein peptides of SARS-CoV-2. The objective of the study was to evaluate the safety and tolerability of three different constructs in healthy individuals that had not been previously vaccinated, with and without HIV, as well as stratified based on whether those individuals had previously been infected through the virus as a confirmed infection or based on anti-N IgG seropositivity at baseline, or individuals that were anti-N IgG seronegative at baseline. This study is funded by Gritstone, and the formulation has been produced by Gritstone, in addition to which my institution has received other grants, related to COVID-19 and other vaccine trials from other companies. What I'm going to present are data related to one of the three constructs, that are currently under investigation. The population, as I mentioned, in whom these, vaccines were evaluated, were those individuals that had not been vaccinated, that were presumed to be SARS-CoV-2 naïve based on anti-N IgG seronegativity, and individuals that were considered to be convalescent, either based on a past infection at least six months or greater before enrollment into the study, or who tested to be anti-N IgG seropositive. What I'm going to do in this presentation is summarize the safety results and immunogenicity results, which are provisional results at this point in time. The three constructs under investigation include two constructs that includes the genome of the Beta variant spike protein and one construct that includes the genome of the Omicron variant spike. In addition to which each of these constructs include either the full length nucleocapsid or parts of the nucleocapsid, as well as parts of other peptides of the reading frame three, the membrane protein, non-structural protein genes. What I'm focusing on is the initial construct that has now been evaluated, where enrollment has been completed, which includes a Beta variant spike protein genome, and as I mentioned, peptides of other proteins of SARS-CoV-2. The rationale for including multiple additional peptides over and above only the spike protein in this particular vaccine formulation is based on the appreciation that the nucleocapsid, for one as an example, is highly expressed in infected cells. In addition to which, based on experience with SARS-CoV, what has been shown is that T cell responses to the nucleocapsid are long-lasting for up to 17 years. In addition to which, based on household transmission studies, what has been shown is individuals that showed T cell activity to the nucleocapsid were less likely to be infected with the virus when there was an introduction of the virus into that household compared with individuals that did not have T cell responses to the nucleocapsid. In those individuals, in all likelihood, those T cell responses to the nucleocapsid were based on previous infection due to endemic coronaviruses. In addition to which, what has also been observed over the past 2.5 years is the relative conservation of the genome of the nucleocapsid, coding for the nucleocapsid protein, compared even when there are mutations occurring with the spike protein genome. Other evidence and rationale for including multiple T multiple additional epitopes is the recognition that up to 50% of CD8 responses in individuals that have recovered from COVID-19 are specific to the ORF3a as well as the nucleocapsid, as well as the ORF1a and ORF1b non-structural proteins and the membrane epitopes also induce TCR responses. The T cell responses in individuals that have recovered from COVID-19 have also been found to be longer-lasting than IgG responses. I'm going to focus on the first part of the study, which basically evaluated the Beta variant construct together with peptides of other proteins. As I mentioned, in this particular part of the study, individuals were stratified into naïve group and a convalescent group. The naïve group received two doses of three different dosing concentrations, 3 mcg, 10 mcg, or 20 mcg. Those doses were given 28 days apart. The convalescent group, and those were individuals that were anti-N IgG seropositive with a past history of SARS-CoV-2, received a single dose of vaccine. The enrollment into the study was restricted to individuals between 18 and 65 years of age. The median age across the study was around about 27 years. As shown here, not unexpectedly, none of the SARS-CoV-2 naïve group were anti-N IgG seropositive. There were some individuals in the convalescent group that were anti-N IgG seronegative, but those individuals that were previously documented to have had COVID-19 and hence included in the study. Looking at systemic and local, solicited, adverse events, what we observe is that reactogenicity was the lowest in the lowest dosing concentration at 3 mcg. There were slight differences between the 3 mcg, 10 mcg and 30 mcg group in terms of, solicited adverse events, and in particular in relation to induration being more common in the 30 mcg group, as well as malaise being more common in the 30 mcg group. When looking at the 10 mcg group in the immunogenicity and reactogenicity data after the first dose of vaccine, the percentage of individuals reporting adverse events is probably first very similar compared to what is observed with messenger RNA vaccines that are currently in use. After the second dose of vaccine, again, a very similar profile of rate of reactogenicity, especially for the 3 and the 10 mcg group. However, this time around, the 30 mcg group demonstrated significantly higher rates of local as well as systemic reactogenicity compared to either the 3 mcg or the 10 mcg group. Looking at those individuals that were stratified into the convalescent arm, for both local as well as systemic, solicited adverse events, a very similar sort of picture as what we observed. After the first dose of vaccine in those individuals that were considered to be naïve, we had reactogenicity in the 10 mcg group was in a ballpark of what has been observed for messenger RNA vaccines, whereas for the 30 mcg group, there was a trend towards higher adverse events compared to either the 10 mcg or the 3 mcg group. There were three grade three adverse events that were documented both in the naïve group as well as the convalescent group. Two in those that received a 30 mcg formulation and one in those that received a 10 mcg formulation. All of those grade three adverse events resolved within a 72-hour period. Now I'm going to touch on briefly on the immune responses to the vaccine, and in particular I'll be touching on the IgG responses to the wild type spike protein as well as live virus-neutralizing antibody responses, both to the Beta variant and the Delta variant. The T cell responses at this stage, unfortunately, those assays are still ongoing, so those results are unavailable yet. Look, when looking at the group that were considered to be SARS-CoV-2 naïve, what we observed first and foremost is that these individuals stratified into two groups. After having done a baseline serology, we observed that up to about two-thirds of these individuals that were considered to be SARS-CoV-2 naïve had probably been previously infected despite testing anti-N IgG seronegative, and those individuals are shown in the orange dots. Individuals that were anti-N as well as anti-S IgG seronegative are shown in the blue dots. What we observe across the three groups, and now just looking at immune responses after the first dose of vaccine, is that the 30 mcg group induced the highest magnitude of change fold increase, compared to the other two groups. At this stage, what we also observe is that data is unavailable for day 57 for the 30 mcg group because those samples are still being tested. When looking at immune responses after a second dose of vaccine now, what we observe is that immune responses in those individuals that received a 10 mcg group is higher compared to immune responses in those individuals that received a 3 mcg dosing. That higher antibody titers to the spike protein was evident across both the anti-N as well as anti-N IgG seropositive, as well as the anti-N IgG seronegative groups. The 10 mcg group, especially after the second dose of vaccine, appeared to be more immunogenic compared with the 3 mcg group. Looking at the neutralizing antibody responses to the Beta variant, and again, just to emphasize that the formulation that I'm currently presenting data on includes the Beta variant spike protein genome in addition to epitopes of other peptides of SARS-CoV-2. What we observed after the first dose of vaccine, similar to what we saw for anti-N IgG anti-S IgG responses, was the highest immune response was in the group that received a 30 mcg formulation after the first dose, compared with either the 3 mcg or the 10 mcg group. After the second dose of vaccine and now a restricted analysis to the 3 mcg and the 10 mcg group, what we observed is a similar pattern to what I just showed you for anti-S IgG responses, is that both in those that were anti-N IgG negative as well as those with the anti-N IgG seropositive at baseline, immune responses in the 10 mcg group was higher compared with utilizing antibody responses observed in those individuals that received a 3 mcg. In addition to inducing neutralizing antibody against the Beta variant, what was also observed for this particular construct that includes the genome of the Beta variant spike, as well as additional peptides of other proteins of SARS-CoV-2, was an increase in neutralizing antibody to the Delta variant. After the first dose of vaccine, what we observed, similar to what I had previously described, was that the 30 mcg group induced a high GMT increase in neutralizing antibody against the Delta variant, compared with either the 3 mcg or the 10 mcg group. In addition to which, similar to what was observed for the Beta variant, neutralizing antibody responses against the Delta variant was higher after the second dose in those individuals that received a 10 mcg formulation compared to those individuals that had received the 3 mcg formulation. Moving on to that group of individuals that were considered convalescent, and those, as I mentioned, were individuals that received a single dose of vaccine that had tested anti-N IgG seropositive or had past documented history of COVID-19. What we observe, once again, is that, immune responses, as measured by anti-S IgG were induced after a single dose of vaccine, both for the 3 mcg, the 10 mcg, and the 30 mcg group. However, interestingly, what the 30 mcg group itself, those changes compared with baseline, were not that, marked. What we also observe, at least for the 3 mcg group, is that although they only received a single dose of vaccine, those GMTs, persisted, through to day 57, whilst there was a slight decrease, of about 40% in individuals that had received a 10 mcg formulation. Again, those 95% confidence intervals overlap, and these are provisional data. Looking at neutralizing antibody responses that were induced in these convalescent participants after a single dose of vaccine, what we observe across all three different dosing formulations is that a single dose of vaccine resulted in about a three- to four-fold increase in neutralizing antibody responses against the Beta variant. Looking at the 3 mcg group, again, what we see is persistence of those neutralizing antibodies through to day 57 after having received a single dose of vaccine, with slight decrease in the 10 mcg formulation group. Looking at a single dose of vaccine in convalescent individuals in relation to neutralizing antibody responses for the Delta variant. Again, a single dose of this particular vaccine formulation resulted in an increase in neutralizing antibody responses against the Delta variant by day 29. Those titers were maintained through to day 57, both in the 3 mcg group as well as the 10 mcg group. In conclusion, we believe this is the first report of a self-amplifying RNA COVID-19 vaccine, and in this particular formulation, it includes the genome of the spike of the Beta variant spike protein, as well as multiple additional epitopes of other proteins of SARS-CoV-2. Our findings were that all three dosing formulations were well-tolerated in individuals that were anti-N IgG seronegative. The majority of adverse events that were solicited were mild to moderate. Reactogenicity was slightly increased in those individuals that received a 30 mcg dosing formulation compared with those that received either a 3 mcg or a 10 mcg formulation. All of the adverse events, including the grade three events, are resolved within a 72-hour period. All 3 dosing concentration levels were immunogenic across all of the cohorts. What we found essentially is that although the 30 mcg group induced higher antibody responses, including neutralizing antibody responses in either a 3 mcg or a 10 mcg group after the first dose of vaccine, when looking at immune responses after the second dose of vaccine for which data weren't available for the 30 mcg group, what we showed was that the 10 mcg group had higher neutralizing antibody responses as well as anti-S IgG responses compared to individuals that had received two doses of the 3 mcg formulation. The vaccine also induced neutralizing antibody responses not only against the Beta variant, but also against the Delta variant in those individuals that were anti-N IgG seronegative, as well as in the convalescent group. What is still pending are data in terms of the durability of the neutralizing antibody responses beyond day 57, as well as neutralizing antibody responses against the Omicron variant, and importantly, the TCR responses that have been induced by these vaccines. In conclusion, I'd like to thank the clinical trial participants and their families for their participation in the study, the investigational sites, the site investigators, study coordinators, nursing staff, and other site staff, and also Gladstone and their staff for support in the study. Thank you for your attention. Great. Thank you, Shabir. Now you've heard about the basics of SAM from Karin. You've heard clinical data from around 150 subjects, both young and old, as a boost and as a de novo vaccine. Now to help put all of this into context, it's my pleasure to invite Professor Larry Corey, who's President and Director Emeritus of the Fred Hutch, also a professor in the Vaccine and Infectious Disease Division, to put some color around what you've heard and around the current COVID-19 pandemic and state of play as it were. Larry, over to you. Thank you. Thanks, Andrew. Let's have the first slide, the next slide, first data slide. Just to give you an overview, I think we're gonna spend a fair amount of time in this short talk talking about where the COVID-19 pandemic is. It certainly entered a new phase, but it's continuing to generate substantial morbidity in our country and throughout the world. Likely we will still continue to see antigenic change, which are more challenging to manage and certainly uncertainty and risk remains. It is clear we don't have an ideal vaccine. It certainly got us out of the wilderness. It's markedly, it could save millions of lives. At the moment, the virus has escaped us substantially, and boosting is required, and a durable boost to the widely prevalent kind of hybrid immunity in SARS-CoV-2, and to protect against novel variants is, you know, desirable. Now, that boost could include self-amplifying mRNA. There's talk about mucosal vaccines. There are protein nanoparticles. There's even some novel viral vectors that are out there. There's no question that using chimeric immunogens that include whole proteins or conserved T-cell epitopes to try and offer and broaden the immune response, both the T-cell and potentially antibody response has been discussed. Expanding the vaccine assessment framework to include T cells is likely to be an important step forward. CD8 T-cell immunity can prevent severe disease. Evidence of probably that is out of the J&J vaccine, the ChAdOx vaccine, very different hemagglutinin responses, but T-cell responses suggesting that T-cell epitopes can protect against severe disease, and T-cell epitopes certainly can arise from conserved regions of the viral genome. There is proof of concept that if you do this with SARS-CoV-2, it opens the door to novel vaccines against other important high mutation viral pathogens such as influenza and even HIV, which has the highest genetic variation of any virus on the planet. Next slide. These are very up-to-date data from the United States of sort of new PCR cases reported to the CDC since April. Really, you see that, yes, since the first Omicron wave, it has gone down. This is a severe underestimate because we're not capturing home antigen testing. Whether you multiply this by four or eight is sort of debatable here with respect to the number of daily cases. Next slide. What you have here is more accurate data, which is, the yellow line is in the right-hand y-axis is hospitalizations, which are still averaging over 3,000 a day in the United States. Deaths, which are the red line, which are still around 350-380 per day, which is really still very substantive and significantly greater than anything we would ever see in an influenza outbreak. Next slide. The variants that are circulating in the United States are essentially 99.9%, labeled with Omicron. Having said that doesn't mean there's a lot of similarity. In fact, there's continuing to be antigenic variation in the virus. There are a lot of different Omicron variants, and you can. You know, so they're starting to emerge here on this graph. The red, the dark green, the mustard yellow are sort of increased. BA.5 is the predominant one, and you sort of start seeing this genetic diversity of variants. Essentially all of them are Omicron, and seeing as that there's no latent reservoir, you would look at the fact that where their new variants will come from will be, you know, with just a high degree of certainty, even if they're from immunocompromised patients with long-standing persistent, we've essentially had an Omicron only epidemic for many months in the country since essentially January, February of this year. Next slide. Regionally, you see the, you know, again, this variation of BA.4 or BA.5 being the predominant strains, but increasingly you see the heterogeneity in these wheel diagrams of different Omicron variants. Next slide. You're seeing the same thing in Europe. There have been sort of an increase in new cases. Next slide. In some countries in Europe, we're starting to see increase in hospitalizations. Lots of travel between the United States and Europe, and lots of cross-fertilization as it relates to Omicron variants. Next slide. This slide actually is in the left-hand panel where you sort of see the red to orange and the mustard green. Those are the sort of rising, what we call, replication threshold times of the new Omicron variants, BQ.1, BA.2.75.2 are the ones that are most illustrated here, and the variants of BA.2.75. Sort of seeing that these new variants are increasing their threshold and BA.5 is sort of decreasing in its replication threshold. These are data from my colleague at the Hutch, Trevor Bedford. Next slide. One way to think about this is to not think necessarily about the names, but to actually look at what are the mutations, what we call convergent evolution, that's occurring. By grouping these mutations, we're sort of starting to see this, these overlapping Venn diagrams. These mutations are increasing resistance. There are mutations at select areas that are essentially requiring higher rates of neutralization, escape from neutralization. We are seeing this in starting to lose some of the monoclonal antibodies. Probably one of the most concerning is Evusheld. To start looking at this as just sort of, without naming things, looking at the percent of virions that are developing escape mutations, that are going to affect both vaccination and the therapies that we currently have, as directed by neutralization. Next slide. The current reality is that while we have created vaccines, monoclonal antibodies, and antiviral drugs, COVID-19 is still with us. It's still causing medical, economic, and psychosocial havoc. While mRNA vaccines have given us a remarkable benefit in abrogating the huge death rate and morbidity of the epidemic, COVID-19 has not at all gone away. Excess mortality in the U.S. is at 350 potentially preventable deaths a day. That's 125,000 deaths yearly, which is 4 x what is seen in a severe influenza season. The virus is still evolving. It's evolving at a pace we have not seen on a population level. It's still evolving at a reasonably rapid pace. You're still seeing these persistent outbreaks. Current mRNA vaccines, while still providing benefit from hospitalization and death, we're seeing an erosion in these effects in select populations, especially the elderly. I'll show you those data. Especially those without recent boosting, and even when you get the boosting, it is transient in effect. You know, when we first started out on the vaccine trail, when we initially did these trials, symptomatic disease was 95%. It went to 70% in Delta. It's now down to 50% as we move from ancestral strains to Delta to Omicron variants. There's reduced durability of asymptomatic efficacy. There's essentially no protection against acquisition, and there's increased severity of breakthrough infection as measured by ER visits for COVID-19. Next slide. This is really illustrated, and this was recently in the MMWR. This slide is actually from the ACIP, and really what you see is, when you look at ED visits, and this is the VISION Network, so a lot of people in the Kaiser Permanente programs, going to the ER means that you're sick enough to come to the ER, and you're sort of seeing vaccine efficacy in real-world effectiveness really dropping down even with greater than 120 days after three doses to 33%. Four doses improves it, but it's back down to 50% after two months with the fourth dose of ancestral strain and increasing hospitalizations. Next slide. We still have a problem with the elderly. This is from a MMWR in August looking at weekly COVID-19-associated hospitalizations, again from the surveillance network. This sort of big peak panel is the initial Omicron wave. The second panel is the BA.2 wave. You still see that the elderly, especially those over 85 and even high rates in 75, are still having high rates of hospitalization. Next slide. Again, these are data from both South Africa and the United States, really just illustrating the point made of the sort of loss of durability in Omicron to hospitalization. In this study on the right-hand panel, which is from South Africa with looking at Pfizer vaccine and during the Omicron early outbreaks in South Africa, where Omicron was first came, hospitalization protection was essentially at 50%. In ancestral strains, it was 85%-90%. Next slide. The implications of this is that investment in second-generation vaccines and monoclonal antibodies are needed to solve two major issues, prevention of infection on a population basis and durability of protection on an illness hospitalization basis. I would say to you, these to me are engineering issues and not basic biological obstacles that require novel scientific concepts. The current scientific technologies exist to, I think, solve the above issues, as some of which you heard earlier in the presentation. Next slide. One approach to improving RNA durability is with samRNA. As has been outlined, they deliver small amounts of antigen-coded RNA in an LNP. It leads to strong, durable antigen expression, driving superior antibody responses. The intermediates activate a broader set of innate sensors, and appear to prime for a superior CD8 T response. Novel immunogen design allows one, in addition to spike, to generate greater T cell responses that conserve viral epitopes. It offers a flexibility of synthetic design that can be utilized for essentially a wide variety of other vaccines, potentially that require improved immunotherapy. I think that's our last slide. Next slide. Yep. Thank you, Larry. Yep. I think that's back to me. Just to wrap up. Thank you so much for that. And just in conclusion, I won't repeat everything you've just heard, but obviously we have the SAM platform that's now got clinical flesh on its bone. We've shown you some proof of concept data for immunogenicity and tolerability through the prism of COVID-19. And obviously, Gritstone is uniquely positioned here as a pioneer in the field of SAM. With that, we'll bring the formal presentations to an end, and I'd like to thank our speakers and invite any questions, and I'm handing over to Tara, our moderator, to bring our analysts into some Q&A. Thank you, Tara. Great. Thank you, Andrew. At this time, we'll be conducting a Q&A session with our speakers. To our analysts, we kindly ask that you limit your questions to one. Our first question comes from Eva Privitera from Cowen. Please go ahead, Eva. Hi. Congrats on the data, and thank you for taking our questions. My question is a pretty broad one. Can you talk about how CORAL validates the EDGE platform, specifically for other infectious diseases? And how is this CORAL data translatable? How can we think about that? Sure. I think Karin, maybe you could handle EDGE. Yes. Thanks. Good question. I think the best example is our first construct that we are using in the CORAL-Boost study in the U.K., which contains TCE5, which contains sequences from ORF3a, membrane, and nucleocapsid. At the time, the design of TCE5 was exclusively based on our EDGE prediction. It was in the early days of COVID. No one had found T cell responses or knew what they were directed against in convalescent subjects. So it was via an applied EDGE. We designed TCE5. As the pandemic then progressed, and especially Alex Sette's work on identifying T cell epitopes in convalescent samples, many of the EDGE predicted epitopes actually drove T cell responses in convalescent individuals. I think as the pandemic progressed and we learned more about the T cell targets in convalescent individuals, that was for me the most beautiful validation of our EDGE prediction platform. Thanks, Karin. In answer to your second question about generalizability, obviously these insights can be shared across viruses. There is no major substantive difference in the biology of antigen processing and presentation. The sequences, of course, will change between viruses, but the biology is relatively similar. We've adapted EDGE for use against viruses. We refer to that, unsurprisingly, as viral EDGE. It can then be stretched across into other pathogen spaces. Indeed, the work we're doing with the Gates Foundation is looking at a potential therapeutic HPV vaccine. One of the first questions there is, what are the relevant targets for a therapeutic response? They're clearly going to be different from the antigens contained within something like Gardasil, which of course is about prophylaxis. The bridging across the use of EDGE is sort of inherent to all of the programs that we're now running, where we're designing chimeric immunogens. Usually the B cell target, the antibody target is well understood. It's the T cell targets that take some work. Thanks for the question, Eva. Back to you, Tara. Thank you, Eva. Our next question comes from Kaveri Pohlman from BTIG. Please go ahead, Kaveri. Yeah, good morning. Thanks for taking my question and congrats on the progress. Based on the boost study data, any insight into what you expect the repeat dosing interval would be for these SAM vaccines? In other words, what kind of durability are you expecting? Are there any learnings from preclinical studies? Do you provide any details here? Karin, do you wanna take that? I'm not sure we know. The simple answer is I think we don't know, but Karin, maybe you have super clear insights. Yeah. The simple answer is we don't know. We see the durability in mice. We see the durability now in humans. Interestingly, we moved SAM together with the chimpanzee adenoviral vector into clinic in our oncology studies six years ago in the early days of Gritstone, and at the time, you know, we designed the study with monthly boosts. We followed the T cell response in these cancer patients, and we realized that the T cells are really durable, and then we come back with a boost vaccination at the peak of the T cell response, and then we relaxed it to two months. Now, we learn from the ongoing study here in the COVID space that the durability lasts up to six months. Also during the pandemic, some of our patients, oncology patients missed vaccines, but we followed the T cell response. Again, the T cells persisted for months in these individuals who missed their vaccine and didn't really get any intervening therapy. We know it's durable, but we don't know if, you know, it requires annual boosts or even less frequent. That's to be determined, and the data will be coming in. Yeah. Larry, perhaps do you have any perspectives on what your expectations might be for durability and requirement for reboosting with SAM? I don't. I think we need another data point to really calculate a good curve, but the stability is looking optimistic. Very good. Thank you. Thanks for the question, Kaveri. Thanks, Kaveri. Our next question comes from Sean Lee from H.C. Wainwright. Please go ahead, Sean. Good morning, guys, and thanks for taking my questions. One question is, would you still have the longer term data from the CORAL Study? With that activity data that we'll be able to show to the market? Yeah, we'll have obviously longer-term data, 12-month data early in the new year. We'll be looking for the right forum to share those data. That'll be the 12-month data initially from the boost study, and of course, then we'll get data out of the South Africa CEPI study as well at 12 months. As we all recognize, I think those obviously are important data, but merely having flat antibodies out to six months, of course, represents a significant change from where we sit with first generation programs. Of course, it'll be very interesting to see what we see at 12 months. It'll be early in the new year. Great. Thanks. Great. Thanks for your question, Sean. Tara? Thank you, Sean. Our next question comes from Corinne Jenkins from Goldman Sachs. Please go ahead, Corinne. You're on mute, Corinne. You're on mute. Thought I clicked the button. You've outlined a few, but what infectious disease indications do you think are most appropriate given the relative strengths of the sam RNA technology, and perhaps which of those do you think have the greatest unmet need as you think about potential future directions for this program? Thanks, Corinne. Perfect question for you, Larry, I think. Well, I think there's lots of need in respiratory viruses. Obviously better flu vaccines are needed both for durability as well as efficacy. The parainfluenza viruses, the human metapneumoviruses, which you know there appears to be you know some breakthroughs in RSV. You can debate whether that you know as we see you know vaccines move forward. All the herpes viruses are open with respect to CMV prevention, HSV prevention, EBV prevention. The Zika virus is likely to come back with global warming. You know, there's a plethora of vaccine-preventable diseases which technologies have been created that should move this field, make these infectious diseases vaccine preventable. Very good. Thank you. Thanks, Larry. Thank you for the question, Corinne. Just take one question that came in from Yuan Zhi at B. Riley asking about the scientific rationale for the durable antibody response. I think Karin touched on this. The working hypothesis relates to antigen persistence within the lymphoid compartment and this notion that's emerging of slow priming, whereby you can give antigen vaccinations on multiple days as a way of delivering antigen on a more continuous basis. You don't want it there permanently. That obviously can induce a state of exhaustion. But having antigen present for multiple days as opposed to a day or two may be sufficient to actually help drive that superior durability of immune response. I think Karin touched on that in her presentation, but thanks for the question, Yuan. Okay. Tara, I think with that we are done. We will now wrap up the session. Thank you very much for your attention this Tuesday morning. Wish you all a wonderful day, and thanks for your interest in Gritstone. We'll look forward to our next update. Thank you to our speakers as well. Thanks, Larry.