Vaxcyte, Inc. (PCVX) Earnings Call Transcript & Summary

Good morning, and welcome to Vaxcyte conference call to discuss the OPUS-1 Phase III Top Line Results. [Operator Instructions]. I will now turn the call over to Andrew Guggenhime. President and Chief Financial Officer of Vaxcyte. Please go ahead.

Thank you, operator, and good morning, everyone. Welcome to Vaxcyte's conference call to discuss top line results from OPUS-1, our pivotal Phase III trial evaluating VAX-31 in adults aged 18 and older. VAX-31 is our investigational 31-Valent pneumococcal conjugate vaccine or PCV designed to prevent invasive pneumococcal disease or IPD and pneumococcal pneumonia. I'm joined today by Grant Pickering, our Chief Executive Officer and Co-Founder; James Wassil, our Chief Scientific Officer and Chief Operating Officer; Luis Jodar, our Chief Medical Officer; and Mike Mullette, our Chief Commercial Officer. Earlier this morning, we issued a press release announcing these results. Copies of this and our other press releases, latest corporate presentation and SEC filings can be found in the Investors and Media section of our website. Before we begin, as noted on Slide 3, I'd like to remind you that during this call, we'll be making certain forward-looking statements about Vaxcyte, 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 a 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-Q for the quarter ended June 30, 2026, and any subsequent reports filed with the SEC. With that, I'll turn the call over to Grant.

Thank you, Andrew, and we appreciate you all joining us today. On behalf of the entire Vaxcyte team, I am immensely proud to share that OPUS-1 met all prespecified primary immunogenicity endpoints across all ages studied. VAX-31 was also well tolerated and demonstrated a safety profile similar to the license comparators in the study. Capvaxive or PCV21 and Prevnar 20 or PCV20. These results represent what we believe to be clear validation of VAX-31's potential to substantially broaden disease coverage while maintaining robust immune responses. They further support the potential of our site-specific carrier-sparing platform to deliver broader spectrum PCVs that address currently circulating disease-causing serotypes while maintaining pressure on historically prevalent serotypes. Today, we are presenting top line results. We will present the full data in a peer-reviewed scientific setting and the complete OPUS-1 data set will serve as the cornerstone of our planned BLA alongside OPUS-2 and OPUS-3 results and the manufacturing consistency study. I'll begin with the opportunity we see for VAX-31. The framework used to evaluate success in OPUS-1 and the top line results. Jim will review disposition, demographics, tolerability and safety, followed by Luis with the immunogenicity results. I'll return with our next steps and closing remarks before we open the call to questions. Turning to Slide 6. The pneumococcal vaccine class remains one of the largest and most durable segments of the vaccine market with combined global sales of approximately $8.5 billion in 2025. Despite current vaccination efforts, the disease continues to be a major driver of global morbidity and mortality and broader spectrum vaccines are needed. While the Infant segment currently represents the majority of revenues, the adult population is expected to be the primary driver of growth with the combined market projected to reach $12 billion by 2030. To put the opportunity for VAX-31 in context, I'd like to spend a few moments to orient you all as to how the category has evolved and the present trade-offs we have an opportunity to overcome with VAX-31 and in order to prevent a substantial residual disease burden. Turning to Slide 7. The success of pediatric PCVs reshapes pneumococcal disease 25 years ago. These vaccines protected children and reduced carriage and transmission, providing substantial indirect protection to adults. As vaccine covered serotypes declined, other serotypes filled that void. The serotype replacement phenomenon drove the development of [indiscernible] including PCV15 and PCV20 that retained the earlier serotypes while adding new ones. But broader coverage has historically come with lower immune responses. This was evidenced with PCV20 compared with PCV13 in adults, where the responses for all but one of the overlapping 13 serotypes were numerically lower with PCV20 despite meeting non-inferiority for those shared serotypes. With substantial circulating disease over and above PCV20 coverage, the challenge has been to expand coverage while maintaining the magnitude of immune responses. PCV21 took a different approach to expand coverage, focusing specifically on the serotypes causing adult disease today. It added 8 serotypes not included in PCV20 while leaving out 9 of the historically important serotypes retained in PCV20, that approach increased the coverage of currently circulating adult disease, but forced health care providers to make a choice between 2 vaccines, each of which has meaningful coverage gaps. Now with the resurgence of serotype 4 from very low levels following pediatric vaccination, it is now one of the fastest-growing serotypes in Western states and in Europe. Likewise, Serotype-19F also continues to persist and requires continued inclusion to prevent further resurgence. Both are included in PCV20, but absent from PCV21. This has resulted in a difficult trade-off for health care providers as they choose between 2 equally recommended vaccines with partially overlapping coverage and at present, the [indiscernible]. VAX-31 was designed to overcome these trade-offs by retaining all of the PCV20 serotypes, adding serotypes responsible for adult disease that are covered by PCV21 and expanded coverage even further. That required the incorporation of 31 serotypes into a single vaccine and demonstrating that immune responses can remain [indiscernible] conjugation and carrier sparing technology is designed to rise to the challenge. And as you can see on this epidemiology, Slide 7, VAX-31 incorporates serotypes responsible for 95% of invasive pneumococcal disease and 88% of pneumococcal pneumonia in U.S. adults 50 and older, a greater proportion either PCV20 or PCV21. The strength and consistency of our Phase II data gave us confidence that we could broaden coverage without sacrificing immunogenicity. That gave us the conviction to take on the more stringent non-inferiority standard in our Phase III study. With that backdrop, let's review the approval standard for immunogenicity and the prespecified framework we use to evaluate VAX-31 head-to-head with PCV20 and PCV21 in OPUS-1. Turning to Slide 8. This slide puts the immune response standards in context. Opsonophagocytic activity, or OPA, is a functional measure of how well vaccine-induced antibodies help immune cells kill pneumococcus, because there is no established antibody threshold that reliably predicts protection in adults. We compare these responses. For each serotype, we measure the OPA geometric mean titer or GMT, after VAX-31 and after the licensed comparator and calculate a ratio between the two, which is the geometric mean ratio or GMR. The dots in this slide illustrates the point estimates of the GMR so VAX-31 divided by the comparator and the horizontal lines show the 2-sided 95% confidence intervals, the left end of each line is the lower bound of that confidence interval, which we use a shorthand LBCI going forward. The pivotal PCV20 and PCV21 trials required their lower bound to be greater than 0.5. Given the concern that repeated bridging would lead to progressively lower immune responses, we aligned with the FDA to inaugurate a more stringent threshold of the LBCI greater than 0.667 in OPUS-1. In this slide, moving from left to right, the shaded blue area represents the historical threshold of 0.5. The gray area represents the higher OPUS-1 threshold of 0.667, approximately 2/3 of the comparator response rather than 1/2. Further to the right, the green area represents a lower bound greater than 1, which indicates statistically greater immune responses. And finally, the purple area represents the primary superiority assessments involving the 3 unique serotypes and cross-reactive [ 20B ], where the lower bound must exceed 2.0. We believe meeting the higher non-inferiority standard with a broader spectrum vaccine will set a new bar for future adult PCV development. Turning to Slide 9. Let's review what VAX-31 needed to deliver to meet the study's primary end points. OPUS-1 was a complex study with 2 comparators, partially overlapping serotype coverage at 2 different age groups. So let's break it down. It begins with the four co-primary immunogenicity endpoint groups in adults 50 and older. The first group contains the 11 serotypes shared by all 3 vaccines, VAX-31 31 was compared with both PCV20 and PCV21. For each serotype, the primary criterion required non-inferiority to 1 or both comparators via the OPA GMRs, requiring the lower bound to exceed 0.667, inclusive of a prespecified alpha penalty on a serotype-by-serotype basis in the protocol to account for the 2 comparisons. For the second group, the 9 serotypes unique to VAX-31 and PCV20 were compared to establish the OPA GMRs with the primary criterion for non-inferiority requiring lower bound to exceed 0.667. For the third group, the 8 serotypes unique to VAX-31 in PCV20 were compared using the same non-inferiority criteria. Together, these 3 groups account for all 28 shared serotypes evaluated for non-inferiority. The fourth group assessed superiority for the 3 serotypes unique to VAX-31 along with cross-reactive serotype 20B. These assessments used a superiority margin of 2.0 for the OPA geometric mean ratio with success required against one or both comparators inclusive of a serotype-by-serotype prespecified alpha penalty and the protocol to account for the 2 comparisons. Overall, co-primary success in the trial required all of these 32 assessments to succeed. All 28 non-inferiority assessments and all 4 superiority assessments. If all 32 assessments were successful, we can then proceed to the formal primary amino bridging analysis. Comparing VAX-31 responses in adults aged 18 to 49 versus those aged 50 to 64. All 32 comparisons, including the 31 vaccine serotypes and cross-reacted 20B also had to meet the same non-inferiority criterion using the 0.667 margin. Safety and tolerability were also evaluated as a primary objective in each age cohort. Separately, we will show the prespecified individual non-inferiority comparisons with PCV20 and PCV21 for the serotypes shared with VAX-31. With that comprehensive setup as reflected on Slide 10, we are thrilled to report the VAX-31 met all 32 prespecified or primary immunogenicity assessments inclusive of all 28 non-inferiority assessments and all 4 superiority assessments. It was a clean sweep of the prespecified co-primary endpoints, an outcome that exceeded our expectations. That success continued with Immunobridging, all 32 new comparisons across the age groups also met non-inferiority. Importantly, VAX-31 was well tolerated with a safety profile similar to the comparators. The individual comparative results, which we know many of you were closely watching also surpassed our expectations. For the 20 overlapping serotypes with PCV20, we went 20 for 20 on OPA GMR noninferiority with lower 95% confidence bounds greater than 0.667. For the 19 overlapping serotypes with PCV221, VAX-31 went 17 of 19. For serotype 3F and 12F the low 95% confidence bounds did not exceed 0.667 versus PCV21, but both exceeded the historical 0.5 threshold. That historical threshold was prespecified as a secondary endpoint in the study, and as a reminder, was a standard used in the pivotal PCV20 and PCV21 trials. The complete data set and remaining studies will be subject to FDA review. However, based on regulatory precedent we believe these results support with the potential to combine broader disease coverage and robust immune responses in a single 31-Valent vaccine, if approved, we see the potential for a blockbuster commercial opportunity for VAX-31 in the growing adult market. With that, I will turn it over to Jim to take you to the next section of the presentation.

Thanks, Grant. I'm extremely pleased to be able to share the results of the OPUS-1 study with you today. In terms of the trial design, as seen on Slide 13, OPUS-1 is a randomized double-blind active-controlled Phase III trial that vaccinated 4,047 adults in the United States. 3,572 aged 50 and older and 4,075 aged 18 to 49. As shown here, adult 50 and older randomized equally to receive either VAX-31, PCV20 or PCV21. Adult aged 18 to 49 were randomized 3:1 to receive either the VAX-31 or PCV20 arms, respectively, with PCV20 serving as the safety comparator in that younger cohort. The primary OPA [indiscernible] was assessed 1 month after vaccination, solicited reactions were collected for 7 days and unsolicited adverse events through 1 month after vaccination. Medically attended adverse events, [indiscernible] chronic illness and serious adverse events were followed through 6 months. Turning briefly to the Study Disposition, Slide 14. OPUS-1 was well executed with high participant retention and nearly complete safety and immunogenicity follow up across both age cohorts. In adult 50 and older, at least 96% of vaccinated participants were included in the immunogenicity evaluable population across 3 treatment groups. We saw similarly high follow-ups in adult 18 to 49 with approximately 98% of VAX-31 recipients contributing evaluable immunogenicity data. Overall, these high retention rates provide a robust data set for the prespecified safety and immunogenicity analyses. Turning to Slide 15. In terms of demographics, approximately 2/3 of participants were between 50 and 64 years of age and about 1/3 were 65-year or older with comparable distributions of sex, race, ethnicity and body mass index across VAX-31, PCV21 and PCV20 with substantial diversity amongst enrolled partisans. Importantly, more than 1/4 subjects enrolled had 1 or more at risk conditions for pneumococcal disease. Overall, there are no meaningful baseline imbalances that would be expected to affect interpretation of the comparator safety or immunogenicity results. In adults 18 to 49, as you can see on Slide 16, baseline characteristics were generally similar between the randomized VAX-31 and PCV20 safety groups. For the immunobridging analysis, the relevant comparison is between VAX-31 recipients aged 18 to 49 and and VAX-31 recipients aged 50 to 64. Because those 2 age groups were not randomized against each other, expected baseline differences [indiscernible]. The prespecified immunobridging model, therefore, adjust for baseline OPA titers and the pneumococcal disease risk status rather than relying on [indiscernible]. On Slide 18, we are looking at local and systemic solicited reactions in adults 50 and older. Let me orient you to the slide. The green columns present VAX-31, the blue columns PCV20 and the gray columns PCV21. More severe reactions are represented by darker colors. VAX-31 was generally well tolerated, solicited reactions were predominantly mild to moderate and transient, but the majority resolved within 48 hours. Reactogenicity was broadly consistent with the license comparators although some reactions particularly injection site pain and muscle pain were somewhat more frequent with VAX-31. We see the same overall profile in younger adults here on Slide 19. Reactogenicity was similar to PCV20 predominantly mild to moderate [indiscernible] both in systemic symptoms. Moving beyond solicited reactogenicity monitoring. Slide 20 summarizes the broader safety experience across both adult age cohorts. Unsolicited adverse events were collected through 1 month while medically attended adverse event, new onset of chronic illnesses and serious adverse events were followed through 6 months. The broader safety profile was reassuring and generally balanced across groups with no apparent pattern suggesting a safety signal. No serious adverse events were considered vaccine related, and there were no study discontinuations due to adverse events. 4 deaths occurred in the older cohort, 2 in the VAX-31 group and 2 in the PCV21 group, and all were assessed as unrelated to vaccination. With that, I'll turn the call over to Luis to review the Immunogenicity results. Luis?

Thank you, Jim. Let's now turn to the Immunogenicity results, starting with the 4 prespecified primary immunogenetic [indiscernible] groups Grant outlined earlier. First plots on the next few slides show OPA geometric mean ratios or GMRs, under 95% confidence interval. And for the primary analysis involving 2 licensed comparators we also apply the prespecified [ hopper ] adjustment for multiplicity. For the first endpoint group, the 11 serotypes contained in all 3 vaccines, the prespecified statistical analysis plan required VAX-31 to demonstrate non-inferiority against at least 1 license competitor for each set of [indiscernible] the multiplicity adjustment we just described. As reflected on Slide 22, VAX-31 met that criterion for all 11 of 11 serotypes. The blue points show the comparisons with PCV20 and the gray point the comparison with PCV21. For serotype 3 and 12F, the PCV21 comparison did not meet the more stringent 0.667 threshold, while their PCV20 comparison met the higher 0.667 non-inferiority criterion with a prespecified [ hopper ] adjustment. Therefore, both serotypes met the prespecified primary criteria. I will address these serotypes with respect to the individual comparisons compared to PCV20 and PCV21 on a later slide. For the second and third point groups, the 9 serotypes shared only with PCV20 and 8 shared only with PCV21, the comparison is simpler because each serotype is contained in only 1 of the 2 licensed comparators. On the left side of Slide 23, VAX-31 met the prespecified non-inferiority criteria for all 9 of 9 serotypes shared with PCV20. On the right, it met the criterion for all 8 of 8 serotypes shared with PCV21. Importantly, every 1 of these 17 comparisons clear the more stringent 0.667 non-inferiority margin. Together with 11 serotypes on the previous slide, VAX-31, therefore, met the prespecified non-inferiority criteria across all 28 serotypes shared with the license competitors. Turning to Slide 24. The fourth endpoint group includes the 3 serotypes unique to VAX-31, 2, 7C and 20C, together with a cross-reactive assessment of 20B. For this group, the statistical bar was higher. The lower bound of the 95% the OPA GMR had to exceed 2.0 versus at least one license comparator with the prespecified adjustment for the 2 comparator assessment. VAX-31 met that superiority criterium for all 4 assessments, demonstrating a strong functional immune response to the 3 unique serotypes and cross-reactive 20B. Together with the 28 shared serotypes, VAX-31, therefore, met the criteria for all 32 prespecified primary assessment in adults 50 and older. For the primary immunobridging analysis, comparing VAX-31 recipients aged 18 to 49 with those aged 15 to 64 as seen on Slide 25, VAX-31 met the non-inferiority criterion across all 32 evaluated responses, demonstrating consistent immune responses between these age groups. These results provide the immunologic foundation for our planned request for an indication beginning at subject, of course, to regulatory river. Finally, let's turn to the individual competitor as specific results on Slide 26. Again, PCV20, VAX-31, met the more stringent 0.667 non-inferiority threshold for all 20 of 20 shared serotypes, against PCV21, 17 of 19 shared serotypes met the 0.667 threshold. The 2 exceptions were serotypes 3 and 12F, while neither met the higher threshold versus PCV20, the lower bound of the 95% confidence interval, both exceeded the historical 0.5 threshold. For serotype 12F, other immunological measures, including [indiscernible] responses rates and supportive IgG responses, were consistent with a robust immune response. Serotype 3 is biologically atypical. Difference in serum immune responses have not consistently translated into proportional differences in biological effects. The complexity is intrinsic to serotype 3 rather than specific to VAX-31. Now given the current adult epidemiology, we expect that the PCV21 comparison to be a particular focus of U.S. regulatory review. PCV20 remains an important license comparator. Taken together with the successful primary analysis, we believe these data provide a strong foundation for the planned BLA. I will now turn the call back to Grant for a few concluding remarks and next steps.

Thank you, Luis. OPUS-1 marks a defining milestone for Vaxcyte. VAX-31 met all prespecified primary immunogenicity endpoints in this pivotal Phase III trial, including immunobridging while demonstrating a safety profile similar to the license comparators, took on a higher immunogenicity standard with a broader spectrum vaccine and to enforce our conviction in VAX-31's potential to become a best-in-class pneumococcal vaccine and provide strong clinical validation of our carrier sparing platform. Turning to Slide 29. OPUS-1 will be the cornerstone of the BLA application supported by OPUS-2 and 3 with the results expected in the first half of 2027, along with the Manufacturing Consistency Study. Following completion of the remaining clinical and manufacturing work, we expect to be in the position to submit our U.S. biologics licensing application for FDA review in the first half of 2028. Turning to Slide 30. We have already made substantial investments to prepare for commercialization. We have completed the build-out of a dedicated manufacturing facility designed to produce over tens of millions of doses a year, with the finished product to come from the new line we're building in Greenville, North Carolina. Together with our existing supply chain and the medical and commercial capabilities that we are building, these investments should enable us to capitalize on this significant opportunity, beginning with the adult market. The opportunity extends beyond adults, with important pipeline milestones ahead noted here on Slide 31. We expect VAX-31 Infant Phase II results from the primary immunization series and booster dose either sequentially or together by the end of the first half of 2027. We are also advancing VAX-XL, our third-generation PCV, which is in preclinical development to help maintain our anticipated leadership position. For VAX-A1, our Group A strep vaccine candidate, we expect Phase I results in the second half of next year. Before we open the call for questions, I want to thank our study participants, investigators and everyone at Vaxcyte who made this milestone possible. More than a decade ago, we set out to protect human kind from the consequences of bacterial diseases. These pivotal results bring us one giant step closer delivering on that mission. We are tremendously proud of this achievement and focused on the work ahead. Thank you for your continued support. Operator, we are ready for questions.

[Operator Instructions] Our first question today comes from Dave Risinger with Leerink Partners.

Thanks very much, and congrats Grant and team on the phenomenal data. So I have two questions, please. First, can you discuss your vision for vaccine franchise to lead the market and the durability that you expect of that leadership. And also comment on the 0.667 non-inferiority margin creating a new bar for future PCV competitors? And then separately, we've received a lot of questions about competitor Merck's serotype 3 coverage. So I was hoping you could contextualize the results that Merck presented at the Pneumococcal Disease Conference in May in Copenhagen for its 15-Valent which showed no correlation between OPA GMR results and actual serotype 3 protection, and just add some perspective on why that dilutes Merck's serotype 3 messaging?

Thanks for the question, Dave. I appreciate the congratulations Super exciting for the company. And so yes, I appreciate the questions. Our vision for the franchise we've had a really long-term mindset from the beginning. We started with VAX-24. We felt like we could stretch VAX-31. We've proven that now. And this is a class that has had extremely long durations of [ leadership ]. So right, starting with Prevnar, 26 years ago, that franchise possesses majority of market share today, both in the adult and infant class. And I think we view this as the baton being passed to our PCV franchise in light of the data that we've been able to generate. And as much breakthrough as the historical chemistry was we realized that there was a limitation some time ago when we started focusing on this back in 2015. And we have an opportunity to rise to the occasion of the need for substantially broader coverage without sacrificing the immunogenicity to give us confidence that we're going to continue to see really good protection against the pneumococcal disease. So we believe that we're really set up for a long-term type of franchise here. We say that because given the coverage of VAX-31 already at 95% of circulating disease in adults in the U.S. and even higher in Europe, it's closer to 98% there. We are already effectively blanketing the disease coverage today. The theory behind VAX-XL is a recognition that we believe we do have additional headroom to go further, but that's really going to be driven by the epidemiology. At this stage, additional serotypes add really de minimis incremental coverage. So for us, we want to have a level of readiness with VAX-XL to the extent serotype replacement makes a meaningful impact on the coverage for VAX-31. But frankly, we think that will come predominantly from widespread use of VAX-31. That's how the class has unfolded, right? We use a really broad spectrum vaccine, those contained serotypes tend to be taken out of circulation. So we want to have readiness for that, but we believe that VAX-31 is going to be in a position to durably lead this space, but we still have some more work to do to get the BLA in, et cetera. But for us, that's how we're thinking about the franchise sooner and later. As to your second question, appreciate that reference to the recent SPPD data. So yes, this is a one known phenomenon that Serotype 3 is very much of an outlier in this class. It truly is the exception to the rule. What we have seen with this class of vaccines is that they provide really effective outcomes associated with the prevention of disease and -- disease, carriage and transmission. The exception to that is serotype 3. So even though it has been included in the licensed pneumococcal [indiscernible], it continues to circulate at the highest rates. It is effective. It was proven in the [indiscernible] trial in adults that we do see the prevention of disease with pneumococcal conjugate vaccines. But unfortunately, the durability of protection is not consistent the way it is with the other serotypes that have been included, and that carries forward to the actual carriage of the bacteria, and then it's transmission from one person to another. So there was some initial excitement when, as you say, the 15-Valent PCV showed higher titers against serotype-3. But frankly, there was real skepticism about whether or not that would translate to anything meaningfully clinically. So when it was first received, that was the reaction. So it was a prove it kind of moment, and what happened was there was work done to look at these higher antibody titers to see if it had effect on carriage which is the leading indicator of what will turn into transmission, that was reported in May of this year at ISPPD. And the reality is there was no effect even with higher OPA titers it did not produce any change in the rates of transmission. So I think the reality is we just have not cracked the code on serotype 3 as an industry. We believe our data puts us in really positioned with the comparator vaccines by virtue of the clarity of what we've produced in evidence today. So yes, serotype 3 is very much the exception to the rule in this class.

Our next question comes from Seamus Fernandez with Guggenheim.

Congrats on the data. And just a couple of quick questions. How you see these data potentially offering incremental information relative to the opportunity in the pediatric, I think, in particular, just given the fact that, that's your next major catalyst, it does seem like the data on 22F is particularly encouraging. Here, but just interested to know how you guys are thinking about that opportunity? And then incremental to that, as we think about the commercialization and the opportunity to commercialize. Just the time frame of the filing, the sort of launch potential, if you could just provide us a little bit of the kind of out of the gate supply that you see being available given the opportunity to potentially dominate this market on the adult side very quickly.

Awesome. Thanks, Seamus. I think that's a five-parter. So I will start and then I would distribute to the team as we go through. And so thank you for the questions. Yes, so obviously, the data in adults, as we said, we think, is extremely clear. The next 2 studies that we'll read out for us will also be in the adult segment. But as we've guided, we have this fully enrolled Phase II study with VAX-31 using the same formulation that's read out today but bracketed with a slightly lower dose and a slightly higher dose. So we're going to learn a lot as it relates to guiding to the appropriate dose think about a Phase III program going forward. I think we need to be careful about adult data and how that can read through to infants. We do have the benefit now of having conducted both adult and infant studies with VAX-24. We have the VAX-31 adult studies now Phase II and in Phase III, but we've yet to be able to connect the dot to the infant segment. You pointed it out yourself the fact that 22F was one of those serotypes where we expected to miss on the relative comparison to Prevnar 20, we got a really nice surprise when we saw the results with this 4.4 microgram dose of 22F in adults, where we did see a meaningful improvement relative to what we had seen in the prior study. So for us, that makes us feel really good. As a reminder, in the VAX-24 formulation, we had only dosed 22F at 1.1 micrograms or 2.2 micrograms. So we had had confidence that doses have worked out for us. We've seen a really nice consistent dose response. So we have 22F dosed at both 3.3 micrograms and 4.4 micrograms in that upcoming study. So yes, that makes us feel good about things. 22F is the second highest circulating serotype. So it is a priority. And it is one of the things that gives us a bit more hope heading into that particular outcome. But I think we need to be careful about going too far with the adult results. Obviously, the safety is clean. That's super encouraging. The robustness of the immune responses across the board is encouraging. We just need to be clear that these are two different populations that we're talking about. But the VAX-24 data was positive, right? We hit on all of the incremental serotypes in that study from -- in the VAX-24 Peads Study from a superiority perspective, we hit on all the key circulating serotypes at post-dose 3 microgram, and the handful of misses that we had in that setting were all with low circulating or not circulating all serotypes. So we felt very good about what we saw with VAX-24. And the key thing is to flex on the incremental coverage that comes from VAX-31 and it's 11 incremental serotypes relative to Prevnar 20. So yes, this data gives us a lot of confidence given how we performed versus Prevnar 20. And as a reminder, we don't have that same complication that we have in the adult segment. It's Prevnar 20 has dominant market share. So it is a bit more of a straightforward set of circumstances we think about that data coming forward. So with that, you asked us about commercialization, delay timing, launch potentials, Mike first, to make some comments about commercialization, then I'll hand it to Andrew to talk about the BLA timing. Or we can flip it, you want to do BLA?

Yes. Maybe I'll start, Seamus, thanks for the question. This is Andrew, and turn it over to Mike. Look, to your question, we are preparing for not only the BLA submission but readiness for approval and launch of the product. So to your question, I would look at -- think about 3 separate tracks that we're running in parallel. First would be the BLA [indiscernible] activities, right? As Grant mentioned, the OPUS-1 study is absolutely the cornerstone of that BLA application, but it's not the only component. But we've got the OPUS-2 and OPUS-3 studies. Those are not fully enrolled. We expect data for those in the first half of next year as noted. And we've also had the manufacturing consistency study that we need to both align on, commence and conclude. And across all these activities, both clinical and commercial, as we have been doing for the last several years, we continue to engage with the FDA on that to ensure that the BLA, we ultimately deliver kind of meets with their support. So that's track one. And then track 2 would be just manufacturing readiness activities as we prepare for a launch that includes building inventory levels to meet the opportunity in the adult market. So I'll have Mike talk about that in a minute. And then the third track would just be commercial readiness activities from both the medical affairs and commercial standpoint. So we feel like we're in a good position. There's certainly a lot to do, but with this data in hand, I think it's a -- we couldn't imagine a better start to enable us to pull all this together to not only submit the BLA, but to deliver a product that we can successfully commercialize in the market.

And just before we hand it to Mike, just to pick up where Andrew left off as it relates to the supply. Just to be clear, we have been manufacturing with our CMO material for quite some time. We are in the mode of not only validating the manufacturing process, but as it were hinted at already beginning to build inventory. So yes, we are already preparing for a launch, consistent with the kind of profile that we've been expecting, although we will say that these data exceeded our expectations. But yes, we are going to be ready for the inventory build. And as we commented in the prepared remarks, we've already built out that dedicated facility for which we can make tens of millions of doses per year. That facility is already in production and being validated itself. So it should be a relatively quick handoff from the initial supply to the even larger supply. With that, let me hand it to Mike to talk about launch potential and commercialization.

Yes, of course, Seamus, thanks so much. I'm thrilled about these data from a commercial perspective. Of course, we feel we have a best-in-class vaccine with the broadest coverage available. So we're excited I think, first of all, we've been able to develop a really strong team, starting out of the gates really well. I think secondly, this market is highly concentrated in the adult space, specifically around rebill pharmacies and large health systems in the U.S. So that concentration gives us the opportunity to really focus at launch and prepare ourselves effectively. And we feel like we're on a really great path to do that. Maybe third, I'll say is we're preparing for recommendations. So obviously, in the United States, that means getting ready for a strong ACIP recommendation and generating the data necessary. We feel like we're on a great start to that work already. And in the event, of course, that the ACIP is either nonfunctioning or perhaps lack some of the credibility that it had in the past, we're really encouraged by the fact that other recommending bodies like AAFP, AAMA, AAP, Vaccine Integrity Projects are all coming out very proactively with vaccine recommendations over the course of this respiratory season, which gives us very strong confidence as well there. So we'll continue to monitor that progress, but we're really excited about the opportunity in front of us and feel like we will try our best to put pressure on our supply to deliver.

We'll take our next question from Jonathan Miller with Evercore ISI.

Congrats on a really stellar results. I want to start by asking about some of the cross reactivity comparisons that you obliquely mentioned on the call a little bit, but I want to get a little bit deeper into that. So you're looking at, for instance, serotype 20B cross referencing serotype 20C, that's already in the line. But I'm curious about other serotypes, where there may be cross-reactivity. Other things that are not formally [indiscernible] that may be cross-reactive with serotypes that are in the shot and whether there's potential for showing analyses on those cross-reactive serotypes going forward? And then secondarily, I guess I'd love to ask about the things that aren't in today's release. Obviously, you've got a ton data on secondary endpoints, et cetera, et cetera, that you haven't presented today, when should we expect to be seeing more detailed information from the deeper analyses from this trial?

John, thank you so much. I really appreciate your use of the word stellar. So as it relates to the cross reactivity, yes, so we've already shown the 20B data. There are a few more cross-reactive examinations that will be performed. Today is the top line result delivery. So between top line and final, those data will emerge. And so we're going to not go further than that in this moment. But yes, that is a feature of OPUS-1 and something for people to look forward to. As it relates to the secondary endpoints like superiority and statistically greater immune responses, those fall into the same category. But as we had defined at the setup we've said how those will be defined. So to the extent statistically greater comes from the lower bound of the confidence interval exceeding the [indiscernible]. It does -- it will include a multiplicity adjustment. But you can look at the data that's in the presentation and get a sense for how things are likely to fall out, and those will be incorporated in the final results.

And we'll take our next question from Roger Song with Jefferies.

Great congrats for the real blue sky scenario for the readout. A couple of questions from us. The first one is understanding the primary endpoint comparing 2 vaccine either or to lead us then noninferiority criteria. Just curious about the importance of the individual vaccine approval, at the comparison number, you have [indiscernible] is against PCV21 or Capvaxive. How should we think about FDA regulatory consideration and then maybe the commercial adoption [indiscernible] is missing PCV21, but pretty high for PCV20. And then on the other secondary end point, just to follow on the previous question. Does, any of those key secondary endpoint will be particularly impact for the BLA package and the overall profile, for example, the security and the [indiscernible] comparator? And then that's the number two. And the last question, just can you comment on your assay quality because you use the historical study and then modeling to predict potential misses since this is better than your expectation, maybe the [indiscernible] outlier? And then can you comment on the variability of [indiscernible] and then how you're confident about the quality and then for the FDA review?

Thank you, Roger. I appreciate those questions. So why don't I hit it to Luis Jodar to open up with your questions with regard to those 11 overlapping serotypes in the [indiscernible] and the importance of the individual [ miss ]. Do you want to take that on, Luis?

I'm just going to try to explain very simply for everybody listening via statistical framework for the 11 shared serotypes. For the serotypes that are present in both licensed competitors, we have to prespecify comparison against PCV20 and PCV21 and success required non-inferiority to at least 1. So as you know, having 2 comparisons give you two, statistical opportunity. So therefore, what a pre-specified multiplicity adjustment in this particular case the [indiscernible] adjustment. What it does is to control any false positive barriers associated with that. That doesn't mean that it relaxes the 0.667 or the noninferiority margin. In fact, if only 1 competitor [indiscernible] evidence of non-inferiority, that comparison has to meet a more stringent one-sided P-value threshold of 0.0125 rather than 0.025. So the adjustment is a statistical safeguard, not a mechanism to facilitate success. And with regard to the FDA what we've learned about the FDA. The historical tracking is to compare with the broadest coverage PCV, and I think as you have been looking at the evolution of the epidemiological landscape. The FDA has indicated during our discussions that given the current U.S. epidemiology, they give PCV21 a particularly relevant competitor. We incorporated that feedback before the data were known. I think what is more important here is that regardless of which competitor regulators ultimately places greater emphasis on in its review, our data set includes preplan individual competitor assessments, against both PCV21 and PCV20, so FDA will have the full head-to-head immunogenicity profile against each licensed vaccines available for review. You've mentioned also about the importance of these two misses against PCV21. I'd just like to remind you that those 2 misses were again the most stringent 0.667, non-inferiority comparison. Both of these serotypes met the historical noninferiority comparison, and additionally, both of these serotypes met the 0.667 stringent comparison against PCV20. We see this statistical misses as part of the totality of the evidence, and this is how the FDA have traditionally reviewed and evaluated this vaccine. So we feel very confident with the data set that we have presented today. And I will turn...

Thank you, Luis. Yes, I appreciate you kicking that off. Yes, Roger, I mean, the bottom line is OPUS-1 was a complete success. We acknowledge that ultimately, if everything goes the way we plan, we will be competing with each of these 2 comparators in the marketplace. We think we have very clear data. We have a product with 10 or 11 more serotypes in the vaccine, and we know that perfection is not the price of admission in this class. Every pneumococcal conjugate vaccine that is on the market today was licensed with at least 1 miss to as many as 6 misses in their formal co-primary endpoints of their pivotal studies. So we feel extremely good about the setup for VAX-31, and let me transition to your second question. You asked about the secondary endpoints and their criticality. See, what's left, what's to come is those statistically greater analyses on the overlapping serotypes and superiority for incremental serotypes relative to the individual vaccines. In our view, superiority is [indiscernible] air in this class. This is -- and greater immune responses for that matter, are rarefied air. It's really icing on the cake. It's never been the case that there's been more than 1 serotype shown to be statistically greater in a pivotal study on a relative basis, for a [indiscernible]. So you can see that the data is suggesting that we were substantially higher than that. So we're super excited about that. The cross reactivity is kind of -- we feel great about the setup for us. 31-Valent vaccine based on this data. I think [indiscernible] position to look at [indiscernible] coverage. I think you asked about the OPA assay. What we would say is when we were looking at the Phase II data and meeting projections, we will acknowledge that the [indiscernible] that has come out has less variability than what we kind of seen with the prior assay used in Phase II. And if you look across the pivotal Phase III studies for the comparative vaccine, the variability was tighter than indicated in either of those 2 studies. So yes, this was something that probably worked in our favor. So yes, everything worked extremely well and in a very clean fashion to put us in a position to end up with a result like this.

And I'll just add in terms of the variability of the Roger. We did do a validation prior to starting the Phase III demonstration of reproducibility or variability. There is a WHO standard in terms of what you need to meet to move forward in Phase III. And in terms of assay variability, we met those standards.

We'll take our next question from Salim Syed with Mizuho.

Congrats on the great data set. Just one for us, just the commentary that you guys provided in the press release, in the slides, et cetera, on the FDA focusing a little bit more on PCV21 given the way the population is today. Are you hinting at all here that the FDA or you guys think that PCV20 will eventually get pulled from recommendation? And if that were to happen, what would be the commercial implication here for you, especially considering that that PCV21 do not have serotypes 4 and 19F?

Thanks for the question, Salim. Well, let me just first say, no, we are not suggesting that PCV20 is going to get pulled from the market. I think if anything.

From recommendation. Recommendation, sorry. Just to break it.

No, I don't -- we're not making that suggestion either. Louis touched on it. The commentary is really to reflect the following, which is historically, it's always been extremely straightforward to look at a novel, more broad-spectrum pneumococcal conjugate vaccine. You compare it to the market and standard of care product that has the broadest coverage. That was pretty straightforward when the history was just layering serotypes on top of overlapping serotypes at the base. So what's different about this moment, as we set up in the prepared remarks, we have 2 standard of care vaccines that are not recommended with any differential recommendation. And there they have nonoverlapping coverage. And so the reality is in the history of the class, you're always comparing against the most broad spectrum comparator. In this moment, that is Capvaxive, the 21-Valent vaccine. So the regulators have expressed a preference for that comparator, but it's indisputable that the 20-Valent vaccine still has an important role, particularly given the epidemiology as it has shifted, right? What was the expectation was that those historically controlled serotypes, some of whom had disappeared altogether would stay that way. But serotype 4, which is the best example, has reemerged very aggressively, and it requires pressure to ensure it does not begin to circulate at even higher levels. So both of the vaccines today are playing a vital role in suppressing disease. We just believe that in a single vaccine that covers all of those serotypes, we have a much better solution.

Our next question comes from Nick Jennings with Goldman Sachs.