Vaxcyte, Inc.

¶¶ . . . . . ¶¶ Good afternoon.

My name is Chloe, and I will be your conference operator for the VACC site fourth quarter and full year 2025 financial results conference call. All lines have been placed on mute to prevent any background noise. After the speaker's remarks, there will be a question and answer period. If you would like to ask a question during this time, simply press star followed by the number one on your telephone keypad. If you would like to withdraw your question, press star two. Today's call is being recorded. I will now turn the call over to Andrew Guggenheim, President and Chief Financial Officer of VACCITE. Please go ahead, sir.

Thank you, operator. Good afternoon, everyone, and thanks for joining us today as we review our 2025 results and provide a business update. I am joined by our Chief Executive Officer, Grant Pickering, and our Executive Vice President and Chief Operating Officer, Jim Wassel. Earlier today, we issued a news release announcing our results. Copies of this and our other news releases, latest corporate presentation, and SEC filings can be found in the Investors and Media section of our website. Before we begin, I'd like to remind you that during this call, we'll be making certain forward-looking statements about Backsite which are subject to various risks, uncertainties, and other factors that could cause actual results to differ materially from those referred to in any forward-looking statements. For discussion of the risks and uncertainties associated with these statements, please see our press release issued today, as well as our most recent filings with the SEC, including the risk factors set forth in our Form 10-K for the year ended December 31st, 2025, and any subsequent reports filed with the SEC. With that, I'll turn the call over to Grant Pickering. Grant? Thanks, Andrew. As we close out 2025 and look forward to multiple clinical readouts beginning later this year, I'm proud of the progress we made across the company, particularly within our pneumococcal conjugate vaccine or PCV franchise. Despite decades of vaccination efforts, pneumococcal disease continues to drive substantial morbidity and mortality worldwide, particularly among young children and older adults. While current vaccines have made a meaningful impact, gaps in serotype coverage persist and the public health need for broader spectrum protection remains clear. Consistent with that need, we are seeing accelerating growth in the adult PCV market driven by expanded age group recommendations in the United States and increasing international adoption of adult PCV vaccination. Continued momentum in the PCV class has reinforced the size of the opportunity and demand for a PCV that increases disease coverage by protecting against both historically and currently circulating serotypes while maintaining robust immune responses. Taken together, this underscores our opportunity to improve public health as we prepare to enter an increasingly attractive commercial market. The unprecedented results from our Phase II study in adults demonstrated that Vax31 may offer substantial improvement over existing products and achieve our objective to significantly expand disease coverage while maintaining high immunogenicity responses. And with the Opus Phase III program underway, we believe that we are uniquely positioned to set a new standard by which future adult pneumococcal vaccines will be measured. In December, we initiated Opus 1, our pivotal non-inferiority study, and expect to announce top-line safety, tolerability, and immunogenicity data in the fourth quarter of this year. In January, we initiated Opus 2, a Phase 3 trial evaluating Vax31 when administered concomitantly with a licensed seasonal influenza vaccine, reflecting real-world vaccination practice. And earlier this month, we announced the initiation of our Opus 3 trial to evaluate the safety, tolerability, and immunogenicity of Vax31 in adults who previously received lower-valency pneumococcal vaccines. For this population, Vax31 could represent a substantial incremental benefit and could be well-positioned to obtain a catch-up recommendation. We look forward to the readouts for both Opus 2 and 3 in the first half of 2027. In infants, we reported the final data from the Vax24 Phase 2 dose-finding study in November. These data were consistent with the previously reported positive interim results and provided important encouraging insights into immune responses, concomitant administration with other vaccines, and dose responsiveness. Based on these learnings, we modified the ongoing Vax31 infant phase two study to include an optimized dose arm in order to evaluate multiple higher doses than those explored in the Vax24 infant study. Enrollment for this study is now complete and we expect to announce top-line safety, tolerability, and immunogenicity data for both the primary three-dose immunization series and booster dose either sequentially or together by the end of the first half of 2027. In parallel, we continue to make strides to fortify our manufacturing capabilities, commercial readiness, and financial foundations. On the manufacturing front, I'm pleased to report that we have now completed the construction of the dedicated large-scale manufacturing facility on time and on budget that has been designed to support global commercial demand for our PCB candidates throughout the developed world. In addition, the build-out of a high-volume, custom-filled finished production line in North Carolina is underway as part of a long-term investment of up to $1 billion in U.S. manufacturing and services. In advance commercial readiness, we began to scale the organization, including the appointment of our first chief commercial officer, Mike Millett, and the initiation of launch planning activities in earnest. These actions reflect our conviction in the long-term potential of our PCB franchise and our focus on a highly successful commercial launch. Turning to our balance sheet, we strengthened our already robust financial position with the successful completion of a public equity offering in February. We believe we are well-positioned to advance our programs through multiple upcoming data readouts while continuing to invest in the capabilities needed to prepare for commercialization. Overall, 2025 is about focused execution on our clinical programs and establishing the infrastructure clinically, operationally, and organizationally to support what we believe will be a defining period ahead. None of this progress would have been possible without the expertise and dedication of our teams across the organization, and I want to thank them for their commitment. With that, I'll turn the call over to Jim to walk through our clinical programs in more detail, including the Opus Phase III program, the infant program, and an important update on VaxA1, our Group A strep candidate.

Jim?

Thanks, Grant.

I'll start with an update on our Vax31 Adult Phase 3 program and then turn to our Vax31 Infant Phase 2 program and broader pipeline. Beginning with adults, the Phase 3 OPUS program represents Vax31's transition into late-stage development and is designed to support a planned VLA submission. The Phase 3 clinical trials were finalized in consultation and alignment with the FDA and are intended to generate a broad and robust safety, tolerability, and immunogenicity data set across relevant adult population and real-world vaccination scenarios. Opus 1 is our pivotal non-inferiority trial evaluating Vax31 for the prevention of invasive pneumococcal disease and pneumonia. This trial is evaluating the safety, tolerability, and immune responses of Vax31 in adults age 50 and older through direct head-to-head comparisons with both PREVNR20 or PCV20 and CAPACTIV or PCV21, which are the current standard of care of PCVs for adults. We remain on track to announce top-line data in the fourth quarter of this year. Opus 1 was designed to establish a best-in-class profile for Vax31. Based on the unprecedented clinical results we have generated to date, We believe this trial can deliver that profile and thus set a new standard in adult pneumococcal vaccination. We believe the current standard of care vaccines, PCV20 and PCV21, have hit the ceiling of what conventional approaches can achieve. Each of these vaccines represented a meaningful advancement over prior generations, yet in both cases, tradeoffs were required to obtain licensure. In the case of PCV20, they focused on making incremental stereotype additions to PCV13 but falls short of coverage of the 31 serotypes in Vax31. For PCV21, though it covers a greater percentage of circulating disease than PCV20, the tradeoff was sacrificing historically circulating strains, some of which are still circulating meaningfully, and others that are likely to return if we fail to protect against them. Vax31 is designed to overcome each of their limitations. By using our validated carrier sparing platform, we have shown Vax31 can provide protection against both currently circulating and historically prevalent serotypes while maintaining robust immune responses. With the Opus 1 study, where PCV20 and PCV21 are the comparators, totality of data framework supports our objective to deliver a best-in-class PCV. In this context, regulators assess both the public health impact and the overall strength of the data package, for which perfection on an individual stereotype basis has never been required, nor is it our expectation. With this in mind, we are confident we can deliver an outcome to support a robust BLA submission, and with 10 or 11 incremental stereotypes over our study comparators, We believe Vax31 has the headroom to miss on a handful of individual stereotypes without risking the ultimate goal of licensure with what we believe is a best-in-class profile. Now I'll briefly review the other OPUS trials, which are also currently enrolling subjects. OPUS 2 is designed to evaluate the safety, tolerability, and immunogenicity of Vax31 when administered either concomitantly with or one month following a licensed high-dose seasonal influenza vaccine in adults. This descriptive study reflects clinically relevant real-world use scenarios, particularly for older adults who routinely receive multiple vaccines at one time. Opus 3 is evaluating Vaxxer1 in adults who have previously received lower-valency pneumococcal vaccines. This descriptive study is intended to evaluate the safety, tolerability, and immunogenicity of Vaxxer1, including whether Vaxxer1 can boost serotype-specific immune responses while providing the broadest coverage in a single vaccine in this adult population. Opus 1, 2, and 3, complemented by a planned manufacturing consistency study, are designed to generate a broad and robust safety, tolerability, and immunogenicity data set. The three ongoing trials will enroll approximately 6,000 adults in total, of whom approximately 3,400 will receive Vax31. Turning to our infant PCV programs, We completed the Vax24 Phase 2 dose-finding study with final data confirming dose-dependent immune responses and a safety and tolerability profile consistent with the standard of care comparative. As Grant noted, we used those learnings to modify the ongoing Vax31 infant Phase 2 study to include an optimized dose arm. The higher doses being evaluated are designed to enhance and optimize immune responses to provide short-term and long-term protection while maintaining tolerability and safety. Enrollment in this optimized study is now complete with 900 infants' dose. In U.S. children, Vax31 is designed to cover over 90% of IPV and acute otitis media due to strep pneumonia, which represents a significant increase over today's standard of care. By the middle of this year, we expect to provide an update on our unblinding and disclosure plans for this study. Beyond our PCV franchise, you will recall that we made a decision to pause non-PCV pipeline programs last year. I'm now pleased to share that we plan to resume development of our most advanced preclinical program, VaxA1, our group A strep vaccine candidate, which is designed to provide protection in both the adult and pediatric setting. We expect to initiate a phase one study in adults this year with the primary objective of assessing safety and tolerability. We claim to conduct a study in Australia where Group A strep has been especially problematic and with our experienced investigative networks with expertise in Group A strep. This approach is designed to generate high-quality initial safety data and provide a foundation for evaluating next steps in this program's development. Group A strep remains a major global cause of morbidity and mortality due to its wide-ranging clinical manifestations and potential for severe complications. Group A strep causes common illnesses such as strep throat and skin infections, but it can also lead to serious conditions like sepsis, meningitis, and rheumatic fever, and is a leading driver of antibiotic use, most notably in children. Each year, it's estimated that group A strep is responsible for over 600,000 deaths and 800 million cases of illness worldwide. In the United States, the medical and economic impact of group A strep is substantial, with the estimated annual healthcare and productivity costs exceeding $6 billion. This underscores the importance of advancing a preventative vaccine approach. With that, I'll turn the call over to Andrew.

Thanks, Jim. I'll begin with a brief overview of our financial position and then touch on our public affairs and policy engagement. As of December 31st, 2025, we reported $2.4 billion in cash, cash equivalents, and investments. Subsequent to year-end, we further strengthened our balance sheet through a public equity offering, raising approximately $600.2 million in net proceeds. The offering further enhances our financial flexibility as we advance our adult and pediatric VAC31 programs, continue to invest in manufacturing readiness, and prepare for potential future commercialization activities. Based on our current operating plan, and including the net proceeds from our recent financing, we believe our cash on hand provides runway to at least the end of 2028. This supports execution across multiple planned clinical, regulatory, and manufacturing milestones over this period. From a total spending perspective, we saw an increase in 2025 compared to the prior year, driven primarily by continued investment in commercial manufacturing readiness and advancement of our clinical programs. R&D expense growth reflected manufacturing scale-up and validation activities and late-stage clinical execution. Separately, we saw an increase in capitalized costs, primarily related to the build-out of our dedicated manufacturing facilities. Our full-year audited financials are available in our Form 10-K filed today. Looking ahead to 2026, we expect total expenses, particularly within R&D, to increase meaningfully relative to both full-year 2025 and fourth quarter 2025 annualized levels. This expected increase is primarily driven by a few key factors. First, an increase in manufacturing spend to support commercial readiness, including the buildup of VAC31 commercial supply in advance of potential launch. And second, higher clinical spend to support a greater number and size of clinical trials, with multiple VAC31 adult Phase III studies and the Phase II infant study. Within manufacturing, there are several initiatives running in parallel. preparing for the potential VAC31 adult launch at the current Lanza shared facility, running batches at the dedicated large-scale manufacturing suite, the construction of which has now been completed, and to a lesser extent, bringing the dedicated still-finished facility online. With respect to capitalized costs, we expect these to trend down in 2026 compared to 2025. As I mentioned, we have now completed the build-out of the dedicated large-scale manufacturing facility with Lonza, and as a result, the majority of the costs related to this facility going forward will be expensed rather than capitalized. Turning to public affairs and policy engagement, during the year, we formalized and expanded our efforts to engage with policymakers and public health stakeholders. This included targeted outreach to federal government stakeholders and discussions focused on the importance of science-based vaccine policy, domestic manufacturing readiness, and the role of broader spectrum vaccines in reducing disease burden and healthcare costs. We continue to engage constructively with the FDA as our programs advance, and we believe the regulatory framework for PCVs remains well supported. These engagements are focused on process and clarity, and we view them as an important part of responsible development as we move into late-stage programs. With that, I'll turn the call back to Grant. Thanks, Andrew. As we close our prepared remarks, 2025 was a year of executional excellence, laying the foundation for advancement into late-stage development and continuing our transition toward becoming a commercial enterprise. The progress we've made across clinical, manufacturing, and commercial readiness reflects an organization that will be prepared to seize the opportunity our PCV franchise affords. We believe the breadth of this franchise, the underlying strength of our platform, and our ability to deliver disciplined execution position the company well for what we expect will be a catalyst-rich 12 to 18 months ahead. With that, we're happy to take your questions. Operator?

Thank you. Ladies and gentlemen, if you wish to ask a question for today's question and answer period, you will need to press star 1 on your telephone keypad. If your question has been answered and you wish to remove yourself from the queue, please press star 2. If you are using a speakerphone, please pick up your handset to allow for optimal sound quality. We'll take our first question from Roger Song with Jefferies. Your line is open.

Great, Tim. Thanks for the update and take care of the question. Two from us. One is for Office One. How is the study powered to show the statistical non-inferiority against each the comparator independently? Just curious, if FDA look at the population, they want you to show the non-inferiority against either, you know, Prima 20 and then laxative, independently, would you be able to show that? And then the other thing is the things that you have, you're about to reach the alignment on the manufacturer consistent study as the last phase three study. Just curious what's remaining to be discussed. Would that involve the U.S. and ex-U.S. regulatory? That's it. Thank you.

Yeah, thanks for the question, Roger. Nice to hear from you. The first question was about Opus 1 and the powering. I think the first clear key thing to point out is that we locked down that pivotal phase three study in consultation with the FDA. The non-inferiority, you asked whether or not it was independently assessed. The way the study is set up, first of all, as it relates to the power is we've already performed a head-to-head study against PREVNR20, and so we have really good data to perform the powering to set expectations as to our ability to hit the non-inferiority. We think we have exceptionally high power across the board to deliver relative to Prevnar 20. We have not performed a head-to-head study against Camp Axis, so we need to look across their own comparisons to Prevnar 20. So we do have high confidence there as well. But as it relates to the serotype-by-serotype comparisons, the way the study is set up is such that for the 10 serotypes that are in all three vaccines, the analytical plan has it such that We only need to show non-inferiority to one or the other to declare success. And then as it relates to the incremental serotypes, there are 10 more that are exclusively in Vax31 and in Prevnar20. Those will be head-to-head comparisons. We've already seen the results in our phase two. We're quite confident there. And then as it relates to the exclusive serotypes in Vax31 and CapActive, There are eight of those, and we've been able to look across, you know, their GMRs compared to PREVNR20, our GMRs compared to PREVNR20, the magnitude of the OPA responses, the magnitude of the IgG responses, the mean-fold rise over baseline. And taken together, it gives us confidence that we're going to see a successful result. A successful result, as we pointed out in the call today, is not perfection, right? No pneumococcal conjugate vaccine has ever had a perfect slate of comparisons to the standard of care vaccines. These vaccines are approved based on the totality of what they offer over and above the standard of care vaccines. And when we bring 10 or 11 more serotypes to the equation, you know, totality is tilted in our favor by design. And so, we believe and the FDA has told us we don't need to be perfect. We can miss on a few. We know that we have really robust immune responses and it gives us confidence. But we don't know, we know we don't need to be perfect. We believe even if we were to miss on a handful of comparative serotypes, that would still put us in a terrific position with an approvable BLA that would have a best-in-class profile. You also asked about manufacturing consistency. Indeed, that is the last incremental study that we need to lock down on top of the three opus studies that are already underway and enrolling. And I would say those conversations with the FDA are moving apace. They're constructive. And the real key agreement that we reached last summer was the ability to advance into Phase 3, for which there was an exhaustive review of all of the manufacturing to date for this complex biologic. And we feel good about where we're tracking, and we anticipate that that study will get underway and conclude in conjunction with our expected BLA timing.

Thank you so much. Thanks, Robin.

We'll take our next question from Jonathan Miller with Evercore ISI. Your line is open.

Hi, guys.

Thanks so much for taking my questions and looking forward to the, as you say, catalyst-rich time coming in the next year and a half. I would love to ask,

First, you mentioned a catch-up wreck being possible in the adult market.

And obviously, it's in the context of PCV21, which does deliver strong results across many serotypes that are relevant to the adult market.

So what do you need to show specifically versus PCV21 for that catch-up wreck to seem possible to get or to seem likely to get from the ACIP?

Dose response, which you've shown a couple of times, looks good for many serotypes, but it's not the same across all serotypes in those infant studies that we've seen. So when we think about the new dosing regimen in the updated Vax31 infant study, what drives your confidence?

that the serotypes that need the additional immunogenicity boost are going to get what you're hoping for out of the increased dose.

Yep. Hey, John, thank you for the question. And, indeed, we're really excited about the catalyst-rich year ahead for us, starting in the fourth quarter and then into 2027 with the three readouts we expect then. As it relates to the Opus 3 study, which is the one that was set up for a catch-up recommendation where we're giving Vax31 to adults who have previously received a lower-valent pneumococcal vaccine, you know, the convention has been to run these types of studies and to demonstrate the ability to improve the responses to those serotypes for which they received vaccination in the past, so effectively see a boost to what they came into the study with after having previously been vaccinated. and then to demonstrate that the incremental serotypes on top of what they saw previously are also delivered with robust immunogenicity. So, I mean, what we're looking to do is to demonstrate across the span of historical vaccines, you know, inclusive of Prevnar 13, the 15-valent, the 20-valent, the 21-valent Capvaxib and then also against Pneumovax, that we can expand coverage over and above what they have benefited from with a previous vaccination and potentially boost the responses to the strains they saw previously. That's what the competitive programs have showed. That is what we would expect to show. And the broadest spectrum vaccine has enjoyed this sort of catch-up recommendation in the past. And that's what we'll be shooting for. One of the challenges for us is that capexid is only recently on the market. So there will be fewer individuals who've received that vaccine, but we'll do what we can to produce evidence to suggest that there's a benefit there too. Then your question about the infant expectations, appreciate that comment about the demonstration of dose responsiveness. That is definitely what we see in the data. there are some serotypes that are more responsive to increased doses than others. And what we're looking to showcase in the Vax31 data that we'll see next year is a continued ability to demonstrate the incremental serotypes that we bring over and above the standard of care can produce that sort of expanded coverage footprint. And that has been reasonably straightforward to show based on our VAX 24 infant data and for others historically. So we have high confidence that the incremental 11 will come through over and above the 20 valent. And then, as you'll recall, the 20 for which we have compared already in the context of the Vax24 study, most of the serotypes looked great for our product. There were a handful that showed room for improvement. Fortunately for us, they weren't key circulating strains. But what we're looking to show is continued improvement. strong, robust responses on the serotypes for which there is the most strategic importance. Those are the strains that are circulating. And then for those serotypes where we did show room for improvement that aren't circulating, we'll look to recover as many of those as possible. And what we've done is introduced multiple doses in the context of the VAX31 Phase II study that are using higher doses for any of these serotypes that showed room for improvement. uh as is the case in adults most certainly in the infant setting you know we've seen as many as six missed uh non-inferiority comparisons already in this uh segment and you know we're looking to recover as many of those as possible but we know perfection is not the requirement so even if there were still a handful of misses at the end of the day in the context of a 31-day vaccine that increases coverage from in the 60th-ish percentile of circulating disease to the 90th-plus percentile of circulating disease, that would be a huge step forward for the class.

Great. Thanks so much.

Apologies. We'll take our next question from Salim Syed with Mizuho. Your line is open.

Hi, guys. This is Eric on for Celine. Yeah, just curious about the Group A strep. I understand that it's early yet, but just trying to think about, you know, what we might expect to see, the plans for development, you know, what other things are out there. Is there an accepted standardized standard for immunogenicity? Do you think that, you know, longer term, you know, all things going well with phase one, phase two, that you might expect to run an efficacy trial for phase three for submission? Thanks.

Yeah, hey Eric, thank you for the question. I'm going to hand it off to Jim in just one second, but really appreciate the acknowledgement around Vaccine One. This is a program we've been really excited about for quite some time. It was a really tough decision to pause that program last year, but we're thrilled to be able to guide to the initiation of clinical development this year. This is a really important vaccine. This has a blockbuster kind of profile. It's an important unmet need in both adults and infants. So, yeah, I think it's going to get substantial attention as we move into the clinic. But I want to hand it to Jim, who's been the chief architect of this program, to answer those questions as it relates to setting expectations around clinical data coming out of Phase I. Jim?

Thanks, Grant. Eric, our plan is to start in adults with a safety assessment. We will also be looking at immunogenicity, both IgA and IgG. We're going to be looking at both serum and saliva to see what the responses are to our antigens. There is no correlate of protection, so we will not be able to predict whether or not there is efficacy. However, What's unique about Group A strep is, you know, strep throat is so ubiquitous in school entry kids that we can do a very small study, you know, and you're talking hundreds, maybe, you know, just barely in the thousands, and you can really get an early read on proof of concept even before going into a phase three. So our intent here is to get some safety from adults as well as in the organicity and dose ranging analyses, move into the toddlers, and then do a proof of concept.

And Eric, this is Andrew. Consistent with prior practice, you know, we've obviously guided to initiating the Phase I study this year. We're excited about that. As we've noted, consistent with our prior practice, we would intend to outline the specifics of the trial design upon the commencement of enrollment in the trial.

Great. Super helpful. Thank you, and thanks for taking the question.

We'll take our next question from Seamus Fernandez with Guggenheim Securities. Your line is open.

Hi, guys. This is Evan Wang on for Shamus. Just one follow-up on group-based draft. Great to see that back, by the way. Just curious if you mentioned that does this reflect more of the updated financial position or any incremental confidence around either the vaccine or development path? And then on VAC 31, can you just describe some of the work with respect to the pre-commercialization planning underway now and some of the regular discussions around post-marketing FCs? and then maybe on the post-marketing studies, just how you should be thinking about how you're tapping these versus to some of what we've seen in the past from Merck or Pfizer. Thanks.

Yeah, maybe I can take the second one first and then punt the first to Andrew. As it relates to the post-marketing efficacy studies for Vax31, what we have worked out with the FDA is entirely consistent with the same agreements that were made with the currently marketed standard of care pneumococcal conjugate vaccines. So in the case of Merck and CapAxiv, they agreed to a test-negative design surveillance approach where you monitor pneumonia cases in the environment to confirm that you see the amelioration of disease from your product in relation to the other products that are out there. So that's a standard study that has already been blessed, and we will be following an extremely similar approach. So I hope that answers your question. And then, Andrew, can you address the Group A strep-related question, either you and or Jim? Yeah, sure. Thanks for the question, Evan. You may recall last year, you know, when we announced our decision, as Grant said, difficult, but we think the right one to pause advancement of our pipeline programs in the clinic. principally for financial reasons to extend our one way to ensure we could deliver on the key milestones for our PCB franchise, which of course remains the biggest value driver. You know, we obviously executed financing at the close in February this year, and in our discussions with investors and others, you know, one of the benefits of the financing was to enable us to, again, resume advancement of the pipeline programs, and we specifically highlighted DAX A1 in those discussions. And so, you know, we can now move into the clinic with confidence and at the same time, you know, preserving all the significant milestones across our PCB franchise that we can continue to deliver on with cash now through at least the end of 2028. Great. Thank you.

We'll move next to Carter Gould with Cantor. Your line is open.

Great. Good afternoon, guys. Congrats on all the progress. Looking forward to an exciting 2026. Back to Opus 1. Jim and Grant, I appreciate your comments around the regulatory flexibility on individual serotypes, but I guess I wanted to pressure test how much that commentary should be read to extend even to scenarios around serotype 3 comparisons against PCV21, given its importance in IPD prevalence. and maybe just speak as well to the commercial importance of demonstrating that inferiority there to avoid counter-detailing. Thank you.

Yeah, hey, thank you, Carter. Appreciate the question and the recognition of the moment for us. Yeah, so I think, you know, the key for us is that the test for vaccines in this class is the totality of the vaccine's contribution on a relative basis. And so, in our conversation and exchanges with the FDA, you know, we acknowledged that they said in writing we could miss on a few serotypes, and that was without designation. So, there isn't a serotype that would be a disqualifier. Now, that said, I can completely appreciate why you're raising serotype 3. It is the outlier in the entire pneumococcal space. It is an infuriating serotype that, despite its inclusion in the market in pneumococcal conjugate vaccines for now over 15 years, it continues to be the top circulating serotype. And the reason for that is, unfortunately, none of the vaccines have produced a magnitude of antibody responses that can keep that particular serotype in check. This is a complete outlier relative to the remainder of the serotypes that have been included now up to as many as 21. And our objective is to include that up to 31 soon. So yeah, serotype 3 is just the total outlier. And even though there have been some of the vaccines that have been able to show higher serotype immune responses relative to others, unfortunately, they're all still well below that protective threshold. So we've seen this play out already. When the 15-valent from Merck came out, you know, they had higher immune responses to serotype 3, but the reaction from all the key decision-makers was, well, better to have more, but not enough for it to be meaningful. And so that is the reality of where we find ourselves is in a situation where no one has been able to produce meaningfully different antibody responses that anyone thinks would produce a better outcome, unfortunately. So serotype 3 has not proven to be a differentiating feature for anyone. And, you know, we already have our serotype 3 responses. Ours looked better than Prevnar 20, both in the adult setting for Vax31, as well as for Vax24, and in the infant setting for Vax24. So we know we're on the right track, and we'll have to see what ultimately our immune responses look like in a direct comparison to Capvaxiv. But ultimately, it has not proven to be a benefit to the products that had had slightly higher immune responses. So we do not expect that to be a competitive deal. coming out of these studies. Appreciate that. Thank you.

We'll take our next question from Jason Gerberry with Bank of America. Your line is open.

Hi, good evening. Congrats on all the progress this quarter, and thank you so much for taking our questions. This is Dina on for Jason, by the way. I guess maybe just a follow-up on the prior discussion of the various open one data scenarios. You kind of outlined a clear base case in order to kind of clear the regulatory bar for approval. Curious, in your view, just maybe thinking about the future competitive landscapes, What is the bull case on data? Is it hitting statistical superiority on a certain number of strains or statistical superiority on, you know, some high-priority strains? And then just a quick one on VaxXL. Can you talk about where this program just kind of generally sits in terms of development? You know, if you felt compelled to advance it, how quickly could you move it into the clinic? Thank you.

Well, thank you for those questions, Dina. Thank you for being a pinch hitter for Jason. So the first question as it relates to Opus 1, I'm glad the base case is clear, and thank you for asking about the upside case. I mean, the first thing to emphasize is that coverage is king in this class. We've seen it over and over and over again. And we're seeing it playing out once again. Even in the context of Capvaxiv relative to Prevnar 20, which are the two currently recommended vaccines for adults, Capvaxiv is obtaining market share at a really rapid clip based on its coverage advantage. and yet it has this Achilles heel of not covering 10 of the historically circulating serotypes, a couple of which are still circulating significantly. So we think we have an opportunity to once again prove that coverage is the key adoption feature, and we'll have an improved coverage advantage that exceeds what has turned out to be a substantially winning strategy for others in the past. So coverage, coverage, coverage. But then as it relates to superiority on a relative basis for immunogenicity, that is something that we haven't really seen much of in this class. The only example of that, ironically, was with serotype 3, and it was a really difficult uphill climb to use that to their benefit because even though they were statistically higher, and this is kind of consistent with what I was saying in the last response, That serotype statistically higher immune response that was in the case of one product, it didn't turn into a competitive advantage because everyone acknowledged that while statistically higher, it was not clinically meaningful for a serotype that continues to circulate in earnest. So that's the only example we have to look at, and that was a single serotype for a broad-spectrum vaccine. We have an opportunity to potentially have a different set of arguments. Obviously, we have the phase two data relative to Prevnar 20, where we showed consistently higher immune responses across an array of the common serotypes, along with and incremental 11 serotypes on top of their 20. So I think it's a very different set of arguments when you're combining coverage and improved immune responses. So as you may recall in our phase two study, 18 of the 20 common serotypes we were directionally higher, and seven of those 20 had statistically significantly higher immune responses. So, I think it is a different set of arguments when you're combining coverage and a broad array of improved immune responses. And of course, this is in the context of the historical tradeoff where your training coverage for lower immune responses. So, we've really flipped the script on being able to have the opportunity to demonstrate both. So, yeah, I think we're incredibly confident that coverage will carry the day, and then we'll see how much improved immune response may or may not further the advantage as the data comes into focus. Now, he also asked about VaxXL. That's our third-generation, broader-spectrum vaccine over and above the 31 serotypes in Vax31. This is a lifecycle management strategy. As we've said, when you have a vaccine like Vax31 that covers 95 to 98% of the circulating disease in the U.S. and in Europe, respectively, there really isn't enough headroom to warrant bringing out a third generation vaccine just yet. But the reality is that serotype replacement is a key phenomena in this class. And we believe that with the utilization of Vax 31 broadly, we will begin to see serotype replacement from those very modestly circulating serotypes today to something more significant. And in that regard, We want to have the readiness to expand coverage over and above the 31 in order to produce the most beneficial vaccine societally. We also want to make sure that we continue to flex a coverage advantage relative to any potential competitors. Yet, in this moment, it's really more about preparedness and identifying those serotypes for which may circulate and having readiness to add them on top of X31 to have this third-generation program move forward into the clinic in earnest at the appropriate time.

Thank you so much. We'll take our next question from Tara Bancroft with TD Cowan. Your line is open.

Hi, good afternoon. So I feel like we have a pretty good grasp of data expectations, you know, your regulatory commercial readiness. So I kind of want to ask something more qualitative, perhaps your thoughts on Opus 2 and 3. Between those, I'm curious to hear from you guys, which of these do you find more or really the most meaningful in the commercial setting and why? And how could these specifically impact an ACIP recommendation beyond the Opus 1 data? Thanks.

Thank you for that question, Tara. I always appreciate you being a student in the vaccine space. Yeah, I think for Opus 2 and Opus 3, you know, each of these studies will contribute meaningfully to, you know, the overall BLA package. First of all, they're going to help us round out the safety database to ensure we get enough adults exposed to Vax31. But then each of them provide their own additional facilities. elements to the set of arguments that we want to make, both in the context of the VLA, but then also in the context of the recommending bodies as they determine how to slot BACS 31 into the schedule. You know, Opus 2 and its examination of concomitant vaccination with flu vaccines and with Vax31, it's important. Pneumococcal conjugate vaccines are given, you know, only so often versus flu vaccines that are given annually. So I think it will be helpful, but I wouldn't call it instrumental. I do think the Opus 3 study is perhaps a more strategically important outcome. And, you know, when you think about the context of a potential catch-up recommendation where we've had adults now vaccinated in earnest in the United States for 12 years, you know, you have an entirely massive potential catch-up population of individuals who have received lower-valency vaccines. And that could create a really large bolus market that we would work through over many years to give as many people the benefit of the breadth of coverage that Vax31 could provide. So, yeah, if I had to pick one of the two, I think it's Opus 3 that could unlock the most commercial potential for the company.

Okay, great. Thank you so much. And I also, I have to say, specifically to Jim, I'm very happy for you guys that you have strep back.

Appreciate that. I'm really pleased that we can start this program again.

We'll take our next question from Asad Haider with Goldman Sachs. Your line is open.

Great. Thanks for taking the questions and congrats on all the progress. A lot of them might have been answered already. Just two quick ones. First, just on the infant program, what factors are you considering in whether to announce the infant data either sequentially or together and maybe just talk about the pros and cons of each approach? And then on the competitive front, as you look out over the PCV competitive landscape, what are the key developments that you're monitoring and how can you ensure you'll lead longer term? Thank you.

Maybe I'll take the competitive landscape question and then hand the question about the tradeoffs to Andrew in just a moment. So, yeah, I think as it relates to the competitive landscape, Saad, we're, you know, in front, right? We've got two vaccines that are the standard of care today. One's a 20-valent. The other's a 21-valent. Our 31-valent is, you know, in the midst of its phase three program, as we've discussed. The only other 30-something that's out there is the program that we're aware of from GSK. They're in phase one. They just announced today the initiation of a second phase one study on top of the phase one that they started last year. Apparently, it's a new formulation. We don't really know much more than that. But I think their expectation is to hope to have phase one safety data by the end of this year. And of course, we're anticipating having the outcome of our pivotal phase three foundation of our BLA filing by the end of this year. So I think we're comfortably in front with a technology that is much more based in certainty. And then, of course, Pfizer and Merck have their own programs. We're not aware of any further development in the adult side from Merck. We are aware of the program that Pfizer has in Phase 2, which is a 25-valent vaccine. And as we understand it, there are as many as 15 different formulations currently in Phase 2 for that program. So it sounds like they're still working it out. So, of course, we're watching everybody, but those are the folks that are at the top of our list. And then Sanofi has a 21-valent infant program. It did not work in adults, but they did proceed with the 21-valent in infants. So, yeah, I mean, we're obviously trying to keep our finger on the pulse of everyone who's working in the space, but that's the landscape as we see it. Andrew, do you want to comment on the first question? Yeah, sure, and thanks for the question, Asad. And just to set the context, as we've said, the current disclosure is that we would announce the PD3 and PD4 data either sequentially or together by the end of the first half of next year. And the real question that we are interrogating is whether there are any operating benefits that we would announce when it's such a reality. And, you know, those potential operating benefits, you know, we're interrogating would be, would it enable us to engage with the FDA earlier in an end-to-Phase II meeting? Would it allow us to initiate a Phase III program sooner? So that discussion is still underway internally. That's the primary driver of our decision here. And as we've noted, we expect to provide an update on this and kind of declare what our plan is by mid-this year.

We'll move next to Tom Schrader with BTIG. Your line is open.

Thanks for taking the question, and it's certainly going to be an exciting 18 months. I have kind of a question on Opus 3. Is that the same format as Merck's equivalent, Stride 6?

I guess what motivates the question is if you're looking at the relative boost of two different vaccines, With people who've had a prior PCV maybe a year before, maybe 10 years before, I'm just wondering if the final immunogenicity is so broad that it's going to be hard to say anything. So I guess the question is, did Merck run the same trial?

And is the trial tricky because of that big window of how long they had a prior PCV? Thank you.

Yeah. Yeah, Tom. Hey, thank you for the question. I'll tag team this one with Jim. But indeed, both Pfizer and Merck have run similarly designed studies as ours. Ours is of similar size in terms of enrollment and similar design, but not precisely the same. I would say Your question is an interesting one as it relates to the duration between vaccinations. It was interesting, the Pfizer study, they did present the baseline presentation immune responses, which was helpful. The Merck study did not include that, at least in the published findings. So we didn't get the benefit of that particular effort to look across the magnitude of immune responses. based on which vaccine and how long ago they received it. But we did see some of the data from Pfizer. So I just wanted to acknowledge that first part. Jim, any other comments? I don't recall if STRI-6 was the name of their study or not, but what would you have to say?

Yeah, what I would comment is I think you're absolutely right, Tom, that there's a lot of heterogeneity here. What we want to show is is that if you give up that 31 that you don't have what's called hyporesponsiveness which is a reduction in the immune response with subsequent exposures to your vaccine now that has been seen with people who receive pneumovax which is the polysaccharide only vaccine it has not been seen in this category with pcbs the conjugates so our goal is to show that we can expand coverage for these other vaccines, give them the extra coverage that whichever vaccine, you know, 13, 15, 20, 21, that they would be getting and not have any hyporesponsiveness. And I think if we achieve that, then we can go forward and work with recommending bodies to see if we can get a recommendation for a catch-up or an expansion for those who've been previously vaccinated. So if you get more breadth, the bar for common serotypes is just being no harm, is that? That has been the case historically. And like I said, when you had pneumovacs and then you got a PCV, you did see some reduction in diminution in the immune response, but you haven't with PCVs. So I think that's the bar we're hoping to achieve. Great. Okay. Thanks for the detail.

Yep. Yep. Thanks, Bob.

And once more, that is star one for your questions. We'll move next to Joseph Stringer with Needham & Company. Your line is open.

Hi. Thanks for taking our question. You commented that FDA has historically required greater than 3,000 patient exposures from a safety database perspective. Sounds like you'll have more than that in total from your Phase III trials. Could you just characterize how your conversations with FDA have gone on the safety database requirement and your level of confidence to having at least 3,000 would be sufficient? Any additional color in this would be helpful. Thank you.

Yeah. So, we have been aware of the 3,000 minimum standard for quite some time. We have not seen a shift in that thinking. you know, initiated these three opus studies on the merits and in order to not only meet the minimum exposure for Vax 31, but to also set us up to have the ammunition to make that best in class set of claims. So I think our view is that it's been a consistent request and really not sure I have anything to add on top of that. Jim, would you add anything?

No, I think historically there's been 3,000 subjects exposed. And like Grant said, we're going a little bit above to make sure we get a really robust label. And I leave it at that.

Yeah, I would just say this is one of the many components of the protocol that was developed in alignment and consultation with the FDA.

And once more, that is star one for your questions. We'll pause just a moment to allow any questions to queue. And we'll take our next question from David Reisinger with Learing. Your line is open.

Hi, I'm Edward going in for David Reisinger. So just a quick question on PZV uptake for those who are like 50 years old and above. What is the current trend right now? Thanks.

Yeah, thank you for that question, Andrew. I think I will turn that one over to our Chief Commercial Officer, Mike Millett, who is with us. Mike, do you want to comment as to what we're seeing with regard to uptake of pneumococcal conjugate vaccines now that the age has been reduced down to 50 and up from 65 and up?

Yeah, sure. So first of all, thanks for the question. It's, you know, I think a really exciting time and opportunity for commercialization of that 31. So we're getting ramped up and ready to go. Some positive signals we're seeing in the marketplace already. Obviously, the drop to 50 to 64 is progressing. We start to see both Pfizer and Merck sales in the segment account for immunizations in that age group, 50 to 64. I would say that in some ways those immunizations were probably lower this year because of the lower influenza vaccination rates over the course of Q4 of this year. So we'll continue to monitor those and see how they progress. Also, I would say encouraged to see the market share that CAVAX has been able to achieve. Again, solidifying this market dynamic of shifting from lower serotype vaccines to higher serotype vaccines. We continue to see Merck report strong earnings in the United States and strong market share figures targeting in the high 30s, low 40s, depending on the segment of the market that we saw last year. So we'll continue to follow that trend as well, which which we see as a supportive signal for the market likely moving to Vax 31 in the future. We also, I would just say quickly, are encouraged by the uptake internationally of some of the adult vaccination programs in European countries, Japan, Canada, where Merck and Pfizer continue to make inroads in driving adult immunization. in the pneumococcal space, which, again, we hope to follow on with the licensure of X31. So I would say really positive and encouraging signals so far from the market, and we'll continue to keep everyone updated as we progress with preparations.

Excellent. Thank you, Mike. Yeah, I think I just want to caveat that the U.S. is a bit of an outlier making the universal recommendation for adults 50 and up. While the international adoption is increasing at a terrific rate, most of the major developed countries have now made recommendations. They're sticking with a slightly older age group, more like 60 and up and sometimes 65 and up. But these are, you know, countries for which there was no universal recommendation. So it's really leading to a substantial increase in the overall opportunity for pneumococcal conjugate vaccines in adults. And, Mike, thank you for bringing that up. And, Edward, thank you for the question.

That concludes today's question and answer session and also concludes today's VACCITE fourth quarter and full year 2025 financial results conference call. Please disconnect your line at this time and have a wonderful day.