I think we can start early, and we can get you guys out five minutes early too. Well, good morning, everyone. Thank you for joining us, our day two, and I'm really excited to kick the day off with our friends from GSK. There's a lot to talk about, in particular because what makes this fireside chat exciting is we're gonna focus specifically on the vaccine business, and it's gonna allow us to do a little more of a deep dive on this aspect of the broader GSK story. But just before we do that, I realize GSK is not a vaccine-only company. So Jeff, maybe I'll turn it over to you, kick things off. I realize there's a bunch of other higher-level GSK topics, too. Maybe you can spend about five minutes on that on a couple things, and we'll jump much more specifically to vaccines. Sure, yeah. I mean, vaccines is key, and we're happy to have Phil here, who leads our vaccines R&D efforts. You know, GSK is big in HIV, and if you didn't see it, we had an HIV Meet the Management event back at the end of September. So slides and transcript are available there if you wanna thumb through that. But we've been pioneering long-acting injectables in HIV and two-drug regimens for some time, and that's been key to our business. And then, tomorrow, we're actually doing one on respiratory. So you can learn more about Nucala, depemokimab, some of the assets in our respiratory health space, which has been a big legacy for GSK for some time. Excellent. So... Over the last couple of years, Jeff, obviously, there's been a couple of legacy issues which have weighed in more heavily than the rest of the business, including some of the litigation stuff. Could you just remind us and orient us where things stand on that front and where we are now? Yeah, so there's been ongoing Zantac litigation. The next event that I think people have their eyes on is in January 2024, there will be a hearing in Delaware to consider what is included in the class action that's ongoing there. But the federal MDL case was effectively tossed back in December of last year, and a couple of the cases in California have been addressed through settlement as we've moved through the course of this past year. So it's not as hot of a topic in conversations with investors as it once was, but we're working through that litigation process. Got it. But just to be clear, I remember we really looked into this at length. We spoke to you at length about it. Yeah. I recall much of the, like, the origin of the suit, some of the players involved in that suit origination, courts found and got to the bottom of a lot of that. When that ruling came out, I think it was about a year ago in December, I thought this was all over, so I was still puzzled to see some of these Delaware and some of these cases- Yeah ... later on. Well, that was the federal case. So that was. That handled a number of different claims. But after that, there were state-level cases. Okay. So many emerged in Delaware over time, and that, you know, process kind of started off much later than the federal one. So that's why we're just kind of getting now to the point through the process where Delaware is having a hearing. And, you know, the judge will make a determination on timing for when to decide on that hearing, but, you know, that, that will come in due course throughout 2024. Okay, excellent. Here's what we'll do: We'll jump right into the vaccines now. Yep. Spend a fair amount of time, and if we have about five minutes in the end, we can come back to a couple of GSK-specific topics again. It's good. Broader biz dev strategy, financial, et cetera. So really looking forward to this. I know there's a ton to talk about. Maybe we can kick it off on your RSV launch, which has been tracking very well. I know there's a lot of broader interest, and I also know it's quickly picked up a fair amount in sales. So could you maybe... Like, can we start there and maybe turn it over to you, and both of you, perhaps? Oh, sure. So, we're obviously, we're very pleased with the way this has started off. We've had a very effective rollout. The uptake is excellent, and we're now really working on making sure that we maintain this lead. We're looking at, for example, age expansion, so, looking to... We have good data on 50-59-year-olds, which we hope will maintain differentiation, and then we're looking beyond that to potential combinations in the future to make sure that we maintain the early lead. So maybe let's start there. I was going through, in preparation for this, I was going through the ACIP recommendations, and they're specifically focused on 60+ cohort. I know I was speaking to my colleague, Jessica, about it, and she was sharing some of the data on 50- to 59-year-olds. Was that reviewed in ACIP or not? And sort of what's the path to regulatory indication for that? Yeah. So, we're going to particularly focus on 50-59-year-olds at increased risk. Okay. And we are on track to file, looking to get the expansion in this year. You know, we can't guarantee what the regulatory outcome will be, but we're on track to- This as in 2024? 2024. Okay. Correct, 2024. Got it. But the existing, the study one, study two, those were 60+ only? Yes, that's right. Yeah, they were 60+. We've done another study at 50-59 and 50-59-year-olds at increased risk. Okay. Another thing, of course, we're very interested in is continuing to accumulate data, hoping at some point to be able to move from a shared clinical decision-making to a straight recommendation. I think that's gonna be include so real-world effectiveness studies and just building the case for the impact that the vaccine is having. And that will take a careful monitoring- Got it ... of what's going on out there. Yeah. Phil, I know, vaccine was not necessarily a topic investors did much work on until, I would say, COVID. And then since then, there's been a lot of work on the COVID side of it. But I still think there are some vaccine-specific topics which are not well appreciated. So for the purposes of everybody, can we perhaps go through shared clinical decision-making versus straight recommendation? How does that actually impact commercially? Sure. And why is it so significant a priority for you? Yeah, so these are ACIP differences in recommendation. In a straight recommendation, a full recommendation, it simply says, "Those over a certain age or potentially with comorbidities are all to get the vaccine," as opposed to a shared clinical decision-making model, where it's left to a conversation between the provider and his or her patient on whether to get the vaccine. It makes it a more complicated conversation. I mean, you really you can't simply say, "CDC recommends you get this vaccine." There needs to be more of a discussion. But who's a provider? Like, if I walk into CVS- Yeah ... and I say, "Oh, I want the RSV shot," then the pharmacist just kind of looks at me, but he really wants to give me the shot. Is that the conversation, or does it, is there, like, some sort of a prescription? I don't think there is one, to my knowledge. Yeah. And certainly between a physician and patient, there'd be that conversation. I'm just thinking of—I don't want to date myself, but having received the vaccine myself, I—when I went into the pharmacy, there were no questions asked. But the- I mean, generally speaking, a pharmacist is also a healthcare provider. Right. That decision can be routed that way. In most states, I don't think that you need to take a piece of paper prescription to- Right ... to the pharmacy from your doctor. But the conversation with the physician can prompt the decision to go get your vaccine. And- Got it ... in most states in the U.S., I think maybe even all of them, you can get a vaccine directly from the pharmacist. My point is, is there? I mean, since you've looked at so many vaccines, is there evidence of step-up in volumes when a product transitions from shared decision-making to a full recommendation? Yeah. Or is it more on market share versus a competitor within that category is where- Yeah. You know, this is universal right now across the RSV vaccines that are out there. You know, I'm trying to think of precedent. Certainly, you know, as it became more and more simple recommendation, it says it's just simply recommended for everyone above this age, as opposed to a more complicated recommendation, uptake certainly increased. And I'm trying to think of other precedents. I'm looking at- Yeah. I'd have to look back at, like, the pneumococcal- Yeah ... older adult analog to see how that started out over time. But, you know, it's not unusual for a shared clinical decision-making type of recommendation to begin with a vaccine. Got it. We have one with our meningococcal vaccine for adolescents as well. So it's not unusual. Got it. Okay. And I want to get into the broader RSV landscape, too, 'cause there's multiple players. There's an antibody, there's some mRNA players coming, et cetera. Yes. But just before that, the basis of granting shared decision-making was because your second study was slightly weaker, or is that because just how they progressed? No, you know, the discussion that took place at that time seemed to be much more around, you know, pricing and not so much about the scientific data. So that's my recollection of the discussion that was held at ACIP. Got it. And the pricing here is, how much is it? I forget. 280 a dose. Got it. Got it. Okay, makes sense. And is that comparable for Pfizer as well? I think Pfizer is a little bit higher, but- Okay ... yeah, the same general ballpark. Okay, got it. Which then takes me into the study, too, you guys have. I know, I was looking at ACIP slides, RSV-associated lower respiratory tract disease, 83% in first study, 56% in second study. I was curious, was there anything about the second season which made it less strong in the second over the first season? The second season, there was a higher pressure of infection. It was a stronger RSV season. But I also think that some of this may simply be some waning of immunity from one year to another. Oh, so you took one shot, and it lasted a couple of years. That's what- That - I think. That's right. So there were both groups that received a single shot and were followed over the course of two years. Yeah. There were some who also received one shot the first year and a second shot the second year. What's interesting is the boost at one year didn't increase titers. It increased T cell responses, but not titers so much- Interesting. ... and not- Why would that be? ... antibody titers. Well, that's a very interesting question. So there are no vaccines out there, except for those where the virus changes every year, where you boost after one year. So it did surprise us at the time, but of course, hindsight is sort of 20/20. And so there are gonna be a couple of important information that'll come out. First is, we'll see what the immune response looks like when you immunize at the beginning and then after two years. We'll also look at what that does for efficacy. And then, following that, there'll be additional studies where we look at a three-year interval and even a four-year interval to see how far you have to wait. From both animal studies and human immunization experience, the longer you wait between a prime and a boost, the better the response to the boost is. And of course, there's lots of interesting scientific discussion about why that is. For example, in infants, who have maternal antibody but have not seen a pathogen before, while that maternal antibody is there, you can boost T cells well, or you can immunize to elicit T cell responses, but not antibody responses so well. So the presence of antibody does seem to suppress subsequent antibody response, so you seem to let things fade a bit. The details of the science aren't so clear, but the phenomenon is pretty clear. So the anticipation is, we'll have to see how long you have to wait before you have an effective booster. Makes sense. Makes a lot of sense. Okay, excellent. So let me just get it right. Year one, 83% efficacy, year two, it was in the low 50s, and again, the difference was a lot of patients did not take a shot in that second year? Correct. For the subgroup that did, was the efficacy again in the 80s in that second year? Was that broken? No. The boost after one year- Sure. ... it didn't do much. It did not increase efficacy. It did boost antibodies a bit, but not nearly to where they were after the first dose. So we'll now, you know, we'll be later this year, we'll have the data on what the two-year interval boost does for efficacy and for immune responses. And then, at the end of this season that we're entering now, we'll see what the efficacy is with a single dose and with a two-year boost after three seasons. Got it. That makes sense. Yeah. So I guess, when's the next big data update on this one versus two-shot issue? Well, because I guess ultimately, the question we're getting at is, how often should we be taking shots? Exactly. And so, it's a booster interval question now. We need to set the timing for the second dose. I don't know the exact date of those data, but it shouldn't be that long for the second shot immune response and efficacy data. Then- From the existing two trials? From the existing trials. So we have the existing trials that are continuing, and we're going to be looking at the intervals, and then we have extensions, so we can look at every three-year and every four-year dosing. So we really set that interval. I think my guess is that the third-year data will be very important when we see the every three-year interval. When you say three-year data, you're referring to shot at the third year and track for a season after? Oh, so, we will have the- Shot at two year? Shot at two years and tracking afterwards, and the shot up front, and then tracking for efficacy for three years after that first shot. So I think we'll know quite a bit at the end of that. Jeff, when you guys put some of this stuff out, do you intend to break it out like that? I didn't again, and as I was going through some of this data, it wasn't very clear if it was shown like this, but is that the intent, to show in tables, like folks that only got it once, track for two, three years- Right. Folks that got it at year two, track for a year, something like that? Right. I mean, I think, the focus needs to be, once we have all in hand that we need to have- Right ... is this a vaccine that should be administered every two or every three years? And when we have that much information, then, you know, we can show the evidence that supports that. And then you have to bring it to the public health officials and- Right. ... share it with the ACIP, and, you know, showcase what you've got in that regard, and eventually at a clinical congress as well. Got i t. Yeah. This is data, like, this is important data for first half next year, for example? Certainly, the immune response data for the two-year interval boosting will be there. We need to wait- When you say there, you're talking about a potential ACIP in first half? Yeah. Well, I don't think the ACIP is likely to make a decision- Okay ... on dose interval at the next meeting for the reason that there's still more data to come in. So that might be delayed a little bit just 'cause they're likely to wait for more data, and also to see the season three efficacy data, and that has to wait till the end of this RSV season, which will be sometime in the spring. The other thing is that because this is the first year, 2023, of RSV vaccines, the ACIP, knowing that you don't need to dose it at a, you know, successive years, they don't really need to make a decision until 2025- I see ... really. Yeah. Got it. So the next big data update is titer data, as well as end-of-RSV season data on efficacy. And when you see that data, just so I understand, the first metric you look at is lower respiratory tract disease, or are you looking at the medically attended? Yeah. The primary outcome is lower respiratory tract illness. Okay. Yeah. Not the medically attended? Not the- Because the definition could be a little different between the trial. It can be a little bit different, but the primary is lower respiratory tract disease, but we also track medically attended, but not as the primary- Got it. ... endpoint. Is it your expectation that some of your competitive programs, like Pfizer, might need annual dosing while you don't, which ends up becoming a big differentiation commercially? I think what we're just going to let the data speak for themselves. I mean, there is a difference in that we do have an adjuvant in the vaccine, and we'll have to see- Well, Pfizer doesn't have an adjuvant? Pfizer does not have an adjuvant. Yeah, so- What's the adjuvant for you? Is it aluminum? Same one as in SHINGRIX. Yeah. Okay. AS01, though at half the dose level that's in SHINGRIX, for better tolerability. So you think that's what's driving maybe the lack of titer boosting, too, potentially, 'cause it's, there's a residual level of titers hanging out from the very first dose, but also why it's more durable, potentially? Yeah, I don't know that the increase in lack of increase in efficacy or the modest increase in antibody titers after the first boost at one year is a differentiator between the two vaccines. But we'll have to see as we go to subsequent time points if it becomes a differentiator or not. Got it. Yeah. Any last questions, Jessica, on RSV before we move on? Yeah, one question I have is, I know after seeing the second season data, you guys raised the price for the dose. I guess, in the scenario that immunity doesn't wane into the third season, would you guys consider a price change to take into account that this is a vaccine that can last three years? Well, I mean, we're not gonna comment on anything about our pricing strategy, but just to point out that the analysis that we did for health outcomes purposes was based on only one year of data initially, but then once we had two years of data, we did a new analysis for health outcomes purposes, and then that's what drove the final decision on pricing. So we didn't raise it, we just launched it at a price that reflected the benefit of two years of data. Right. Yeah. Yeah. Misspoke. Um- You know, we wouldn't comment on... Strategically, there's so many different things to weigh in terms of how you go about the pricing strategy. If I could just ask one more follow-up. I know you guys have data from a co-administration study with high-dose and adjuvanted flu vaccines. Given that, the CDC has already seen some sort of safety signal with COVID vaccines and high-efficacy flu vaccines administered the same day, some sort of, like, ischemic stroke signal, you know, p-value kind of wavers between lower than 0.05. Have you guys seen any sort of safety concerns of co-administering your vaccine with like an adjuvanted flu vaccine? No, we've done the co-administration studies, and we have co-administration is allowed, and then there's been no important safety signal there. Yeah. Thank you. Okay, maybe one last one. On the adjuvant you are using, I know, this point has not been commercially relevant, but Pfizer's trying to drill that. You said AS01, which is SHINGRIX. Yeah. How's that different from AS03? Okay, so they are different adjuvants. AS03 is the adjuvant we typically use, for example, for pandemic purposes. For the COVID vaccine. It was distributed for COVID and in the past for flu. Yeah. Whereas AS01 is the adjuvant that is in SHINGRIX at double the dose of that, that we have it in, in the RSV vaccine. Got it. Because the reason I ask is, if I remember correctly, AS03, there was some underlying not causality, but the link between narcolepsy increase and AS03. I wonder if some of those... If I was your competitor, I would be looking and digging for that type of information. Yeah. So it's a different adjuvant- Okay, got it. ... in this case. The narcolepsy was particular to the pandemic flu vaccine, has not been seen generally. It was in a special subset of people, and actually, it actually tended to be northern European teenagers where that was seen. So it was not seen generally- Northern European teenagers. Different and different. Yeah, it seemed to be a idiosyncratic reaction. There's been a lot of back and forth. That's where we do our recruiting for our team, by the way. And there's been a lot of scientific trying to figure out how real was the signal? Got it. Because ascertainment bias comes in very quickly, once you declare a signal. Excellent. Yeah. All right. Well, listen, I think we got through all the key issues. Oh, one last. Yes. Nirsevimab versus Moderna, how does that tie into the bigger picture? I know people are thinking about it as a GSK Pfizer thing, but this is a more complex picture here as well. Yeah. And the antibody is primarily for infants. It's because you'd have to dose too much to treat an adult, so it's not pertinent to the adult market. But for the infant market, there's nirsevimab, and we are not targeting this vaccine to the infant market. We're looking just at older- Why is that? We had a non-adjuvanted version of the vaccine in pregnant women, and we saw an excess of preterm births in that study, and we stopped it at that point. Pfizer is developing in infants? They're developing it for pregnant women, to go into infants, and I'd just invite you to look at their data and the preterm births, those who did and did not get that. I see. So it mean... Okay. Yeah. Okay. So- So these vaccines in infants are. Okay, there's question marks. Yeah. But the antibody is for infants. The antibody is for infants. Yeah. I guess, my question is, why is it limited to 50 plus? Why not, perhaps even lower? Because hospitalization rates are lower? Well, for those at greatest risk, there is interest in going lower, particularly for the immunocompromised- Okay. ... where there's a disease burden. Got it. So RSV causes substantial disease in infants and substantial disease in older adults, but the third group is people with underlying conditions, either immunocompromising or other conditions, such as severe respiratory conditions. We're starting with the older adults. We would address infant disease burden in a different way, and but this vaccine could potentially be extended in the future to those at risk- Got it. ... at younger ages. What about mRNA? Are they going high and low? I believe they are. Sorry - I'd have to check with Moderna on that, but I believe they are going high and low. Infants as well as adults? Yeah, I think so. And they don't have- I'd have to check. ... this preterm birth. They'd be starting older, because you have to age de-escalate to get down to infants. Oh, so they haven't even started infants yet, or they're in very early stage. Okay. I'll have Moderna sort of address exactly where they are on that. Okay. Makes sense. Makes sense. Yeah. But from their efficacy data to date, how are they positioned versus you guys? What I'd say is there's no apparent advantage at this point of mRNA over the subunit or adjuvanted subunit technologies. Got it. You know, for viruses that change over time, the ability to match strains more nimbly with RNA appears to be a real advantage. When you're talking about viruses that really don't change much year to year, the advantages are less clear. Got it. Makes sense. So I didn't realize we'll end up spending 20 minutes on RSV. That was way longer than I had planned on. But I know there's a bunch of topics- It's an interesting topic. ... I wanted to go through. Yeah. Let's go right into your mRNA collaboration with CureVac. Sure. Well, maybe let me fill you in on a perspective from an investor perspective. There's two things. One, there's been this perception that they've been slow at the development program. GSK folks had to step in to change the strategy from not using chemical modifications to actually doing them. It looks like finally things are starting to work. But even at this point, the COVID vaccine that they have, that they showed us data for, is on the older Omicrons, and they're not up to date. I guess, where do things truly stand? And is it truly GSK R&D running the trial design and strategy on their development efforts? So, first, it's a collaboration, so both sides have input. I think the switch to using nucleoside-modified RNA was very important. There's a clear advantage. Was that your idea? I'm not the only person who- Okay. You know, that came from Katalin Karikó and Drew Weissman, who's, you know, got the Nobel Prize. Okay. So I didn't come up with that idea, but it was clearly an idea that is well worth adopting. Okay. You may or may not know, I was at Pfizer before, and sort of, COMIRNATY was in my- Is that right? We were well versed there, so- I should know that. So I've kind of done this before- So you really know the pneumococcal, which I'm gonna ask you next. Yeah. We can talk about pneumococcal, too. We are in phase II with both a flu and a COVID vaccine. Our primary goal is getting to the flu-COVID combination. And I think you'll see that we are rapidly closing on the leaders. You think you can do infants with this? Um- This mRNA combo flu construct, 'cause it sounds like your other one, which you're currently approved, AREXVY- Yeah. ... I I think is the name, that's not intended for- Yeah. So, you know, the RNA COVID vaccines, they go down, I believe, to six months, I believe. So, you know, they haven't been down to the youngest babies yet. Okay. I see no reason why this RNA vaccine can't have a similar- Got it ... once all the appropriate studies are done, of course, to the existing RNA vaccine. So as you guys sit down with the leadership team and the board internally, is there a goal or a timeline set out that, "Listen, by 2026 or so, we got to have our mRNA vaccines on the market"? Is there anything like that internally? I am certainly strong- Because CureVac has always been- ... strongly encouraged from the top of the company to move at pace here, and- I see. ... and we are on track. Is there- You know- ... Jeff, have you guys- Yeah. ... communicated any sort of, like, a registrational data timelines for the CureVac mRNA? We haven't given any detailed timetables, you know- But it's progressing towards registrational now, 'cause I think it was- Yeah. ... phase I, phase II still, but sounds like you're about to initiate something more registrational in nature. Yeah, so we are looking to move at pace, I would say, with you know, phase II data coming out soon. And then- This will be phase II data? Okay, remind me, this is phase II data on flu plus COVID shot combined? No. Okay. So right now, they're separate, but our strategy is to go quickly to the combination vaccine. And, you know, I think there could be a market for a RNA flu vaccine alone, but, say, a new COVID standalone vaccine, there's probably not so much of a market for. So we view right now the COVID as a steppingstone- Got it. ... to the combination. This phase II data is first half? Phase II data... Yes, I think we should be- Yeah. I think we should be putting- Yeah. ... some data out there in the first half. Yeah. O kay, got it. So this phase II data is coming up. Remind me, the COVID construct, is that updated for the latest, the XBB.1.5? I- Or is it an older one? 'Cause that's always been, every time we go through the data, we realize they're still doing the older one. Yeah, phase I was older. We've done an update for phase II, and I would anticipate that we may update again for phase III. Right. But we are- But this COVID shot- ...you know. ... data coming up now will be same strain as what's Moderna and Pfizer in the marketplace right now? Yes, and we're benchmarking as well. So yes, we... there should be able to make apples-to-apples comparisons. But the construct of- But not for the phase I. But again- Yeah. ... then you can look to the older data. Sure. But the phase II that's coming up, that's on the same antigen as the Pfizer or Moderna in the marketplace right now, or is it older? I think XBB.1.5, I believe- Yeah. ... was for the phase II, and then we'll update again. It is 1.5 for phase II? Yeah. Okay, that's important. That's important. And are you guys in any way it's a 50/50, I think, with CureVac, is that right? It depends on if you're talking about flu or COVID. Okay. COVID is 50/50. Okay. Flu is a different agreement. Yeah. Yeah. I can dig it up. I haven't looked at the agreement in a while. It's more economics on flu for you? We have more of the economics, yeah, from- Okay, that's all I need. ... the initial deal. Yeah. Yeah. And there's a lot of litigation between CureVac and the main mRNA players like BioNTech and Pfizer, and there might be some litigation and settlements, but that's not GSK relevant. That's all CureVac. Is that right? On some of the dated CureVac IP. Yeah, we stayed out of commenting on- Got it. ... on any of that. Okay, makes sense. Yeah. One last one: Is CureVac the only mRNA development you guys have, or you have other internal mRNA as well? Because there's been questions- Yeah. I mean, this is not a question on CureVac, but it's been the questions on why didn't GSK just outright have the whole thing in-house? Yeah. Because it was not a very large company. Yeah. But it's always been this collaboration thing. Yeah. You know, it GSK, through the Novartis acquisition, has a long history in RNA, and we are in fact in the clinic as well, with an internal RNA program as well. Right now, it's just with a COVID antigen for benchmarking purposes. But we'll- Oh, including on COVID? Including COVID, but that's just for benchmarking. There's no intention to advance- Got it. ... a separate COVID. Because since the big RNA vaccines out there were COVID, we wanted to see how things compare. Right. Does CureVac not get upset about that? You know, we had RNA vaccine development internally underway at the time- Oh, I see. ... of the deal. So since we had an existing program, it was sort of a fact of life at the time when we did that initial deal. Got it. There are many applications of RNA in the future, so- All right ... and not all of them will be covered by our co- Okay. ... our COVID, CureVac arrangement. Excellent. Yeah. Any questions on this topic before we move on? Okay, so let's go to pneumococcal. But just before we do, and I didn't know this, did you work on pneumococcal stuff as well at Pfizer? I was more of a bystander at Pfizer. My responsibilities were for the viral vaccine R&D. I see. Now it's more broad. I saw a lot of what was going on- Okay, got it. ... but on the other hand, it was not my responsibility. Okay, makes sense. I mean, this is not Pfizer questions anyways. I was mostly just orienting. Yeah. Obviously, the focus is- Yeah. ... Affinivax and the MAPS platform internally at GSK. Yeah. There are several layers to this. I mean, the first one is Pfizer's gone from Prevnar 7 to Prevnar 13 to Prevnar 20, and now going beyond. But the basis of your Affinivax deal is you could do 24 in one clean shot, both in infants and adults. However, what Pfizer and Merck are saying in the marketplace is, "Look, we can go beyond as well," even though they have a big gating factor for the sheer amount of carrier protein they have to put in there to go beyond, which is why it's not a coincidence Merck is now doing a separate, I don't know, V116, however valent that is, and as an add-on or an adjuvant shot. Yeah. Do you foresee some of the traditional players being able to do what you're intending to do with the Affinivax 24-valent? Or do you not see them- Yeah. ... with the amount of carrier protein they need to get to that? Yeah, so we have the 24-valent program. We also have a 30+-valent program that's currently pre-clinical. And when you look at the Pfizer data, as they've gone to higher valencies, what you see is a reduction in the response to each individual component as you go to the higher valencies. And we believe that that is a limitation of the classic glycoconjugation technology. What we've seen in the phase II data for older adults with the glycoconjugation, or the MAPS technology, is we're able to get to higher valencies without the reduction, the level of reduction in response to each individual component. You know, the physical arrangement of the carbohydrate component and the protein component as we go to those higher valencies is different with the MAPS technology. It's a more ordered kind of arrangement. We refer to it as beads on a string for the MAPS technology, as opposed to spaghetti and meatballs for the glycoconjugation classic technology. We also have the fact that the carrier protein is not an irrelevant, for example, diphtheria or tetanus-related antigen, but is in fact a pneumococcal antigen as well as sharing anti-protein immunity as well. So first, because of the different arrangement, because of the anti-protein immunity, and just empirically- Yeah. ... we're seeing the ability to go to higher levels of valency without the drop in individual component immunogenicity. So Phil, I'm just, sort of processing what you just said. It sounds to me like you're saying they may be able to go a little beyond the 20-valent. Again, when I say beyond 20, I'm saying they keep the first 13 in that construct. Yeah. They may go a little beyond 20, but they're certainly not catching up to... So they may get close enough to your 24, but not all the way to 30. Yeah. And it's 30+. We haven't actually disclosed- Right ... what the actual valency is, but it's, you know, it's the plus. Okay, but you are in agreement that- Yeah. ... the carrier suppression is a gating factor for those traditional constructs to go well beyond 20? Yeah. What I'd say is, it's an empirical observation- Sure. ... that the response to the individual serotypes is going down. And, you know, originally, the MAPS technology was intended primarily to make it easier to manufacture it. Sure. It's a simpler technology. It was an empirical finding- Yeah. ... in the older adult phase II study that, in fact, it seems to also be better at this. We also, as we go higher, we have the option of going to more than one carrier as well. Got it. it. What's your sense for... And I want to get into MAPS much more specifically but what's your sense for? Because the perception is they control much of the market right now, and it makes it incrementally harder for others, especially if they can expand the valency of their current construct. What's your sense for if they're at 20? So there's a PCV 20 in the marketplace right now from Pfizer. They wanna go broader. There's two ways of doing it. One is what Merck is trying, which is a different construct for adults, where it's broader spectrum. Yes. I don't know how successful that would be, because that wouldn't cover infants. A second strategy would be increase, add a little more carrier protein, so you can add, like, two or three more serotypes in there. Do you think that's what they're doing, or are they going down the direction of two carrier proteins? Because then it starts to get very complicated. I probably won't comment on the Pfizer program, because I have to be very careful there. Sure. But since certainly our approach is to both go to more carbohydrate serotypes, and as we go beyond 24, to consider an additional carrier protein. No final decision there. Even for MAPS? Even for MAPS, yes. How- It's an option. Yeah. ... so the perception is, if there's two carrier proteins, it starts to get very risky. I think there was a GSK construct, it, the 10-valent, where it's two carrier proteins. Is that right? Am I thinking right? I don't- There's a- No. ... there's a PCV 10-valent, I forget whose it is- Yes. ... with two carrier proteins, and it's not so strong in data. We have Synflorix, it is a 10-valent vaccine. That is not with the new technology. That's with the prior technology. You know, we'll have to assess in the clinic. Okay. ... what it looks like with two carrier proteins. It doesn't add more risk, a second carrier protein? ... So, you know, every time you add a new antigen, you have to do the safety testing as well, and so obviously that will be done. I don't think it's a particularly high level of risk, but every new antigen you introduce, you know, you need to do a safety as well as- Got it. ... efficacy and immunogenicity assessment. Got it. So- So Phil, when Affinivax was a standalone private company, you can imagine a lot-- there were some investors that were acutely familiar with the company, there were private investors in it, et cetera. And one of the feedbacks was FDA... Because of the theoretical risk, FDA mandated anti-linker antibody testing in the phase I trial. And then I also heard from those same investors that, "Oh, in our phase II now, FDA is not asking us to do it." Can you talk about that evolution? 'Cause presumably it was an important diligence issue in your acquisition. Sure. So, the linker consists of two components. On the protein side, it's a protein called rhizavidin. On the carbohydrate side, it's biotin, and rhizavidin binds biotin very tightly. Rezavudin is a protein from a bacterium that infects plants. It has no homology to any human protein. There is about 22% amino acid identity to chicken avidin, which is in eggs. It does elicit antibodies. The- We eat chicken, is that what it is? Sorry? Is it from the meat consumption? Probably from the egg, probably from the egg. Okay. There's a fair amount of avidin in eggs. That's why I didn't have eggs today. Yeah. In people who do have anti-avidin antibodies, those do not cross-react with rezavudin. And on the biotin side, in these early studies, we looked at both antibodies against biotin, comparing those who received vaccine, those who received placebo. We compared pre-immunization and post-immunization anti-biotin avidin antibodies, and we compared biotin levels before and after immunization. In no case was there a signal, so- On a group level or patient level as well? On a group level. If avidin antibodies go up and down, but if you look at the group level, there’s no trend. So on the basis of the data we’ve generated early on, we no longer have to continue looking at those antibodies. So it was a question that was raised, we’ve gathered data on it, and it looks good. So phase I, there was anti-linker antibody tracking. How often was that? Oh, gosh, you know, I think we would've looked pre- and post-immunization. I don't know how... I have to check on- Got it. ... how often. Yeah. There is no pre-immunization reads that are being taken for your phase III trial? So phase III trial, there's no plan for this. Of course, we don't have the finalized phase III protocol yet. But it does appear that we're not going to have, we will not have to continue looking because we've addressed the question in the earlier stages of clinical. Got it. Presumably, that would be in consultation with FDA? Yeah, absolutely. Right. I mean, the protocols will be reviewed- Right. Absolutely. Then the other big question on this program has been, GSK bought Affinivax, and it turns out there was a massive manufacturing problem. Now, GSK is working on it, and we don't know when they're gonna actually start these trials, and infants is even more delayed. Like, what exactly is going on there? No one really understood. So, I'm not familiar with any massive manufacturing problem. Okay, this is... I'm giving you the investor perspective- Oh, okay. I think I would know about it if there- Yeah ... were one. There is a challenge when you're coming up with a 24-valent or a 30+-valent vaccine- To generate the- There, a lot of work to do. You know, because we had the 10-valent vaccine, we were making 10 carbohydrates earlier, but you have to make 14 more for 20-valent and 20+ more for the 30+-valent. So I would say there's a lot of work to do, but we've not run into any- Okay. So there's a perception that somehow your infant versus adult timing is different. Is that not the case? Sounds like your gating factor is generating stable levels of all 24 serotypes- Yeah. ... and that's it. And once you have it, you can do infant and adult. So it's not an infant versus an- No, what did happen in the infant trial is we had a fill-finish issue. It just had to do with sort of quality aspects of the fill finish, and that did cause a delay in the infant trial. So that was stopped last year. It gave us a chance to have an initial look, and then we'll be restarting this year now. But it was nothing to do with the underlying technology. What was the initial look? So when we stopped the infant trial because of the fill-finish issue, we took an interim look at the data. We've not announced it, but I can say we're very pleased with what we saw. It encouraged us to, you know, to continue- Got it. ... forward on the path. Jeff, you guys didn't press release that, the infant look? No. Okay. No. Yeah. Got it. And are very pleased with what you saw. Okay, got it. Yeah. And the infant look, so presumably it was the first one-third or quarter patients, whatever it was, but tracked for three doses, presumably? I won't go into details, but we looked at all the data that were accumulated up to that point. I see. Okay, that's very helpful actually. I wasn't familiar with that. Is that well understood, Jeff, that there was a data readout internally on the infant trial? Phil has said it before, but- Okay, you have- Yeah. Okay, so you guys have said it in passing. Yeah. Okay. It's not new information. Got it. Okay, no, that makes sense. The Th17 responses are in larger trials. And also I noticed for the... I realized it's the same serotypes, and I was trying to match them up, and I noticed on serotype 20, you guys use 20B and not serotype 20, so that's technically a small difference versus Prevnar 20 and perhaps even with Vaxneuvance approach. How relevant is that? That I'd have to go to the real pneumococcal specialist- Okay ... on that distinction. But, have you seen that as well, what I'm referring to? That among the serotypes, serotype 20 somehow is not 20 for you, it's 20B, and I wasn't sure why that was. You know, I'd have to go back and check into that. Okay, no problem. Okay. Yeah. Any other questions on broadly the pneumococcal? I know there's a lot of interest in this space. Jeff, would you agree this is one of the more questions you guys get broadly on the- Pneumococcal is important because it is a potentially very large opportunity, and it's incremental for us. Because even though we have Synflorix, and it's been around a long time, it's mainly an emerging markets vaccine. We've not really been competing in the pneumococcal space. And I think that because Affinivax was a private company, there's varying degrees of understanding on the platform. So I think more to do as data emerges, and we can share that externally, and it gets presented and published. So- Okay. There is definitely interest level. I mean, vaccines overall, part of the reason why we're here, is a high interest area for us, and we spent a lot of time on Arexvy. That's probably the number one question anybody asks us about, so it was good to spend a lot of time on that. mRNA, pneumococcal are kind of new areas for us, so incrementally different, and, you know, if you want to spend a little time on SHINGRIX, that's the other one. Let's do that. Yeah. Let's do that. I mean- Yeah. This looks like it just keeps going. Is there room for taking a shot again? Like, presumably, that could support a new vaccination campaign for you guys to the extent there's any- Yeah ... data on that. So there are sort of two parallel options. One is a booster, another is age expansion. And- Oh, I see. It's a bit of a yin and yang because the longer the duration of protection, the more interesting age expansion is, and the less interesting a booster is. And we're continuing to collect data on duration of protection, and we're now up to over a decade where the protection looks quite good. So although both booster or age expansion are on the table, I would lean more towards age expansion at this point, but at the point where we start to see waning immunity- What is the age currently versus what would the expansion look like? So, you know, this is sort of an area of sort of active discussion. You know, we go down to 18 for those at increased risk or immunocompromised. So, you know, there are a variety of options on where you could go. We're actually in sort of active discussions about where it is. So for those with immunocompromised, you can go, it'll be all the way down to 18. In Europe, I believe it's at increased risk down to 18. Got it. So they're both questions of how far down would you want to go for a broad age-based recommendation, and how far do you go down for those who are immunocompromised? Right. How far down do you go for those who are at increased risk, but not necessarily immunocompromised? So there are a variety of options to expand the age indication. Got it. Okay, excellent. Yeah. Maybe my last point, broadly speaking, since pneumococcal will remain a very big focus from a pipeline perspective- Yeah ... since given your positioning there- Yeah ... do you, are you nervous from the competitive threat from the incumbents as it relates to how broad they can get? Because ultimately, that's really the question everybody's pinning it down to, that if they become really broad spectrum, then maybe your 24-valent may not be as competitive. Yeah. Yeah. So, you know, I see that MAPS technology really does appear to enable us to go to a higher level of valency without the decrease in response. Second, particularly against some serotypes that have been very hard to immunize against, such as serotype three, the technology seems to do quite well. And then, you have the element of any protein immunity as well. So we think as we push to higher and higher valencies, the MAP- the MAPS technology will enable us to outpace the incumbents. Excellent. Fantastic. Yeah. Well, thank you guys for being here. I hope this was helpful. Yeah. Looking forward to being in touch. Thanks a lot. Great. Thanks for having us. That was a pleasure.