biotech summit. We host this event every year, and I'm really pleased once again to have Vaxcyte joining us. To my immediate left is Grant Pickering, CEO, and to his left, Andrew Guggenhime, President and CFO. You know, maybe just to kick us off, you know, it was an interesting year in 2025, but obviously, I think we're off to a very different start in 2026, Grant. Maybe you can just sort of remind folks what is particularly exciting about Vaxcyte in 2026, and then obviously following through into 2027 and beyond. Yeah, I think what we've become known for is our pneumococcal conjugate vaccine franchise. We are building a really important series of new vaccines in what has been the most attractive and important class within the vaccine segment. We have other vaccines that we're working on, but certainly, the pneumococcal conjugate vaccines have become the headliner for us, and this is a really important class of vaccines. These are preventing the primary killer of human beings historically. A century ago, pneumococcal disease was the leading cause of death. We've been able to create vaccines to stop that, but there is still a substantial amount of residual disease, and the current technologies have been limited by particular aspects of their construct. And we've been able to figure out how to take the same immunogens, put them together more nimbly, and create more broad-spectrum vaccines to prevent more disease. And so we think this has the makings of a really attractive business opportunity. It's already an $8 billion segment that is poised to grow substantially as we begin to vaccinate adults as aggressively as we've been vaccinating children. And we think this sets us up to create a really important company and a really important new set of vaccines. Great. So, you know, without jumping directly into the phase 3 program, you know, there's also positioning in the market that's very important. Maybe you can just remind us the importance of having, you know, potentially the broadest vaccine as well as, or approaching pneumococcal disease, you know, as well as just sort of the, the opportunity, for Vaxcyte to actually be able to monetize that opportunity. Yeah, so, pneumococcal bacteria are characterized by having over 100 different serotypes that circulate. Fortunately, not all of those are actually problematic from a disease perspective, and so you have this rank order of importance. And so what was the very first version of a pneumococcal vaccine had 7 different serotypes in it. When you use the vaccine like that, which is so effective, it takes those serotypes out of circulation, but you can't stop vaccinating against them, or they come back. And when you take them out of circulation, other serotypes begin to circulate in that void. And so we've gone from 7- 13- 15, 20, and now 21. And what both of the current makers of pneumococcal conjugate vaccines have said is they can't really get beyond 20 or 21 in a vaccine and get it to be effective. We figured out a way to put together the conjugates in ways that can be sparing of a particular component and allow us to create a vaccine that has more than 20 or 21. So where we are, our current state of play is we have a 31-valent VAX-31 program that's already shown the best data ever generated in this class in adults, and we're awaiting the readout in infants. But we seem to have cracked the code on the ability to expand coverage without sacrificing immunogenicity. And, you know, if we're successful in that mission, the way the market has behaved is there's a rapid adoption and shift to the broadest-spectrum vaccine available, and so we have an opportunity to draft off that historical precedent. Great. And just quickly, in terms of the ability to kind of commercialize globally, should the adult program be successful, which I think many expect, you know, what is the sort of necessary reach in kind of key global markets as you think about the opportunity, you know, to really approach the entire marketplace? Yeah, I mean, as Grant said, you know, there's a significant and growing opportunity outside the U.S. Obviously, this is, again, both adult and infant indication. For adults, historically, the overwhelming share of the market has been in the United States. Most countries outside the U.S. did not have recommendations for universal vaccination of their adult populations. That is changing today. So over the last couple of years, you've seen an increasing number of companies make recommendations, and you're now seeing that market grow. If you look at the numbers reported recently for both CAPVAXIVE and Pfizer, significant growth ex-U.S. They're doing a lot of work to build those markets that we can draft off of when we have the opportunity to come to market with our adult program. You know, we just hired our first Chief Commercial Officer a few months ago, kind of really assessing... Mike Mullette, who's in the audience with us here today, assessing, you know, how we penetrate that ex-US market. But we think it's a significant opportunity now growing in adults, very, you know, significant in the infant population. We're deciding, you know, what that go-to-market strategy looks like, in what countries we would seek to commercialize on our own, and in what countries we might seek to partner. I think, as we've said historically, publicly, given the scope of this, ... the global opportunity, particularly for infants. There's not many scenarios in which we commercialize in every country around the globe on our own. We're gonna be very selective about the commercial strategy in ways that allow us to really maximize the opportunity here and make this vaccine as broadly available as possible. Great, perfect. So, you know, we've talked a bit about adult, and I think our own forecasts would imply, you know, a $4 billion-$5 billion market that's sustainable over time. Obviously, there are catch-up cohort opportunities built into that, but, you know, let's talk about the adult program itself. You know, it's underway. Maybe you can talk about the number of trials that you have initiated already, you know, and just highlight what might be comparable or different, particularly in the context of the, you know, sort of regulatory environment. Yeah. So, on the back of our phase 2 data, we have launched our phase 3 program for VAX-31, and what was unprecedented about our phase 2 data was the norm has been to expand coverage at the sacrifice of the magnitude of the immune responses. What we were able to show in phase 2 is we were able to substantially increase the number of conjugates and actually improve the immune responses. So we're working with a much stronger hand, frankly, as we think about the design and conduct of a phase 3 clinical program. So what we worked out in close consultation with the FDA was a series of clinical studies anchored by a pivotal study that we call OPUS- 1. It's a 4,000-subject study in adults over the age of 50, and we will be comparing VAX-31 to both of today's standard-of-care vaccines in ways that will look to demonstrate non-inferiority for those overlapping serotypes and superiority for those serotypes that are over and above either of those two vaccines. So we're effectively following the same path that others have trod before us. We did agree to a higher standard for the definition of non-inferiority than the FDA has historically applied. They've been actually moving to a higher standard, because for adults, there's some anxiety where this trade for lower immune responses for better coverage could come at the expense of the protective rates for the included serotypes. So our data was strong enough that we were very confident that we could use a higher standard to reassure the agency that the immune responses would be upheld in ways that we'd not only be able to demonstrate broader protection, but also preserved protection over time. So that was a wrinkle that was coming for the class. But for us, you know, we're exceedingly confident that that's gonna be manageable in terms of this pivotal study that's underway. Complementing the pivotal, we have two other studies, one of which launched last month, where we're concomitantly administering VAX-31 with flu vaccines, which is a typical way that these vaccines are given at the pharmacy. And then just yesterday, we launched a third vaccine, where we're administering VAX-31 to adults who had previously gotten a lesser valent pneumococcal vaccine, to be able to demonstrate the ability to boost the serotypes they've already been exposed to and expand the protection with the incremental serotypes that are in VAX-31. And to round out the Phase 3 package that we'll be planning to put together for a filing, late next year, we'll do a manufacturing consistency as well, which is kind of par for the course in this class. Right. So not a lot of changes other than that 0.667 threshold. Yeah. And it sounds like I guess that isn't a new threshold that the agency was actually seeking. It just happened to be one that the companies managed to sort of establish different statistical bars around that to establish non-inferiority. So historically, it was 0.5, now 0.67, and as a result, you know, because of your data, we should feel pretty comfortable from the phase 2 moving to phase 3, that that can be replicated. Maybe just remind us, that path from phase 2- phase 3 historically, how has that kind of matched up- Yeah ... over time? Yeah, so the predictability of this class has been quite high. So every pneumococcal conjugate vaccine that's produced successful phase 2 data has gone on to produce successful phase 3 data and gone on to be approved. And I would say with humility, the data that we've generated in phase 2 is the strongest that anyone's ever generated in the class. So it gives us a lot of confidence that we're on the right track with not only a program that's looking like it should be approvable, but should also be best-in-class. Great. And then maybe just remind us how to think about the comparisons to the two vaccines. You know, serotype 3 is kind of a unique serotype. Maybe just help us understand how the comparisons work versus CAPVAXIVE or the 21-valent, and versus Prevnar 20, how you're thinking about that, and ultimately, when the data comes, how you guys would encourage investors to think about it. Yeah, so just to be clear, so we have two different vaccines that are the current standard of care today. So we have Prevnar 20, which has been the market leader, and then we have a more recent entrant, CAPVAXIVE, which is a 21-valent pneumococcal conjugate vaccine that was launched a little over a year ago. What was done was both companies are working off the same core technology, and so Prevnar 20 was already out, and, Merck was clever, and they said: Well, if we're limited in the number of serotypes that we can put in a single vaccine, perhaps we can shift the coverage over to the newer, more recently circulating serotypes and not include those older serotypes that have gotten under control because we've been vaccinating against them. So it set up a situation where CAPVAXIVE has been able to show a broader coverage footprint in this moment because they're addressing the currently circulating serotypes, but the older serotypes for which they have the greatest fitness to actually cause disease, and the reason why they were selected in the first place, those would not be covered if you give CAPVAXIVE alone. So you have a situation where you've got two different vaccines with two different coverage profiles. Some of those older serotypes are still circulating, and that was the reason why the decision-makers chose to recommend both vaccines instead of one relative to the other. VAX-31 is designed to cover all of those older serotypes and the newer serotypes in ways that would offer a much more improved singular solution to either of those two. So it sets up a situation where we have a current market leader, but a new product that has broader coverage, that is getting a wonderful reception in the marketplace. They just put out their numbers recently. They've sold over $750 million in the first full year since launch. I think you can project their market share is approaching 40%-45%. So it's being recognized by the same primary adoption feature that everyone has applied in this class, which is coverage is king. And so what we have is a situation where Prevnar 20 might be today's market leader, but CAPVAXIVE, it may well be the market leader by the time we launch VAX-31. Right. We chose to set up our pivotal study, where we compare to both of these currently marketed vaccines. It sets up a situation where we're comparing across two different vaccines, some of which have overlapping serotypes and others that are only in one or the other, and then we've got more on top of that. We've set up an analytical plan, where we have a situation where for the 10 serotypes that are in all three vaccines, we need to hit the non-inferiority standard for at least one of the two comparators, and then we have 10 serotypes that are in Prevnar 20 and VAX-31 exclusively. We'll do a head-to-head non-inferiority on those, and then relative to CAPVAXIVE, there are eight that are just in CAPVAXIVE and VAX-31, so we'll do a head-to-head there, and then we've got our number of serotypes on top of that, where we'll show a mean fold rise. So, the history of this class is no one's ever been perfect. You're adding coverage, so there's room to maneuver if you have a lesser response on a particular serotype, if you're adding enough coverage. Yeah. You know, we've been reassured by the FDA that that same trade-off acknowledgement will apply to VAX-31. But, you know, we have really compelling data, so it's good reassurance. Hopefully, we won't need it. Got it. Great. And just to clarify, it sounds like if you have the overlapping serotypes, it's one or the other, not both end, for kind of establishing non-inferiority on those thresholds. Yeah, that's how we set up the- Okay ... analytical plan. Perfect. That's actually really helpful. I mean, I think not a lot of people have fully digested that from my perspective. So I think that's a great thing to chat about. You know, and then just in terms of the different patient populations that can be applied on the adult side, 50-64, 65+, how are you guys approaching that? And what were some of the specific regulatory requirements in- Yeah. So, so for adults and pneumococcal conjugate vaccines, even back to the very first one, they were approved initially for adults over the age of 50, but the recommending bodies chose to only universally recommend the vaccines for 65 and older. So, that has changed just in the last two years. They've lowered that universal recommendation to adults over the age of 50 and up. So, we... They've always been important, both of those subgroups, but now only that much more important to ensure you have adequate immune responses in 50- 64-year-olds. So the Phase 3 pivotal study is in 50 and up. The majority of the subjects will be in that 50- 64-year-old category, but you still want to include a substantial number of older adults to confirm that those who are frankly most vulnerable to pneumococcal disease will be protected. So that's been the convention for each of the currently marketed vaccines as well. So we're following a very similar approach. Right. Perfect. And in terms of what additional learnings we'll get from the other OPUS programs beyond OPUS- 1, you know, what would you say is kind of the most important incremental study? I know every single one of them is important, but which one would you say could reveal some interesting incremental characteristics? I mean, certainly, the pivotal study is the foundational study- Yeah ... that will, you know, pave the way to the approval. The other studies have multiple objectives, one of which is to round out the safety database to confirm this is a safe and well-tolerated vaccine. But, you know, to be able to be concomitantly administered with flu vaccine is helpful, it's not an imperative. I mean, you get a pneumococcal vaccine maybe once every 15 years, so it's not something you're getting annually like you are with flu vaccines. So I'd call that a matter of convenience and nice to have. I think the study that's set up to show that we can not only improve the immunogenicity to already exposed serotypes through prior vaccination, but then expand it with the incremental coverage, is probably more important in the context of getting a recommendation for catch-up. So the reason the catch-up recommendation is so valuable. It gives you an opportunity for the whole populace for whom they may have gotten either Prevnar 13. Mm-hmm. or the even older vaccine, Pneumovax 23, an opportunity to be recommended for vaccination with VAX-31 in ways that it opens up a substantial number of potential recipients in ways that you can really benefit, benefit them with particular protection against the serotypes that are now circulating. Yeah. So I would argue that would be one that we'd want to see read out positively. Great. And then- I was gonna say- Yeah. I would just say that really represents an upside opportunity in the U.S. adult market. You already have a market that is roughly $2 billion today in adults, expected to grow by way of the lowering of the recommendation from 65- 50. Obviously, more Americans who turn 50 every year than 65. You've got 60-65 million Americans who become, as Grant said earlier, immediately eligible for vaccination. There's the prospect of down the road, a recommendation for a booster dose when adults turn age 65, and which those things already grow the market substantially. And then this upside opportunity, which would be, to the extent we're able to get it, a preferential recommendation for anybody that's already gotten a less prevalent vaccine for whom it's been a certain period of time. Right. And just remind us what the setup is in the current market. CAPVAXIVE may have broader coverage, but has a preferential recommendation been established by ACIP between either a Prevnar 20 and CAPVAXIVE at this point? There wasn't writ large. It was a joint recommendation for either vaccine, because they just couldn't select between improved coverage of circulating strains at the risk of losing protection of strains that were already under control. The catch-up recommendation is exclusive to either Prevnar 20 or CAPVAXIVE, at the expense of the 15-valent that's still available. And so there is kind of a pocket preferred recommendation concept that's now shared, but prior to CAPVAXIVE launch, Prevnar 20 had it on a singular basis relative to the other vaccines. So, yeah, it has served as one of the key differentiators in the past in this class. Okay, great. But it isn't sort of a preferential aspect, and the market share gains happen to be coming to the current asset that happens to have the broader sort of circulating coverage. Correct. That resonates, and then the follow-through is very clear. If 31 shows the profile that we believe it will, it becomes sort of the next, incremental recommendation. Yeah, I think it's definitely a possibility. Okay, great. You know, maybe we'll switch to the pediatric. It's probably not enough time to talk about it, obviously, but, you know, just maybe remind us the sort of expectation for what that program is likely to look like, when we're going to see the data from your Phase II VAX-31, and, you know, maybe lastly your thoughts on the need for an outcome study across both the adult and the pediatric opportunity. Yeah, so I think as it relates to outcome studies, we've already answered that question as it relates to the adult study. So we just negotiated the full scope of the phase III program with the FDA over the second half of last year, and the same bargain was struck for our program as it has applied to the two currently marketed pneumococcal conjugate vaccines for adults, and that's in the context of the post-approval setting. You set up a surveillance study to confirm that the vaccine is truly effective, as we all know they are, because every time a vaccine is introduced with broader coverage, the disease rates drop. Yeah. So there's been no disconnect between that from the very first version of the vaccines that came out 25 years ago. We will do a similar surveillance study in the post-approval setting for adults. As it relates to infants, we haven't gotten that far yet because we haven't had an end-of-phase 2 conversation. The same expectation would apply. But for our program, last year, we received the results of our first infant program for our 24-valent vaccine, and next year, we'll be in receipt of the phase 2 data for our VAX-31 program. What we learned from the first study output was we're on track. We have a 24-valent vaccine that looks approvable when you look at its profile and the phase 2 results compared to today's market leader, which is Prevnar 20. You know, in the context of thinking about a 31-valent vaccine compared to Prevnar 20, it would be a really massive improvement in coverage, taking today's coverage rates of around 60% up into the ninetieth sort of percent protection, which would be a huge improvement in ameliorating disease in kids. So for us, you know, we're looking to repeat the immunogenicity of the incremental serotypes. With the VAX-24 data, we showed improved immune responses for the serotypes that are still circulating, that are in Prevnar 20. We did have some misses, as it relates to the non-inferiority comparison. Happened to be confined in the serotypes that were not circulating at meaningful rates, which is good, and we are testing higher doses of the vaccine in VAX-31, for which we hope and expect to see improved immune responses in order to minimize the number of misses that we might have. But the way this class unfolds is, you know, the trade-offs you make are to improve coverage. You know, you can see some lower immune responses for older serotypes that haven't circulated. I'm talking about not having circulated in the U.S. for 10-15 years. Yeah. And so you know, comparing that to a vaccine that's causing 5%-7% of disease right now, that's a really good trade. And it's not a suggestion that it's not gonna work at all in terms of keeping those older strains at bay. You might just have slightly different lower titers of the antibodies, but they still may well be well above the protective threshold in ways that you don't have a particular concern. So that's kind of where we are on the infant side. That has historically been the biggest part of the market, but the adult side is growing really, really fast, so they're both important for us, and as we think about Vaxcyte's evolution, but more questions to answer on the infant side than on the adult side at this stage. Okay, great. And then, you know, when we think about if an outcome study were to be required on the infant side, can you just talk about the importance of an otitis media opportunity and how, you know, that could be attacked very successfully by VAX-31, maybe in contrast to some other potential competitors? Yeah, it's, it's not to suggest that we have an expectation that an outcomes trial would be required, but we do have the unique situation where the amount of coverage that VAX-31 provides, which in the case of acute otitis media, is 92%, and the amount of typed acute otitis media covered by Prevnar 20 is two- to three-fold lower than that. It does create an opportunity where we could run an outcome study to demonstrate the disease prevention with VAX-31 in ways that could be performed and completed in a reasonable timeframe at an affordable amount to demonstrate the utility there. And pneumococcal disease is usually the cause of otitis media initially in children, and then it creates a situation where there's a prolonged inflammatory effect for which other more virulent bacteria tend to cause disease. If you can prevent that initial pneumococcal infection, it would be really, really meaningful to prevent even more serious disease in kids. Great. Well, unfortunately, we're out of time. Grant, Andrew, thanks again for taking the time. Congratulations on the recent successful raise as well. Maybe just as one final point, kind of your sort of full capitalized capacity and how far the cash kind of brings us out. Yeah, I would say pro forma for the financing, we just closed a little over a week ago. We have over $3 billion in cash now, so we're in a really good position to see our way through several milestones over the next couple of years, including the potential approval and launch of the VAX-31 program in the adult population, you know, which, as Grant said, we're planning to be in a position to submit the BLA by the end of next year, would put us on track, and what we're targeting to have approval and launch in 2028 to get through that important milestone as well. Super. It just reminds us that in biotech, cash can be king. So thanks so much. Thank you. Great. Appreciate it. Thanks, Seamus.