All right. I think we should get started. On behalf of Leerink Partners, it's very much my pleasure to welcome you to this next session with Vaxcyte. It's my pleasure. My name is Dave Risinger. It's my pleasure to welcome Grant Pickering, who is the company's CEO, and Andrew Guggenhime, who is the COO and CFO of the company, to be with us here today. They do not yet have the VAX-24 infant results to share with us, but they are not hiding either. Thank you for flying in from San Francisco. Once again, I appreciate you being here. I thought it would be great to have you just kick off by describing your vision and aspirations for Vaxcyte Grant.
Yeah. First of all, thank you, Dave. We appreciate you guys hosting us at the lovely W Hotel and bringing in all these high-quality investors. Yeah, the vision for Vaxcyte has been unwavering. We believe that we have a better platform for initially a means to produce broader spectrum pneumococcal conjugate vaccines that can confer better protection for infants and adults. We believe this platform is also applicable to novel conjugate vaccines that we can develop. Our belief is this is a real opportunity to build an important new vaccine company to bring commercial vaccines to market to the benefit of global health.
Excellent. The company's execution to date has been exceptional. What makes the company unique besides your Chief Operating Officer and his skill set?
He's not here today, but maybe Andrew can.
Wait, what's your other title?
President.
President, I'm sorry. Correct. Correct. Thank you for the correction.
Yeah, I would say several-fold. First, just the opportunity, right? It's a huge opportunity, $8 billion market today, and expected to grow $12 billion-$13 billion over the next several years. The size of the opportunity, the clear adoption criteria in this market has been the case for the last 25 years that broader spectrum coverage wins. I would say, even from a technology standpoint, when you make these conjugates, you can test and ensure if they look a certain way that they will perform. They'll deliver high immune responses. We've seen that borne out in our data. The regulatory pathway is incredibly clear. The kind of external factors make this incredibly unique. I think from a company standpoint, as Grant said, since the company was founded 10 years ago, we've had a maniacal and unwavering focus on pursuing and exploiting this significant opportunity.
From the very beginning, making the investments to deliver on the long game, including on the manufacturing front. We've seen now with three stellar clinical data readouts in the adult population, as you say, we're at the doorstep of our first infant data readout. Those clinical data have kind of confirmed our approach and the investment we've made on the manufacturing standpoint. We now stand ready to actually deliver on this significant opportunity. We've hired great people from the very beginning kind of with this ultimate end goal in mind. I think that stands out as well. It's just the quality of the team, the investment we've made in that team. People can not necessarily just get us to proof of concept, but to get us all the way through to the commercial markets for a potentially global product.
Excellent. Excellent. Great. Hopefully, Jim doesn't take offense if he reads the transcript.
He's usually with us, but just the two of us this time.
Excellent. With respect to the current political situation in Washington, I don't even know how to comment on it without getting myself in trouble. I'll just call it dumbfounding. Given the situation in Washington, particularly with respect to RFK Jr.'s history and views on vaccines, could you just comment? I think that RFK Jr. also did have some response or some commentary and response to the measles outbreak. If you can weave that in, that would be helpful as well.
Yeah. Look, certainly, there's a lot of news and noise and politics around this. I think we expect that to continue to be the case, certainly in the near- term. That's part of the approach of this new administration, both the president as well as RFK. We should expect a lot of news flow and noise. I think the key is really to separate the noise and the news flow and the politics from the actual substance in the policy. That ultimately is what is going to matter here. To your comment, Dave, it's encouraging to see in the context of this unfortunate measles outbreak, RFK's response be more traditional in nature in terms of recognizing the importance of vaccines and that vaccines save lives.
When a real crisis has emerged, we've seen HHS kind of revert to a more, if not entirely, but a more traditional approach. As it relates to PCVs, they've been the bedrock of our immunization programs. Again, we've been protecting kids for 25 years, adults for 15 years. As I said earlier, very tried and true regulatory pathway that we are following and now with stellar data in hand. Ultimately, we think it will be the data that will matter, right? These are still going to be whether by FDA, CDC, HHS decisions based on data and science. We're encouraged about where we stand. The last thing I would say is we are monitoring, obviously, all this very closely. We have a couple of really capable people internally who have a lot of experience in government and public affairs.
We are now leveraging relationships with multiple DC-based advisory firms to give us, at a minimum, great intelligence as to what is happening in Washington, I think, but more importantly, to give us the ability to build relationships and gain access to folks. We are working with the administration. We are working with members of Congress. We are engaging with the agencies as well as we navigate this path forward and developing what we believe are really constructive and collaborative relationships as we move forward here.
Excellent. That's great. Let's pivot to the forthcoming VAX-24 infant readout. The primary endpoint in this primary 3-dose series is different than the adult studies. Could you just remind us about that?
Yeah. So indeed, we have an 800-subject infant study for VAX-24 that's reading out this quarter, which means later this month of March. Coming soon. Indeed, there are some nuances in the ways that you evaluate these pneumococcal conjugate vaccines in infants relative to adults. In adults, we look at the functional antibody responses of the vaccine. We compare the geometric mean titers and the ratios of those titers for the standard of care vaccine versus the novel vaccine. Clearly, our vaccines are working different and better than the conventional vaccines. We've had three phase II studies where we did extremely well and were able to meet the non-inferiority comparisons for all of the serotypes tested using those functional antibody responses. We also looked at the IgG antibody responses in those adult studies. They correlate extremely well with one another.
In fact, we saw a slightly improved IgG response on a relative basis to even that of what we saw with the functional antibody responses, which were stellar. It is the IgG antibody responses that serve as the basis for comparison in the infant trials. That is what is going to read out next for our VAX-24 program. It is these IgG responses. We look at them two different ways in infants. We look at them in the same way that we looked at the adult responses by looking at the geometric mean titers and their ratios of one vaccine for another. That is the way you look at the data after the fourth and final dose of the vaccine. That data will read out for us later this year. The data that will read out imminently is the look after the third dose of the vaccine.
At that time, while we will look at the geometric mean titers and their comparisons as we will look after post-dose four, in this first post-dose three, that's a secondary endpoint. The primary endpoint that you look at is a slightly different way to look at the data. This is the conventional way. This is the way these vaccines get approved in infants. You look at the seroconversion rates. For infants, back to the original efficacy studies, there was a threshold that was established of a concentration of those antibody responses that was shown that if you exceeded that threshold, it was a protective response for which the infant was protected through that first year of life until they get the 4th- dose, which is the boost.
The way that the vaccines are compared is for a newer vaccine that is more broad spectrum, you have to be within a certain percentage points relative to the vaccine that's already on the market. By way of example, if Prevnar 20, which will be our comparator, protected 90% of infants against a particular strain, you have to be within a certain delta of that. At the registration, so in phase III, you have to be within 10 percentage points of that to the lower limit of your confidence interval. If they were at 90, you have to be at 80 to be non-inferior. In phase II, where you're looking at a much smaller sample size and you're really running the study to get the powering coordinates to be able to run your phase III, other sponsors have used a wider bar.
What's been shown is if you're within a 15-point delta, so again, 90%, and you're at 75% to the lower limit of your confidence interval, that would indicate you've got the treatment effect to be able to meet the phase III registration hurdle of a 10-point delta. In other words, this is a different way to look at it for those who've grown accustomed to our adult data. You're looking at seroconversion rates. Keep in mind, these seroconversion rates are all about exceeding that 0.35 microgram per milliliter threshold. The higher your immune responses, the easier it is to exceed that 0.35. The reason we have confidence with our 24-valent vaccine heading into this data set is we showed routinely higher antibody responses in adults than our comparator, which was Prevnar 20.
Having higher antibody responses would allow us to do better on this seroconversion comparison.
Excellent. That's super helpful. Thank you. With respect to Pfizer's experience, could you speak to its weaker efficacy in infants relative to what it had shown in adult trials?
Yeah. This is the manifestation of what I was just touching on, which is when the conventional technology that both Pfizer and Merck use for their commercial vaccines is stretched by adding additional conjugates, it results in lower antibody responses when compared to a less broad spectrum vaccine. When Prevnar 20 was compared to Prevnar 13, for that matter, when Merck's 15-valent was compared to Prevnar 13, you see lower antibody responses across the board. When you have lower antibody responses, it means more of the serotypes will fall below that 0.35 threshold for seroconversion rates. In fact, what we saw in the clinic for Prevnar 20 was they missed on six of the non-inferiority comparisons to Prevnar 13 in their phase III registration study. They still got the vaccine approved.
They were still able to cite all 20 of those serotypes in their label, in part because the post-dose four boost data was non-inferior. For that first year of life, it did mean that more infants were exposed to potential pneumococcal infections because of those lower seroconversion rates. It is purely a manifestation of seeing lower antibody responses across the board and having more and more serotypes that fall below that threshold. If we can see a repetition of what we saw in adults in the infant studies, it means that we have an opportunity to do better than what we have seen with who we expect to be our principal competition with our 24-valent vaccine looking forward.
Excellent. Okay. Thank you. In terms of Prevnar 20, could you just follow on in terms of what the experience has been in terms of adoption in Europe and the challenges that they've faced as a result of this questionable data?
Yeah. Thanks for the question, Dave. Grant talked about the study, the U.S. study, right, which is in the U.S., we dose infants at two, four, and six months. Three in the primary series and the booster dose. Whereas in Europe, it's a two plus one series. They give two doses in the first six months of life and then a booster dose. Pfizer ran studies with both the three plus one and the two plus one. As Grant said, in the U.S. study, the three plus one schedule, they missed on six of the 20 endpoints in the first. Yet in the European study, where it was two plus one, they missed on 11. One fewer dose. You could clearly see the impact of that in them having missed on 11 of 20 serotypes.
While the Prevnar 20 has been approved in Europe, what was approved was the U.S. schedule, which is the three plus one. Unfortunately, the well-baby visits in Europe do not coincide to the three plus one schedule, which effectively makes Merck's VAXNEUVANCE, the PCV15 product, the market's leader still in Europe just because of the conflict between Pfizer's approved label, if you will, and the well-baby visits in Europe. That is leading to the challenges they are seeing.
Got it. Yeah. That's very helpful context. In terms of the strains, how should we think about some of the strains that are more important? How have you tried to optimize your vaccines to offer protection against those specific strains?
Yeah. Each of the serotypes have their own epidemiological footprint, right? They're all circulating at different rates. This data is put out regularly from the government. We all know the value of each serotype on a relative basis to one another. It's not hard to weight them. That said, it's a little perhaps counterintuitive for the data that we've been referencing. They missed on six of the non-inferiority serotypes, yet they were still given credit for them in the label. The reason for that is in some cases, the responses are high enough, even though they're dropping, to protect kids durably. There may be some exposure in that first year of life. If we can rectify that, that will be a meaningful advance and improvement.
As it relates to the specific serotypes, there isn't one in particular that we feel like would be a disqualifier for us. We will obviously be looking to see the data here soon. We did take steps initially when we designed the doses that we would take into the clinic for not only adults and for infants. In those instances where there were serotypes that were circulating at higher rates, we employed kind of an extra bolus of material. It's called the mixed dose cohort in our study design. We have a 1.1 microgram across the board dose that's being tested in the study. We have a 2.2 microgram dose across the board for all 24 that's being tested. Then we have this mixed dose cohort where seven of the 24 are dosed at 4.4 micrograms per serotype.
The idea behind that was for some of the strains, Dave, to your point, that were circulating more aggressively, we wanted to make sure we'd have enough material on board to ensure we got good immune responses. That will read out as per the timing we've just talked about. In the adult setting, it turned out we didn't need to push dose on those seven. As we're moving into phase III with our pneumococcal programs, we found that we don't need to push dose for those strains of interest. We might see something differently in infants. If that's the case, we'll be able to manage it because we've found that when we do push dose, you do get improved immune responses. It's just a question of where does it make sense to do that.
We showed going from VAX-24 to VAX-31, when we did increase the dose of a few that we thought we could see benefit, we saw that benefit. We know that we have a lever that we can pull between phase II and phase III in infants. We will let the data determine what, if any, changes would be warranted.
Excellent. In terms of seeing this data soon, I wanted to ask a few questions about how we should think about the read-through to VAX-31. Could you just talk about the amount of carrier protein that's being studied and that potential read-through to VAX-31 since you'll have an additional seven serotypes?
Yep. Yep. Yep. The name of the game in this space is managing the amount of carrier protein. Just a quick refresher, the reason this class of vaccines has been so successful at preventing disease is you get T cell help, which allows for durable protection. That T cell help comes from the protein carrier, the carrier protein that's attached to the polysaccharide sugar. The more protein you have, though, creates more of a distraction. The immune response skews toward the protein and away from the protective antibodies that protect against pneumococci. You want to use as little protein carrier as you can get away with. We developed a method of making these conjugates that uses less carrier but does not reduce the immune responses.
We can go into the details of that, but the chemistry we have allows for that, and no one else can do it. We have carrier-sparing conjugates. When we think about the read-through between VAX-24 and VAX-31, what we found when we got our initial adult data for VAX-24 was that mixed dose cohort that I described earlier, where seven of the conjugates are at 4.4 micrograms, the other 17 are at 2.2 micrograms. If you add up all of the carrier protein that is in that VAX-24 formulation, it is equivalent to what the middle dose of VAX-31 was that we took into the clinic as a follow-on. What we saw from that VAX-31 data was that it was fantastic, but it was also predicted by that mixed dose data that we had gotten from the VAX-24 phase II studies.
Once again, we're about to get this data in infants with that mixed dose cohort, which will be a leading indicator of what we can expect from VAX-31 in infants. Most of you will know we've already started that VAX-31 infant study. It's well underway. We completed the stage one and acknowledged that we moved into the stage two portion earlier this year. We'll get that data from the study, this same one that's reading out for VAX-24 this quarter. We'll have it by mid-year next year. Anyway, we'll have a leading indicator with this VAX-24 data as to what we can expect with VAX-31, which is pretty cool.
That's phenomenal. It would be great to turn to the platform's pipeline optionality as well. Turning to VAX- A1, your Group A Strep vaccine, it obviously has the potential to be a mega blockbuster. Now it's in preclinical development currently. Could you discuss the market opportunity first, and then I had a couple of follow-ups?
Yeah. It's substantial. It may not necessarily ultimately be equal to the size of the PCV market, but it also may not be far behind, right? It has the hallmarks, as you say, of a blockbuster opportunity. You have both adult, and in this case, toddler or school-aged children populations. It wouldn't be an infant vaccine. You have growing rates of disease, right? Non-invasive disease, invasive disease, increasing utilization of antibiotics, and the growing antibiotic resistance. It's really a recognized and increasing problem here. In the U.S., there was a health economic study done just a few years ago that identified $6 billion in costs associated with Group A Strep in direct costs alone and over $10 billion when including indirect or societal costs. Again, that's just the U.S. market. It's a substantial opportunity just driven by the challenge in terms of disease and antibiotic consumption.
Excellent. Could you also talk about the challenges historically in strep vaccine development and how you've potentially cracked the code here?
Yeah. Like RSV, Group A Strep was an area for which there was no research done for quite a period of time. Back in the early days in the 1950s and 1960s, the NIH did certain crude vaccine development work with denatured versions of the bacterium and virus. Those created certain issues from a safety perspective. Until we could unlock what the problem was, those were areas for which vaccine developers stayed away. Over the last 15 years or so, both of those areas opened up. We all saw the fruits of that labor with the RSV class, as we now have three approved RSV vaccines. While the vaccine developers focused on RSV as it came back to the fore, Group A Strep was kind of the next one up.
There has not been as much competition there, but we have very much identified what the issues were. There were some overlapping issues with the bacterium and certain parts of cardiac tissue. What we realized was you could not use a whole bacterium-based vaccine approach. You needed to selectively identify portions of the bacterium that you could use for a vaccine. That work was performed over quite a number of years. There was a proprietary antigen that was identified that is a polysaccharide that is species defining. There are lots of different serotypes of Group A Strep, like there are with pneumococci. There is a polysaccharide that is uniformly represented that is devoid of that aspect of the bacterium that caused the inflammatory issues. We exclusively licensed that IP from UCSD.
We have the optimal antigen of interest to drive immune responses. We're conjugating that antigen to a protein carrier that's conserved on the protein sequence of the bacteria that's accessible. We think we have the optimal antigen construct to ensure that we don't see any repeat of what had been seen historically, but also sets up for the highest probability of effectiveness. For a novel class of vaccines, you have to prove you're effective. Whereas pneumococci, we already know what it takes to be effective. If you had antibodies at a certain level, that's adequate. For a novel vaccine, we'll have to show efficacy. We should talk a little bit about those aspects because the thing that's working for us is the attack rates of this particular bacteria are extremely high.
The higher your attack rate, the smaller the sample is that you need to conduct in terms of an efficacy study.
Yeah. Maybe you could just take the next step and just walk us through the potential path if you're successful in bringing it into the clinic.
Yeah. Yeah. I mean, the good news is we have convinced ourselves that we have a really exciting vaccine. We've gotten there because the efficacy we've been able to show in the animal models has been quite impressive. We've been able to show with this single construct, we can get broadly protective responses against an array of the different Group A Strep serotypes. Those serotypes are well chronicled around the world. We think we'll have a broadly protective vaccine. For us, we've been working for a while now to get the vaccine made under GMP conditions. We're in the finishing stages of completing that GMP work. We've already completed the preclinical toxicology work. We're getting very close. In the clinic, what we'll be looking to show is obviously antibody responses.
That will give us some confidence that we'll see effect. That effect will be measured in the form of looking at the highest circulating disease associated with Group A Strep. Group A Strep causes a wide array of infections. The more ubiquitous forms are the pharyngitis, cellulitis, impetigo that most people are familiar with. That extends all the way to the invasive forms like necrotizing fasciitis, like toxic shock syndrome. There are all sorts of really bad invasive diseases that are caused by Group A Strep. Those numbers have only gone up. The antibiotic resistance rates have gone way up over the years. We will look to capture, of course, these more invasive cases of disease. The primary events that will drive the efficacy rates will be more in the form of those more ubiquitous forms like pharyngitis.
For instance, toddlers and primary school-aged children face attack rates of 15%-20% of them getting sick in their first year in school. That's a whopping attack rate versus, for instance, the RSV vaccines, where they were looking at efficacy studies where the attack rate of RSV was more like 1%-2%. That required really large clinical studies to get to an answer. We'll be able to do these efficacy studies on a much more manageable form. That's probably good for today.
Yeah. It is great to hear that you're in a very good place and you're excited about potentially advancing it. We will look forward to future updates.
We appreciate you're helping us build some buzz on that. You put out a report right during JP Morgan. And more and more people are getting excited about this program. I don't think we're getting a lot of credit for it yet. I think as soon as we get it in the clinic, people will start taking notice.
Excellent. Thank you. It is great to have you both here. Thank you so much for coming to Miami.
Of course. Thank you.
Thanks, Dave.