Welcome to the GSK event. I will hand you over to Jeff McLaughlin to introduce today's call. Jeff, please go ahead. Good afternoon and good morning. Welcome to GSK's Investor Science event, Getting Ahead of RSV Disease in Older Adults. I'm Jeff McLaughlin from the GSK IR team, and your moderator for today's call. We are here today for an update from the IDWeek 2022 conference on GSK's vaccine portfolio, of which the highlight is the pivotal phase III data on our vaccine candidate for the prevention of RSV in older adults. As usual, the presentation materials are available on gsk.com and were sent to our distribution list earlier today. Please also note that the data presented on today's call are available on the IDWeek website and have been submitted for publication in a peer-reviewed scientific journal. Moving to slide two, I wanna remind you all of the usual cautionary statement regarding forward-looking statements. On slide three, we are joined today by Dr. Tony Wood, Chief Scientific Officer, Dr. Phil Dormitzer, Global Head of Vaccines R&D, Roger Connor, President of Vaccines and Global Health, and Luke Miels, Chief Commercial Officer. We are also delighted to welcome Dr. Michael Ison, Professor of Medicine and Surgery at Northwestern Medicine. Dr. Ison is the lead investigator for the 006 phase III trial of GSK's RSV vaccine candidate in older adults, and presented the detailed results of this important study yesterday at the IDWeek conference. Moving to slide four, shows our agenda for today's call, which we anticipate will last around 75 minutes. We will try to ensure we take as many other questions as possible in the Q&A session, and in that spirit, would ask that you limit yourself to one question. You can always jump back in the queue if you have additional questions. As a reminder, questions can be asked via telephone by using star one. Before I hand over to today's presenters, I'd like to remind you that the call is being recorded and that a replay and transcript will be available after the event. With that, I will now hand over to Tony. Thank you, Jeff, and hello, everyone. I'm Tony Wood, and it's a pleasure to be here with you on today's call. Please turn to slide six. This is my first Investor Science event as Chief Scientific Officer of GSK, and it's also the company's first event of this type since the demerger of Haleon in July. I hope you'll forgive me for setting out a quick reminder that GSK is a global biopharma company with the ambition and purpose to unite science, technology, and talent to get ahead of disease together. Our R&D efforts remain focused on the science of the immune system, human genetics, and advanced technologies, with an emphasis on developing novel specialty medicines and vaccines. Please turn to slide seven. As Roger will discuss later, GSK has a long history of developing innovation in vaccines, stretching back many decades. The groundbreaking data presented at IDWeek continues this tradition of innovation and excellence. The pivotal phase III data on our novel RSV vaccine candidate in older adults demonstrates, we believe, a best-in-class profile. It's important to recognize the significance of these data as the industry's been trying unsuccessfully to develop an effective vaccine for more than 60 years. This represents the first clear demonstration to reduce the risk from this serious disease. In addition to pivotal data, you will hear tomorrow the results of a key study in which our RSV vaccine candidate was co-administered with an influenza vaccine in older adults. It's important in this population to be able to safely co-administer vaccines, flu and RSV. There are clear attractions in doing so when addressing two of the most serious respiratory pathogens in terms of disease burden. I'd also like to highlight the latest data on our herpes zoster vaccine, Shingrix. This is again completely groundbreaking. Shows that the duration of protection against shingles can extend to 10 years. With efficacy approaching 90% at this time point, this is tremendous news for people affected by shingles and its devastating effects, and also sets a new gold standard, which we believe will be incredibly difficult to match. Please turn to slide 8. There is no doubt that the pivotal results are a key highlight for our vaccines R&D organization in 2022. However, I do want to draw your attention to the strong progress GSK is making elsewhere in strengthening its vaccines and pipeline capabilities. We accomplished several important regulatory approvals, an advanced number of novel vaccines, including our mRNA candidates for influenza and COVID, and a therapeutic vaccine candidate against herpes simplex. We also expect the late-stage readout from our pentavalent meningococcal vaccine candidate before the end of the year. Last but not least, we recently added to our platform capabilities as well as our pneumococcal vaccine pipeline through the acquisition of Affinivax. The novel disruptive MAPS technology we acquired will allow us to pursue higher valency vaccines than is possible with conventional conjugation technologies. This, in turn, enables us to investigate vaccine candidates with broader serotype coverage, which may significantly improve the potential for pneumococcal and other bacterial vaccines. Please turn to slide nine. Looking more broadly at the successful execution of our RSV program in older adults, I truly believe this is a testimony to the unique capabilities we possess within GSK and the synergies from our focus on vaccines and specialty medicines. No other biopharma company replicates our dedicated approach towards the science of the immune system for the prevention and treatment of disease, our leadership in infectious diseases, our one capital allocation approach and one development organization, and our incredible suite of platform technologies. As a consequence, and Phil will expand on this point, we are able to select the right candidate and the right technology, leveraging our expertise in adjuvants for older adults from our Shingrix heritage. Having the right candidate alone is not enough in a competitive environment, of course. Here, our excellence in clinical trial design and execution meant we are not just the first company to recruit patients into our phase III study, but also our team accurately modeled RSV prevalence and anticipated infection rates, which informed our recruitment strategy. The design and execution of the clinical trial program set the positive results observed during this interim analysis. I am exceptionally proud of what our vaccines R&D organization has achieved in the battle against this serious viral pathogen and would now like to hand over to Phil to provide more details on how we designed and executed this program. Phil, over to you. Thank you, Tony. It's a pleasure to be on today's call. Please turn to slide 11. RSV is a very common contagious virus that causes respiratory disease. It's one of the highest value remaining unmet medical needs in infectious diseases. The risk of exposure to RSV is universal. We experience repeated infections through life. In developed countries, RSV is associated with about 420,000 hospitalizations, 29,000 deaths per year, and close to half of those arise in those 65 and older in the United States. Older adults and those with underlying health conditions such as cardiovascular disease, respiratory disease, and diabetes are at particularly high risk for severe disease. The consequence of this is a substantial clinical and economic burden on which Roger Connor will speak later. The last and critical point is that natural immunity wanes, which is behind the reinfections that occur throughout life. Please turn to slide 12. GSK is fortunate to possess the broadest suite of vaccine platform technologies available, and this allows us to select the right approach to develop the best vaccine for each pathogen be it a virus or bacterium. There are three key platform technologies among the large number that we have at our disposal. The first is subunits with or without adjuvant. Our adjuvant portfolio is a particular area of strength for GSK. Among the adjuvants, AS01, the adjuvant used in Shingrix, is being applied in a number of our pipeline assets. AS01 induces a more robust immune response. We believe it compensates for immune senescence, the waning of immunity with age, and potentially allows increased efficacy. A second key platform is mRNA, where we're pursuing both, advances within our collaboration with CureVac and are increasing internal RNA capabilities. Most recently, as Tony referred to, is our MAPS technology, MAPS standing for Multiple Antigen Presentation System, which is particularly useful for bacteria with key carbohydrate antigens. The MAPS technology allows for a more highly multivalent approach to a complex pathogen that have multiple serotypes. Now, RSV, we selected a protein with adjuvant approach, particularly to deliver high efficacy in older adults in the presence of immune senescence. Please turn to slide 13. How did we, GSK, go about designing an effective vaccine after 60 years or more of unsuccessful attempts by the industry? Well, the vaccine candidate was intended to overcome the challenges of protecting against RSV in vulnerable older adults. It combines the RSV pre-fusion F3 surface antigen with a proven AS01 Adjuvant. Key to this was a scientific breakthrough from NIH when the pre-fusion structure of RSV was determined and techniques were found to engineer the protein to stabilize it in the pre-fusion conformation. In fact, what was learned is that much of the frustration of the previous 60 years was from the fact that the protein switched to an ineffective post-fusion form. Knowing the structure, it could be stabilized in the pre-fusion form, which is much more effective at eliciting neutralizing antibodies. The inclusion of AS01 was also key as this has been proven to be very effective adjuvant for another vaccine for older adults. This approach is unique, and the combination has delivered exceptional efficacy. Please turn to slide 14. This slide sets out the accelerated clinical program for RSV, the RSV vaccine candidate in older adults at greatest risk. The candidate entered the clinic in January 2019, started a phase III program in February 2021, and reported positive headline results from the pivotal 006 study in June 2022. This is a little over three years, and during that time, over 29,000 participants were involved in the studies. This pace is remarkable and speaks to the excellence in clinical trial design and execution that Tony referred to. It's especially impressive given that the pivotal trial took place against the backdrop of the COVID-19 pandemic. There are three phase III clinical studies included in the regulatory package. The pivotal 006 efficacy study from which positive headline results were announced for a prespecified interim analysis will continue to examine the benefits of annual revaccination over three seasons, and in addition to looking at annual revaccination, will also look at the consequence of the single immunization as observed over those multiple seasons. The 004 study primarily examined safety, reactogenicity, and immunogenicity. The 007 study examined whether RSV vaccine candidate could be safely co-administered with a quadrivalent influenza vaccine. Those results will be presented tomorrow at IDWeek, and this is particularly relevant when you consider the typical seasonal overlap for RSV and influenza viruses and the practical considerations of administering vaccines against both these illnesses in the fall. The pivotal 006 study is obviously the main study for today's call, and it's my pleasure to hand over to our guest speaker, Dr. Ison, Principal Investigator of the 006 study, to discuss the results in detail. Please turn to slide 15. Thank you, Phil. It's a great honor to share some of these results with you today, as I did yesterday in a standing room only room. Starting with slide 16, which shows you the clinical trial design of this study. The study was designed to enroll about 25,000 individuals that would be randomized in a 1:1 fashion to receive a single dose of the RSVPreF3 OA vaccine, and follow them up over the following flu season. Blood was drawn at day 31 to assess immunologic response. The study is ongoing into the subsequent two RSV seasons. This year, patients will be randomized again to receive either a booster dose of the vaccine or placebo to really assess the need for secondary or boostering in subsequent seasons. The primary endpoint of this study was vaccine efficacy of a single dose of the vaccine in preventing RSV lower respiratory tract disease in adults greater than 60 years of age during the first RSV season. The criteria for success was to have a lower limit of the two-sided confidence interval for vaccine efficacy greater than 20%. In addition to the primary endpoint, there were a number of other secondary endpoints, including the vaccine efficacy against severe respiratory RSV lower respiratory tract disease, RSV-specific ARI, acute respiratory illness, and then these primary and secondary endpoints in certain subgroups, including the protection against both RSV A and RSV B, protection in various age ordinals, protection in those patients with various baseline comorbidity and frailty status, as well as key safety and reactogenicity endpoints. Moving on to slide 17. This is a graphical representation of the enrolled patient population. To orient you, the blue is the patients who received vaccine. Gray is the population that received placebo. As you can see across all measures, the populations were well-balanced across the treatment and placebo group. We did have relatively low proportions of patients, 8.2% in both arms, that were greater than 80% and a relatively small percentage of patients, about 1.5%, that were frail on enrollment. On the next slide 18, you can see the results of our current estimate for our primary endpoint, RSV lower respiratory tract disease. The vaccine efficacy is estimated to be 82.6% overall, with seven cases of breakthrough infection in the vaccine arm and 40 cases of breakthrough infection in the placebo arm. Going on to slide 19, you can see our other key secondary endpoints that there was significant protection against RSV acute respiratory infection, with an estimate of 71.7%, as well as a significant protection against severe RSV lower respiratory tract disease with an estimated vaccine efficacy of 94.1%. Moving on to slide 20, this is where we look at the vaccine efficacy for both on the top half of RSV lower respiratory tract disease and in the bottom half for RSV ARI between those patients who have breakthrough infections with RSV A or B. As you can see, vaccine efficacy is consistent across the two subtypes for both of these primary and secondary endpoints. Next slide 21. This is where we look at the vaccine efficacy across age groups. Again, you can see excellent vaccine efficacy against RSV lower respiratory tract disease across the two larger age groups that we enrolled in the study. The population greater than 80, we had very few cases of breakthrough RSV in a relatively small population. We will need to collect further data over subsequent years to understand the true vaccine efficacy in these populations. We have on slide 22 some important immunologic information that helps us feel comfortable that protection should be preserved in this older age population. A subset of patients had immunologic testing looking for neutralizing antibodies. In blue is at time of enrollment. Green is in those patients 31 days after their vaccine. As you can see, you had excellent development of novel or increased boosting of neutralizing antibodies across all age groups for both RSV A and RSV B. Moving on to slide 23, this is where we look at the estimated vaccine efficacy by comorbidity and frailty status. Again, we maintained excellent vaccine efficacy, particularly in those patients with one or more comorbid conditions, as well as excellent vaccine efficacy in those patients that were fit or pre-frail. Much as with the older age population, those that were frail represented a very small population and too few cases of breakthrough infection to have a reliable estimate of vaccine efficacy. We'll continue to follow these patients over subsequent years, which will better refine our information with regard to the vaccine efficacy in the smaller subset. Moving on to slide 24, this is a critical set of curves that look at the protection of the vaccine over time. Really, this seems to be maintained throughout the entire study period that we're reporting on today, which is about 10 months of follow-up. For those patients that got vaccine, low levels of breakthrough infection are persistent throughout the entire study period, suggesting protection over at least the first season. Moving on to slide 25, this is our data on adverse events and SAEs. On the top half, this is the adverse event profile of our safety subset of patients. As you can see, the expected effects of the vaccine with local pain at the injection site, fatigue, headache, and myalgias did occur as the most common adverse events. These tended to be transient. As you can tell from the color coding, almost all of these events were either grade one or grade two, so relatively mild. Likewise, looking at other safety signals, there were no imbalances observed between the vaccine and placebo groups in overall rates of SAEs, vaccine-related SAEs, or markers of immune-mediated disease or enhancement of breakthrough infection with a vaccine. To conclude on slide 26, our vaccine in this study met the primary endpoint that we had designed in the protocol. A single dose of RSVPreF3 OA vaccine is highly efficacious in preventing RSV acute respiratory infection, RSV lower respiratory tract disease, and severe RSV lower respiratory tract disease in adults greater than 60 years of age over one RSV season. Vaccine efficacy remains similar across both subtypes of RSV A and B, and was consistently high in patients 60-69 and 70-79 in pre-frail adults and in those with comorbidities. RSVPreF3 OA vaccine was well-tolerated and had an acceptable safety profile. The study is ongoing and will follow participants to evaluate both an annual need for revaccination and long-term protection over multiple RSV seasons. Thanks for the opportunity to present, and I'll turn it back over to you, Phil. Well, thank you, Dr. Michael G. Ison. If I may, I'd like to ask you a few questions. Sure. First, on the next slide, what do these important data mean when addressing the burden of RSV disease? In particular, what do they mean for physicians and for older adults? Yeah. Well, I think I'll focus on the older adults because that's who our focus really needs to be. Every single year, we see patients that get admitted to the hospital and suffer through RSV, and some end up. The ability to reduce the burden of disease at a level that we're seeing in this study at a relatively high rate of protection, it really has the potential to markedly improve the quality and quantity of life for older adults. I think that this hopefully will represent a significant advance for the field and a great opportunity to reduce morbidity and mortality in this at-risk population. That, that's great. How did the study investigators determine the degree of severity of lower respiratory tract disease? Yeah. The investigator, when they were seeing these patients, had to categorize patients based on the type of respiratory infections they had. There were standardized definitions for the definition for severe lower respiratory tract infections. They had to have at least two lower respiratory signs as well as evidence of severe disease in the clinician's assessment. Or they had to be on therapies that would be reflective of severe disease, such as supplemental oxygen, CPAP, or mechanical ventilation, in those patients that had tested positive for RSV by PCR. Very good. That's helpful in understanding the study. Actually, maybe could you elaborate a little further on the rationale for the clinical study design, specifically, with the endpoint that is focused on adults with comorbidities? Yeah. Well, I think as you highlighted in the introduction to this, really, older adults in general have a much higher rate of complications and progressive disease and death as a complication of RSV, even though all of us get RSV throughout our lives. Among those that are over 60 years of age, those that have underlying comorbidities, particularly cardiovascular or pulmonary disease, diabetes, as well as other underlying medical conditions, those that are immunocompromised and those that are frail have the highest risk of having progressive disease and severe infection. It makes sense to design a study that's really targeting the population that will get the greatest benefit from this intervention. Very well. Well, thank you very much, Dr. Ison. I'd like to turn it over now to Roger Connor. Thanks very much, Dr. Michael G. Ison, for a really clear and compelling presentation of the data. Let me also just add my welcome to everybody on today's call. If you please turn to slide 31. I think Tony mentioned earlier on, GSK, we have a really long history of vaccine innovation. We've built our leadership position over many years, developing and launching novel vaccines to address genuine unmet medical needs. Consequently, we now have the broadest vaccine portfolio in the industry. We supply 35 vaccines across 160 countries and with market-leading positions in multiple key categories that include pediatrics, meningitis, and shingles. We've really got a deep innovative pipeline of assets. As Tony just outlined earlier, our pivotal RSV data is a key highlight from a strong year of R&D delivery in vaccines. You know, it's this relentless innovation that really drives our growth. With the help of more than 15 new product launches, our vaccines business has grown sales at a 10% compounded annual growth rate since 2000. Over the period between 2021 to 2026, we expect to deliver a high single-digit compound annual growth rate, excluding pandemic sales. If we please turn to slide 32. The impressive data you've just heard about today from Dr. Michael G. Ison is gonna further strengthen our vaccines business with a potential best-in-class profile. Our older adults RSV vaccine candidate looks set to further enhance our growing portfolio of vaccines to help those populations who, due to age and comorbidities, often face the most severe consequences from vaccine-preventable viruses. Furthermore, if approved, our RSV older adults vaccine will be joining a family of vaccines portfolio that is already built around excellent efficacy. Just as a reminder, 90% of our portfolio by sales has an efficacy level of above 90%. That's an incredibly high bar which protects us from potential disruption from new technologies. Now, and while Shingrix is not the focus of today's call, the new duration of protection is unprecedented and will, we believe, help us in our ambition to double sales by 2026. Just as a reminder, the commercial opportunity for this incredible vaccine is still very substantial. With roughly 100 million adults aged 50 and above in the U.S. remaining unvaccinated against shingles, and with our plans to expand our geographic rollout to more than 35 countries by 2024. If you please turn to slide 33. By focusing now maybe on the market potential for RSV in older adults, it's important to realize that when we think about who of those adults who are exposed to RSV are at the greatest risk of severe complications, namely hospitalization, death, or serious long-term health consequences, the key risk factors are age and comorbidities. The elderly are inherently more susceptible to RSV infection, and the risk among older patients is even higher among those with underlying health conditions, including cardiovascular disease, for example, congestive heart failure, or those with respiratory disease or diabetes. Data from the CDC shows that over 90% of adults hospitalized with RSV disease have underlying medical conditions, and around half have at least three conditions. The consequence of RSV infection is a substantial economic and societal burden. The direct medical cost of RSV-related hospitalizations in the U.S. alone is estimated to be up to $3 billion. This figure does not take into account the cost of lost productivity or of the long-term health consequences among those discharged from hospital. For example, in a recent study of patients hospitalized with RSV, around 60% of those aged over 75 required home health services or additional care post-discharge. As you heard today, our vaccine candidate showed exceptional overall efficacy of well over 90% in the most vulnerable at-risk older adults, namely in those with severe RSV, in those with underlying comorbidities, and in 70-79-year-olds. These are the individuals that result in the greatest impact on healthcare costs. The magnitude and consistency of our results is why we believe our vaccine candidate offers a best-in-class profile in these vulnerable populations. Given the sheer scale of the unmet need and our potential to positively impact the health and well-being of vulnerable adults, we are confident our vaccine represents a significant commercial opportunity for GSK with multi-billion GBP Shingrix-like annual potential. I'll now hand over to Luke to wrap up our presentation today. Thanks, Roger, and I want to close now on slide 34. I'm gonna summarize what you've heard today and touch briefly on our plans to maximize the opportunity of this important potential new vaccine. We've shared data that showed consistent high efficacy in the individuals who suffer most and have the greatest impact on healthcare costs. The magnitude of this result, along with the consistent high efficacy shown across adults aged 70- 79, and the A and B strains, we think clearly demonstrates a best-in-class profile. This is just the latest milestone in a long, proud history of vaccine innovation for this company. You've heard about the unmet patient need and the health economic burden of RSV disease. This is why this common contagious virus has been in the sights of the industry for decades. You've also heard that our vaccine candidate was uniquely engineered to deliver efficacy in the most vulnerable patients, and that is precisely what the data shows. For these reasons, we're convinced that our vaccine candidate represents a multi-billion market opportunity. Right, that being said, what are the next steps? We'll cover this more in Q&A. Well, this quarter, we expect to receive FDA acceptance of our regulatory submission and to complete our filings in the E.U. You may have seen, just this morning, we've announced that we filed in Japan. Looking into 2023, we're confident that we're on track for consideration at the critical ACIP meeting in June, and we plan to launch in the U.S. soon after, subject of course, to FDA approval. Our confidence level is such that we're already prepared the bulk material for launch at risk so that we can fully meet the anticipated demand. I wanna reinforce that this is a novel, underdeveloped vaccine category in the older adult setting, so be focused on appropriately raising awareness, employing both our vaccines and long-standing respiratory expertise. Looking further ahead, we will continue to seek to deepen the competitive profile of our vaccine through clinical work on revaccination, multi-season protection, co-administration with other adult vaccinations, and also other lifecycle innovation initiatives. In conclusion, this is an incredible potential new vaccine, and these are exciting times for GSK Vaccines. With that, I'd like to hand back over to Tony to moderate the Q&A session. Thanks, Luke. I will moderate the Q&A. Operator, perhaps you could introduce the first question for us, please. Of course. Just to remind everyone, please press star then one to queue up for questions. The first one is coming from Richard Parkes from BNP Paribas. Please go ahead. Hi. Thanks for taking my question. I'm hoping you'll allow me to squeeze in a quick clarification and then a question, if that's okay. The clarification is just, can you help me understand the definition of lower respiratory tract disease that's in the back of the pack? It says at least two lower respiratory symptoms/signs for at least 24 hours, including at least one lower respiratory sign. Can you just help us understand the difference between sign and symptom? And that wording suggests there might be some cases where patients had two symptoms but weren't classified as having lower respiratory tract disease. Just a quick clarification there. The question, hopefully for Dr. Ison. I wondered if you might be able to help us with anything to help understand likelihood of durability of protection. Is there anything we can learn from durability of protection from reinfection, post-infection in the real world? What do we know about how RSV strains evolve over time and accumulate changes in the F3 surface protein that might predict how often patients need a revaccination? Thanks very much. Thank you, Richard. Let me just repeat both of your questions, first for clarification and then on durability. Dr. Ison, if you don't mind, I'll go to you to answer both of those. First of all, there is a request for clarification of signs and symptoms, and then a broad question with many facets to it, Richard, on the nature of durability. Dr. Ison, over to you. Perfect. Yeah, I think the first thing is clarification what a sign and a symptom is. Symptom is something that a patient reports. A sign is something that usually the clinical team is assessing for. That may be respiratory rate, it may be, oxygen level, things like that. That's sort of the differentiation between a sign and a symptom in the case definition. All of these do have some degree of subjectivity. It's the patient's perception and the clinician's perception. The signs are relatively firm. Again, there is sometimes some subjectivity to interpretation. Is the low oxygen because they have underlying lung disease, or is this something new, based on the infection that they have? Usually the clinician is taking other information into context. If the patient's known to them, and they had normal pulse ox before and now it's lower, that would be a reasonable sign for low respiratory tract infection. Again, while there is some degree of subjectivity that's different from person to person, the way that this definition is designed and has been used across a range of respiratory viral infections is a relatively standard definition that's generally agreed upon. I think getting to your question is revaccination and the need for that. I think, you know, the first thing was the question I got the most yesterday and the question everyone wants to have answered, but that's why we have the study designed as it is. We're going to need to see what the data in subsequent seasons show and from the data that comes from this second randomization, where some people get a second season dose, some don't, to see if that changes the vaccine efficacy. I think this is the data that we need to really make that decision about whether or not we need to vaccinate on an annual basis or at a broader range. I think getting to the kind of second part of that question, which is: How much does RSV change over time? There's a couple of things that typically occur with RSV. There's kind of this cyclic change in prevalent RSV every year. Textbooks say that it sort of alternates for one year RSV A and then flips to RSV B the second year. We've just completed a study looking at 10 years' worth of data at Northwestern for all of the patients admitted to the hospital there and really found that over the 10 years, we saw a cycle that was a kind of a hybrid season with both and then the subsequent season with three. It's sort of this every three-year cycle instead of the classic every two-year cycle. That is part of the driver. We know that patients have waning immunity after infection, so they have an antibody level that decays over time naturally. This is part of the reason why it's thought that there's reemergence of infection in previously exposed patients. There is change in the fusion protein over time. That change currently is relatively low, and so probably will not require the same degree of updating as we see with influenza vaccine. That being said, like everything, we'll have to wait and see. Once we introduce a vaccine in a broad segment of the population, does this drive further change in the virus? Really, again, I think only time and future studies will inform the need for updating of the vaccine and changing frequency of redosing. Thank you, Dr. Michael G. Ison, for a comprehensive answer. Perhaps we might move on to the next question now, please. The next question is coming from Vamil Divan from Guggenheim Securities. Please go ahead. Hi, guys. Thank you for taking my question. Following up on the topic of durability, you know, when do you expect to see potential data that'll answer that question? Is that likely before the June 2023 ACIP? Just similar to that, you know, in terms of whether, you know, we've seen durability across, you know, two or three seasons, are there any kind of experience internally or externally that kind of support, you know, the timeframe that we'll see potential waning or protection? Thank you. Thank you, Vamil. Two questions again that I will repeat. Phil, if you wouldn't mind, I'd like you to start on answering those. The first question was related to the collection of durability data and in particular in the context of what we might know in time for the June 2023 ACIP. The second one was about the dynamics of the immunological response and what we might conclude from that with regards to longer-term vaccine efficacy. Phil, why don't you start, please? Sure. Although the timing will be tight to get data from the second season before the June ACIP, I think it's a goal and I think it can be possible. It is tight, but the team has shown what they can do. That's what we will attempt to do. We do have data on greater durability of the immune response than we do at this point on the duration of efficacy. What we see from the 004 study is that. We do not go back down to baseline, between, at the end of our 12 months. Now, exactly what that will translate to in terms of efficacy, we will have to determine, by the study, because we don't have a clear immunological correlate of protection. I'd say that we are hopeful, that there could be something. However, we really have to see what the data tell us. Thank you, Phil. I suggest we move on to another question now, please. The next one is coming from Michael Leuchten from UBS. Please go ahead. Oh, thank you very much. Just wanted to go back to your commentary about best-in-class profile. The ACIP working group contrasted and compared your agent with the competitor one, and I guess their conclusion is maybe less clear on which one's better. Just wondering at what data point you would point to that you think you are clearly differentiated both in terms of efficacy and also in terms of tolerability. I noticed the injection site reactions seem to be a little bit higher for you than maybe for the competitor. Thank you. Thank you, Michael. A question relating to differentiation in the context of the ACIP discussion yesterday. Phil, I might start in answering that question by including you. Sure. First, it is challenging, in fact, to compare directly the numbers that come from different studies. There's limitations to what we have. What I can say about the GSK profile, vaccine profile is that it really does show not only very high efficacy, but a great consistency of efficacy across subgroups, whether this be different levels of disease severity, RSV A and B, or those with and without, for example, comorbidities. That gives us high confidence exceptional profile that we believe to be best in class. I think an important comment on the reactogenicity is first, that it is predominantly mild to moderate and transient. Certainly compared to the consequences of RSV disease, a reactogenicity that is mild to moderate is a sort of a small price to pay for what is really exceptional efficacy. The other point I would make is that we need to make a very clear distinction between reactogenicity, which is expected after many immunizations and is commonly found after immunization, and safety. What we have is some mild to moderate reactogenicity. The safety profile is excellent. Thanks, Phil. Perhaps Luke, if you don't mind, I might go to you to ask for any thoughts. Sure. On how the profile that Phil has described might work through to your commercial thinking. Sure. I always try and keep this practical, obviously, hopefully a scientifically fluent way. Look, I think based on what we know today, I'd rather have our data set than theirs. I think Phil's made the point around the consistent, the tightly bound nature, this robust activity in age groups like 70-79 years, and groups with comorbidities. I think, again, just operationally, when you look at those side effects and you look at the percentages, it can be misleading. I think if you break it down, as was done on slide 25, these are very small rates and I think very manageable based on our experience with Shingrix. I think the other element which is intriguing. COVID has, I think, upregulated individuals understanding, both physicians and also patients, of the consequences of respiratory infections for people with comorbidities, you know, such as heart failure, diabetes, et cetera. This group is primed to be more aware and more sensitive. I think, you know, our market research is very clear that these people are gonna be naturally biased to efficacy because of their concerns around their underlying disease. Our market research is very clear that this profile is compelling. Net, I think these are all elements which support the statement of a best-in-class profile. Thank you, Luke. Why don't we move on? I wonder if I Sorry, Phil. Please, go ahead. If I can make one additional point. You know, at the ACIP, some of the co-administration data with influenza are real and tomorrow there'll be a presentation that ideally covers this data. The non-inferior influenza vaccine responses there in co-administration with the RSV vaccine is presented at the ACIP. I think it could also be a very important factor given the likelihood that it will be desirable to have a schedule in which you might give both vaccines at one visit rather than requiring two visits, one for RSV immunization and one for influenza. Yes, Phil, I would also add. I mean, our indication, this is a pharmacy vaccine, if you contrast it with some of the other vaccines. I mean Prevnar has in terms of retail utilization, you know, our expectation is that around 2/3 to three-quarters of shots given will be given in a retail setting. That contrasts to, you know, Prevnar is about 7%, you know, Fluzone is about half. Shingrix, as you know very well, is sort of 55%-60%. These considerations are material in that setting. Thank you both for a very informative dialogue in answering that question. Shall we move on now to the next? The next question is coming from Graham Parry from Bank of America. Please go ahead. Great. Thanks for taking my questions, and thanks for doing the call today as well. I just want to follow up actually on some of the ACIP working group commentary and just your sort of points you'd made, some of the questions they raised. They seem to bracket the vaccine primary efficacy endpoint of 83% within the range of the 67%-86% from Pfizer as well. They didn't sort of break out their 86% as being in line with your 94% more severe disease. Do you think that's how the market will, you know, view the efficacy broadly, so less differentiation than perhaps previously thought? They also, ACIP suggested it would like to see data on the same endpoint basis, just given the difference from the vaccine endpoint. Is that analysis that can be performed? Can you actually go through your existing data in order to generate that? Could we see a same endpoint analysis at an ACIP meeting next year, for example? They also criticized the low recruitment into older cohorts for both yours and Pfizer's vaccine. Obviously, you've got the statistically significant data in the 70-79, but neither of you has enough events in the ove-80s, where the hospitalization rate is significantly higher. Do you actually need more data there, and could we see a sort of staggered ACIP recommendation across narrower age cohorts to start off with, but then expand over time as you get additional age cohort data? Thanks for that. Okay. Graham, thank you. Again, quite a lot there. Let's return to both components of it. I think in your first question, you're re-asking the question with regards to endpoints and in particular highlighting the ACIP working group table that made comparisons against both. Perhaps this time, Phil, I might ask you to comment on that, and perhaps in the context of the broader dataset. Then we'll return to the question on recruitment or low recruitment in the 80-year-old category. I will come back to that after we've heard an answer on the endpoint comparison. Phil, why don't you start on the endpoints, and I will make sure we return to the 80+ category. Perhaps for that, Dr. Ison, I'll come to you first. I think that one of the challenges is the older age population is just hard to recruit into studies overall. I've been working in studies of prevention and treatment of respiratory viruses, where the older age population consistently is the population that has the highest risk of complications but are the hardest to enroll in studies. Particularly the ones you really wanna enroll are those that are frail, that have underlying comorbidity, and are significantly older. These are the people that can't get out of their home or nursing home very easily. It may be hard for them to become involved in clinical trials. Part of the reason why I'm making this point is not only is it hard to actually enroll, I think that both regulators and groups like ACIP recognize that it is challenging to study those populations. Given other markers of protection in other populations, particularly with safety, which would be expected from the data presented across age groups, that they would allow this to be used in those older adults while additional data is being collected. That I think is gonna be the, you know, the way to think about this is to understand some of the challenges as far as kind of the comparative issues. I'll turn it over to Phil to finish up. Sure. You know, I think there's a couple of questions asked on the comparative issue. One is, can we expect that we're all gonna have sort of the same case definition in the latter parts of the study? You know, there is no standard definition for either the lower respiratory tract disease or for the severe severity. Of course, we have to pre-specify what our definition is. While we all have our definitions approved by FDA, we can't mid-study change the definition because then we'd actually lose the ability to compare the second season to the first season. As an alternative to that, I think what you have to look at is the overall pattern that we see. One result that I'd really like to highlight is not just the very high efficacy we see in the more severe disease, but the fact that even with acute respiratory illness, which includes relatively mild illness, and upper respiratory illness, as well as lower respiratory illness, and conventionally been thought of as relatively difficult to protect against, we also see very strong efficacy. I think that the degree of strong efficacy that we see across different categories of illness suggests that this is not just a matter of specifics of case definition, that we're seeing a very broad pattern of very strong efficacy from the GSK vaccine. Thank you, Phil. Let's move on to another question, please. The next one is coming from Peter Welford from Jefferies. Please go ahead. Hi, thanks for taking my question. Just if I go back to the safety comment and the point that was made by Luke, I wonder if just when you talk about what you saw with the reactogenicity, could you put what you see in the RSV trial in context for us versus what you see with, for example, Fluzone, Shingrix, and some of the other vaccines, just to help us to understand, I guess, where it lies when we think about what we're seeing in this study. If I could just ask, do we have any data yet on actually preventing hospitalizations, CPAP use, supplemental oxygen? I guess what would be hard endpoints, if you like, that can go to payers as well to convince them, not only that this vaccine actually is also preventing those costly potential endpoints for the elderly. Thank you. Thank you, Peter Welford. What I might do, again, Phil Dormitzer, if I can ask you to comment on the reactogenicity question, particularly in the context of the experience with other adult, commonly used adult vaccines first, and then we'll move on, and Dr. Michael G. Ison, perhaps you could comment on the question regarding CPAP or hospitalization data and what we're learning there. Phil Dormitzer, please, reactogenicity relative to other well-established adult vaccines. Sure. Although precise quantitative comparisons are challenging because there are differences in the way that reactogenicity is collected between studies, I think what we can say with confidence is that the reactogenicity that we see with this vaccine is well within the range of reactogenicity that we see with commonly used vaccines for diseases in older adults. I think we're confident that we are in a range where this should not have a significant impact on uptake. This is the sort of reactogenicity people are used to experiencing after immunization. As with regard to the second question about kind of those hard endpoints, these are data that are in the process of being collected and have been collected in the first season. These will be looked at as we move forward. I don't personally have the specific details of that in front of me at this moment, but clearly, it's something that is being collected. One of the challenges, again, thankfully, particularly in the vaccine population, the rates of breakthrough infection was very low, and so it will likely take data over multiple seasons to really get a firm estimate of the impact on hospitalizations, supplemental oxygen, need for enhanced CPAP, those kind of things, over time. Thank you. Let's move on to another question. Thank you. In interest of time, we'll need to limit to just one question, please. The next one is coming from Emmanuel Papadakis from Deutsche Bank. Please go ahead. Thank you for taking the question. Maybe just to follow up on efficacy and the consistency by subgroup you've referenced several times. It was indeed the case in most of the key subgroups except for the over 80s, which was relatively significant subgroup in your study over 2,000 patients. The efficacy dropped to 34%, whereas it seemed to in fact be better in the competitor study for Pfizer. Any perspectives on why that might be the case? Just to follow up to the question that was asked earlier about any implications from that potential ACIP recommendation, do you expect to still be recommended for that subgroup of patients based on the data you have? Thank you. Thanks for that question. Given the time, I won't repeat it. Perhaps, Dr. Ison, you could take it first. Yeah. So kind of as I highlighted, while there were 1,000 patients over 80, that's still a fraction of the other populations where we had about 12,000-15,000 patients enrolled in those age populations. It's still a relatively small population, and the number of breakthrough infections was relatively low in both arms. Really, it's going to take more data over more seasons to really refine the estimates. While we were able to generate a number, the reality is that the reliability of that, because of the small numbers, is quite challenging. I suspect over the next year or two, we'll have much more refined endpoints. Then, you know, my personal perspective, I will have to wait and see what ACIP does. Again, I think with safety and particularly looking at the totality of information, where again pointing to the antibody neutralizing antibody levels where they're consistent across all age groups, that will probably give them the comfort to authorize it in all age groups over 60. Thank you. Before closing out on the call today, Phil, perhaps I might give you an opportunity to make any additional comments you'd like to on this final point. Yeah, no, I agree completely with Dr. Michael G. Ison. When you have such small numbers of breakthrough cases in both the vaccine and placebo group, the numbers are not statistically meaningful at that point to get an actual rate. Where you do get substantial numbers is in the number of people who contribute sera for immunogenicity testing. There we see consistent level of immunogenicity between those in their 60s, 70s, and 80s, which gives some confidence. We'll have to see what the data show when we accumulate more breakthrough cases over eighty. The immunogenicity results are very encouraging that we see certainly consistent immune responses across the ages. Thanks, Phil. I'm aware that there are some additional questions, so why don't we run for an extra 15 minutes to cover those. Please, operator, if we could have the next question. The next one is coming from Jo Walton from Credit Suisse. Please go ahead. Thank you. My question is about expected penetration. I think we all understand the flu vaccine market, and still the latest data suggests only 67% of people over 65 get vaccinated. How well-known is RSV, and what sort of level of penetration of the market do you think that you could get to over the next few years? Would it be right for us to think that it would be better if there were two of you, each with an annual vaccination to drive that level of education? Thank you, Jo. Great question on penetration into the market. Luke, that would be one for you, please. Sure. Yeah, thanks, Tony. Yeah, you're right, Jo. I mean, we modeled 60%-70%, 67%-68% for flu. I mean, I think it's interesting because COVID has changed things somewhat in terms of bringing adults who historically may not have presented for an annual vaccine. That's the positive side. I think that physicians are aware of the impact of RSV infections, particularly in compromised individuals, older individuals. You know, we've got strong data there. So I think these are all favorable elements. I think the market research, when we've had groups who have been educated and then we've tested their motivation to be vaccinated, their willingness actually goes up significantly with a profound change in people who obviously have complicated health conditions. I think the fact that it's retail-dominated, as mentioned earlier, will be helpful, because they have a different incentive structure and just more structured workflows versus, say, doctor's offices. I think the negative element, or the drag on that will be, as you rightly say, the lack of awareness. You know, this is difficult to quantify. In some cases, vaccine fatigue. The fact is, yeah, with Shingrix, Prevnar, flu, COVID-19, Tdap, etc., the adult schedule is getting more complex. You know, I don't think we'll see, in the next five years, the type of penetration we've achieved with flu. That being said, I can imagine that this class continues to grow over the next 15-20 years. I think it is beneficial for two companies that have a heritage in innovation and a heritage in terms of building markets and informing patients in place. I think that's definitely a positive element. I think on top of this, the Inflation Reduction Act, removing what would have been between, let's say, a $30 or $50 copay in individuals 65 and above, will be a positive element and help with penetration in those groups. I can't give you an exact percentage, of course, but it will be lower than flu. Thank you, Luke. Apparently, we have four questions left, and I'm trying to move us through those promptly. Go to the next one, and if you could be as concise as possible to help me with that ambition, that'd be fantastic. Thank you. The next one is coming from James Quigley from Morgan Stanley. Please go ahead. Hello. Thank you for taking my question. Just a quick one on durability. How important is the adjuvant in durability of protection? And from what you're seeing from the immune responses so far, are they behaving as you would expect or in line with Shingrix that could give you a clue on durability across the different age groups? Thank you. Thank you, James. I'll be equally quick about this. Phil, for you, please, the question on durability and the role that the adjuvant plays in that. Sure. I say that we are hopeful that the adjuvant will provide good durability. At this point, we can certainly say we've developed durability over the course of a single RSV season, and we will collect data on the durability over multiple seasons. In fact, three seasons. Although, of course, with our 10-year Shingrix data, we would love it if we saw something like that for RSV, but I. The biology of those viruses is so different that I don't think we can predict one on the basis of the other. Thank you, Phil. Let's move on to the next question, please. It is coming from Kerry Holford from Berenberg. Please go ahead. Thank you. Just any comments that you or Wayne are able to make on pricing. How do we think about pricing a vaccine when you don't yet know how frequently the population will need to be immunized? Should we be thinking about Shingrix-type pricing for the course here? Because you would have had a similar debate, no doubt, when you launched Shingrix with regard to unknown durability. Any comments you're willing to make there, please. Thank you. Thank you. Thank you, Kerry. Pricing, Luke, that one's for you. Sure. Thanks, Tony. Look, I think let's assume it's an annual-based vaccine. I think if you look at the Fluzone price of around GBP 60 and the Shingrix price of around GBP 170, and you draw a midpoint between those two, the price will be on the right-hand side of that side. I just don't want to speculate how far or how little on the right side of that midpoint. Obviously, if it's multi-year potency is demonstrated, then we would revisit that assumption. Thank you, Luke. Kerry, I apologize. I didn't quite hear your name over the line. By my arithmetic, we've got two more questions left. Let's have the penultimate one. It is coming from Steve Scala from Cowen. Please go ahead. Well, thank you so much. GSK has articulated why its vaccine is superior to the competition. Dr. Ison, what do you see as most important factors physicians will consider when choosing between the available RSV vaccines? Will these factors compel you to argue for the GSK vaccine if the Pfizer vaccine is what's stocked in your clinic? Thank you. Well, thank you for helping me with my job, Steve. That one's for you, Dr. Ison. No problem. I think you bring up a very valid point. We, at least here in the United States, work in generally in systems. Those systems have system-wide decisions that are made as far as which vaccines are stocked. You know, where I work, we have one flu vaccine, even though there's a whole range of available vaccines. Any provider within the system can advocate for one vaccine or another. The other advantage that we have is with the majority of people accessing vaccine through pharmacies, our system doesn't have the vaccine that I think is most effective, I can send people to a pharmacy and recommend that. You know, for an individual provider, usually, you unfortunately have to follow the formulary in your system. How they make those decisions are very complex, a balance between cost effectiveness as well as the overall efficacy of the vaccine. There are alternatives if you feel very strongly advocating within your system or sending them to a commercial pharmacy. Thank you. Let's move to what I believe is the last question now. The last question is coming from Emily Field from Barclays. Please go ahead. Hi. Thank you for taking my question. I just had a follow-up to the penetration question. I was wondering how much do you think that ultimate penetration rate will be influenced by durability, i.e., you know, durability lasts more than a season or even if seasonal vaccination is required, that the efficacy remains as high as it is. You know, why couldn't that penetration rate be higher than influenza? Is it simply a matter of awareness? Thank you, Emily. Question of penetration in the context of durability. Luke? Sure. Thanks, Tony. Thanks, Emily. Yeah, I think, look, the sweet spot is probably a three-year durability, which will take time to establish, of course. Again, you know, we are very intrigued by the presence of the adjuvant and any potential influence that could have. I think one to two years is less impactful, but, yes, if we did get to 3+ years, then I think you could potentially see flu levels of penetration over a 10-year timeframe. It really just depends on how effective we are. I mean, I think the epi's quite interesting, when you break it down. You know, if you look at the 60-64 high risk population, and then you add in the 65+, it's 80 million people in the U.S., so sizable group. I think, you know, our market research shows these people are very engaged in their health, so it could be higher if the frequency is lower. Emily, Luke, thank you. I believe that brings us to a conclusion today. Thank you everyone for an engaging session. I think that's us done.