PCVX - NASDAQ

Good afternoon, my name is Jess, and I will be your conference operator today. At this time, I would like to welcome everyone to the Vaxcyte Fourth Quarter and Full Year 2024 Financial Results Conference Call. All lines have been placed on mute to prevent any background noise. After the speakers' remarks, there will be a question-and-answer period. [Operator Instructions] Today's call is being recorded. I would now like to turn the call over to Andrew Guggenhime, President and Chief Financial Officer of Vaxcyte. Please go ahead, sir.

Thank you, operator, and good afternoon, everyone. I'd like to welcome you to Vaxcyte's earnings conference call to discuss our 2024 results and to provide a business update. I am joined today by our Chief Executive Officer, Grant Pickering; and our Executive Vice President and Chief Operating Officer, Jim Wassil. Earlier this afternoon, 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 & 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 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-K for the year ended, December 31, 2024, and any subsequent reports filed with the SEC. With that, I'll turn the call over to Grant Pickering. Grant?

Thanks, Andrew, and all of you on the call and webcast, thank you for joining us today. Vaccines are one of the most powerful innovations in modern medicine, transforming public health by preventing disease, reducing hospitalizations and saving millions of lives every year. Beyond protecting individuals, vaccines are essential to global health security, curbing outbreaks, alleviating pressure on healthcare systems and delivering substantial economic benefits by reducing the significant financial burden of infectious diseases. This outsized impact is particularly critical for bacterial infections, where vaccines play a key role in reducing antibiotic use and combating the growing threat of antimicrobial resistance or AMR, one of the most pressing public health challenges of our times. Against this backdrop, 2024 was a defining year for Vaxcyte as we continued to advance our mission to protect humankind from the devastating impact of bacterial diseases, including invasive pneumococcal disease or IPD. While pneumococcal conjugate vaccines or PCVs have long been an important element of global immunization programs, our vision extends beyond pneumococcal vaccines. We are building a robust pipeline of novel broad-spectrum vaccines designed to address some of the world's most widespread bacterial threats, including Group A Strep, periodontitis, and Shigella. These programs alongside our PCVs reinforce our commitment to delivering life-saving vaccines that can have a meaningful impact on public health. As we continue to advance our pipeline, our PCV franchise remains the cornerstone of our efforts to address one of the most persistent and deadly bacterial threats today. The global pneumococcal vaccine market, currently valued at approximately $8 billion in annual sales, continues to expand with the adult segment poised to grow significantly, driven by expanded vaccination guidelines in the US and in other developed countries. The infant segment remains the largest piece of the market today at an estimated $6 billion in annual sales. However, despite decades of vaccination efforts, it is estimated that streptococcus pneumoniae accounts for about 300,000 deaths globally each year in children under five years old and remains a leading cause of vaccine-preventable deaths in this age group. In the US alone, more than 150,000 hospitalizations occur annually due to pneumococcal pneumoniae, underscoring the urgent need for broader spectrum coverage. Over the past year, our team has made meaningful progress in the clinic across our PCV franchise in the pediatric and adult populations. The pinnacle achievement for Vaxcyte in 2024 was the stellar VAX-31 clinical data in adults. In September, we announced those top-line results comparing VAX-31 to PCV-20 in healthy adults aged 50 and older. We believe these results validate the potential of our site-specific carrier sparing platform to deliver the broadest spectrum PCVs, providing protection against both currently circulating and historically prevalent serotypes. Based on the robust strength of this data, we are advancing VAX-31 into a Phase 3 program for adults. We are also encouraged by our progress in infants with the VAX-24 study fully enrolled and data expected by the end of this quarter and the VAX-31 infant program underway with the first key dataset expected in mid-2026. Beyond our PCV franchise, we continue advancing our early-stage vaccine candidates that address diseases that contribute significantly to AMR, which is a global health crisis that if left unaddressed, is expected to become one of the leading causes of death by 2050. While no single solution can fully address AMR, vaccines play a critical role in reducing reliance on antibiotics. We are incredibly proud to be at the forefront of developing vaccines that target drug-resistant pathogens and we look forward to providing further updates on our pipeline throughout the year. Our clinical progress continues to be driven by strong operational execution, including manufacturing scale-up. As part of our long-standing partnership with Lonza, we are executing on our plan to establish a purpose-built large-scale manufacturing suite within Lonza's Ibex dedicated biopark. The build-out of this dedicated facility began in late 2023 and remains on track to be completed by early next year. This facility will play a critical role in supporting the future of global commercial supply for both the adult and pediatric indications, ensuring we have the capacity to meet anticipated demand. Also, as a reminder, we are leveraging our existing manufacturing infrastructure with Lonza to support the anticipated US launch of VAX-31 for the adult population. With this foundation in place, we are well-prepared to execute on our plans and bring broad-spectrum vaccines to market. Our ability to advance these programs is underpinned by a strong financial position, ensuring we have the resources to advance clinical development, scale manufacturing, and drive commercialization. To provide more details on our financial strength and outlook, I'll now turn it over to Andrew.

Thanks, Grant. The details of our fourth quarter and full year 2024 results and the reasons for the variances to the comparable 2023 periods are reflected in our 10-K filing and summarized in today's press release. Vaxcyte's financial position remains strong with $3.13 billion in cash, cash equivalents, and investments as of December 31, 2024, which includes $2.2 billion in net proceeds from the two successful follow-on equity offerings last year. Turning to the income statement, the increase in R&D expenses in 2024 was due primarily to increased development and manufacturing activities in connection with the adult and infant PCV programs, including to support the potential future commercial launches as well as growth in R&D personnel. The increase in G&A expenses was driven primarily by higher personnel costs due to the growth in the number of employees in these functions. For the build-out of the dedicated manufacturing suite at Lonza to support the potential global launch of our PCV programs, Vaxcyte incurred an additional $127.8 million in capital and facility expenditures last year, bringing the project to date total to $214.3 million, about 60% to 70% of our original $300 million to $350 million estimate to which we continue to track. As we look ahead, we expect a substantial increase in both R&D and G&A expenses in 2025, particularly within R&D, over both full year and Q4 2024 annualized levels. This expected increase is primarily the result of manufacturing-related investments to prepare for our initial launch in the adult market, including to build inventory, the initiation of the VAX-31 adult Phase 3 clinical program and the growth in the number of our employees to support these and other initiatives. Consistent with historical results, we expect R&D expenses to fluctuate by quarter, largely based on the timing of manufacturing activities. The significant majority of the costs related to the construction and build-out of the dedicated manufacturing suite will not run through the income statement and instead will continue to be reflected on our balance sheet in two separate line items, property and equipment and other assets. Once the build-out is complete and manufacturing activities commence, the costs will then run through the income statement. Turning to cash runway, we expect that our cash, cash equivalents, and investments, which as I noted, totaled $3.13 billion as of 2024 year-end will be sufficient to fund our operating expenses and capital expenditure requirements through several expected key milestones over the next few years. These include the VAX-24 infant Phase 2 study, primary series and booster dose data readouts, the initiation, completion, and data readouts from all of the anticipated Phase 3 studies for the VAX-31 adult Phase 3 program, the VAX-31 infant Phase 2 study primary series and booster dose readouts and the completion of the build-out of the dedicated manufacturing suite at Lonza. We remain committed to financial discipline and to making strategic investments that maximize long-term impact and the steps we are taking today position us for sustainable and meaningful growth. Beyond financial and operational execution, 2024 also marked the establishment of a dedicated public affairs function, enhancing our engagement with policymakers and public health stakeholders. We have been working constructively with the new administration to ensure that science-driven evidence-based policies continue to guide vaccine development and public health decision-making. In parallel, we will continue to engage with the FDA, CDC, and ACIP to foster a regulatory framework that continues to encourage investment in vaccine, innovation, and manufacturing. During our engagement with key government stakeholders, we have been encouraged by a bipartisan acknowledgment that vaccines are not only a cornerstone of public health, but also one of the most cost-effective interventions available. It is estimated that vaccination in children over the last 30 years in the US will result in direct savings of $540 billion and societal savings of $2.7 trillion, and expanding vaccine uptake among adults is equally important, as vaccine preventable diseases cost the US economy an estimated $27 billion annually in direct and indirect expenses. At Vaxcyte, our mission remains clear, to deliver broad-spectrum vaccines that address significant unmet needs. We are confident in the strength of our science and the broad understanding of the critical role vaccines play in protecting global health. I will now turn it over to Jim for additional commentary on our clinical development highlights and the upcoming VAX-24 infant study data readouts.

Thanks, Andrew. Our PCV franchise continues to advance with major clinical, regulatory, and manufacturing milestones, reinforcing our leadership position in pneumococcal vaccine innovation. Over the past year, we have made strong clinical progress across both the adult and infant programs with compelling data in adults reporting the potential to set a new standard in disease coverage with our carrier-sparing platform. For the adult indication, VAX-31 delivered strong results in its Phase 1/2 study, demonstrating robust opsonophagocytic activity or OPA responses across all 31 serotypes. VAX-31 was observed to be well-tolerated and demonstrated a safety profile similar to PCV20 at all dosing studies through the full six-month evaluation period. The middle and high dose of VAX-31 met or exceeded the non-inferiority criteria for all 20 serotypes shared with PCV20. At the VAX-31 high-dose, average OPA immune responses were graded for 18 of 20 serotypes compared to PCV20, with seven of these serotypes achieving statistically higher immune responses. At the middle dose, OPA responses were greater for 13 of 20 serotypes, and five serotypes achieved statistically higher responses compared to PCV20. Additionally, all 11 serotypes unique to VAX-31 met the superiority criteria at all dose levels, reinforcing the potential for VAX-31 to deliver the broadest spectrum protection to date. Based on these results, in November 2024, the FDA granted Breakthrough Therapy Designation for VAX-31 in adults, recognizing its potential to set a new standard in pneumococcal disease prevention. This designation unlocks expedited regulatory pathways with more frequent and senior FDA engagement potentially streamlining our progression towards launch. Pending an end of Phase 2 meeting with the FDA, we remain on track to initiate the VAX-31 adult Phase 3 pivotal non-inferiority study by mid-2025 with top-line safety, tolerability, and immunogenicity data expected in 2026. We also anticipate initiating the remaining Phase 3 studies for VAX-31 in 2025 and 2026 with the last of the studies to enable a BLA submission expected to read out in 2027. For the infant indication, we continue to advance both the VAX-24 and VAX-31 programs in parallel. In March of last year, we completed enrollment for the Phase 2 study of VAX-24 in healthy infants, enrolling a total of 802 participants in a two-stage study designed to evaluate safety, tolerability and immunogenicity. By the end of this quarter, we expect topline data from the primary immunization series comprising the first three doses administered in the first six months of life with data from the booster dose administered at 12 to 15 months of age anticipated by the end of this year. As you will recall, the primary immunization series, which is referred to as post-dose 3 serves as a critical indicator of disease protection during the infant's vulnerable first year. The booster, referred to as post-dose 4 evaluates anticipated durability of protection through the first few years of life, ensuring sustained immune protection during this heightened period of risk to pneumococcal disease. In this study and for all precedent infant PCV studies, the primary immunogenicity endpoints, both post-dose 3 and post-dose 4 are based on immunoglobulin G or IgG antibody concentration, whereas in adult PCV study, the primary immunogenic endpoint is OPA. This VAX-24 infant study is evaluating the IgG responses compared to PCV20. For the 20 serotypes common with PCV20, the primary endpoint post-dose 3 is based on the percent of participants who achieved the predefined IgG concentration threshold of greater than or equal to 0.35 micrograms per ml. This represents the seroconversion rate. To meet the historical non-inferiority requirement in the Phase 3 trial, the lower bound of the 95% comps must be within 10 percentage points of the PCV20 conversion rate on a serotype-by-serotype basis. Based on present PCV programs, the four incremental serotypes unique to VAX-24 will be compared to the lowest performing PCV20 serotype other than serotype 3. In Phase 2 studies for which the confidence intervals are wider due to the smaller sample size compared to a Phase 3 trial, sponsors have considered non-inferiority success to be a 15 percentage point differential. We feel encouraged as we head into the infant clinical data readout based on the strength of the data from our three adult clinical studies, including the higher immune responses relative to PCV20, the historical translation of adult to infant data and the precedent regulatory approval bar. With each iteration of approved PCVs, there have been misses on the non-inferiority bar for individual stereotypes, up to six misses in the case of PCV20. In our case, we would be disappointed with this type of outcome. However, given this is a proof-of-concept dose-finding study, the purpose of which is to determine the dose and the design of Phase 3 program is reasonable to expect a few non-inferiority misses. Even in this scenario, we would still expect VAX-24 to be well-positioned to advance to Phase 3 and demonstrate best-in-class potential, particularly if we see higher immune responses across multiple serotypes as we saw in all of our adult studies. While we await the data from our VAX-24 infant study, we are also making significant progress on our VAX-31 Phase 2 study in the same population. Following its initiation in December 2024, Stage 1 of the study used the dose-escalation approach to evaluate the safety and tolerability for low, middle and high doses. In early February, we advanced to Stage 2 based on a blinded safety assessment, marking an important milestone in the study's progression. We anticipate announcing topline safety, tolerability and immunogenicity data from the primary three-dose immunization series by mid next year with top-line booster dose data expected approximately nine months later. Despite the effectiveness of current pneumococcal vaccines, IPD, including meningitis and bacteremia, remains persistent in the first years of life. The public health community has made it clear that a broader spectrum pneumococcal vaccine is needed to provide expanded protection against this disease. Our PCV programs are designed to address this gap and VAX-31 has the potential to cover approximately 94% of IPD and 93% of acute otitis media in children under five, offering significantly greater coverage compared to the standard-of-care PCVs. Outside of our PCV programs, we remain focused on advancing our pipeline, including VAX-A1 for Group A Strep, our most advanced pipeline program. Group A Strep is a leading global cause of infectious disease-related death and disability and a major driver of antibiotic prescriptions in young children, underscoring the urgent need for a preventative solution. As VAX-A1 advances towards the clinic, we have continued to progress activities, including analytical method development, immunological assays and process scale-up for the production of GMP-grade drug substance and drug product. We will provide updates on our anticipated timeline as this program advances. Across all of our programs, our commitment to vaccine innovation remains unwavering. With a strong foundation in place, we are well-positioned to drive our pipeline forward, achieving key clinical milestones and accelerate progress towards launch. I'll now turn it back to Grant to share closing remarks.

Thanks, Jim. Before moving to Q&A, I want to express my deep gratitude to our investors, partners, clinical trial participants, and most importantly, our employees. Your support, dedication, and belief in our mission continued to propel Vaxcyte forward as we work to develop vaccines that address some of the most pressing unmet needs in bacterial diseases. With the strength of our science, the dedication of our team, and the momentum we've built, we are well-positioned to execute on our vision and deliver meaningful impact. As we look ahead to the rest of the year, we do so with confidence and optimism. This will be a milestone-rich year marked by key clinical and regulatory advancements, continued expansion of our manufacturing capabilities, and the next steps in building a global platform for vaccine innovation. With a strong foundation in place, we are poised to drive Vaxcyte's next phase of growth and ultimately bring life-saving vaccines to those who need the most. We appreciate your interest and look forward to sharing further updates as the year progresses. With that, let's take some questions. Operator?

[Operator Instructions] We will go to Roger Song with Jefferies.

Great. Thanks for the update and congrats for all the progress. Thank you for taking our questions. A couple of questions from us. So the first one is regarding the Phase 2 VAX-24 infant primary series data readout. Can you just give us some color around what factors play into the timing of the data readout given you already finished the enrollment by 1Q last year and then how should we think about how much safety data you will provide and then all the immunogenicity data will be analyzed by the time by the end of 1Q this year. Thank you.

Yeah, thanks for the question, Roger. Yeah, I mean the primary endpoint for the infant indication, as you know, are actually split across two different co-primary endpoints, the first after post-dose 3, the second after post-dose 4 and those are all based on the IgG antibody responses. So this is a top-line data readout and this is the standard accrual for the accumulation of those antibody responses. So, that's the primary thing that we'll be focused on at this particular occasion. Jim, do you want to comment on the amount of the safety data you'll expect to have by the end of the quarter?

Yeah. So we will cut the safety data just prior to when we have all of the prerequisite immunogenicity data. So that will include whatever we have at that point in time. So my expectation is the vast majority of safety data from post-primary all the way up to boost will be included. There will be some post boost as well, but that won't be as robust as obviously post-primary through boost.

And you had a second question, Roger?

Yes, if I may. And so for the -- I think on the call, you said if you missed six serotypes in the inferiority will be disappointed. So that speaks to the confidence. Maybe just I think you mentioned something given the Phase 2 sample size is smaller than the typical Phase 3, how should we think about the non-inferiority criteria? Maybe just give us a little bit clarity what we are really looking for. You mentioned 15 percentage point differential, how should we think about that is the bar for the lower bound confidence interval or what's the -- it is the point estimate difference? Thank you.

Yeah. Thanks, Roger. Yeah, per the prepared remarks, the precedent for the most broad-spectrum PCV to date which would be the 20-Valent. When they were comparing themselves to the prior standard-of-care, the 13-Valent vaccine, indeed they actually failed on six of those 13 non -- well, six of the 20 non-inferiority comparisons, and yet that was still enough for them to gain full approval and for them to gain the overwhelming market share. So when we look at the data that we've generated across three different adult Phase 2 clinical studies with VAX-24 and VAX-31, we've shown such consistently higher average immune responses, that was not the case for the 20-Valent versus the 13-Valent, certainly in adults and even more so, a widening of a gap with falling immune responses in infants. And so our view is that given the continuity of immune responses from adults to infants affords us the confidence to expect a better outcome. So of course, we're comparing with the 24-Valent vaccine, so we'll see precisely what our immune responses are on a relative basis. But indeed, we would be surprised to the negative if we were to have seen as many misses as they saw. So we're expecting something more bullish. We could imagine missing on a few, but on the other hand, if we did, we would expect perhaps at least that many with higher immune responses given how many we were better on in the adult setting. So that is one feature. But then to your point, the other thing in drug development for pneumococcal conjugate vaccines is the size of the study, particularly when you're doing your dose-ranging is considerably smaller than the ultimate Phase 3 pivotal non-inferior study that will need to be conducted. So like we had talked about in the adult setting, the sponsors that have come before us and for us going forward, you have a right to take into account the smaller sample size and the way that's manifested itself in the past is even though the ultimate difference in the absolute rate of seroconversion needs to be within 10 points at Phase 3, in Phase 2, given how much smaller the studies are, other sponsors before us have considered a 15-point absolute difference as adequate as a predictor of what it will take to hit the endpoint in Phase 3. So we're going to take a similar approach, knowing that we'll have that same opportunity to take advantage of the much larger sample size, which clearly closes up the confidence intervals in ways that can allow you to hit the 10-point absolute difference. So, yeah, two key features of how to think about this upcoming data. So Roger, thank you for raising both of those.

Thank you so much. Very quick last one. Given we are looking for this primary series data, how should we think about the read-through from the primary series data to the booster, which will be nine months later? Should we have a higher confidence the booster will more likely going to hit if -- even if you have a few misses for the primary? Thank you.

Yeah. So -- and we've been trying to condition the market to appreciate that the two co-primary endpoints are different, right? The first of which is a seroconversion comparison, whereas the second after the fourth dose, the booster is a comparison of the magnitude of immune responses. So as everyone knows from our adult data, we've shown a great ability to not only show non-inferior magnitude of immune responses, but in fact, showing in most cases, higher immune responses and in many cases, statistically higher immune responses. So we've really thrived on that second comparison that we'll have later this year, and while the seroconversion data will be the main event with this upcoming data readout, you should expect that we'll also present those IgG antibody comparisons, which will give us an indication of how to expect the post-dose 4 data to look. And while it's not the headline for the prior vaccines that are currently marketed the 15 and the 20, they saw an even more pronounced drop in the magnitude of immune responses at this post-dose 3. So if we reverse that trend as we did with adults, not only would it indicate that we've done quite well on the initial seroconversion, but it would also set us up for our confidence heading into the next data point at the end of the year.

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

Great. Thanks for all the color, guys, and congrats on the progress. I wanted to spend a little bit of time just focusing on the macro discussion, just kind of given it's had such a heavy impact on the stock in the 4Q and 1Q, totally appreciate the commentary in the prepared remarks about the conversations being constructive with DC, but could you perhaps give us a little bit more granularity there if possible as it relates to whether there have been actually discussions with distinction to PCVs versus other vaccines, how we should interpret this last ACIP meeting delay or any other particular granularities there? Thank you.

Yeah. I think Andrew and I can tag team this one. I'll start and then let Andrew jump in, but just taking up that last topic and the ACIP delay, I mean, I think one of the things that was not widely reported was that as a matter, of course, for every ACIP meeting historically, there is an opportunity for public comment and no one knows precisely why it happened. I think it was -- I think people believe it was inadvertent, but somehow in early February, that public commentary mechanism was not opened up. So that would have been atypical to not allow for that. So, it could be as simple as that and that is what is precipitating that delay. I don't think people should overread into that situation, but there is a lot going on. Andrew is right in the thick of it, maybe you can take up the first two conversations as it relates to PCV vaccines being implicated and just the macro discussion at large.

Yeah, no, Salim, appreciate the question as many of you in this call, no, this is something we've been actively following and actively engaged in as I noted in the prepared remarks, yeah. Salim, we aren't commenting on the very specifics of the folks with whom we've had discussion, but as I said in the prepared remarks, not only are we active, but we've been encouraged by truly bipartisan support for the important role vaccines play in public health. In addition to obviously the health benefit, the significant economic benefit given the cost-effectiveness of these vaccines. And as we've said, it is our view and continues to be our view that PCVs are the bedrock of our immunization programs, particularly in the infant population. And so we'll continue to monitor things, we'll continue to stay engaged, we'll continue to stay active, but I do think there is broad understanding as I said of the important role vaccines play and really no better testament to kind of the demonstrated benefit than that of PCVs over the last 25 years for infants in the last 15 in the adult population.

Okay, cool. And then maybe just to add on to that. Thanks for the color. Is there anything in particular when you're having any discussions with the folks in DC, is there anything particular that sort of comes to light that the market can potentially look at as sort of -- getting this market over the macro hump that's sort of arisen in the past several months, is there anything particular that we should be looking for you think that the market is missing? Thank you.

Well, I guess I would say, we ourselves, we should all just kind of take with caution the noise, if you will, and the news and there's a lot of it and there's been speculation and there's been talk what I think is most important for us and all of us is what ultimately transpires here and we're certainly doing our best to continue to advocate for the important role vaccines play. So, let's -- I've just -- not to overreact to noise or potential changes. Changes are par for the course in general and certainly in connection with changes in administration. And it's the actions ultimately, if any that will be the most important thing rather than kind of the words or these discussions about potential changes. So, certainly watching it closely. But again, as I said, encouraged by what we have heard and hearing firsthand over the course of our discussions about kind of the support on both sides of the aisle for vaccines.

We will move next to David Risinger with Leerink Partners.

Hey guys. Yeah, Brian on for Dave. Thanks for the updates and we appreciate you taking our question. We have two, if that's okay. So first, could you provide more color on the expected Phase 3 program for VAX-31 in adults, including the likely timeline from the initiation in mid-25 to the top-line results in '26? We're just trying to get a sense for approximately how many months do you think it will take after initiation that we might see top-line results.

Yeah, maybe I'll start there and Jim can certainly chime in. Just to remind the guidance that we again reaffirmed today that we would anticipate starting the pivotal non-inferiority study for VAX-31 in adults by middle of this year and to have the top-line safety, tolerability and immunogenicity data from that study next year. So that gives you some idea of the timeline from initiation to data. If you look back at our VAX-24 study, which would be a good kind of comparator, that was 12 to 15 months or so between the initiation of study and data readout at this juncture. So, I have no reason why it would be any different for this study. And then that is one, of course, of a few studies that comprise the Phase 3 program in total. And as you saw today, we've just confirmed our pre-existing guidance and just adding some more clarity to it. We expect the balance of the studies that comprise that Phase 3 program to start either also this year alongside or along with the non-inferiority study or next year, but those studies would read out in either 2026 or 2027. Those studies in general, Brian, tend to be on par or faster than the non-inferiority study, to give you a sense of kind of the expected timing for those programs.

Okay, that's super helpful. I appreciate that. And then just one more on your preclinical Group A Strep vaccine. Could you explain why Vaxcyte's technology is well-suited to potentially succeed? And how close might this be to IND-enabling studies?

Yeah. I can start on that one. For bacterial vaccines, conjugate vaccines have really been the primary approach that's been effective. So just like we're leveraging with our pneumococcal conjugate vaccines, we have special technology that allows us to perform site-specific conjugation of polysaccharides that are found on the outer coat of the bacteria and then proteins to drive a memory response to prevent infection and preserve protection against bacteria over a durable period of time. So, we're leveraging the same fundamental technology that has created a broader spectrum class of pneumococcal conjugate vaccines, which is really what we've become known for. Group A Strep, on the other hand is a vaccine for which there has never been one developed to date. So there's a novelty feature to this, but it's also an area where there is very little to no competition. So we have an opportunity to be a first-mover. We're leveraging an approach that has been effective across a number of different bacterial vaccine targets. We have a proprietary polysaccharide that is resident across the full spectrum of different strains of Group A Strep that's unique to us and we're able to site-specifically conjugate it to a conserved protein on the surface of this bacteria that is accessible to antibodies to clear the bacteria. So we think we have two ways to win with this particular approach technologically. And then important from a market opportunity, we also have two ways to win to the extent this is a problem that afflicts not only infants and primary school children, but also older adults. And in fact, the magnitude of invasive disease afflicting adults by Group A Strep exceeds that of what was accessible for pneumococcal vaccines when they were approved for adults. So, it's a really big opportunity for us. We're really gratified to be in the lead in this area. We have mentioned further work that we've been doing to complete the VAX-A1 program to get it in the clinic. We're stopping just short of when we're saying that clinical study will get underway, but rest assured, we're getting closer and are excited and we'll keep everyone updated on our progress there.

We will move next to Umer Raffat with Evercore.

Hi guys, can I ask 25 questions like Salim also?

You can ask 31, Umer.

All right, 31, that's a good number. In all seriousness, three quick ones, if I may. First, I realize you mentioned on the call that the non-inferiority margin is 10% delta. I feel like that's the right delta for a registrational trial powered appropriately. Are you being too stringent with the choice of that delta knowing that Merck had used a more wider 15% delta to define non-inferiority? That's number one. Second, if I just step back and think about it very simplistically, most serotypes, seroconversion rates are 80% to 90% on Prevnar 20, except two, which is serotype 3 and 12F where their serial conversion rates are more like 50%. And I guess that's my question to you. Let's say you're non-inferior, but you're 40% seroconversion. Is that a successful outcome to you? And I ask because on those two serotypes 3 and 12, at least in adults on IgG, not OPA, you guys were fairly ahead. And last point, I realize the focus is entirely on post-dose 3. Would you happen to have any post-dose 4 data even if it's in 100 out of the 700 or 800 patients? Thank you very much.

Yeah. You've got it exactly right, Umer, the 10% delta is the registration hurdle. And we are not trying to make things more difficult on us than we should. We will look at that same 15-point delta that Merck used when they developed VAXNEUVANCE as the hurdle that we should be looking at for all the right reasons. It's purely because of the wider confidence intervals when you've got a smaller cohort of subjects. So we're trying to not only acknowledge where we'll want to be. I guess the point that people will have taken is even with our smaller Phase 2 studies in adults, we were able to meet the registrational non-inferiority hurdle, but that's a luxury, not a necessity. We really want to see that 15-point delta exceeded at this stage and that will guide us to what the sample needs to look like in Phase 3 to ensure that we could hit the 10-point delta when it matters, which is that pivotal registration study to your point. Then as it relates to the second question with regard to the seroconversion rates, Jim, do you want to talk about that? And obviously, Umer is pointing out there were two big laggards for Prevnar 20, but like how are you thinking about that?

No, I think Umer, as always, I think you're spot-on your assessment. If you've got greater than 90% seroconversion rate, that means that your GMCs are much higher than the level of the 0.35 level, whereas for serotype 3, their GMC is almost the same as the 0.35 level. And so any slight miss on serotype 3 could have a greater impact on percent of individuals who achieve that protective threshold. I do think that given our results in adults so far and with the results of serotype 3 being higher and there being translatability between adults and infants, I don't expect us to see that type of result, but if we do, we had said before, if we have a few misses, we feel that that's still a very good product that we can move forward and get approved in the Phase 3 trials.

And then to your last question, I think the 31st question that you asked, the PD3 versus PD4 data, we will wait and unblind all that PD4 data in mass. So, while we could theoretically look at some cases by the time we got the PD3, that would not make good clinical quality sense. So, we'll wait until we get critical mass on that. That's what we'll be able to read out later this year. It will not be cherry-picked.

We will move next to Seamus Fernandez with Guggenheim.

Hey, guys, thanks for the question. So just a couple of quick ones here. The first question is, the opportunity or if it makes sense at all to consider the possibility of 31 potentially advancing directly to peds, should the -- depending on obviously the '24 data and 31 data, is there an opportunity to kind of assess moving that 31 forward or is there a compelling reason to move both 24 and 31 forward given differences in the sort of international dosing decisions, what would be the decision points that you would be looking at that would be most critical to making that decision? And then the second question is really around this discussion and debate over efficacy studies. It seems a bit ridiculous and quite redundant in the pneumococcal space, but there is an efficacy study that the team could conduct in the pediatric setting post-approval that could be quite compelling, which is in otitis media opportunity, hoping you could just kind of put some context around that and what you see as the opportunity for potentially VAX-31 perhaps securing an otitis media claim and what that study might look like? Thanks so much.

Yeah. Thanks, Seamus. So your first question was about the VAX-31 versus VAX-24 pivot opportunity in infants. Obviously, we navigated that last year in association with the strength of the VAX-31 data to make it obvious to graduate from VAX 24 to VAX-31 as our singular approach for adults, but in that case, we didn't really have a time delta between the two programs based on how things lined up from a product availability perspective, so that was a very straightforward choice. Here we are on the verge of receiving our first pediatric data with VAX-24. As we've declared, we've not waited to get VAX-31 into the clinic in infants, so we have two trains that have left the station, the one is going to get to the next station before the other. We'll have a period of time where we managed -- where we'll be managing what would be the most broad-spectrum vaccine available to the market at the fastest pace, which would be VAX-24, which of course here in the US, the principal competitor would be the 20-Valent from Pfizer, but as you point out, in Europe, the 20-Valent was not able to meet the European schedule of the 2+1 approach versus the US schedule where they give an extra vaccination. So the competition in Europe is really the 15-Valent. So we do have a winner in our mind for which the data is reading out here shortly. But of course, the VAX-31 data as we've guided, we're expecting to get that data by the middle of next year. So, it is not far behind VAX-24. So once we receive that VAX-24 data, we'll be able to better handicap how much headroom there was for the 31-Valent to be effective. Recall, in this 24-Valent study, we do have that mixed dose cohort, which gives us a leading indication of how much of the incremental protein carrier will affect immune responses. For the studies to date, we haven't seen much of an effect of the incremental protein carrier, at least not nearly to the extent the previous technologies have faced. So yeah, we're going to have hopefully a decision to make. I think we're going to be in a good position with either VAX-24, but arguably an even stronger position to the extent the VAX-31 data is positive, but we'll be taking all those things into consideration, Seamus, as we have that data read-out over the ensuing 12 to 15 months. Your question about efficacy studies, I think you're kind of hinting at some of the macro backdrop of what's going on. There's no question that pneumococcal conjugate vaccines have been studied with the utmost integrity, clarity with placebo-controlled studies, certainly at their outset, when they were developed initially in infants. So there is absolutely no question of the clear and present danger of pneumococcal bacteria and the effect of these vaccines that prevent 90% to 95% of infections. So I think the way you kind of phrased it was, is there an opportunity there for us to distinguish ourselves with an efficacy study that's manageable, and I think Jim has something in mind as a potentiality.

Yeah. No, I'd say up to 80% of infants get a case of otitis media, almost 50% get multiple cases, so this is a very common ubiquitous type of manifestation, and the majority of causes, the main driver is strep pneumonia. Now for the current PCV20, they prevent roughly mid to 30s to high -- to low 40s percentile in terms of overall serotype coverage, but with R31, we are in the mid-80s to low-90s, and so we think that even with a comparative study, we will have enough cases with that type of incidence and that type of improvement in coverage to be able to do a study of otitis media and actually determine the efficacy. As I said, it's going to take longer than an immunogenicity study and safety, so most likely, we would see that come in after the approval, but we do plan on exploring the possibility of doing an efficacy study with media for our 31-Valent.

We'll go next to Jason Gerberry with Bank of America.

Hi, good afternoon. This is Dina on for Jason. Congrats on all the progress this year and thank you for taking our questions. We just had a couple on the VAX-24 infant study. First, we would like to get your view on if and/or how this initial primary dose series dataset will provide read across to derisking VAX-31 in the infant population. And can you just remind us if you have the ability to tweak VAX-24 doses in certain serotypes depending on what's seen in the Phase 2, and if that would be a consideration for Phase 3 dose selection? And then we just have a quick follow-up on the regulatory front. What specific measures would RFK have to take in order to actually change the PCV routine child vaccination schedule? I guess, said in a different way, what are kind of the hurdles that he would have to overcome and does he have the sole power to do so? Thanks so much.

Yeah, thanks, Dina. So, as it relates to the VAX-24 infant data reading across the VAX-31, yeah, to be sure, I mean just like we saw in adults, we were able to look at, in particular, the dose ascension from the low middle to the mixed and that mixed dose cohort was able to take a look at a similar amount of the protein carrier that is in our VAX-31 formulation and was definitely a leading indicator of what we thought we could expect with the VAX-31 data when it read out in adults, and of course, it was even better than we could have predicted from that mixed dose data. So I think that we will have a similar opportunity with this infant data to use it as a bellwether for how to think about the VAX-31 data when it does read-out. So of course, what we found was with that incremental protein carrier, we really didn't see a fall off in the magnitude of immune responses when compared to Prevnar 20. So if the VAX-24 data is good, I think it will definitely only triangulate our confidence that came from the adult data for VAX-31. To your question about tweaking the doses of individual serotypes, most definitely that will be afforded to us. We have seen a really nice consistent pattern of dose response across all three of the Phase 2 studies that we've run, and there's a wide birth that's afforded based on the toxicology studies that are conducted. And so indeed, we will reserve the right to potentially tweak certain doses if we see responses that should and could be improved. And then your third question would be related to potential changes to the immunization schedule for pneumococcal conjugate vaccines, I think it's really hard to predict what might happen. There has been no discussion of pneumococcal conjugate vaccines to-date in any forum. So, I don't think there's anything to go on to make us think that there would ever be an effort to reduce the schedule associated with pneumococcal conjugate vaccines. This is not some distant memory of a pathogen. This is a pathogen that is routinely circulating and inhabiting the upper respiratory tract of a substantial portion of our population. And the moment you pull back a dose or pull back rates of immunization with pneumococcal conjugate vaccines, more kids and more adults will get sick, and more adults and more infants will die. There's no question of that. So I don't think there's really a thesis to suggest that there would be a path or an impetus to do something like that.

And may I just add to Grant's comments. I mean the environment is right, as I said, 25 years of vaccination of infants, 15 years of adults, the health and economic benefits are very clear, right? The current system is incredibly complex. It's really an institution involving multiple, multiple stakeholders. And I would also maybe say and perhaps to Salim's earlier question, refer us all to the comments that Senator Cassidy made in connection with his decision to support the nomination of RFK Junior to the Senate, speaking directly to a number of commitments that he obtained from both Kennedy and the administration, including kind of maintaining the ACIP that is one of the important bodies in terms of the recommendation of immunization schedules among other commitments kind of all geared toward kind of the status quo as it exists with respect to vaccination. And there are other bodies as well, the AAP, American Academy of Pediatrics that itself put out a statement a while back plays an important role in the immunization of our infants as well.

We'll move next to Tom Shrader with BTIG.

Hi, good afternoon. Thank you for answering so many of my questions. With all the noise about ACIP, I wanted to squeeze in one more about current medical practice. Adults with risk factors have gotten PCVs at 50 for a while now. Is it standard practice to boost them at 65? And I guess really the question is, if everyone is getting them at 50 now, is it kind of the expectation they'll get boosted at 65 or do you really need ACIP to hardwire that? And if you have any thoughts on whether insurance will pay for that second shot, it would be great as well. Thank you.

Yeah. So hey, Tom, thank you for the question. Maybe Jim and I can tag team this one. I mean, going back prior to the pneumococcal conjugate vaccines being approved in adults 15 years ago and only up until recently was there a two-vaccine schedule. So, 15 years ago, there was only the polysaccharide only vaccine and then Prevnar 13 got approved. And until Prevnar 20 was approved, Pneumovax was also recommended on top of the pneumococcal conjugate vaccine. And in the case of the polysaccharide-only vaccines, that was administered by recommendation every five years. So multiple vaccine doses have been a consistent feature of the adult vaccination range. And at the last ACIP meeting, there was quite a bit of discussion around how long should you wait for a second vaccination once we start giving the routine universal vaccination at age 50. To your point, Tom, people with certain health conditions have been getting vaccinated in that range for some time. And there was a real recognition that another vaccination dose should come in when they turn 65, but there was reticence on the part of the ACIP to go there just yet. And what they were really looking for was the newer, higher valent vaccines to come out. And then those could be the second vaccination when people turn 65 and it was gratifying to see that we were the vaccines that they were referencing, both VAX-24 and VAX-31. So yeah, I think that is where the future is headed. It hasn't been codified. But to your point, if an individual goes in and they're within the right age range, it's likely that they'll get the vaccine if they ask for it. I mean that's just kind of how we're conditioned.

There haven't been any controls on reimbursement for multiple doses to date that I have seen.

And these vaccines have such a great return on investment. Every dollar you spend on vaccines return, depending on the class, $7 to $11 in savings to the healthcare system. And that's why given their safety profile, given the efficiency when people go in and ask their pharmacist for a vaccine, more often than not, they'll get it, even if it's a second vaccine that they had gotten to one previously in their history. So yeah, I think you're kind of setting things up. Not everything has been totally solidified, but the ground is fertile for what should be the case, which is people getting multiple vaccinations over the course of their lives, particularly as their immune systems begin to wane as they get into their 60s and 70s.

We'll move to our final question from Joseph Stringer with Needham & Company.

Hi, thanks for taking our questions. If we assume the eventual approval of either VAX-24 or VAX-31, what's your current thinking on the likelihood that ACIP would not grant preferred recommendation? I realize this would sort of go against precedent, but could you give your updated thoughts on the puts and takes on this hypothetical scenario? And has your outlook on this changed at all with the new administration? Thanks.

Yeah. Hey, Joey, thanks for the question. Yeah, I mean we've got, VAX-31will be first up. As we look ahead, we've got to obviously complete the Phase 3 studies, but given the strength of the treatment effect in Phase 2, we're extremely confident heading into the Phase 3 experiment. Once we have that package together and we have to get all of our BLA together, et cetera, et cetera. But looking ahead to a potential ACIP review, we have a product that has the makings of the most compelling profile that they would have reviewed to-date and even the last occasion where an adult pneumococcal conjugate vaccine was debated, I think there were expectations that, that profile could have warranted a preferred recommendation, but for the fact that while it had improved coverage, it did not cover historically circulating strains, some of which were actively circulating in the moment. And so for us, we have a product profile, at least based on what we've seen to-date that has even higher coverage than that particular vaccine while covering the historically circulating strains and improving immune responses to boot, which are multiple advantages relative to what anyone else has ever seen. And we have seen preferred recommendations granted in the adult setting and it gives us the kind of confidence that it's certainly something that we can plan for. It's not a guarantee, but something that we can plan for. In the infant setting, the last conversation was when Prevnar 20 was approved and debated. And really the coverage there based on the dialogue they had was enough to warrant a preferred recommendation, but they explicitly did not grant it, the preferred recommendation because of the diminished immune responses that were evident, which is the reason why as we think about our 24 valent and 31 valent moving forward, it gives us a lot of confidence that VAX-24 which is ahead, truly does have a differentiated superior profile in that if we can see anything similar to the adult results where we're not only conferring broader coverage with additional conjugates, but also potentially higher immune responses, that would have been precisely what they were looking for when they last considered a preferred recommendation. And then I think as it relates to what will happen in the future, we're ways away from that ACIP conversation, that ACIP composition, et cetera. So I think it's premature to suggest anything other than the basis for which these decisions have been made historically, which is based on the merits of the vaccine for which they're considering relative to the vaccines that are the standard-of-care up to that point and to what extent the newer vaccine can provide better protection and better return on investment for this country.