Good afternoon, everyone. Thank you for joining the 24th Annual Needham Healthcare Conference. My name is Joseph Stringer, and I'm one of the biotech analysts at Needham & Company. It's my pleasure to introduce our next presenting company, Vaxcyte. Joining us today from the company is CEO Grant Pickering, CFO Andrew Guggenhime, and Chief Operating Officer Jim Wassil. For those of you joining on the webcast, if you would like to ask a question, please do so at any time. You can submit a question using the chat box feature at the bottom of your screen. With that, we'll go ahead and get started. Members of the Vaxcyte team, thank you so much for joining us today. Thank you for having us, Joey. Certainly some interesting times, but I want to start off with a general question, Grant. Can you just give a brief overview of Vaxcyte, why your approach is unique, in particular for developing pneumococcal conjugate vaccines? What gives you the advantage over some of the entrenched pharma players in this space? Yeah, so Vaxcyte is totally dedicated to developing bacterial vaccines that can prevent disease that is unchecked today. We are leveraging a cell-free protein synthesis platform that is proprietary to us. You mentioned pneumococcal conjugate vaccines. That's really what we've become known for. We do have other vaccines that are earlier in our pipeline, but we've been able to develop not only a 24-valent pneumococcal conjugate vaccine, but also a 31-valent pneumococcal conjugate vaccine. We call them PCVs, so we use that for short. What we've been able to show is we can leverage our cell-free protein synthesis platform to take the same immunogens that have been used historically in this class, but our chemistry and our platform allow us to more nimbly assemble these conjugates. We have shown that we can dose them at the same amounts of the polysaccharide component, but with lower amounts of the protein carrier and get immune responses that are at least as good as today's standard of care vaccine, which is a 20-valent vaccine. Yet, we have also shown that we can add conjugates to increase coverage, and we can add them at higher doses of the polysaccharide where we give similar amounts of the protein and generate even higher antibody responses. Those higher antibody responses are, you know, critical. The higher the responses are, the better you would imagine that the recipient is going to be protected from disease. For us, the latest adult data that we generated last year had the highest antibody responses in that higher dose with our 31-valent vaccine. We are really excited about the platform. This is a really critical class. This is kind of the bedrock of the vaccination schedule. We believe we really have something important and different in our PCV candidates, but then are also excited about leveraging this technology with additional bacterial vaccines that are in our pipeline. Great. Before we get into some of your programs and the data, just want to get your take on the recent developments and layoffs within HHS and FDA, and specifically what long-term impact do you think it will have on your vaccine program? Andrew, you want to take that one? Yeah, no, happy to. Thanks, Grant. Thanks for the question, Joseph. Look, I, you know, we recognize that, you know, the news flow on this topic in general over the last few months is seemingly incessant and can be disconcerting. Feels like we're, at some level, careening from one headline to another over the last few months, right? We've seen prior headlines about canceled ACIP meetings, canceled flu strain meetings, right? The vaccine position of the prior CDC director nominee. And now, of course, more recently, the news flow with respect to the FDA and HHS layoffs, and of course, including the Peter Marks news. You know, what we are reminding folks, and we think it's really critical, is to kind of separate this noise, news flow, and headlines related to the politics of the administration change to separate that from, you know, potential true substance and policy impact. In fact, as we look now over the last couple of months, right, that ACIP meeting has in fact been rescheduled, right? The flu strain meeting did in fact occur. The prior CDC director nominee was pulled and replaced with somebody who has a really strong background in public health and science-driven policy. Now, even related to the more recent FDA and HHS headlines, we're seeing that many of those individuals are now being asked to stay at those respective agencies. Even looking over this weekend as well, right, related to the growing measles outbreak, you know, RFK Jr. has made his strongest statements yet as it relates to the vaccine, saying that, right, the MMR vaccine is the most effective way to prevent the spread of measles. Again, really important to distinguish kind of the political rhetoric, the headlines from actual policy changes. To date, at least as it relates to Vaxcyte, right, we've seen no disruption to regulatory timelines. We've seen no change to the personnel with whom we've been interacting over the last several months and quarters, right? We haven't seen any direct challenges to the longstanding platforms for vaccines, you know, including PCVs, right? This is a pathway, a regulatory pathway that's incredibly well established, and we've seen no indication that recent developments are going to impact core vaccine platforms like PCVs. As it relates to vaccines, you know, more of the attention has been put on kind of mRNA platforms and COVID-related programs that are not related to us. Look, we feel very confident in the PCV programs we have and the recognition, bipartisan recognition of kind of continuing to protect both adults and infants from pneumococcal disease. We continue to focus, as I said, on the substance and not the noise, and are very active and engaged with policy stakeholders to ensure that kind of science and public health kind of remain critical elements. We're engaged with the White House and HHS levels, and we're engaged with folks on Capitol Hill as well. Got it. That's very helpful color. Maybe just a brief follow-up on ACIP. Been some recent votes and some, you know, news around RSV, et cetera, seem to be relatively positive for maintaining vaccine schedules. I guess, can you comment on anything you've heard or you're hearing about ACIP vaccine schedules and the current administration's plans for any potential changes to that? Yeah, I'm happy to take that one as well. We're, you know, we're not hearing about changes to schedules, just to be succinct. Got it. Okay, great. Let's talk about the market, the data, your programs here. Just provide us with a brief overview of the pneumococcal vaccine market. How big is it? How fast is it growing year over year? Where are the next opportunities for growth? Jim, do you want to take that one? Sure. The overall pneumococcal vaccine market is around $7 billion-$8 billion currently. We see growth over the next several years. The first growth is, of course, you know, price increases in the U.S. market. Pfizer just announced that they moved their price up to $275. It is more than a 5% increase. I think while the overall infant market is saturated, price increases, I think, will contribute somewhat to that growth. The majority of the growth is really going to be coming from the adult market. In the U.S., we saw that the recommendation was moved down from 65 years of age to 50 years of age. That obviously increases the cohort size, but they have not made a booster recommendation at 65 again. I do think they've sort of given a few Easter eggs, so to speak, that they will eventually evaluate that and consider that. If you do that, then you're essentially doubling the U.S. adult market. Ex-U.S., because of the expansion of the serotypes with PCV20 and now Capvaxive, you see other countries implementing an adult program where they didn't have one previously. Germany had announced one last year. Australia had been doing one for a while, and most recently, France had just announced that they're going to start doing an adult program as well. I think we'll see some growth over the next few years, and you could get above $10 billion, maybe $11 billion, $12 billion in the overall size of the market over the next three to five years. Got it. You guys announced VAX-24 phase II infant data. Just came out last week. Can you give us a high-level refresher on the key takeaways that you reported in that top-line readout? Yeah, happy to. Obviously, we were disappointed with the market reaction. We put out the news last Monday. Probably could not have been worse timing to the extent that Peter Marks had just resigned, and there was a lot of chaos last week that is obviously even continuing into this week. It was a tough backdrop. It was really a positive release. I mean, we have a 24-valent pediatric vaccine that is able to pass the primary test of a phase II study, which is looking good on safety and tolerability, where we compared ourselves to today's standard of care, the 20-valent vaccine. We saw very similar safety and tolerability. As it relates to the immunogenicity profile, we were able to show that all 24 of the conjugates were very immunogenic, and you measure that across a couple of different ways to measure the immune responses. Critically, you can't have a pediatric vaccine if you don't show a meaningful boost to the initial prime. This is the beauty of this class, is you get memory responses, you get T-cell dependent responses, and that's what confers durable protection for these infants. We saw all of those things in the study. That said, we did not see perfection the way we had seen for VAX-24 and for VAX-31 in our adult studies. We were managing expectations when we had had three phase two studies where everything looked perfect on safety and immunogenicity. You know, we had been guiding that in the infant class, it's more expected that you won't hit on all of the immunogenicity endpoints. Now, the reason that that has been acceptable to the regulatory authorities for the prior versions of today's marketed vaccines is that each of the subsequent generations of this class of vaccines is adding more conjugates in order to create more broad protection. The vaccines, when they're used widely, the strains that are included in the vaccine are largely taken out of circulation, and in their place, newer strains begin to circulate, causing disease. The FDA is always balancing the benefit of a broader spectrum vaccine in relation to what would be the concern if the responses are getting lower to some of the strains that are under control. We had been guiding the investment community to expect that we might miss on a few of the comparative serotypes. We did end up missing on four at the initial co-primary endpoint, which I think was perceived as more than we'd expected and certainly more than I think they were hoping, given the perfection we'd shown to date. In the scheme of this class, that's a manageable number of misses. We believe we have an opportunity, Joseph, to look at the doses of the conjugates where we've seen really nice dose responses, where we test higher doses of the conjugates and get higher antibody responses. We very much have conviction that we have a path forward in infants. It's just a matter of taking this dose-finding data that read out last week and making the right modifications to optimize dose to get the right responses to be on track for a phase III program and advancing a product to the market. To follow up on that, I think we talked about missing non-inferiority on serotypes, but sometimes the number of misses that gets proclaimed good or bad is somewhat arbitrary. I think you guys have mentioned this before. Regulators care more about serotype coverage to a large extent. I guess to that point, can you put the recent phase two results of VAX-24 in infants in context and maybe use Prevnar 20 as an example, where in their phase III infant trial, it actually missed on several serotypes relative to Prevnar 13 and ultimately got approved with no issues? Yeah, that's right. Each of the different, each of the unique pneumococcal serotypes have their own circulation profile. We're able to leverage the databases where they collect the information for confirmed disease caused by pneumococci, and then they trace it and type it specifically to the serotype. We know that each of the serotypes have their own circulation rate. It does just so happen that one of the most encouraging things that we saw from the data that read out last night, or sorry, last week, was that while we expected to miss on a few, the few that we did miss on were not circulating either at all or in any meaningful percentage. Of the four that we missed on at the first of the two readouts, only one was circulating, and that was less than 1%. The other three weren't circulating at all. Conversely, the serotypes that are circulating at the highest rates were we showed our best comparative immune responses. If we could have picked ones to miss on, I think we found ourselves in that kind of ideal outcome. Now, going forward, we're going to do what we can to improve them with higher doses. You're right, there are multiple precedents where strains are missed on the comparative endpoints, and yet they're still able to be included in the vaccine because the totality of the evidence supports the vaccine. You can look at each serotype and look at some of the confirmatory additional secondary responses to gain confidence that you're on track. We did get very encouraging secondary data to support those serotypes where we fell short of the mark. As I said, I think we have confidence that we have the lever of dose to see better immune responses, for which we've already taken a VAX-31 infant program into the clinic where we're already testing these higher doses, which is giving us confidence that that next readout for us, at least for VAX-31, will address some of the issues that we saw in this dataset. Got it. You touched on it a little bit earlier, Grant, but just kind of a couple of follow-ups. Just given that you had seen such stellar data with VAX-24 and VAX-31 in adults, you know, the overall responses post dose three and post dose four for VAX-24 in the infant was lower than I think what Vaxcyte had expected. Can you maybe provide some context on those results, just given the adult data? As a follow-up, you know, I think the IgG, GMR point estimates post dose four were generally a little bit lower, numerically lower than post dose three, which is a little bit unexpected. What is the explanation there on why that was the case? Yeah, we had been guided by the doses that had, let me back up a little bit. When we took our first formulation of VAX-24 into the clinic, you always start in adults. We were establishing doses to test based on the historical dosing with the other marketed vaccines. What we saw with the VAX-24 formulations in adults was that when we dosed at the same amount of polysaccharide relative to the standard of care, we could get equivalent immune responses and in some cases, better immune responses. Keep in mind, when we dose at the same amount of the polysaccharide, our vaccines actually have less protein carrier in each conjugate relative to the standard of care. We went on to show in the VAX-24 adult studies and the VAX-31 adult studies that we could increase the doses of the polysaccharide beyond the standard of care dose. When we do that, we end up giving a similar amount of the protein carrier, Joey. We were able to show that at the equivalent doses, we could show equivalent immune responses when it is the sugar. When we showed equivalent amounts of protein on a relative basis to the standard of care, we got even better antibody responses. I am referring to the VAX-31 high-dose data where we had increased the doses across the board. Unfortunately, we did not have that VAX-31 data that read out in September when we started the VAX-24 infant studies. We took the same doses we had taken in originally for adults into infants. We started the study right after we'd gotten the adult results. What we found, and we knew this, was that the infants who are totally naive to these immunogens, right? These are two-month-old infants that are getting vaccinated. You compare that to adults who have already been exposed to components of the vaccine. To remind everyone, the protein carrier that the standard of care vaccines use and we use, now we make some modifications in how they're assembled, is a diphtheria toxin. Everyone gets, you know, DTaP, which is a diphtheria vaccine. We all have some baseline immunity to these components. When you vaccinate adults, they've already effectively been primed. They have some baseline immunity, and you're boosting them. We were able to use lower doses in adults the way that it did not translate to as good of an immune response in infants. You know, I think that is, you know, we have to be very clear about that, the magnitude of relative immune responses for VAX-24 at that middle 2.2 dose were not as good as what we had seen in adults. We believe that is because when we are using carrier-sparing conjugates in the infant population, we just did not bring enough protein carrier to that naive host in ways that we are able to build the prime in order to permit the kind of magnitude of boost that you see after the fourth dose. That is the key learning for us. We were able to show in the infants that for those serotypes that we dosed to the highest level, which is 4.4, we saw the benefit of that. We saw the immune responses going up in almost every case. We know that in infants, just like we know very clearly in adults, that when we increase dose for these conjugates, we get better antibody responses. That is the next step for us, to prepare a VAX-24 formulation with those conjugates at higher doses that would benefit from it where we missed the mark. We also know that we have already started this VAX-31 study, Joseph, where we are already testing those higher doses. We made a strategic decision before we decide on which phase three dose and which phase III program. We're going to wait until we get that VAX-31 data middle of next year to inform on what could either be a VAX-24 phase III program to advance or more ideally, like we were able to show in adults, an opportunity to graduate to an even broader spectrum 31 valent vaccine where the coverage advantage for us is even more dramatic than the coverage advantage we have with VAX-24. You'll be disclosing VAX-24 phase II infant data, the post dose four data, the full dataset, I should say, for that in the fourth quarter of this year. What can we expect to glean from that additional data? Yeah, so that's exactly right. Before we get the VAX-31 data middle of next year, we will get the benefit of the balance of this dataset for VAX-24 in infants. We made a choice to look at an interim for the post dose four data. What we saw was that we had a number of serotypes that very narrowly missed the actual licensure standard, which is having the lower limit of your confidence interval exceed 0.5. What we said, you know, the headline is we missed on five of our targets for this post dose four at this interim look. When we get the complete dataset, we're going to be able to get the full balance of the participants. We were able to get two-thirds of the data in this interim look. We'll get the balance, which is a 50% increase. Those confidence intervals will tighten up because of the number of events that are included. There is that possibility that some of those where the lower limit fell into the below 0.5, they're very, very close. They could tighten up, which would obviously help the headline value to potentially minimize the number of the five. That will be something to watch between now and the end of the year. Thank you for asking about that. Great. You touched on it a little bit before, Grant, but considering the VAX-24 or going from VAX-24 to VAX-31 in adults, you were clearly able to adjust dose and improve or maintain some of the immune responses on the individual serotype level. I guess my question is, can you remind us of the dose level for each serotype in the VAX-31, the ongoing phase II infant trial? Maybe I'll ask, what gives you the confidence that this type of dose level or optimization that worked in the adults would translate to the infant population in that phase II infant readout next year? Yeah, so just to ground everyone, the conventional dose for today's standard of care vaccine is 2.2 mcg of the sugar. They do have one that's dosed at 4.4 mcg. When we originally set out the doses for VAX-24 in adults, we had used 2.2 mcg for all 24 of them. For seven of them, we tested them at that higher 4.4 mcg dose. What we saw there was that when we do go to a higher 4.4 mcg dose, we get higher antibody responses. That was a key learning from the original adult data. We took those same formulations, took them into infants. To your question, with VAX-31, what we saw was that while things look great at 2.2 mcg, we saw that there were a few serotypes that when we intermingled them with higher 4.4 mcg serotypes, they suffered a bit in their antibody responses. We made two key changes to the formulation that we took into the clinic for VAX-31. We stuck with a 2.2 mcg dose as our middle dose. For those few serotypes that had suffered, we increased them on a relative basis. We put them at 3.3 mcg. For the high dose, we moved them all to 3.3 mcg, except those same three, we put at 4.4 mcg. That is the exact same formulation that we have taken into infants. To remind you, the adult outcomes were that that middle dose where they are all at 2.2 mcg or higher, they all look great. They all passed on all 20 of the comparative immune responses and hit on all 11 of the incremental serotypes in the vaccine. For the high dose where they were all at 3.3 mcg or a few at 4.4 mcg, the antibody responses only went up on a relative basis. That is setting a bar that we think will be higher than, well, we think it will be harder for others to meet. That is the, those are the formulations that we have in the clinic in infants. We will be testing the serotypes at higher doses. Those same three serotypes that we dosed upward in adults based on the adult data also missed the mark at lower doses in the infant data. We already have them pushed to the 4.4 mcg level. We feel like we have already taken most of the steps that we would have taken in light of this VAX-24 infant data that read out last week based on learnings that we had from the adult data that we used to inform for the VAX-31 doses. Got it. Looking ahead to the VAX-31 phase II infant data middle of next year, just a quick refresher on the trial design there relative to what the VAX-24 phase II data, phase II trial was, and what top line data should we anticipate? The design is very, very similar, if not identical, to what we saw with the VAX-24 infant study. As other sponsors have done, there is an opportunity to look at the first of the two co-primary endpoints after the third dose. Just to remind everyone, in both studies, we have three different doses of VAX-31, just like we did with VAX-24. They are slightly different. We have skewed higher for VAX-31. You look at the immune responses after the third dose, and then a fourth dose is administered to the infants who are now toddlers at this stage. You look after that dose to see the immune responses after the boost. We were able to look at all of post dose three for VAX-24 and an interim look at post dose four with the data we put out last week. What we've been guiding is that for the data for VAX-31 and our guidance to mid-year next year, that is for the post dose three data. It is too early to say whether or not we'd have any post dose four data yet. It will all depend on how the enrollment rates go. For now, the guidance should be expected to be just post dose three data. Okay. Makes sense. That's very helpful. You have the VAX-31 phase III trial in adults starting middle of this year. Any quick updates on that one? Yeah. We, oh, Andrew, you want to take that one? Sure. Yeah. We just in connection with our announcement last week, Joseph reaffirmed our guidance to initiate the VAX-31 adult phase III non-inferiority study by the middle of this year, right? That's the most important of the few programs, studies that will comprise your overall phase III program. Reaffirm the guidance as well that we expect that study to read out top line data next year. The balance of the studies that will comprise the phase III program for VAX-31 in the adults will start either this year or next reading out in 2026 and 2027. Okay. Great. NextGen PCV VAX- XL, you think you publicly disclosed it for the first time last week. I think it may have gotten lost just a little bit with all the news and some of the phase two infant data. What is the purpose of this program? If you already have a 31-valent PCV in development, which could be best in class, at least based on serotype coverage, what is the goal of VAX- XL? Yeah. Thank you for that question. To be sure, I think VAX- XL got caught up in the vortex last week. To be very clear, VAX- XL is a program for which we will have additional conjugates to create additional coverage over and above VAX-31. To your point, there is not a lot of headroom in this moment when VAX-31 covers 95% of the circulating disease in adults. It covers 92% of the circulating disease in infants. Yet the positioning for this program is to recognize that, you know, when we're imagining bringing VAX-31 to market and we imagine a world where we're vaccinating broad swaths of the population with a 31-valent vaccine, this class of vaccines is so effective. You take those strains out of circulation, and in their place, there are other serotypes of pneumococci that will find purchase in people's upper respiratory tract where these bacteria are part of the normal flora. What will happen is there will be more strains that will begin to circulate at higher rates, which will make it justifiable to bring out an even broader form beyond VAX-31. For us, this is something that we think we are uniquely able to do in light of the technology that we have developed and the data we've generated that we believe certainly in adults have shown that we can go beyond 31. We think that could be something that's unique to us. We think it's a competitive advantage for the company. We have made such a fulsome investment in this pneumococcal conjugate vaccine franchise. As you know, we're building a dedicated facility to be able to manufacture adequate capacity to address the full demand from the developed world. We believe we have an opportunity to make additional conjugates, have them at the ready, Joseph, monitor the epidemiology, and as appropriate, identify a next-gen vaccine. This is something for which we won't be giving the same level of routine guidance. It'll be more along the lines of making sure we've made the right stable of incremental conjugates that we would want to roll into a third-generation vaccine in order to, what would ideally be us maintaining our lead going forward on top of the lead that we think we will create with VAX-31. The last thing I would say is the reason we chose to put out that news last week was continuing evidence that we had seen in adults and infants that we were not seeing carrier suppression at the rate that others have seen with the conventional technology, which we believe not only sets us up for future generations in adults, but also ultimately in infants. That is what is behind VAX-XL. Okay. Makes sense. Competitive landscape, wondering if you could comment briefly on the recent developments in the space and what this means for Vaxcyte. Of course, Sanofi, they've got a 21-valent that's in phase III for adults. GSK's got a 30-valent and Pfizer, 25-valent, I believe, in phase II. Any quick thoughts on competitive dynamics here and what it means for your company? Yeah, I think it speaks to how highly coveted this space is. And, you know, when you have an $8 billion category that is expected to grow dramatically, largely because of the adult vaccination and that becoming something that is appropriate for more adults, certainly here in the U.S., as they lowered the age last year from 65 years and up to 50 years and up, but then also more and more developed countries outside of the U.S. adopting pneumococcal conjugate vaccines for their adults. This is, you know, a real bedrock kind of vaccine for the entire vaccination schedule. You know, as you say, Sanofi has recently initiated a 21-valent PCV program. They have said very publicly that they didn't see a path forward in the adult segment, yet a 21-valent in the infant segment is attractive enough for them to invest in a fulsome phase three program. When we acknowledged last week that we see a path forward for our 24-valent PCV and are, you know, a year away, 15 months away from a VAX-31 readout to have that sort of opportunity to exceed today's standard of care, which may not be moving much between now and our vaccines, it just goes to show how big this opportunity is. Coverage has always been the primary adoption factor. With a 24-valent vaccine, we'd have broadest coverage. When you think about our 31-valent vaccine, that coverage advantage grows dramatically to the point where it not only could justify a preferred recommendation, but history has shown even without a preferred recommendation, doctors understand that to be able to vaccinate one of their patients with something that will prevent more disease than less, that's the choice that they've always made historically. That's the reason why we think we really have a winning hand with our franchise in pneumococcal conjugate vaccines. Last question from us. It's on the cash burn. What's the outlook on cash burn and any guidance for cash runway? Yeah, we remain very well capitalized, you know, over $3.1 billion on the balance sheet as of the end of last year. The guidance we've given is under the all systems go case across all of our programs, including our pipeline, sufficient capital to fund through several milestones over the next few years, all the milestones in 2025, 2026, and 2027. Capital gets us into 2028 milestones, of course, not only related to our adult and infant indications, but potential milestones related to the pipeline as well. Fantastic. Thank you so much, Grant, Andrew, and Jim for participating. It was a very informative discussion. Thank you for hosting, Joseph. We really appreciate it. Good seeing you. Thanks, everyone. Thanks everyone for joining us on the webcast. Have a good day.