Good morning or good afternoon. Welcome to Moderna fourth Vaccine Day, or welcome back. For those of you that are here in town, you have the bonus of having a beautiful spring day. On behalf of the team, welcome. Before we start, let me just remind you that we'll be making today forward-looking statements that investing in Moderna involves risk. You can find those statements or the risk factors on our website or in our SEC filings. I think you will agree with me that if you think about the last 100 or 150 years, the impact that vaccine had on humanity has been really profound. The health impact, obviously, reduction of disease, eradication of some diseases, some prevention of cancer, huge long-term benefit to people. The social impact and also of course, the economic impact.
If you look at this interesting data on slide four, the CDC has estimated that children born in the U.S. between 1994 and 2013 have seen a prevention of more than 700,000 deaths in the U.S. If you look globally, most probably vaccine is the best return on investment for healthcare dollars. Despite this great progress and this great impact, we believe there are still challenges and there's more to be done. First, there are still viral infections that drive diseases that do not have vaccines. We have an aging population around the world, and older people are more susceptible to severe disease with infection. We still have a lot of latent viruses driving cancer that don't have vaccines available. Climate change is also impacting human pathogenic diseases. Let me start with the first one.
If you look at the four major viral diseases, RSV, flu, norovirus, and HIV, that does not include COVID. There's an estimated 1.7 million deaths globally. That's deaths every year that we believe can be prevented. There are around 220 viruses known to scientists around the world that hurts human, but there are vaccine available only against 18 of these. If you look at one of the impact of a pandemic, actually the fight against infectious disease after the COVID has actually taken a back step versus what it was in term of trajectory pre-pandemic. Aging comes with issues. Look at the T cell, naive T-cell productions based with age on the left panel. After 40, it kind of go downhill. I just turned 50 last summer, so I know which part of the graph I stand in.
If you look at what's happening in the world, there's aging population, as we all know, not only in OECD countries, but around the world. If you think about it from healthcare standpoint, you have older and older people on the planet, and more and more of them, and what happens to naive T-cell production with aging. We need new solutions. There's still a lot of latent viruses that have massive long-term healthcare implications. You are highly aware of HPV, and what it has done in term of cancer prevention. CMV infections drive birth defects, is a big issue with transplants, EBV, multiple sclerosis, lymphomas. There's still a lot of work to be done here to help people. Last but not least, with climate change, we are seeing a shift in species of animals.
We're seeing animal moving closer to humans with deforestations and enhanced risk of outbreaks and, God forbid, pandemics. The good news here is we believe that Moderna's mRNA vaccine platform can address those challenges in multiple ways. The first thing that we have been very excited about this platform since starting the company is the ability to do high biological fidelity. We can do complex antigen, like we've shown with CMV, with a pentamer. Five protein made in a human body, like when you have a virus infection, coming together to form a very complex antigen. The ability to do combinations, the ability to have high efficacy, as we've shown. Speed, we talked a lot about for the first nine years of the company.
I think now everybody got a good sense of the speed of mRNA technology and the speed of Moderna's platform because of our investment in manufacturing, in robotics and in digital. The flexibility of manufacturing. In traditional vaccine, you need to dedicate a plant for every product. With mRNA, it's really amazing. We use the same reactors in the same room with the same people to make all of our vaccines. It's all the same raw materials, but one component that's different by product. We have a really interesting capital efficiency. As you know, since we first went into the clinic in December 2015, we have been working on vaccine against viruses. Today, I'm very excited to share with you that the team has been working really hard to expand that field of application of our vaccines to bacterial infection.
The team will walk you through one of our candidates, which is against Lyme disease, that is our first step into a vaccine against bacterial targets. I won't go through the slide in detail. Obviously, it's for your reference, but you can see how just in the last two years there's been a not only an acceleration in our pipeline. You know, we had three phase II in 2021. We're now nine phase II ongoing in vaccines. We're now five phase IIIs. Not only an acceleration toward approval of those products, but an expansion in the pipeline's breadth at the same time. I have to really give a big kudos to our teams in the labs, in clinical development and in manufacturing because this is a lot to make happen every day.
With this quick intro, I'm going to start by turning it over to Stéphane to talk to you about development strategy. Then Jackie is going to talk to you first about respiratory viruses, and there's quite a lot there with our team. We'll take a coffee break. We'll come back to talk about latent viruses. Then Jackie will talk to you about our new kids on the block, the enteric virus for norovirus candidate, which is announced today, and the Lyme disease I just talked about. Arpa will give you a bit of an update on our thinking in terms of commercial. Jamey will share some financial framework, including what we put in the press release this morning, the 2027 financial framework about the respiratory franchise. I will come to close with just two slides before the team and I take questions.
With this, Stephen.
Good morning. Good afternoon, everyone. Thank you for being here. In providing a little bit of an overview of our R&D strategy, I'd first like to frame up where we are with the platform. Today, our platform really has two major vaccines franchises where we have multiple products in development. The first is respiratory. We'll spend a good amount of time talking about that today. The 2nd is latent, which we'll talk about as well. Everybody understands we've talked about before that respiratory viruses really drive an incredibly high burden of disease, particularly in the very young and the very old. That drives seasonal disease and is one of the major causes of hospitalization and death globally. There are also high-risk populations that also benefit from protection against those respiratory infections. Latent's a little different.
In latent, the immediate impact of infection does exist and creates burden of disease, but in many cases, it is the long-term sequela of those disease from those latent infections that drives the largest burden of disease. We've got vaccines against both that we've been developing. Today, in addition to those two larger franchises, we've been expanding our list of emerging programs. We've already had substantial efforts in global health. We'll talk through some of that again today. We've added to that the two vaccines that Stéphane referenced, a vaccine against norovirus, our first enteric virus program, which is a leading cause of diarrheal deaths globally, and our vaccine against Lyme disease, which is our first expansion into bacterial pathogens, and we're very excited about that.
We'll provide a number of updates across that pipeline, obviously starting and relying heavily on our work in our respiratory franchise. We'll be presenting our next generation COVID-19 vaccine, which as we announced today, has actually already moved out of phase II and into phase III with the initiation of that pivotal study. Jackie will present some of that phase II data. We'll talk about our flu vaccine program, actually mRNA-1010, our first of five flu vaccine programs, and some really encouraging data that we've seen today that we think this keeps us on path for potential approval as early as next year.
That data, while we didn't yet accrue enough cases in the efficacy study, the P302 efficacy study, to demonstrate efficacy, we would've had to have been substantially superior to the licensed comparator in order to do that in this first-term analysis. At the same time, as we announced today, we've now seen immunogenicity data from that study, which, as Raphael will walk you through, gives us a high degree of confidence in the performance of that flu vaccine and the potential, again, for an accelerated approval next year. We'll also talk about some exciting next-generation flu vaccine data as we continue to advance multiple rounds of improvement, and I'll talk through that in a second. Raphael will cover that. It's a real honor to have Dr.
Schief here today to talk us through the incredible progress and work that he's been leading in HIV vaccines. Particularly our first mRNA vaccine HIV, mRNA-1644. We'll provide quick updates on some of the new development programs, as I mentioned, norovirus, Lyme disease, and our next-generation COVID-19 flu combo. Let me just provide a little bit more framing on the role of the platform in developing our vaccines, portfolio. As Stéphane referenced, there are three key features to that platform that we think are really, advantages. The first is the high biological fidelity of how we make our vaccines work.
Just like a virus infecting you, we use mRNA to make the protein in situ in the body, and we think that allows us to do a number of things, including complex antigens, the ability to combine multiple different vaccines, and creates the potential for high efficacy 'cause the vaccine might look more like the virus that it's trying to protect against. We've all seen, Stéphane referenced, I'll talk through some examples of the speed of the platform, not just in COVID, but beyond. As others will speak to later, we'll talk about the flexibility and substantial capital efficiency of our platform, particularly on the manufacturing side. First, just a couple of examples. You're all familiar with the potential benefits of mRNA vaccine in terms of efficacy.
Our COVID-19 vaccine, mRNA-1273, the first generation of that COVID vaccine, saw 93.2% efficacy in its phase III study. Now we were announced late last year, or early this year, I should say, that our RSV vaccine met its primary endpoint, saw very strong efficacy of 83.7% in its phase III trial, and we'll provide some updates on that today. We've also demonstrated speed. Now, if you look at COVID, in all three cases with mRNA-1273 as well as both of the bivalents, we were able to move forward from phase I to phase III data in less than a year, which is pretty remarkable. You might say that's COVID. Well, we'd say that there are other examples out there that show the potential speed of our platform.
For instance, the flu vaccine went from its phase I trial less than one year ago, or less than two years ago when we filed the IND, to phase III data now in multiple studies and ongoing studies at that. RSV was able to accomplish that in about two years and four months from phase I to the phase III pivotal data readout that we now intend to file for approval this coming this quarter. That pace compares, we think, quite favorably with the more standard industry timelines of six to eight years from sort of phase I to phase III data, and really underscores the potential power of this platform to move incredibly quickly. We also benefit from using the same manufacturing across. In fact, that's one of the reasons we can move so quickly.
That manufacturing platform, which we first built in Norwood starting in 2016, and we leveraged throughout the pandemic to address a global public health threat, is a manufacturing platform that makes both of our bivalent boosters. It makes all of the vaccine candidates in our clinical pipeline, which are quite substantial and varied in presentation and form. Of course, it also supports our discovery work in the preclinical side, which allows us to move that forward. The fact that we use that one platform across all things is why we are able to move so quickly across so many diverse sets of vaccine candidates.
Now, the last thing that I wanna emphasize before turning it over to Jackie is that those features of the platform, that biological fidelity, the speed, and the agility of that manufacturing capability, also allows us to have one more advantage, which is we can think differently about how we drive cycles of innovation in our clinical pipeline. Traditionally, you might think of these as long serial investments, with lifecycle management really driving over perhaps decades how you drive improvements in your product. mRNA doesn't require that. mRNA allows us to think in parallel about as soon as we have opportunities to improve, how do we drive those improvements in the product? Now, let me give you a few quick examples of what that looks like. In COVID, we've actually already seen this.
We went through rapid updates to meet the evolving threat of the virus, but that we also to meet the needs of the endemic market. That started with our Spikevax vaccine, mRNA-1273. Moved quickly within almost less than a year, to bivalents, two different bivalents, mRNA-1273.214 and 222 launched last year. As we announced today, the start of a phase III of a next generation bivalent that is refrigerator stable. All of that in just two and a half years. Not the exception, more the rule. Look at what we're doing in influenza. In influenza, we've been able to drive rapid expansion of antigens to improve the potential for matching against the influenza strains that circulate every year.
Again, mismatch or the incorrect matching of vaccines is something we've all lived through and seen regularly with these vaccines. Started with a quadrivalent vaccine. We've now read out a couple of phase IIIs there, and we've still got, importantly, our efficacy study cooking. We're moving on to pentavalent and even hexavalent products with mRNA-1011, mRNA-1012, and moving on to neuraminidase products. Raphael, as I said, will present some of the data from the mRNA-1020 program and why we were so excited about how those additional antigens might improve the performance of influenza vaccines long term. Then of course, RSV, let's not leave that out. We've demonstrated quite quickly the progress of the mRNA-1345 program, but actually have already moved it into multiple combination products.
Combination products targeting different populations in that respiratory viral illness spectrum, from pediatric combinations to two different adult combinations, mRNA-1230 and mRNA-1045. All of these have been happening in parallel over the course of just two to three years. That kind of rapid cycle of innovation is what gets us most excited about the potential of mRNA to really have an incredible impact on the burden of respiratory disease going forward. Okay. With that, I'd like to invite Jackie Miller, our head of development for infectious disease, to come up and frame some of the next few slides. Jackie?
Good morning. Thank you so much for the opportunity to be with you today to talk about our respiratory portfolio, our latent portfolio, also known as herpes viruses and HIV, and then our emerging portfolios. First I'd like to talk about the respiratory platform, and as Stéphane was mentioning, we've made quite a bit of progress over the last few years. What you see on the left side are our approved and phase III programs, and we refer to these internally as our big three. Why? Not just because they're first, but because they're foundational for the rest of the portfolio, as Stéphane was just explaining. First, there are our COVID-19 vaccines, our influenza vaccine, for which Raffael is gonna share some additional data.
RSV, we'll give a very brief update from one of my team members, Christi Shaw, who will talk to you about some of the emerging data. If you're interested to hear more, we'll be presenting more data next week at the ECCMID conference in Copenhagen. As we think about iterating on those programs, the next generation platform in the middle column really talks about improvements upon the initial formulations and sequences of those vaccines. You've already seen this with the COVID-19 bivalent vaccines, where we've worked quickly to update our vaccine to try to keep pace with the evolution of the virus. For influenza, as Stéphane mentioned, we're looking at expanding on current quadrivalent formulations to be able to cover an additional spectrum of strains.
Finally, we're actually looking to improve the breadth of immunogenicity by including other antigens, neuraminidase, that we know can be quite effective and important in protection against disease. Finally, we're taking all of these products and combining them. Because we are able to iterate, manufacture, clinical supply relatively quickly, we're able to make combinations of these products at various stages of their improvements. You'll see that we have a couple of COVID flu combos in development, capitalizing on improvements that we're making to the COVID vaccine. Then, we'll talk a little bit about some of the other RSV-containing combinations as well.
Today, the new data that you're about to see come from our COVID-19 program, we actually have an improvement on the formulation of COVID-19 that will really assist in making presentations that are more feasible for public health implementation, so improving refrigerator shelf life and introducing the potential to utilize pre-filled syringes. This is really important for people on the front lines of vaccinating because it will increase their ease of use. We have some updates to provide you about influenza. Some emerging data from our seasonal influenza program, mRNA-1010, from the pivotal phase III efficacy and safety trial. We have immunogenicity data today. Also some data from the neuraminidase-containing next generation influenza vaccine formulations. Let's start with COVID-19 because COVID-19, it feels like, at least for the last few years, everything starts and ends there.
Although I hope now we're in the period where we're moving beyond that. What's happened recently with COVID-19? We just got back from another VRBPAC meeting, where there was a discussion around what do we do to simplify implementation of the vaccine? You may be aware that if you were getting boosted this fall, you were able to get a bivalent vaccine. Hopefully, you all did. If you were getting a primary series, however, regardless of your age, you were still getting the original formulation of mRNA-1273. The discussion at the VRBPAC really centered around, does that continue to make sense, or should everyone get the same formulation of vaccine? If we decide that these strains are prevalent, these strains are important for protection, should everyone have the opportunity to receive that formulation?
Based on data that the Moderna team developed, pediatric population, which primarily is getting primary series, of course, we showed some human clinical data to the VRBPAC, and there was general consensus. Even if there's not consensus about what that new formulation should look like, there's consensus that we shouldn't be doing different things for primary series or booster doses. This not only gives everyone access to the same vaccine, but again, reduces errors because there aren't so many vials to choose between. That kind of sets us up for moving in the fall to manufacture the vaccine that will ultimately be recommended. We're anticipating a VRBPAC meeting later this quarter to confirm what product will we be making for the U.S. market, come the fall.
We have also, in the meantime, been investigating both the immunogenicity and efficacy of the bivalent vaccine as compared to the original monovalent formulation in order to demonstrate that we actually are providing an incremental benefit. I'm looking forward to sharing those data with you today. Finally, as I mentioned, we'll talk about next generation, what's coming next in the COVID portfolio. In addition to harmonizing the primary and booster schedule, the VRBPAC also had debates around evolving our COVID vaccination program to something that looks a little bit more like flu, where we take the temperature, so to speak, every year from an epidemiologic perspective and try to predict better matched strains for the fall.
There was also general agreement that there may be some populations for whom we want to give more than just an annual fall booster. That's because severe COVID disease continues to occur more frequently in older adults and those with compromised immune systems. As I mentioned, we're now in the process. I feel like VRBPAC has become a bit of a cottage industry for the COVID team. We're preparing for another VRBPAC where we will share some of the work that we're doing to make some selections about how we pre-prepare to manufacture for the fall. I'll tell you a little bit more about that in the coming slides.
Finally, what we were able to demonstrate last year where we prepared an Omicron BA.1 containing vaccine was that when there is a need to pivot, we can do so with this platform. In the US, in the fall, we received a BA.4-5 containing vaccine, that was a process that we initiated upon a VRBPAC meeting on June 28th of 2022. Okay. Now I'd like to talk to you about that data I mentioned that we've been generating to try to really get our arms around what is the incremental benefit of giving a bivalent vaccine. Last fall in the United Kingdom, 2022 fall in the United...
2021 fall, sorry, in the United Kingdom, we investigated a BA.1 containing bivalent vaccine, so half mRNA-1273, half BA.1, and we randomized and compared it to the original mRNA-1273. This is in the same study, randomized one to one to receive same subjects in the same country being exposed to the same circulating strains. What we were able to show was about a 10% incremental benefit. This was not statistically significant. We did not capture enough cases, which maybe isn't surprising in a highly vaccinated population. All of these subjects were getting a second booster dose. We decided, as we saw, a trend towards improvement with the BA.1-containing vaccine, to look and see what does that mean actually at the circulating strain level. This slide is a bit complicated.
I'll take you through it slowly. When you look at the BA.1 strain, so disease caused by BA.1, a strain matched to what was put in the vaccine, we see that the randomized cumulative distribution curves separate. We also saw clear separation of the curves when we looked at a BA.4 containing strain. That really indicates that by including this variant, we're able to improve upon mRNA-1273 even for a strain that's not matched in the vaccine. You combine them, we combined these two together to have sufficient cases for a statistical analysis, we saw a relative vaccine efficacy of over 37%, and that was statistically significant with a lower bound of 6.9.
When we compare that to BA.5, a strain that actually was known to be more virulent and more transmissible, than BA.4, we didn't see the same level of incremental benefit. It does suggest actually that strain matching is important and then, that's really the importance of this VRBPAC discussion. We'll finalize our selection closer to the fall booster campaigns and closer than we've been able to accomplish with influenza vaccines. Again, because an mRNA platform is relatively easier anyway to pivot. What about though the BA.4-5 containing vaccine that all of us received? In addition to the randomized control trial, we also partnered with some larger organizations to deliver some real-world evidence.
We've had an ongoing collaboration with Kaiser Southern California, and they have evaluated vaccine effectiveness now, since the vaccines were originally launched for emergency use authorization. On this slide in the far right column, they looked at absolute vaccine efficacy for individuals who received a three-dose schedule, so they had two doses and a bivalent-containing booster versus people that were unvaccinated. The vaccine continues to be highly efficacious. Against hospitalization, vaccine efficacy was 83%. Against visits to the emergency department or urgent care centers, vaccine effectiveness was 57%. Now what about with individuals who did not receive an updated booster?
This column in the middle compares those subjects who received at least one bivalent-containing booster compared to subjects who had the at least the full primary series and sometimes even a booster with mRNA-1273, the original vaccine. We still see improved vaccine effectiveness. The relative vaccine effectiveness was 73% against hospitalization and 56% against emergency department care. Putting it another way, against unvaccinated adults across age stratum, we saw improvement in vaccine effectiveness of 12.8 to 24.0 fold higher. In those who did not receive the updated booster, lower because original vaccination is still quite effective, but still demonstrating the improvement on getting that bivalent booster.
In summary, we have generated data to show that updating the vaccine actually does result in a clinically meaningful improvement in protection. We have actually shown that both for the BA.1-containing non-matched vaccine as well as the BA.4-5-containing vaccine across a number of different countries and also different healthcare systems. We believe that this evidence really emphasizes the need to remain vigilant about COVID-19 disease, and so looking forward to the work we will do for the fall. I mentioned this briefly, but just to show you on a timeline what happened last year with respect to manufacturing readiness and then execution of delivery of the vaccines. Starting in the springtime, we begin to ramp up the production of the strains that we think will need to be in the vaccines. Last year, that was BA.1.
We also do preclinical evaluations in mice in parallel. This is to show continued confidence in the ability of these vaccines to generate the desired neutralizing antibody responses. We then move to large-scale manufacturing once the final VRBPAC selection has been made. As I mentioned last year, that was June 28th. We pivoted from the BA.1 manufacturer to BA.4-5 manufacturer and then delivered the bivalent vaccine for the fall booster campaign, which occurred last year immediately after Labor Day. How do we get prepared for what we're going to have to do in the fall? Well, we've been compiling a strain library. You see some of the selected variants of concern on the slide for which we do continuous epidemiologic monitoring.
We also, in some of these cases, produce research-grade lots in order to do initial preclinical evaluations to really be prepared if this is the strain that's going to take off. We will continue to expand that library, which is how we think we can be better prepared for future epidemic strains of SARS-CoV-2. Now I'd like to shift gears and speak about that next generation COVID-19 program I mentioned earlier. A picture is worth 1,000 words, so let's look at the right side of the slide first. The picture that you see of mRNA-1273 represents the confirmation of the spike protein that's currently translated by the mRNA sequence delivered in our vaccine.
What you see in green, is the N-terminal domain containing many of the T-cell epitopes against this virus, and in red, the receptor binding domain, where all the action happens to get the virus into the cell. You'll notice there's lot of gray part of that protein. While there are still, potentially epitopes on that protein, those are not the ones that have been found to be most important in protecting humans against disease. We created a construct of that N-terminal domain, receptor binding domain, connected by a linker molecule. What does that do for us?
Rather than a trimeric conformation, this results in a monomeric conformation, meaning one protein chain, better accessibility of all of those very immunologically rich epitopes, and we believe will result in a more refrigerator-stable product, enabling us to provide some of those improvements in terms of mRNA vaccine delivery. Let me talk a little bit about the study that we conducted as a booster dose with this product and the data I'm going to share today. In our phase II study, we actually looked at this new construct as a booster dose, both as a monovalent vaccine, so those are the three groups in gray, where we looked at a single dose level, as well as a beta-containing bivalent vaccine.
There were two dose levels, 50% of the original Wuhan sequence, 50% of the beta sequence, two dose levels in green. The comparator vaccine was mRNA-1273 in yellow. As there have been some discussions in regulatory agencies about bivalent vaccine versus monovalent vaccine, which could be better, we also thought it prudent to look at a monovalent beta-containing vaccine, so two dose levels in pink. That was a cohort evaluated later, and it's not the data I'm going to share today. I'll share the data from part A. This vaccine was given as an initial booster dose, so everybody had mRNA-1273 as a primary series, and we ultimately looked as a 4th dose or 2nd booster dose with that beta containing vaccine in pink.
We followed now those subjects for about a year, and what I'm going to show you are the data for safety and immunogenicity immediately after the vaccine was given, and then 91 days later to look at antibody persistence. These are the reactogenicity data, and these are our standard local events that we follow: pain, erythema, swelling, and tenderness in the axillary lymph nodes. It's a little bit hard to read the different numbers, let me tell you that in each panel, the mRNA-1273 is the data that are on the right-hand side of the panel. What we observed was despite being able to utilize lower doses of the 1283 formulation, we see relatively comparable rates of adverse reactions across the board.
The same was true for the solicited systemic symptoms. Again, the last bar graph in each of the panels is the mRNA-1273. Across dose levels, we saw comparable results. Here are the immunogenicity data. Despite comparable results and lower dose levels, in all cases, regardless of whether it was a 1273 like Wuhan-like sequence or a bivalent beta-containing sequence, we see higher post-vaccination antibody titers immediately after vaccination on day 29. That improvement in vaccine titers persists until three months after vaccination. That was the Wuhan responses. These are the beta-containing results. Once again, also for the beta-containing variant, in all cases, 1283 and 1283 bivalent, we see higher numerically antibody titers than with 1273.
This really gave us confidence to be able to move forward into a phase III study. In summary, what I've shown you is that the safety and immunogenicity of a much shorter transcript was comparable with this mRNA-1283 product compared to mRNA-1273. Based on these results, we were able to launch our phase III study late last week. Let me talk to you a little bit about the design of that phase III study. We've designed that study to demonstrate non-inferiority of immunogenicity, and we also will be comparing the safety profile to the original mRNA-1273. In addition, because we are vaccinating now and leading into the fall season, we know that cases of COVID-19 at least are still being reported.
We're going to do our very best in advance of the fall season when a new variant-containing vaccine will be launched to capture enough cases to demonstrate efficacy. That's why efficacy is a secondary endpoint. We're investigating this vaccine in those initially ages 12 years and up, and then eventually we'll be moving down into the pediatric populations. The goal is if we move forward, and the results are favorable in phase III with mRNA-1283, we'll replace that vaccine in all populations. To summarize what we've just reviewed with COVID, our clinical data and real-world evidence with the bivalent vaccines have demonstrated an incremental benefit in effectiveness.
We have built a system within the company to be able to respond to the strain selection and implement that in the fall. Those activities include epidemiologic surveillance, proactive preparation for manufacture by our colleagues in CMC, and preclinical evaluation of our vaccine candidates. We have initiated enrollment in our next-generation, phase III clinical study. Now I would like to introduce Dr. Raffael Nachbagauer. He is the program leader for our team for our influenza vaccine portfolio. Thank you, Raffael.
Thank you. Thank you so much, Jackie. Good morning, everyone, I'm really excited to give an update on our influenza programs today. I actually wanna start by going back to our phase II data that we disclosed last year to remind everyone what we had seen back then and the data that actually made us go forward into our phase III studies. The study was conducted in the 2021-2022 Northern Hemisphere season in the United States. We saw immunogenicity data in that population that was in line with the potential for superiority for both influenza A strains, H1N1 and H3N2, which are the major drivers of severe disease in older adults. The data was also consistent with non-inferiority for the influenza B strains in this study.
Encouragingly, the geometric mean titer ratios were also consistent across age groups, which meant that we also expected to see good immune responses in the older adult population. Based off of those data, we then initiated phase III studies subsequently. We had two phase III studies that were initiated last year simultaneously. First, P301, which is an immunogenicity and safety study that we conducted in the Southern Hemisphere in adults 18 years and older. We enrolled about 6,100 participants in that study. We recently disclosed some updated information on this study, where we did see a good safety and tolerability profile in P301. The trial met all its endpoints for influenza A, including superiority for H3N2. The trial did not meet non-inferiority for its influenza B endpoints, unfortunately.
We also started a P302 efficacy trial in the fall of last year. This study was ongoing simultaneously, and we initiated it because as part of the accelerated approval that we were going to file for with P301, we needed to conduct a confirmatory efficacy trial. We thought we wanted to start early because, as everybody knows, influenza made its comeback last season. We enrolled about 22,500 participants in the Northern Hemisphere, with heavy enrollment coming from the U.S. and Europe. The primary endpoint in this study was relative vaccine efficacy to a licensed comparator vaccine. We did, however, also have a secondary endpoint to measure immune responses in a subset of this population. As Stephen mentioned earlier, we have not accrued enough cases to date at the interim analysis to declare early success.
However, we are continuing to follow up for this study until the end of the influenza season. Importantly, again, the DSMB did not identify any safety concerns at the time of the interim study. Looking at the safety holistically, we have now dosed over 14,000 participants in total with mRNA-1010, and what we've really seen is a consistent safety and tolerability profile across all the studies, starting from phase III all the way through phase III, where the DSMBs have consistently not voiced any safety concerns. The reactogenicity profile is similar to what we have previously seen with our COVID vaccines.
The P301 results, I think you've seen the high-level summaries, but if we look at the data in detail, what we saw there was that we still made the non-inferiority endpoints for both of the influenza A strains, and the superiority for H3N2 was actually maintained, which we had previously seen in phase II. We did not make non-inferiority for the influenza B strains in this study. This was a bit of a surprise given that we had seen strong data coming out of phase II. Since we wanted to find out what was really going on, we decided to dig a little bit deeper what the reasons for those differences could be. We really ended up honing in on the study location and study populations being the main driver of the differences between those two studies.
Because phase II, as I mentioned, was completely conducted in the United States, a population that is heavily immunized, based on the broad recommendations that everybody knows here. In comparison, the enrollment in P301 was heavily coming from countries such as Argentina, Philippines, and Colombia, where the recommendations are not as broad. We think this is reflected also in our enrollment data, where we saw that 97% of participants actually had not received an influenza vaccine in the prior season. We don't know the immune history prior to that, but if you didn't get a vaccine in the prior year, there's a likelihood that you might not regularly receive influenza vaccines.
The reason we think that those differences in immune histories could play a role is that there's actually a wealth of data out there that indicates that traditional vaccines that are currently licensed actually struggle to elicit potent and consistent immune responses in heavily immunized populations, where they do quite well in people who have not recently received influenza vaccines. We're actually quite encouraged that it is this heavily immunized population where we might actually see an indication that mRNA-1010 gives consistent performance and actually outperforms on the influenza A strains. We decided to dig a little bit deeper by looking at a subcohort of our P301 study. We had only 200 participants enrolled in Australia, but the reason we looked at this country is that Australia has a similar broad recommendation for influenza vaccines as the United States.
When we looked at those data, we actually saw something that reflected more what we had seen in phase II than it did for the rest of P301. We were quite encouraged by those results. Looking at the P302 immunogenicity data, which as we mentioned, we conducted in a subset of about 900 participants, we saw titers that were actually more in line with what we had previously seen in phase II. Importantly, P302 is primarily an efficacy trial, so we did not pre-specify the immunogenicity endpoints. That said, we saw geometric mean titer ratios that were in line with superiority for both of the influenza A strains and non-inferiority for the influenza B strains, just like we did in phase II. Again, this is consistent with more heavily immunized populations seemingly giving similar performance of mRNA-1010.
These data are really encouraging to us and we're gonna base P303, our upcoming immunogenicity trial, off of those data. We are actually planning to utilize the safety data that we have collected to date and generate additional immunogenicity data with an updated formulation of mRNA-1010 that we actually expect to improve the influenza B responses overall. The goal is to seek accelerated approval based on P303 and still wait for P302 in case we are able to demonstrate efficacy in this study, and otherwise conduct a confirmatory efficacy trial subsequently. This study is about to start later this month. To summarize our observations and learnings in mRNA-1010 to date, we saw an acceptable safety and tolerability profile that was very consistent ranging from phase I to phase III.
In our phase I/II studies, we saw strong immune responses for influenza A that were consistent with the potential for superiority. Those strains are the main driver of disease in older adults in particular. We saw titers in line that with non-inferiority for influenza B. In P301, in a very different study population, we did not see non-inferiority for influenza B strains. Looking into subsets of populations that were more heavily immunized, as well as P302 immunogenicity data coming out of the U.S., we yet again were able to confirm the results from phase II as we previously had. As I mentioned, phase III efficacy is still ongoing. We're still following the participants until the end of the season.
Unfortunately, we did not pre-specify the immunogenicity results. P303, our upcoming immunogenicity trial, is intended to allow us to file for accelerated approval. As you all know, mRNA-1010 is just the start for us for our influenza programs. We're actually planning to build upon mRNA-1010 with vaccine candidates such as mRNA-1020/1030 that will include an additional antigen, the neuraminidase. Another improvement that we are also working on are our mRNA-1011-1012 candidates, and those vaccines are supposed to broaden our immune responses against influenza A strains, where currently we have to pick one H3N2 or one H1N1 strain out there when we know there's a lot of different clades co-circulating. Providing public health authorities with the ability to choose more strains gives us a higher likelihood of actually matching the right strains that are currently circulating.
As Stéphane alluded to, we actually generated some immunogenicity data in our mRNA-1020/1030 program last year, and I'm really excited to show an initial sneak peek of those data today. We had Flublok, an enhanced influenza vaccine, as a comparator in this study. It is a very efficacious vaccine, and it actually does not contain any neuraminidase at all because it's a recombinant vaccine that only contains HA. One reason why vaccines don't contain a standardized amount of neuraminidase to date is that it's really hard to quantify and standardize in the vaccines, and in the context of a recombinant vaccine, it's just really hard to make. It's important that this limitation does not translate to mRNA vaccines, where we can actually encode for NA with our mRNAs quite well.
Why NA is an attractive target is also related to data that shows that NA is independently correlated with protection from HAI titers. In addition to the protection that you're getting through the hemagglutination inhibition titers, you get also protection through NAI. What we saw in this study was that we actually got similar HAI titers to Flublok with our lead candidate from our mRNA-1020/1030 phase I/II study. If you look at the bottom, you see that for neuraminidase inhibition, of course, only mRNA 1020/1030 lead was able to elicit NAI fold rises that actually were in the 2- to 4-fold range, which makes us really excited. What's really important to highlight also is that nobody to date, to my knowledge, has been able to deliver 8 mRNAs for influenza vaccines encoding for both the HA and NA.
This is really exciting clinical proof of concept data for us. This build slide only shows that if you plot mRNA-1010 in this graph as well, in the bottom you see similar to Flublok, it does not elicit NAI titers as we expect since it doesn't encode for neuraminidase. On the top, you actually see that even mRNA-1010 elicits similar titers to this highly efficacious recombinant vaccine. With that, I want to bring you back to our overall view of our influenza portfolio. I told you quite a bit about mRNA-1010, which we consider really the foundation first step towards our influenza portfolio that we think is gonna consistently improve over time. Building on top of mRNA-1010 are mRNA-1011, mRNA-1012, which are candidates that encode for additional HA antigens that really broaden the coverage against circulating strains.
Building on top of that, mRNA-1020, mRNA-1030 will essentially include the NA antigens. If you look all the way to the right, we actually think that subsequently we could include all the features of those different candidates into a single vaccine, which we think could really improve efficacy of influenza vaccines quite substantially. With that, I'm gonna hand it over to Christi, who's gonna talk about RSV.
Hi, everybody. Christi Shaw. I'm leading the infectious disease portfolio for respiratory. First, I'm gonna be talking about our RSV vaccine and sharing some of the data that we've presented at a recent medical conference. And as Jackie mentioned, we do have another conference coming up very soon where some additional data will be presented. Starting with the epidemiology, RSV is a very common respiratory pathogen, where the burden is most relevant or evident is in both young children and in older adults, as articulated on this slide. In the U.S., there's actually millions of medical visits that are associated with RSV every year, and it leads to high healthcare costs associated.
Most kids have had RSV or have been infected with it by the time they're two, and kids and adults continue to get RSV throughout their life. It's usually not such a big problem in a healthy adult, but becomes more of a disease risk in older individuals, as shown on the right on this slide here. Recent publications have shown that in high-income countries, there's up to a half a million hospitalizations yearly due to RSV. That number is actually probably an underestimate considering that testing is not routine for RSV, particularly in older adults. Our RSV pipeline is actually addressing both of these areas of where there is a high burden, both of these populations.
You've heard a lot recently, and I'll tell you more today about our older adult program, where we have successfully demonstrated efficacy in a pivotal study. We have a very competitive, we feel, portfolio compared to the other vaccines out there. We do hope to file, as mentioned already, for a BLA in the U.S., this quarter with, in our best case or up scenario, getting a regulatory action towards the end of this year or maybe into early next year. We also do have a very active pediatric program. Not getting into too much detail of that today, but some specifics are on this slide here. We actually just recently initiated a pediatric study in children five to 24 months of age.
This study not only evaluates our RSV vaccine in those kids, but also a new combination vaccine for pediatrics that also includes human metapneumovirus, which is another common respiratory pathogen in kids. That study is ongoing, so hopefully data to come soon from that study. We also, in our phase I study, did evaluate our RSV vaccine in women of childbearing potential. This sets up the stage should we pursue a maternal vaccine program for RSV, the mechanism of protection there would be passive transfer of antibodies to protect infants from disease. We're really covering the spectrum of age here and also interested in pulling RSV into our combination respiratory vaccines.
I'll speak a bit more to those, but you can see here that we have adult combination vaccines with flu and also with flu and COVID that are in clinical development now. I think one of the really neat things about this platform is that you see on the bottom, RNA right now, to our knowledge, is the only technology that is addressing all of these populations with a single vaccine, a single platform. This is not true for some of the subunit vaccines or live attenuated vaccines, for example, which only addresses certain niche of the burden. Digging into the older adult program. This is the update we have on our Phase III pivotal efficacy and safety study. This is a big study.
We've enrolled more than 35,000 participants across the globe in 22 countries, Northern and Southern Hemisphere, to capture RSV wherever it happens to be circulating. Individuals were randomized to either receive a single dose of vaccine or placebo, and everyone's followed through two years of the study. The endpoint here is prevention of lower respiratory tract disease. It is a case-driven study. We were continuing to accrue cases through the study from when it started, and we still are. About a year after we started the study, in November, this past year, we had accrued sufficient cases to trigger our first analysis of efficacy. Those are the data that we have presented on, and I'll share more today. The primary endpoint of lower respiratory tract disease actually has two symptom definitions.
We have two co-primary endpoints. They both require PCR-confirmed RSV infection. They differ only in the number of symptoms that trigger or that encompass that case definition. You can have two or more symptoms shown on the right of the slide to meet the first definition of LRTD with two or more symptoms. A subset of those individuals have three or more symptoms, and those same set of symptoms, again shown on the right. These have to occur starting, the definition is from 14 days after vaccination, through a year for our primary endpoint. Although I, as I mentioned, we are continuing to look at data through the 2nd year after vaccination. Getting into the data from the study. This is the demographic or baseline characteristics in the study.
There are 35+ individuals, 35,000+ as mentioned. First, you can see the quite balanced across the two groups, vaccine and placebo, in terms of characteristics. I wanna point out a couple of key features that we have been able to recruit a high number of individuals that we think or that we know will be more susceptible to severe RSV disease. Of course, this is the population we're even most interested to treat with this vaccine. Specifically, if you look at the age, we have more than 30% of individuals that are above 70 years of age and also, more than 5% that are above 80 years of age. Also interested in those individuals with underlying conditions that put them at risk for more severe RSV disease.
Those are, we call comorbidities of interest, and the specifics are at the bottom: COPD, asthma, chronic respiratory disease, diabetes, CHF, and advanced renal or kidney disease. In that population, we have about 29% of those as well. We're also pleased to say that we have more than a third of the participants that are non-white and similar number that are Hispanic or Latino ethnicity. Okay. First, the safety, and then we'll move to efficacy. For safety, this is the solicited local adverse reactions that occurred within the first week after vaccination. And it's a pretty favorable profile. This local reactions are driven primarily by pain in this case.
They are more than placebo, the rates are really, the severity is really grade one, which is quite mild in severity, with very few of a higher grading. When we move to the systemic, solicited adverse reactions, while there are slightly more reactions of arthralgia, fatigue, headache, and myalgia in the vaccine group, again, they are more mild and some moderate reported events. Overall, a quite well-tolerated vaccine. Moving to the efficacy results. This is the top-line primary endpoint efficacy. Again, we had two case definitions and two co-primary endpoints associated, RSV, LRTD with two or more or three or more symptoms.
On the top are the two or more symptom data, at the time of our analysis, we had accrued nine cases in the vaccine group and 55 in the placebo group, which equates to an efficacy of 83.7%. We saw a very similar level of efficacy in the 3+ case definition, 82.4%. As expected, there were fewer cases there as this is a subset of the individuals that had two or more symptoms. The case split was very favorable, as was the efficacy. Both of these actually did meet the predefined success criteria for the lower bond of the confidence interval, higher than the level that we had predefined for success. Okay.
Once we had achieved success and efficacy and have a safe vaccine, we're starting to look more into other, more nuanced or in, detailed analyses of efficacy. Here, and on the next slide, I'm just gonna show two of them that we have shared so far. This is subgroups by age here, and comorbidity is on the next slide. By age, again, older individuals are at more risk for disease. We looked at it by decade here, 60-69, 70-79, and you can see that the efficacy is maintained as individuals age, which is very good to see.
as with all of these graphs, the confidence intervals are wider for the 3+ LRTD case definition just because there are fewer individuals that met that criteria at the time of the analysis so far. You might see that there are no data on here for the 80+ individuals, although we did recruit more than 2,000 or about 2,000 individuals. That's only because at the time of the analysis, there just had not been any cases in that 80+ group. There may be as the study continues. The second analysis by subgroup that I'm sharing is that with those underlying comorbidities. Here it splits into at least one or more comorbidity of interest.
It's that same list of symptoms I mentioned or conditions I mentioned earlier, shown on the bottom of the slide, both for 2+ or 3+ LRTD symptoms, definitions. Again, very good maintenance of that efficacy level in both populations, those quite healthy and those with the underlying conditions. There's no, like, drop-off of efficacy as with these conditions. These, again, are those that put individuals at risk for severe disease, we think the vaccine is holding up quite well in the population that matters the most. Okay. Some kind of key highlights, some summary, a couple new points for the data I shared so far. First, we have a very well-tolerated vaccine, mild and some moderate events.
One new piece of information that we shared at a conference recently was we have no cases of Guillain-Barré syndrome reported in our study so far in either vaccine or the placebo group. On the efficacy side, we have high VE as described, and the number of cases that support this are a total of 64, which is a lot. This is a higher number of cases than some of our competitors or both of our competitors have reported for their endpoint. It's a very robust data set in that regard. We have great maintenance and of efficacy in the populations that matter most that get severe disease. All right.
Summarizing again, kind of similar to last slide, efficacy that's maintained in the subgroups that matter, great, tolerated vaccine, and no other safety concerns have been identified. As I said, no GBS. We're on track to submit our BLA file in the US this quarter. We do have an option for a priority review as we've disclosed previously. That's RSV. Moving on to combination vaccines, and many of these do include RSV. These are the adult combination vaccines I'm focusing on. As I mentioned earlier, we do have a pediatric combination vaccine with RSV. In general, our kind of philosophy for combination vaccines is building on that Stéphane and Jackie, and Raphael already alluded to.
We're gonna keep iterating these things until we get it right, and even then we're gonna keep going till we get it even better. We have all of these first generation single virus vaccines. We've already shown efficacy for RSV, for COVID. flu's got some great data. We're gonna keep moving on those. At the same time, we're improving those single virus vaccines. Jackie described some ways we're doing that with COVID. Raphael described how we're doing with that flu. We're gonna keep iterating on that. In parallel, we're also putting these things together into combinations. We see a lot of benefits for individuals and healthcare systems to do combination vaccines. We're not stopping at a first generation.
We're going to, as we improve the components, we're gonna keep putting them together and keep making this vaccine updated more and better vaccines. They may be better for different reasons. It could be stability, efficacy, safety, other things, shelf life, these kinds of things. Lots of ways we can improve, and we will improve. Here is a visual of where we are with our adult combination vaccines for respiratory. First, we are really pursuing those vaccines where we see the most benefit to our healthcare and to individuals. In terms of what are those concrete benefits, they're shown on the right, better compliance and uptake, and benefit to healthcare, and also, to an individual for consumer, rather get one shot instead of two or three.
The specific vaccines that we have developed or are developing so far are shown on the left. Again, these are the adult combination vaccines, and with a status update where we are in their development. We have maybe our first or most advanced vaccine is a COVID flu combination. This one is called mRNA-1073. We had completed enrollment on this study, and it was a combination of our Spikevax mRNA-1273 vaccine as well as our first-gen mRNA-1010 vaccine. We also recently completed enrollment in a study that evaluated two other combination vaccines, the mRNA-1045 and mRNA-1230 vaccines. These include RSV also. We have an RSV flu, which is mRNA-1045. This makes sense because those pathogens are well known to circulate at the same time.
They cause very similar disease, we see some advantages there. We also, if there's any unusual timing of COVID update sequences and so on, that would not be a problem for the flu RSV combo. We're keeping that as an option. That's moving along. We think, you know, the ultimate... one of the ultimate vaccines would to put all three of these together into a triple combo. That vaccine is also in this phase I study. Enrollment's complete. Data will be forthcoming. That also, the triple combo, included our first generation programs for the components. Lastly, as we announced earlier, we have a new vaccine. This is, I think, our first example of our second generation combo vaccine. We're already pulling in the improved components that we have for the standalone single virus vaccines.
As shown here, you can see this combo will include the mRNA-1283 that Jackie described today, which has the shorter mRNA, better, ability to have long-term storage and potentially refrigerator or potentially prefill-filled syringe. That vaccine, also the mRNA-1010, also includes some updates in the flu, component as well. Overall, we think this could even be a better, for a number of reasons, including storage and even potentially efficacy and safety. News on that vaccine is that we have submitted the IND. It's with FDA currently under review. Next steps, for combos. We are really continuing to build on the data that we have for the individual programs to put them together into the best, and next, combination vaccines.
We are continuing to focus on the diseases that we think matter the most and will have the most impact on healthcare around the world. For this new combination vaccine, the second-gen FluCOVID, as I said, IND is under review, and if that goes well, we do hope to start enrollment in that study soon, definitely in this quarter. I think that's it for me, and we're at a break.
Okay, I've been requested to tell you that we'd like to get started again. Oh, yeah, you did. Thank you. Excellent. Okay. I know that was a brief break. Hopefully, you got a chance to get up and stretch your legs 'cause we have now the second half of the presentation, and unfortunately, the clicker is not working for me. Oh. Yeah. Can we go back one, please? It advanced two, actually. Excellent. Thank you. Okay. Now we're gonna shift gears a bit and talk about some of the platforms that are earlier in development. As Stéphane mentioned, these viruses, the herpes viruses and HIV, I think are incredibly impactful. It's a very exciting part of our portfolio, because these not only cause near-term disease, but can cause long-term impact for people as well.
We're gonna focus today on cytomegalovirus, which is currently in phase III of development. We also have age de-escalated down to adolescents. Why? Because there's an existing adolescent vaccination platform. The important thing with these latent viruses is that to actually vaccinate people before they become seropositive, because many of the long-term complications are because people have already been infected, and those viruses reactivate. Finally, as Stéphane mentioned, CMV is actually a real problem in the transplant population. There was a famous paper, actually written in the 1980s, called The Troll of Transplantation, so that's how I think of CMV, the troll of transplantation. I'm so excited to talk about a phase II study that we've initiated. I'm gonna welcome our very special guest, Dr.
Bill Schief, he's gonna talk about the ongoing phase I work we have in the HIV space. First, a bit about cytomegalovirus. We are targeting multiple impacts of cytomegalovirus. The first thing that we are evaluating is an indication to prevent primary CMV infection in seronegative women. The reason for that is when women become seropositive during pregnancy, they can pass that virus through the placenta to their unborn baby. Like rubella, like varicella, there can be a congenital syndrome that comes with infection called congenital cytomegalovirus disease. It actually is the most common infectious cause of congenital sensorineural hearing loss worldwide. We also are potentially interested in investigating the vaccine in women of childbearing age. Again, maternal vaccination is becoming more of a platform.
As I mentioned, the people who really need this vaccine the most are those who are in the transplant and immunocompromised space. We're also looking at what age groups could you really target to address cytomegalovirus before someone ever becomes infected, because if you don't become infected, you can't reactivate it and suffer the longer term health consequences. I mentioned the congenital CMV syndrome. This syndrome on newborn babies can lead to $1 billion in annual healthcare costs. It's not actually as rare as people think. one in 200 babies are born with congenital CMV infection, and of those one in 200, one in five of them will have severe and life-altering complications from their congenital CMV infection.
At birth, this syndrome comprises symptoms such as microcephaly, chorioretinitis, there can be a seizure disorder that accompanies the neurologic complications, along with sensorineural deafness. And then in the longer term, it's not always obvious the problems that an infant will have when born, there can be cognitive impairments, the development of cerebral palsy, and the seizure disorders and sensorineural deafness obviously are not conditions that get better over time. We have a phase III trial ongoing, and I'm so pleased to report that it's now over 50% enrolled, and it will be evaluating the efficacy, the safety, and immunogenicity of our CMV vaccine, which is mRNA-1647. We have 150 sites in the U.S. and globally where we're conducting this study, and we've specifically targeted women at higher risk for contracting CMV. Why?
We're trying to enrich for the capture of those cases. We're following cases after dose three of vaccine. As with our other clinical development programs, diversity and inclusion continues to be an important goal for us, and we have published our targets for enrollment to ensure the generalizability of our results. As I mentioned, primary infection is the key indication we're targeting, so we are monitoring these women carefully for seroconversion to CMV. The reason, as I mentioned, that we de-escalate to adolescence is, again, to increase the likelihood that we are able to vaccinate before someone has naturally seroconverted. We believe that the majority of cases could actually be prevented if we added a CMV vaccination at the same time we're vaccinating teenage girls with other vaccines, such as the human papillomavirus vaccine.
This would ease implementation, and to the vaccination schedule, so it wouldn't require additional visits for the use of the vaccine. Now let me talk a little bit about that adolescent study. We actually are currently conducting a dose-ranging study to select that final dose, including the dose that we're currently investigating in the efficacy trial in adult women. The study includes 770 participants across about 70 sites globally, and the patient population will be nine to 15 years of age, again, meant to target the age range for the adolescent vaccination platform. As we did in our adult dose-ranging studies, we'll be looking at neutralizing antibody titers to both epithelial cells and fibroblasts. Shifting gears a bit to the transplant population, why is CMV the troll of transplantation?
Well, it plays an important role actually in graft rejection. You can imagine that if you've been waiting for your organ transplant and then you develop an infection that eventually causes you to lose that graft, this is a really devastating consequence for these patients. Their immunosuppression puts them at higher risk, not only for capturing or being infected with new strains of CMV, but actually reactivating previous strains. You don't have to have been a seropositive person at the time of transplant. CMV infects epithelial cells, and as such, when you transplant an organ, you can actually transplant your donor's CMV infection into the recipient. They have a lot of reasons to be at increased risk, and they have a lot at stake to prevent their infection.
There are currently no approved CMV vaccines, not only for post-transplant, but overall. There really is a high cost and some toxicity associated with the existing prophylactic mechanisms. Currently, all patients' standard of care are getting CMV prophylaxis at least for some time after transplant. Those medicines, though, over time, just like with antibiotic resistance, can lead to resistant strains of CMV. There's a lot at stake and a lot of good reasons to develop a safe and effective vaccine. There are about 62,000 organ transplants each year in the U.S., 40,000 of which are renal transplants. We're gonna talk a little bit more about hematopoietic stem cell transplant or bone marrow transplant patients, but there are about 22,000 of them.
Enrollment has begun in the study we call P205. It's a Phase II study, and it's really meant to be a proof of concept that this vaccine can impact CMV infection and reactivation post-transplant. Right now, to start, we're recruiting seropositive individuals who have gone high-risk allogeneic stem cell transplants. The primary outcome measure is the time to first reactivation once their initial prophylaxis is over. We are going to give the normal prophylaxis that these patients would receive while they are waiting for their bone marrow transplant to take. The way bone marrow transplant works, you ablate the bone marrow of the patient, and then you replace it with the transplant. It takes a while for that bone marrow to begin producing white blood cells again.
Obviously, initially, while they have no white blood cells, we want them to have their prophylaxis. Once their immune system reconstitutes after about 100 days, we're going to give an accelerated schedule of the CMV vaccine, so 25 days apart. Why? In these patients, we really need protection to be induced quickly. We will be following them very closely. They actually get quite close follow-up as standard of care. If we see signs of increasing either viremia or symptoms of CMV disease, we will then obviously start antiviral therapy. With that overview, I'd now like to turn this over to Dr. Bill Schief. He's a professor of immunology and microbiology at The Scripps Institute, and he's also the Executive Director of Vaccine Design at IAVI.
He designed our mRNA-1644 vaccine program. Excited that he's gonna share the results with you today. Please welcome Dr. Schief.
Thanks.
Thank you.
Thank you. It's great to be here. I've presented at Vaccines Day Before virtually, but I never knew what it was like in person, so it's great to see you guys. Let's see. How do I do this? Okay. I'd like to give you an update on the clinical trial we call IAVI G002, which we're thinking of as a first step toward making an mRNA HIV vaccine. This is actually the first public presentation of data from this trial. The trial is not completed yet, still in the middle of the analysis, so it's really exciting to share, you guys, share with you the data.
We've heard a lot of great presentations about COVID and flu and RSV and other viruses that are similar in HIV in the way that they infect human target cells, their type one fusion spikes, and the spike of HIV is shown in this light gray with antibodies bound to it. Probably the major challenge in making an HIV vaccine and why Moderna hasn't already made one and showing you amazing results like was shown for flu and RSV is that the spike, the surface of the spike and the amino acids that cover the spike change much more dramatically between one isolate and another for HIV than they do for influenza or RSV.
It's really difficult, they were talking about, all the speakers have talked about making cocktails of different antigens to, and updating the cocktails every year to do strain matching. That works for influenza, as we all know, works extremely well, and you saw great data. It works for COVID, as Jackie showed, but it wouldn't work for HIV. It's far too diverse. What do we do? Well, the field has been thinking about this for a very long time and doing a lot of research, and if you look at people infected with HIV, a very small percentage of them make what are called broadly neutralizing antibodies, and those antibodies bind to patches on the spike that don't change as much.
It's not so easy for the human immune system to figure out how to do that. It requires very specific sets of human antibody genes and usually a lot of mutation for the antibody to evolve the ability to just grab on to exactly the right spot. By studying lots and lots of individuals, the field has isolated, and this slide is showing examples of different broadly neutralizing antibodies, they're called bnAbs, that bind to different sites on the spike. The idea here is we know that the human immune system can produce these very infrequently in response to natural infection, but can we design a vaccine that intentionally and reproducibly induces broadly neutralizing antibodies so that when someone is exposed to HIV, they've already got bnAbs in their blood, and they don't get infected no matter what isolate is challenging them.
We have... The bullets here are showing that we have broadly neutralizing antibodies that neutralize diverse isolates, some up to 99% of all isolates. Lots of work has shown that if you give a bnAb to a non-human primate, and then you challenge it with a, with a SHIV, kind of like an HIV that could infect the primate, if the bnAb is present in sufficient high concentration, there is no infection. You get sterilizing immunity. A recent set of human clinical trials showed that bnAbs can also protect humans. The idea is if a vaccine could elicit bnAbs, it could prevent HIV infection, and to really do that of the style of Moderna, 90% infection plus, the responses need to be broad, potent, and durable, and that's what we're going for.
I just wanna say the presentations were so beautiful, and the technology is so beautiful, the examples for COVID and flu that you've seen already. There are analogies here. While HIV is so much more diverse than influenza or coronavirus, the SARS-CoV-2, broadly neutralizing antibodies have been isolated for those viruses as well. You could imagine if the strategies I'm talking about are effective for HIV, you could imagine deploying them also for less diverse viruses, and they could help make the vaccine lower the requirement for strain matching and updating the vaccine every year. Maybe you could make a vaccine that induces bnAbs, and you'd only have to update it every five or 10 years. Even if you did update it, you might just get even higher effectiveness.
It's sort of an exciting new technology. Back to HIV. Today we're just gonna talk about one class of HIV bnAb, VRC01 class bnAbs that bind to the CD4 binding site. What is required to induce protective bnAbs? I mentioned that these antibodies have very specific sets of human antibody genes, and they gain lots of mutation that allows them to bind to the specific patches, epitopes that they bind to that don't change much on the spike. In order for a vaccine to induce these, we need to start. The vaccine needs to trigger naive B cells that have the right. Naive B cells have antibodies on their surface, and antibodies have, each B cell has one set of antibody genes.
We need to trigger the B cells that have the right set of antibody genes that gives them the potential to develop into a bnAb. The vaccine needs to elicit it needs to take those B cells through a set of immune reactions to gain somatic hypermutation, finalize the process of becoming a bnAb, convert the cells into plasma cells that secrete bnAbs in the blood and from the bone marrow. Sounds easy. The strategy that we're pursuing to do this, to achieve this, is called germline targeting, and it really keys off the first the first shot of the vaccine.
The job of the first vaccine component, the vaccine prime, is to find and trigger those naive B cells that have exactly the right genes and expand them and get them to mutate a little bit in the right direction. If that works, then we deliver a series of shepherding or polishing immunogens that are intended to engage the red cells that were generated by the previous vaccination, expand them further, get them to make more somatic hypermutation in the right direction toward bnAb development. Finally, in the last polishing stage, we need to make sure that we have a very high level of plasma cells with the right bnAb sequences on board that secrete bnAbs into the blood. It's more complicated than a normal vaccine strategy, but it's not terribly more complicated.
You see I did multiple shots. Many vaccines, you give multiple shots. Here, we just have to use a different component for each shot of the vaccine. One of the huge assets of this strategy is we know what we're looking for. If we're trying to induce a specific class of broadly neutralizing antibody, we know what genes that antibody has. We can, while we're doing a human clinical trial of the kinds that Jackie talked about, you can interrogate the B cells halfway through and ask, "Are we getting the sequences we want? Is this working or is it not?" If it's not working, you could stop, and you'd know, well, we need to redesign the components before. If it is working, you say, "Oh, we can keep going." It lends itself very well to optimization.
It's a very sort of engineering-oriented approach. We think that even though the problem is very difficult, because it lends itself to this optimization and engineering approach, we can solve this problem. In December, we and our colleagues, and you see there's many authors in this paper, we published a paper in Science that showed clinical proof of principle for that first step. For one example, it showed that we can trigger the B cells that we want that have the right genes that are precursors to one particular class of bnAbs. In this clinical trial, IAVI G001, the immunogen triggered a bnAb precursors in 97% of the participants. In the middle panel here, you'll see this little blue nanoparticle. The vaccine was called eOD-GT8 60mer.
It's a self-assembling nanoparticle, 60 copies of a little domain that we engineered specifically to have affinity for the bnAb precursor B cells we were looking for. On the right, you can see in the low dose, we induced bnAb precursors in 18 out of 18 participants, and in the high dose, 100 micrograms, we induced precursors in 17 out of 18. It worked extremely well, and the responses were very strong. This gave us showed that the concept works in humans, and that opens the door really to our thinking about, okay, how we are we really going to make a vaccine? How are we going to get there?
We, with that data and with lots of other preclinical data that I don't have time to describe to you, we have two major goals in mind. First of all, we've shown, like I just showed you on the previous slide, that we can get that first step to work in humans. In order to induce bNAbs, we have to go through the whole pathway and actually induce bNAbs. The first goal is to prove that we can do that in humans for at least one class of broadly neutralizing antibody. The second goal is more practical, is thinking about, all right, let's really make a vaccine.
We believe in order to make a highly protective HIV vaccine, a Moderna style, highly protective vaccine, we need to induce multiple classes of bnAbs, probably two or three in parallel to get enough coverage against the huge diversity of global isolates. We've got to go through that sequence of vaccines, of vaccine immunogens for multiple different classes of bnAbs and then combine them. We've heard discussions of combination vaccines of RSV and flu and COVID. This would be a combination vaccine for different HIV bnAb. Moderna knows how to do that kind of thing already, and the technology lends itself really well to that. I have to say that formulating those goals would be impossible without partnership with Moderna. You can't plan...
In that previous slide, we're thinking about multiple, many phase I clinical studies to evaluate and optimize the, the vaccine components. You can't really think about that without partnering with Moderna and using mRNA technology. It's been a fantastic partnership to accelerate HIV vaccine development and clinical testing and to enable delivery of membrane-bound trimers, which is another sort of a technical thing. The way the Spikevax works, is with the spike delivered on a membrane-bound trimer, and that's very helpful. In our field, In HIV, we believe that's very helpful too, and it's much more difficult with protein vaccination to try to do that kind of thing. There's a little technical enablement there as well.
We do envision conducting multiple phase I studies over the next five to seven years until we converge on a potentially protective vaccine that merits advancement to phase II. In partnership with Moderna, we're conducting three phase I trials testing Moderna mRNA for HIV vaccine development, and the first trial is IAVI G002. It's following on to the trial I just talked about, and this is the one I'll show you data for today. That is testing this GT8 prime, which is the nanoparticle at the bottom on the left, the same molecule that we tested in IAVI G001 as a protein. Now we're delivering it with Moderna mRNA, and we're testing it. Do we want to know will it do the same thing or better at U.S. sites?
We're also following that with a heterologous boost to ask, okay, if the prime works as we hope it will, can we test the next step in our strategy? Can we advance the maturation of the B cells further like we say we are intending to do? That's happening now. IAVI G003 is testing the prime, the GT8 prime, in Rwanda and South Africa, where a vaccine is most needed. HVTN 302 is testing an entirely different set of molecules, native-like trimers, very analogous to Spikevax. In that case, we're testing different ways to deliver HIV spikes to not to induce bnAbs right now, but to just understand when we need to deploy those in our sequences for our vaccine, what's the best way to do it?
Soluble or membrane-bound or with a modification that we think might help immunogenicity. I'm going to focus on G002 today. Here's the study design. It has four groups. The first group is basically a repeat of IAVI G001, but now it's with RNA. We get two shots, one at week zero and one at week eight. The second group is now looking at can we give a heterologous prime boost? In group two, you get one shot of the prime, and then the second shot is this heterologous boost, this core nanoparticle. The third group is you get two shots of the prime followed by one shot of the heterologous boost.
That's really motivated because in our prior clinical study, we induced VRC01 class bNAb responses, and we made lots of antibodies that were VRC01 class at different time points, and we saw more mutation and higher affinities in the antibodies induced by two shots of the prime compared to by one. It could be that we need to give two shots of the prime in order to get the most to prime a set of B cells most effectively in order for the heterologous boost to work. Comparing two and three, we're really excited about that. Group four is basically a control, if the booster immunogen itself can induce VRC01 class antibodies, we'd be better off.
It doesn't in preclinical models. We don't think it'll here, but it'll help us interpret the results. The aims of the trial are to evaluate the safety and reactogenicity of the vaccines. To test the GT8 60-mer priming immunogen, will mRNA generate VRC01 class responses as in G001? When I say VRC01 class, that's this one class of broadly neutralizing antibody that we're going for in this trial. Then the third point is will the heterologous boost, the core boost, will it generate increased maturation toward bNAbs? I don't have data on that today. Just for the enrollment and safety update, It's fully enrolled. It's slightly over-enrolled. All study vaccinations are completed. For local and systemic reactogenicity, we see them in almost all the participants, mainly mild and moderate, as you would expect for a immunogenic human vaccine.
There have been no serious adverse events, no adverse events of special interest, no study discontinuations, and no pause criteria triggered, so all good. We do see adverse events of this skin reactions, pruritus, urticaria, and/or angioedema in 11 of the participants, 18% of the participants, following one or two doses of the prime or one dose of the boost. The rash is delayed and generalized in distribution. It's not the injection site. It's persistent in several cases, but predominantly managed with oral antihistamines. It's mostly mild or moderate in severity. No anaphylaxis reported. four participants discontinued vaccinations due to the adverse event, but continue with safety follow-up. We're conducting an ongoing evaluation of these adverse events, including consultation with external allergy and immunology experts, and we're planning additional investigations to understand potential mechanisms. For the.
I've just got a couple of data slides on the immune responses that we think are quite exciting. First, just serum antibody binding responses. I've given you another image of what the vaccine looks like there on the left. It's a self-assembling nanoparticle. It's the same nanoparticle that we delivered as a protein in IAVI G001. This assay is a validated assay, so we've plotted serum antibody data from both clinical trials on the same graph, which is allowed by the statisticians. You can see the data in blue. What I'm showing you are serum antibody binding to the monomer, the GT8 monomer. It's one monomer out of the 60 copies that are present on the nanoparticle. You can see the data in blue are from G001.
We've combined data from high and low dose 'cause they sort of cluster all together. You can see the data from G002 are consistently higher in terms of serum antibody binding responses at week two, four, or eight after just one shot of this vaccine. Very encouraging. This is, I think, the first human data from a self-assembling nanoparticle delivered by RNA. I think Stéphane said, you know, the RNA technology allows delivery of these complex antigens, this would be another example. It's pretty non-trivial though from the antigen standpoint. In the first clinical trial where we made protein, we went through a laborious process to purify the nanoparticles and make sure they were You know, what we, what we actually injected as a vaccine were very well, well-assembled, complete 60mer nanoparticles.
With RNA, you don't purify. You give the RNA, and you rely on the amino acid sequence, the mRNA to translate into amino acid sequence that will self-assemble on its own. You know, this works in preclinical models, but it's very comforting to see, yep, in humans, you get these stronger responses, which it doesn't prove that it's self-assembling like a siximer, but it's strongly indicative that we didn't need purification. The RNA just generates the nanoparticles like we want it. You can imagine this as a. Although eOD-GT8 is not going to induce bNAbs by itself, it's not even going to induce neutralizing antibodies by itself. For a different virus, you could imagine making a nanoparticle whose job would be to actually induce neutralizing antibodies.
The fact that you can use Moderna mRNA to generate self-assembling nanoparticles in humans and induce very high serum at least antibody binding titers, I think is very encouraging as a general, thinking of it as a general model antigen. That data. Sorry. I'd really like to thank, you know, the people responsible for that data, Georgia Tomaras's lab at Duke, and Amanda and Alan at the Fred Hutch for VISC. The main aim of the study is to find out, well, does the mRNA version of this immunogen induce VRC01 class memory B cells in blood? That was the big readout in G001, and it's what we want to know in G002. The answer is yes, it does.
What I'm plotting for you here in this graph on the y-axis is the % of IgG-positive memory B cells in a person's blood that are VRC01 class, and we measure that through B cell sorting and sequencing the receptors on those B cells and doing a lot of bioinformatics after that. This data is generated from our collaborators at the VRC and also Jordan Willis working with me at IAVI and Scripps. You can see, although the exact technical details of the assays used in G001 and G002 are not the same, the readout is intended to be the same, so we're plotting it on the same graph. You can see again the data in blue from G001 is exciting all by itself.
It was groundbreaking two months ago. You can see what we get from G002 is like at week eight, it's about 7-fold higher VRC01 class memory B cell responses, which is fantastic. Clearly, 100 micrograms of RNA is performing extremely well compared to protein plus AS01B adjuvant. I would say in our the way we think about it, we'd like to immunize sort of every eight weeks. We like eight weeks 'cause it gives the germinal centers time to run and generate mutation. Week eight is sort of the time point we think about. In group two, we're boosting with core at week eight. That's this is the population of B cells that are that need to be triggered by core. We've talked about somatic hypermutation.
We need the vaccine to induce somatic hypermutation to make bNAbs. From the prime, we don't expect a whole lot of somatic hypermutation, but we wanna see some. And what I'm showing you here are for the VRC01 class memory B cells that we've isolated at weeks four and week eight in the two trials, how mutated is the heavy chain V gene, which in this particular kind of response is extremely important. You can see at week eight, which is the important time point here, the antibody, the B cells responding to RNA have at least as much mutation as they did responding to protein plus AS01B, which is a super strong adjuvant, and maybe more. It looks possibly like the G002 anti...
I don't think it's statistically significant, I haven't tried to do that here, but it certainly isn't worse. That's also very encouraging. Finally, a key readout is if you make the antibodies, how well do they bind? We did that a lot in G001, and we're doing that, we've started to do that for G002. For G002, we've only made antibodies from the first six participants, this is limited data. On this graph, I'm plotting it on the y-axis, the dissociation constant, lower numbers are tighter binding. You can see at week eight, the distribution, the median is certainly a lot better for G002 than it was for G001. If anything, you know, maybe they're the same, but it looks like the affinity's going along with potentially higher mutation. It looks like the affinities might be higher.
Preliminary conclusions and next steps from the IAVI G002. RNA vaccination induced stronger serum antibody responses compared to historical data from G001 protein and AS01B immunization. GT8 mRNA induced stronger VRC01 class memory B cell responses compared to G001, although there were differences in the laboratory methods that could contribute to those differences. If anything, the methods in G002 are just more efficient at recovering sequences. VRC01 class memory B cell responses induced by GT8 mRNA have higher or similar SHM, somatic hypermutation, and affinities at week eight compared to G001. Overall, mRNA delivery of this priming immunogen appears promising for HIV vaccine development, but we have to deal with the dermatologic adverse events. We need to better understand them and the implications of potential mitigation strategies.
The next step in this trial is to determine if the heterologous boost increased maturation toward bNAbs, as I explained. We don't have any data on that yet, but we should be getting it on the next, like, six months. The next step for this priming immunogen delivered as RNA, we think, is to test lower doses to see if we can decrease the adverse events while retaining sufficient bNAbs precursor priming. I've shown you that as far as immunogenicity, as far as the signal we were looking for, it's a lot stronger than it was in G001. We feel like there's room to dial down the immunogenicity a bit by lowering the dose, potentially eliminating the adverse events and still having as strong priming as we got in G001, which we thought was good enough already.
We're really excited to be in this position and to move forward. Finally, I would just say, as I mentioned, I think this is the first human data on mRNA delivery of a self-assembling nanoparticle. That's a general technology that the field has shown can induce much stronger responses than monomers or smaller oligomers. I think it's encouraging overall that we could use this technology for vaccines in general. I'd like to thank all the partners involved. There's many partners involved in all these studies, but particularly IAVI, Scripps, NIAID, the Gates Foundation, the HIV Vaccine Trials Network, Vaccine Research Center, and Duke. There's obviously tons of people involved in these, in this work, and I'd just really like to thank Jordan Willis for making the immunogenicity slides that I showed.
Georgia Tomaras's lab at Duke and the team at Sarah Andrews's team at the VRC for doing all the B cell sorting and sequencing that allowed me to show this data today. I'll stop there. Thank you. Jackie's next, emerging programs.
Okay. The last portion of the scientific part of the morning is to talk about some of our newer programs that are emerging towards the clinic. What's really exciting about these programs is that they're actually in a new space from where we are. I hope I've convinced you this morning that our respiratory portfolio and our latent virus portfolio are really maturing and moving assets towards phase III and hopefully potentially licensure. We're looking at other ways in the infectious disease space that this technology could make an impact. One place that we're looking are in the enteric viruses, my background is actually as a pediatrician, and I can tell you every winter, two out of three kids, they either have a respiratory infection in hospital or they have a gastroenteritis in hospital.
This is kind of a natural progression for our pipeline given some of the successes that we've seen in the respiratory space. Bacterial pathogens are obviously another scourge. While COVID has kind of trained us to think about the viral apocalypse as part of pandemics, actually, in a normal setting, it's really the bacteria that land patients in the intensive care units. You know, just like viruses are proteins, with an envelope, bacteria also produce a lot of proteins for their biology. We're interested to see what we can target there as well. Enteric vaccines, they multiply locally in the intestinal tract. The analogy with respiratory vaccines is they replicate locally in the respiratory tract. Unlike respiratory vaccines, enteric vaccines follow a fecal-oral route. What does that mean?
That means if you're not washing your hands very well, and you touch a surface and then touch your mouth or other mucous membranes, that's how it spreads. You can imagine, especially if there are little kids around who are kind of teething and drooling over everything, it spreads like wildfire through houses, and other kinds of settings like daycares and schools, and at the other end of the age spectrum, also can spread like wildfire in nursing home settings. Norovirus is a leading cause of acute gastroenteritis. It results in significant morbidity and mortality worldwide. Again, it really impacts the two extremes of the age spectrum. That's because newborns haven't yet developed their full immunologic potential, and older adults, as you saw on earlier slides, begin to lose it over time.
We have been able actually to demonstrate you can prevent gastroenteritis due to viruses, and rotavirus vaccines are the big example of that. We're looking now to broaden coverage with another important cause of gastroenteritis. It's associated with about 18% of the overall cases of gastroenteritis worldwide. And I mentioned to you that it's really impactful in very young children, older adults, and then also in the immunocompromised. Just like with respiratory pathogens, the immunocompromised population has a hard time clearing these infections and can also suffer from more severe disease. And the burden in older adults is expected to rise over time, again, as society ages and more and more people are in group living settings. What does that mean just in terms of the numbers?
In terms of infections, and I'll talk about the U.S., but you can see the numbers globally as well, there are 20 million infections in the U.S. and nearing 700 million infections of norovirus globally each year. In the U.S., there are approximately 900 deaths and 100,000 hospitalizations with $2 billion of associated healthcare costs. And that translates to about 200,000 deaths that we know of, worldwide, and about half of those occur in children, because they dehydrate so easily, and $60 billion worldwide in terms of healthcare costs. If it's such an important health consideration, why don't we have a vaccine already? Well, this is a complicated virus. It is classified into 10 genogroups, and then 49 genotypes. Like Dr.
Schief was explaining to you, for HIV, given the diversity of the pathogen, like we've seen with COVID-19, given the diversity of the pathogen, one of the challenges is making a vaccine that's gonna cover enough of the serotypes, which by the way, they change over time. You see where I'm going with this. Again, proof of concept with COVID-19 and the ability to change strains and follow viral evolution over time. We hope to protect about 70%-80% of norovirus-associated acute gastroenteritis in young children and older adults. To do that, we are gonna need a multivalent vaccine because these genotypes really vary worldwide. You just heard a bit about some of our proof of concept data in the HIV space with virus-like particles.
We also have a vaccine in phase II development, our Zika virus vaccine, which is made through delivering a sequence that translates into a protein chain that self-assembles into secreted virus-like particles. That's what we're going to do with our norovirus vaccine. They're structurally similar to native virions, and that's important. You may have heard a phrase in biology, structure determines function. We think if we can get structurally close to a native virion, we can induce an immune response that's close to our response to wild type infection. As we've shown with our COVID program, our platform is actually able to pivot. If the evolution of this virus moves in a different direction, we can change the composition to follow that evolution.
You see that iteration in update one, update two, update three on the right side of the slide. We have two vaccine candidates. They're comprising the virus-like particles. In one, we have a trivalent composition, and that's 1403, so get it. It's also followed with 1405, and that's a pentavalent composition. We're gonna test both and see where we can optimally titrate safety as well as immunogenicity, looking of course for immune interference. Like our respiratory vaccines, we're utilizing exactly the same lipid nanoparticle, again, building off of the platform that we've developed. Shifting gears into bacterial pathogens, we are going to investigate Lyme disease as our first bacterial target. Why?
Well, there are 120,000 cases of Lyme disease each year in the U.S. and Europe, and there's currently no approved vaccine on the market. Our strategy is gonna develop two vaccine candidates in parallel, and I'll explain the strategy why. In the U.S., there's one predominant serotype 1, but in Europe, there's a diversity of serotypes ranging from serotype 1 to serotype 7. If out of the gate, we're successful with a heptavalent or a 7 serotype-containing vaccine, happy days. That's the vaccine we'll develop for both the U.S. and Europe. If, on the other hand, there's immune interference issues we need to work through, we can still move forward with a monovalent vaccine in the U.S.
Maybe just to say, the reason why we're really excited about this, bacteria are actually much more complex than viruses. They contain many more antigens. They have a cell nucleus. It actually, though, allows us maybe multiple targets that you can pursue. We happen to know the target in Lyme disease. The outer surface protein A could lead to an effective immune response, that's really also behind our choice of Lyme disease. Let's see if we can develop an approach to address all Lyme disease in the U.S. and Europe. The infection follows a bimodal age distribution again. It's mainly in children and older adults. There are about 35 cases per year in the U.S. and 85,000 cases in Europe.
This infection is known as one of the great pretenders. It can produce a rash. It's the classic target rash. Although I will say many patients can have different kinds of rashes. It's very easily mistaken for other entities. They have this sort of syndrome where they develop fever, headaches, fatigue, and they can get an arthritis with joint pain and swelling and headaches. Longer-term, if untreated, this infection can lead to some pretty significant cardiac dysfunction. I mentioned to you the different serotypes. We have developed seven sequences of the outer surface protein. We know that the serotype 1 would cover almost all of the infection in the U.S., but ideally, we can use the same vaccine in both the U.S. and Europe.
We know that in the past, OspA-based vaccines have led to the induction of high levels of neutralizing antibody levels. The way it works is you inject the human who develops the antibodies. When the tick bites the human and begins its blood meal, actually, the antibodies are able to kill the bacteria in the tick's gut. The tick actually is essentially getting passively immunized from the human being that we've vaccinated. Okay. With that summary and teaser of things to come, I'm gonna hand the floor over now to Arpa Garay, our Chief Commercial Officer, who's gonna talk about commercial opportunities with vaccines.
Jackie. Good morning. As Jackie mentioned, I'm going to give the commercial overview of how we believe all of the vaccines in our portfolio will translate into commercialization. Okay. You heard this morning about the significant unmet needs across all these different disease areas, as well as the healthcare burden associated with them. As a result, from a commercial perspective, we believe our portfolio addresses large target markets. If we start with the respiratory vaccines and looking just at flu, RSV, COVID, and our combinations, we believe this portfolio will grow to about $30 billion a year. Then from a latent vaccines perspective, if you look at the vaccines that we have in our portfolio, we believe they will play in the $10 billion-$25 billion addressable target market.
From an emerging vaccines portfolio, as Stéphane mentioned, there still is significant unmet needs when it comes to infectious diseases. As Jackie just covered some examples of our emerging portfolio, we believe our future vaccines will address important target markets going forward. Sorry about that. I have something stuck in my throat. As we think about just the next two to three years or three to four years, in fact, you see we have multiple potential vaccine launches. Next year, we do anticipate RSV to be launching around the world. We also expect to have a seasonal flu vaccine. In 2025 is when we believe our combination vaccine portfolio will start launching around the world, as well as our next-generation COVID vaccines that Jackie mentioned.
As we go beyond 2026 and into 2027, we do believe our next generation influenza vaccines as well as combination vaccine and our CMV vaccines will come to the market. Sorry, I have something stuck in my throat. As we look specifically at the respiratory vaccines market, we believe 2023, as COVID enters an endemic stage, will be the reset year going forward. In 2024 and beyond is where we believe the COVID market will continue to grow. As we look at 2023, as well as 2024, there's multiple variables that are really impacting the volume that we're expecting in the endemic market. First and foremost, it will be the medical need associated with viral evolution. What are the continued sort of healthcare burdens around the world, as well as associated public health recommendations?
What do we expect from different NITAGs, public health authorities in terms of vaccination recommendations? Last but not least, which we're seeing quite significantly right now, is consumer motivation to vaccinate. We have seen over the last several months a lot of COVID fatigue from our consumers. As you know from a healthcare burden perspective, we are seeing even in the most recent fall/winter season of COVID, we're seeing almost actually more than 2x hospitalizations coming from COVID than from flu. As consumers continue to get educated about the disease burden, as different health authorities around the world continue to update their recommendations, we believe 2023 will be a reset year, growth will come beyond that. From a global market perspective, the way we're estimating the total addressable market for COVID is really based on two key factors.
First and foremost is really looking at flu as a surrogate, specifically in the elder population, so the 50-65 as well as 65+, where we believe over time the vaccination rates will approach flu vaccination rates. For those who are younger in age, we are seeing lower uptakes and believe over time the younger population will not fully reach the same level, thank you, as the flu vaccine. Given the healthcare burden and the number of hospitalizations, we do believe from a price effectiveness perspective, the pricing of the COVID vaccines will be at a premium to flu, resulting in an about $15 billion total addressable market going forward. From an RSV perspective, we are very excited about the data that Christi shared. External estimates approximate the RSV market to be about $10 billion in the future.
You'll see about $6 billion-$8 billion of that total addressable market is coming from the older adult population, which is the data that was shared today. Over time, as we think about where the significant unmet need is, we do believe there is significant unmet need in the pediatric populations. As we continue to grow our portfolio and our indications, that is where we believe the commercial market will expand. As Christi mentioned, we do have the unique opportunity to have one platform and one vaccine covering the entire spectrum of the population. From a flu perspective, this is again another opportunity from a respiratory perspective where the current influenza vaccine market is about $6 billion.
If you look at the chart on the right, what you'll see is the enhanced flu vaccines, as they brought to the market increased effectiveness, they have driven significant growth for the overall flu market. Over time, with the introduction of newer and more effective flu vaccines, we do believe this market will grow to about $9 billion. Again, the introduction of new, more effective vaccines, as well as in the future of combination vaccines, will allow us to get to that $9 billion total market for flu. From an overall volume perspective, what we have seen over the last several years is globally, we're seeing about 500 million to 600 million doses.
We think about combinations that we've talked about today, we can bring increased value to healthcare systems, increase compliance rates, increase consumer convenience, as well as potential increased effectiveness of flu vaccines, which will grow the overall volume of the market in the future. From a latent vaccine perspective, what you'll see here is we have a number of latent vaccine candidates that we believe individually all address very large addressable markets. From a latent vaccine perspective, what's different here versus respiratory, is we are targeting viruses that have very big and long-term consequences, from lymphomas to multiple sclerosis, as Jackie and team have covered. These different areas, as you'll see from the right-hand side examples for both GARDASIL and Shingrix, have opportunities for multi-billion dollar franchises. Two things to note here.
You'll see not only the multi-billion dollar franchise opportunity, but also as you look at latent vaccines, they do have continued growth over time. In the example of GARDASIL, which launched in about 2006, we still continue to see that franchise grow as the market understands the long-term benefits of addressing latent vaccines. Just to look at CMV for a moment, since we're in phase III for CMV. CMV, we do have the opportunity to be first in the market. Again, here we expect the market to grow to about $2 billion-$5 billion annually. We will start with the high-risk populations that Jackie had mentioned around women of childbearing age as well as transplant patients.
Over time, as we think about the potential for eradication, similar to the rubella approach to eradication, as we grow beyond the adult population into adolescence and into younger populations, this is a real opportunity for us to eradicate CMV. In summary, as we think about respiratory as well as latent, we believe our portfolio targets large addressable markets. The respiratory franchise, we believe will be significant and at more of an annual seasonal basis. From a latent vaccines perspective, we do expect that to be more of a long-term growth with multiple multi-billion dollar opportunities.
As we think about launch readiness and getting ready for the commercial opportunities and bringing about seven new launches over the next couple of years, we will have the opportunity to build on our existing commercial and medical infrastructure to be able to launch these successfully around the world. With that, I'm going to ask Jamey, our Chief Financial Officer...
Thanks, Arpa.
To come up. Thank you.
Well, good morning, everyone, or coming up on good afternoon. Thank you for joining us today, either live and in person or on our webcast. I know we've been going at it for a little over two hours, I'll wrap us up here before handing it over to Stéphane for some closing remarks. As all the speakers have noted today, vaccines play an incredible purpose for patients in the healthcare system, as well as the overall economy. They can save lives, reduce morbidity, save healthcare costs, increase the economic output for an individual or an economy at large. That's all wonderful, but I am the CFO, so I'll walk through the business side of things as well, which I'm here to tell you that the vaccines business is an incredible business model.
I'll walk you through what those characteristics look like for us and why we think that we are well-poised to take advantage of the vaccines market. We'll lay out why we think we have a great return on investment. We'll walk you through our investment strategy over the coming two or three years, we'll try to give you a little bit of a lens to what the return might look like come 2027 as it pertains to our respiratory franchise only to show you that return on investment. I think COVID is a great place to start, both from an example from a ROI perspective as well as what the themes are when we look at a vaccines business.
As most of you know, even before the pandemic hit in early 2020, Moderna invested over $2 billion in our platform. Combined with the $4 billion that we invested over the last two years, both in development costs as well as capital expenditures, that led to a terrific economic return. You can see that we've sold over $36 billion in product sales over the last couple of years. Then we generated more than $18 billion in cash, just to give you a simple data point that you can tie to, we have over $18 billion in cash for future franchise investment, at the end of 2022. As importantly, if not more importantly, we delivered well over 1 billion doses to patients across the globe. Not only that, we've set up a long-term tail.
Unfortunately for mankind, COVID, we believe, will be around for a very long time. Fortunately, on the business side of things, though, we believe that that has a long tail from a revenue perspective. The key themes you'll hear today is the speed of development of how we brought this to market, how we delivered over 1 billion doses over a period of two years. It's not on this page, but that platform cost I'll talk about in the future will continue to shrink in any single category. Once you've made the investment in respiratory as an example, the next vaccines will be cheaper from a platform perspective. There is substantial development costs, and that's the investment that we're prepared to make, and I'll talk you through today.
After that, it has a phenomenal return and a long tail from a revenue perspective, and that's what we really want to hammer home today, and I'll walk you through. When we think about any vaccine or any opportunity, we think about three things, and I'll use what we hope to be our next commercial product, RSV, as an example as I walk you through them. First, we think our platform can demonstrate very high efficacy. In the case of RSV, we achieved 83.7% in lower respiratory tract disease as the team walked you through today for two or more symptoms. We want a large addressable market and serve a large addressable market. In the case of RSV, we think just for older adults, that's $6 billion-$8 billion. If you add maternal and pediatrics, that's another $2 billion-$4 billion.
You get to a roughly $10 billion market overall. It's a very, as I already mentioned, it's a very durable. We don't think RSV is going away either. Once you've made that development investment, we believe that we have a very long tail of revenue, and we believe our peak sales will be in the $2 billion-$3 billion range for RSV. We believe that our platform has inherent benefits that will help us capture the vaccines business and help us perform well. Stéphane and Stephen walked us through it today. Stephen mentioned the speed of development. If you look at the big three in respiratory, as we call them, as Jackie mentioned, it's anywhere between one to two years that we can bring a phase I product to through phase III readout.
We talked about flexible manufacturing. I'll elaborate on that a little bit more. Stéphane mentioned how the heart of our internal manufacturing is in Norwood, Massachusetts. Then we've broken ground in three countries across the globe, so we now will have four sites across the globe. We've invested over $900 million to date. There is more to invest, but by the end of 2025, we think that our manufacturing footprint for the respiratory franchise will be permanently set. Externally, we've invested. We have five partners who have delivered for us in the last two years all across the globe, and we've invested over $600 million in them as well. We feel well set up. We talked about high biological fidelity and the ability to do combination vaccines.
Let me just elaborate on that a little bit more. When we think about one shot having two or more vaccines, I think there's two substantial benefits that can come from that. On the left-hand side of the page, we think that it could expand the market for many reasons, but if you use flu as a proxy, there's 500 million-600 million doses per year and a $6 billion TAM. If we have everything in one shot, I think there's three ways that it could expand. One, it's better for payers and more effective and good for the overall healthcare system from a cost perspective. I think it's an easier administration for patients.
If there's one or more that are highly effective, then I think you'll expand the overall reach of combination vaccines, and that $500 million-$600 million could grow to $700 million, could grow to $800 million, and so on and so forth. We believe the market could expand. Subject to regulatory approvals, we believe that our investment in a combination vaccine could be cheaper than a single vaccine. That's through immune bridging studies as opposed to having to do a more expensive efficacy study to prove a vaccine. We think we can do immune bridging to the standard dose. Lastly, I added a fourth benefit to this, and I call it category investment, and this is what I mentioned earlier. We have invested a lot in our platform to date.
You can see until 2020, we invested a little over $2 billion. In the last four years combined for infectious disease overall, not just respiratory, we've invested $400 million. I think for that category, our continued research on the platform side will go down. Development costs will be there, and I'll walk you through that on the next page, but overall, you can pull from what we've built in the overall platform to date when you look at a new candidate. This is the investment that we wanna lay out, particularly on the R&D side. I already mentioned the capital expenditure side. This rounds it out. This is a much more substantial driver of investment for the next three years. We have more to do to round out our respiratory franchise.
We've invested a lot in COVID, we've invested a lot in RSV and in flu. You'll see here a few things. One is the future investment options on the bottom, which we believe total $6 billion-$8 billion for the years 2023 through 2025, maybe some of this trickles into 2026. I think more importantly, you see the spend drivers. You can take COVID and how it peaked in 2022, and then we'll do 1283 in 2023, and then it'll become a nominal amount in terms of the priority you spend. Take RSV. RSV, we began and completed our first phase I trial in 2022. It'll now go up in 2023 as we look at duration and boosting, as we look at maternal, as we look at pediatrics, everything we've talked about to round out the RSV portfolio.
In 2024, it'll go down, and in 2025, it'll be the number three spend driver, and then you can see it go away because the investment has been made. The same is true for flu. The same will be true for combinations, and then we'll get into next-generation vaccines. I think it's this concept that you have to invest early, which we did on COVID, we will on RSV, we will on flu. After that, you have a long recurring revenue stream that is here for years to come. If you look at 2023 for just the respiratory budget, we've already said that our overall R&D is $4.5 billion. If you look at respiratory, that makes up the lion's share of it. It's about 60% of it.
It's two and a half billion dollars. We think that'll be relatively consistent. It might be some puts and takes over the next two or three years, but relatively consistent. It'll start declining in 2026. By 2027, we really just have a maintenance amount of R&D expense. We actually can't even assume a dollar to that. We put it as a percent of revenue, which I'll walk you through on the next page, that depending upon the size of the P&L, you have more or less to invest in it, but we think 10% of respiratory revenue is where we'll hit in 2027. COVID was a terrific return, $6 billion of investment, at least $18 billion in cash.
It definitely generated more than that when you factor in other items, but that's a 3x return just to date. It has a long franchise. If we look at respiratory, all that investment that I just talked about on the prior page, we wanna show what that return can look like come 2027. I'll walk you through the P&L. There's a fairly broad range on revenue or product sales, $8 billion-$15 billion. You can see the drivers on the right. How effective are our vaccines? What's the vaccination rate that Arpa just talked about? How quickly will combination shares grow? We think that is a total game changer, as I mentioned, in terms of increasing the market size.
I would say that even this $15 billion, whether it happens in 2027 or beyond that, the market will continue to grow, in our opinion, for many reasons. One, the combination I talked about. Two, I think the global population will continue to grow. The % of older adults in the overall population grows faster than the overall population growth right now. That will become another driver. This isn't an endpoint. The entire market will continue to grow, as will we. As I walk down the P&L, we've already talked about 2023, our COGS are elevated as we move from pandemic to endemic for many different reasons that we can get into. This year we'll be at about 35%-40%.
We think this will settle out at a minimum at 25% COGS or 75% gross profit. If we're on the higher end of this range, it's more like 20% COGS and 80% gross profit. We feel great about that. I've already talked about R&D being 10% of revenue. You can kind of back into what SG&A is in either of these scenarios. Overall, that gives us a $4 billion-$9 billion overall operating profit with tremendous cash flow generation. We like the characteristics of this business. It's a leverageable cost base that'll be fully invested in by 2025. It's highly flexible from a cost perspective, and then it requires a limited amount of capital.
A reinvestment ratio, for those of you that don't know it, is the amount of capital you spend over your depreciation, and we think ours will be below 0.5x by 2027. In summary, what I hope you take away is we are hopefully building a terrific respiratory franchise. I think we've already evidenced that in COVID, but the big three are next, as well as some of the things that Jackie and the team went through today. We believe our platform is extremely well-positioned to capture and has inherent benefits that would advantage us versus others. Yes, our.
It takes some development costs over the next three years, and then we try to lay that out for you, but we think the return is well worth it and that by 2027 this is a substantial franchise that continues to kick off cash and will hopefully fund the next franchise, beyond respiratory. With that, I'll turn it over to Stéphane for some closing remarks.
Thanks, Jamey. Dr. Schief, thank you so much for this exciting presentation. Team, thank you so much for the great presentation and most importantly for the work that happens every day at Moderna. You only see the tip of the iceberg, and you see how we're excited about it. I just have two slides to close. As you can tell, we are so excited to be able to launch up to six products in the next few years. Of course, RSV should be the next one. As the team said, we are on track to file the BLA this quarter. Flu, we're very excited about flu. Of course, we'll have hoped we made the cases and be able to announce that today. I hope you got from the great presentation that you got today that the data on the Immuno is very exciting.
The A's are very strong. The B's, as we shared with you, we know how to fix. This preapproved study that's going to start very soon is going to enable us very quickly and with working months to get that data, get a single-dose booster, to get that immunogenicity data, and we believe we're still on track to the original plan, which was to launch in 2024. Even if the data had been positive today, we would have missed the fall of 2023 because we have to prepare the BLA, file it, FDA to review it, go to AC at CDC, ARPA-H do all the contracting. It will not have happened by September. The math did not work. We're still on track for a 2024 launch, which was the plan. That's why we're so excited. The combos are coming and much more.
The COVID-19 is a great base for us to grow, but as Jamey showed you, as we looked at the data with the teams country by country, product portfolios, singles, combos, pricing, we think there's something really exciting for us to come there. The platform allows us to keep growing in respiratory, in latent. You saw what Jackie presented to you on noroviruses, Lyme, and there's much more. Andrea and his teams are not standing still. They are working. Jamey showed you the increased research investment. The infectious disease team is going after a lot of exciting opportunities that we think could have a great impact on patients and as a return create value for the company and shareholders.
I think also Jamey, give you a good sense of how this franchise, we believe after a few years of investment, could create very long tail revenues because those respiratory virus are not leaving the planet. I've not seen a serious scientist who believe that COVID is going or RSV is going or flu is going. Unfortunately for us as a species, we're gonna have to live with those viruses forever. As you see the aging of population, and you saw my slide with the T-cell, this is not a good combo for disease. So we believe the financial characteristic of this respiratory franchise and the beyond that of infectious disease portfolio is really exciting. We believe Moderna should be a key vaccine player in the next few years and for decades to come.
I know it's a vaccine day, but I have one slide that is not about vaccine, just for micros. Because this franchise and this platform we've been building for 10+ years has always been because we believe it's a new tool to go and invent new medicine. It's a new age of medicine enabled by this very exciting platform. You know, for the first nine years of Moderna, I went around saying, "I believe mRNA will change the world." Some people mocked me. Some people called me names, including the media. Some scientists thought, "Are you crazy? This will never work." We put our head down, and we did the work. In the spring of 2020, I said, "I believe we'll have a vaccine working by the end of the year." People called me names.
Some pharma CEOs went on TV saying it was irresponsible to the world to say that we could have a vaccine approved by the end of the year. One other thing I would like to tell you today is I believe the impact we're gonna have in oncology. What a lot of people are gonna know us for in three, five, 10 years. Some people will forget in three, five, 10 years what we did with COVID, what we're doing every year with a combination vaccine they'll get at their CVS or at the doctors, because the impact I believe this company and this technology is gonna have in cancer is gonna be so profound. I can't wait for you guys to see the data at ASCO, which is just this weekend, just a few more days of waiting.
The team is working really hard to get the phase III for melanoma up and running and to get with our colleagues at Merck the LUNG study up and running, again, phase III . We have many more studies that the teams are working on. As we get that finalized with Merck, we'll share those studies. As we've said before, the reason we're increasing so much the R&D budget this year is we believe that the data we have seen in oncology. We'll warrant that investment. We are very pleased to partner with Merck. As Merck has shown with KEYTRUDA, when you have a great product in oncology, being aggressive at investing in clinical studies pays off, first for patients and two, for shareholders. That's exactly what we're gonna do with the personalized cancer vaccine.
Rare disease, we continue to stay very excited from what we are seeing in the data. We're now moving to expansion phase of a study on PA because of the data that we have seen. Our colleagues at Vertex are enrolling, as we speak, kids that do not respond to their drug in cystic fibrosis because too many mutation on their genes. We believe on inhaled, which is a new technology, a new way to get amount into the body, as very interesting proposition for the patients, and we look forward to seeing that data. It should also come pretty quickly because it's in patients, so we should see that data pretty soon. In cardiovascular, not but not least, the number one killer in the world, we are in phase Ib study in heart failure patients.
Again, we should be able to get the data on Relaxin pretty quickly. If it's positive, again, we'll be very aggressive on timelines to move very quickly to pivotal studies. As you've seen with this platform, we can do things quite differently. We have ability to work the disease that you cannot go with recombinant, with a level of efficacy that is not doable with other technologies. The speed is gonna keep increasing. The speed is already amazing, we are not done. Our team are investing in IT. Our team are investing in more tools in robotics, in AI, to keep shrinking and shrinking and shrinking the time. When you take a five, 10, 20-year view on things, every week you can save is gonna have a huge value creation for patients and as a consequence for investors.
We're very excited about where we are. We'd like to do today is to please welcome the team back on stage so that we can take your questions I know.
Oh, starting at you.
Okay. Thank you. It's Michael Yee from Jefferies. Two financial questions, if I may. On the 2027 guidance, if I may, I think a lot of people would ask how the heck you could forecast out to 2027, particularly given COVID. If I may even push a little harder, people don't even have a lot of confidence about 2023 COVID and where the numbers are going. Could you just express your confidence level in 2023 and vaccination rates and what part of COVID is in 2027? On the expense guidance, I think I heard you say $4.5 billion, which is what you're doing now. Did you imply that $4.5 billion is sort of the range going forward, and that's where it is?
Can you just talk to again where the expense guidance is going? That's critically important because people are trying to figure out profitability over the next five years. Thank you.
Yeah. Thanks, Michael. We'll start with the forecast for 2027. Of course, it's difficult. Of course, 2023 is difficult, but we feel like this is our best estimate right now. If you walk through what Arpa talked through, the $30 billion market that we play in is a 2023 number. The $15 billion in COVID, there's obviously some puts and takes of that. You could say that's $10 billion-$20 billion, and we can go through the math on that, but it's $15 billion. We think RSV will be about $10 billion in total, and then flu is $6 billion. That's at $30 billion, and that's today. That'll grow over time, as I mentioned, with population growth, with inflation, maybe with combinations, et cetera, but let's just say it's $30 billion-$32 billion.
The low end of that range is about 25% share. Even if you were to knock COVID down, let's say COVID is a $10 billion marketplace, RSV is $10 billion, and flu is $5 billion or whatever, that's a 33% share. We feel pretty comfortable. That's before you get into combinations as well. That's on the low end. On the high end, it could be a $40 billion marketplace. You could say COVID might be $20 billion. As Arpa mentioned, we believe that 2023 will be a low point, and then it'll grow over time. If it's $40 billion, then $8 billion on the low end is 20% share. We feel very comfortable with our vaccine efficacy, what we have, that 20%-33% market share is a fair number on the low end.
That $15 billion, as I mentioned in my remarks, that we think that's coming. Will it come in 2027? Can't promise that. We will launch the combinations as we mentioned, in 2025, and that can expand the market and hopefully expand our share, and if our efficacy is there, then we think that we could continue to expand. Whether that's 2027 or 2028, that P&L, we believe, is coming to Moderna. That's that. On the R&D side.
2023.
The separate question on 2023? We didn't guide anything on 2023. The only thing we've said on 2023, as you know, is, the $5 billion overall signed APAs and $2 billion in the first half, which we feel we're still very comfortable with.
Mm-hmm.
On top of that, which is often lost because that's not our guidance, our guidance is not $5 billion, it's just what's contracted. On top of that, what we believe we'll have orders in the United States, we believe we'll have orders in other various countries, including Japan and Europe, et cetera. That will add on top of that $5 billion. We're not guiding a number, but we are confident in what we've said already.
Yeah.
R&D side. R&D side, $4.5 billion overall for 2023, $2.5 billion is respiratory. We're not guiding 2024, 2025 around what the total R&D is right now. We're saying that respiratory needs to be at least two and a half. Obviously, we have a lot of exciting things going on with PCV and rare and other areas. PCV is probably one of the bigger, you know, variables or wild cards, I would say. I would anticipate it to go up, maybe not at the rate that we've been going up, which has been 50% a year, and I'll let Stéphane comment more, but that's what I'd say right now. I don't know if you'd add anything else to that.
Yeah. Maybe just to add one thing to Jamey's comment on the market sales for combinations. The piece we should not forget in combination is the value being created for the payers because of higher compliance. A lot of our payers are worried, are people gonna get three shots of winter flu, COVID, RSV in that elderly population, which is the key part of the market. If you talk to the payers, today they already pay the pharmacist or the doctors the cost to inject the vaccine. When you talk to them and you realize that they are willing to pay a premium to even the sum of a part, because how much we're gonna be saving on administration costs. We have a value of compliance, the cost saving on administration.
When you look at this, there's another element to the market, which is the high case scenario of that bar, which is basically the mix between monos and combos. Clearly, on the high case, there's much more combo mix. With the combo, we believe has the potential to have much higher pricing. When you look at that plus aging population in that timeframe, around the world, that's kind of drive that numbers. We're very comfortable with these numbers.
Hi, guys. I wanna ask about the PCV, considering that you have the data coming up at AACR.
Yeah.
I'm wondering-
Great question.
How much do you think the hazard ratio or clinical benefit can improve past a year? Then related, how much follow-up do you think that you'll need to be able to file for accelerated approval based on the phase II data? If that follow-up can come at ASCO or ESMO? Thanks.
Um-
It's a vaccine question.
It's kind of...
Okay, ask it.
Yeah.
PCV question. A couple of questions there. Let me try and pull them apart. We haven't shared the data yet. We will on Sunday about what the shape of those curves will look like. I don't wanna get too far ahead of that. A feature of immune therapies are obviously what you wanna see is durable benefits, and really over time, separation of those curves that has as a feature of it, enriching hazard ratios as data matures. That's one thing to look for when we present our data in AACR. Obviously, the 44% reduction in the rate of relapse or death signals that there's a pretty exciting trend there.
You know, we would hope as people look at it, that they'll see that same trend towards strengthening responses or differences over time. Look at the data yourselves. As far as, you know, the possibility of accelerated approval, it's really too early to, you know, go into those sort of speculations. At this point, we are still following that phase II study ourselves. We are working hard to start a phase III study because in the current environment, we do believe we have an obligation to demonstrate that we're working hard towards enrolling that phase III study before you'd even approach and ask that kind of question. That's where we're focused with our partner, Merck, right now, get that phase III confirmatory study up and running.
As we follow over subsequent analyses, whether they're in June as suggested or as we move through to R&D day in September or towards the end of the year, we'll really be following this on an e-event driven basis. We'll know when we hit certain milestones in terms of the number of events, that it's appropriate time to conduct that analysis, and we'll provide updates. Obviously, our fingers are crossed that we'll see continuing deepening of those responses and ultimately, even more compelling data.
Great. Thank you. Ted Tenthoff, Piper Sandler. I have two, if I may. Firstly, picking back up on Michael Yee's question. When it comes to the negotiations that are ongoing for Spikevax and COVID this year, how big of a factor is this speed or this speed to be able to produce vaccines? Do we think maybe market shares can change from what we kinda saw before as it becomes this negotiated market? Then I do have a question for Dr. Schief, if I may as well.
Sure. I'll take this one on timing. Thank you. As you heard from the VRBPAC meeting, it seems that the agency is gonna do a strain selection toward end of May, early June, versus, as Jackie reminded you, was June 28th in 2022. With our June 28th date, we were still in pharmacies label the weekend, which is like a two-month timeframe to develop the vaccine. I think what the buyers are expecting for negotiation right now is that we'll be able to deliver the same thing, and we'll be ready for label day, which is what they need, so that people at high risk can get vaccinated as they come out of the summer. I think that's what the market expects, which I think is a positioning that only the mRNA technology enables.
think about where the market is going, you start think about combination, where you can do the same for flu and wait much later in the season to be able, as Stéphane and Jackie talked about, is customizing product potentially by market or regions, because we can do that. You know, going over we have a plant that we're building in the U.K. If the U.K. wants a different strain than the U.S. strain, they can tell us that's what they want, and we can still in the summer, based on the EP going on in the U.K. and the surveillance we are doing, get that data for them.
We think that this ability to go fast, and if you look at the OriCiro acquisition we made in Japan over Christmas, we think we can even shrink the timelines in a few years when we get that through the GMP setting and through the regulators in terms of changing the manufacturing process to shrink that even further. I think will allow us to keep the leadership there and to really keep this combination product really as an mRNA-only opportunity.
Yeah. That's really helpful. I appreciate it. Dr. Schief, if I may ask you a question. I really appreciate the work that you're doing, and that was cool early data, the thoughtfulness and the progression of how you're going here. I'm wondering that as you achieve broadly neutralizing antibody proof of concept with the mRNA vaccines, including lower doses as you're doing now
How do you really interrogate these multiple antibody classes simultaneously or in combination? It really becomes sort of a, you know, additive approach, I guess, in this combination. Is there a way to do that in order to maximize vaccine efficacy? How do you envision doing that?
Yeah. Thank you. Is this..
Okay. Thank you for that question. The nice thing about the strategy, as I was saying, is that we're looking for specific sets of genes. I mean, we know what the antibodies look like, so if we just sequence the B-cell receptors at any stage, even if it's a combination, we can see, oh, we got VRC01 class, we have BG18, we have 10E8, we have different things. There we can evaluate the combination. Also, we will hopefully be able to do it at a serological level. If we start to get bNAbs, and we start to see broad neutralization against panels of viruses from sera, we know what certain classes, we know, sort of the strains that they neutralize. You can get a fingerprint for a certain class.
You could see if you're getting three different ones, you should see the combination of those fingerprints in the sera. There are several different ways to tell. Thank you.
Hi, Lisa Walter here from Luca Issi's team at RBC. Just a question for you on the flu data today. Can you clarify whether the interim look for efficacy for flu was for superiority or non-inferiority? If it was for non-inferiority, how do we rationalize that you did hit on superiority for immunogenicity for the strain A in both the Northern and the Southern Hemisphere, but that is not translating to at least a non-inferiority efficacy at the first interim look? Thanks.
Thank you for the question. It's great clarification. First, the study was designed as a non-inferiority efficacy study, and so that's what we're looking for. The first interim analysis of efficacy was a bit of an early look, right? It wasn't powered with the full number of cases that you will have in the final analysis. As a result of that, you leave yourself sort of looking to see whether or not there's evidence of really superiority early. In fact, in order to hit non-inferiority at that early lower case number, the point estimate for efficacy would have had to been, you know, trending towards superior, almost 20%.
That's something you'll do just to see as an early look as to whether or not we've demonstrated non-inferior efficacy technically, but because the vaccine was performing even better than we thought. Given that we didn't see that in this, in this event, because ultimately, as we've talked about with 10/10, it is targeting a non-inferiority profile against quadrivalence right now, we'll proceed to that second instance or the follow-up efficacy analysis at the end of season with more cases and see whether or not we achieve the more appropriately powered endpoint of non-inferior efficacy.
As it relates to the neutralizing titers, it's a version of the same answer, which is, again, because we were looking at a very small number of cases in that first interim analysis, ultimately, we believe the study was underpowered to really provide a clear signal on the performance of mRNA-1010 as a vaccine relative to a licensed comparator.
Is there.
Go ahead.
Sorry. You might just wait for a microphone.
You might want the microphone.
Okay. No, I'm fine. Thank you.
Sorry. Thank you. Just for the next interim cut, is there a set number of cases that you need to hit?
At this point, we expect to do an end of season analysis, end of flu season. We don't have a specific number of cases that we expect to hit. The study itself would be put powered to go up more towards 400 cases in the future if we choose to continue it. Again, right now we're looking for an end of season analysis for this current season.
Okay. Thank you for taking the question.
Good morning. This is Elizabeth Webster from Goldman Sachs, from Salveen's team. Question on study P303. When may we see the first data here? If you could remind us of the specific updates made to the candidate versus the original mRNA-1010. On your work around classifying how differences in the immunization history of the study populations could have contributed to differences in responses, does this imply that there might be some level of priming required? Just wanted to get your thoughts on that.
Good questions all. I'll kick to Jackie on the P303 immuno study. I'll just say first, we haven't disclosed for competitive reasons what the updates are to the 10/10 product. We do have a degree of confidence, a good degree of confidence, as we said previously, that it will achieve non-inferiority and actually will improve upon the B strains we've seen. In fact, if you look at the data that Raphael summarized, even in the P302 study, we were seeing you know, titers that were consistent with non-inferiority against B, so we're improving on a good base. Do you want to just give a sense of the P303 study.
Sure. Sure.
I don't know if you're on.
Is Jackie on the team?
It is on.
Yeah.
I can project. I've been holding back a little bit. The P303 study actually is designed very much like the P301 study. The thing about influenza is that the vaccines have been with us for a while, and the regulatory agencies have issued very clear guidance about what you need to do to qualify for different regulatory paths of approval. You'll see data analyses come out of that study that look really similar to what you've seen from P301. In fact, when we publish the detailed P302 immunogenicity data, they look very similar as well.
You were asking about priming and about whether that could be playing a role. I think that's a bit of the story that Raphael was telling this morning. You know, anytime you see results that you didn't expect, the first thing you do is dig deeper and try to understand why you're seeing what you're seeing. We noticed right away that the population in Australia was very different than the other Latin American populations. There are a number of reasons for that, but one reason is that in Australia you're more likely to have gotten a previous seasonal flu vaccine. You know, again, flu vaccines change yearly over time, so these specific strains can have an impact.
As Stéphane mentioned, there are some upgrades to the vaccine that we're not gonna discuss today, but that may also impact in the future. I'm fond of saying that people are complicated. This comes from working on the D side of R&D. In research we work with mice. We tell them who to breed. I mean, you know, there's not a lot of variability in those mice we use. People on the other hand, do all kinds of things out in the wild. We often see results that you have to dig into a little bit more. Priming may be part of it, but there's also a possibility that that's not all of it.
I could just build on the P303 question too, just a little bit. Jackie pointed to, for those who aren't familiar with those details, that was a study run last year. P303, the immuno study, is really an immunogenicity study, right? We're gonna be looking as a primary endpoint at day 29 or one month after boost with a flu vaccine. That is data in the case of the P301 that Jackie was referencing, that was a study that really enrolled mostly in July and August of last year, and we were looking at the, you know, full six-month, the data at the end of the year, that year, the immunogenicity results.
We're doing this a little bit earlier in the year, actually we're gonna be looking at a relatively early time point, that day 29 endpoint. We think that there's a possibility that we'll be looking at that immunogenicity data, we would hope, in the fall of this year or towards the end of this year. That's why we have some confidence that if we see what we expect, in fact, if we see what we just saw in the P302 study, that that would support an approach for an accelerated approval following the well-established guidance the FDA has laid out for that approach. That's kind of our sense of timing and why we think we are still on path for a launch of ten-ten subject to data and regulatory consultations, but a launch of ten-ten next year.
Hello. Hi. Hi. This is Xu on from Gena Wang team from Barclays. We have two sets of questions, one on flu, one on RSV. On flu, can you or do you still plan to file with the current data on accelerated approval for ten-ten?
I think that I would point to our base expectation at this point is still to file for accelerated approval on the P303 results that we just talked about and launch the product next year. There are two other possibilities. They would be subject to data and consultations with regulators that haven't happened yet. One possibility is that the P302 study, the efficacy study that is still ongoing in a subsequent analysis demonstrates efficacy. If that's the case, then actually that would be the basis of a full approval filing. You know, at the end of the season we'll conduct that updated analysis and update if we're there. You know, as we've kind of accrued most of the cases, that probably is not the base case assumption that we have at this point for this year.
The other is what you proposed, which is the combination of the current phase III results, the P301 and P302, would that suffice? Again, that would be subject to continuing to dig into that data in a consultation with regulators about how they would view that. We haven't had those discussions, and again, I think our focus as a company right now is on the things that we know we can control and that are well precedented, which really is this phase III, P303 study we just talked about on the timelines we just talked about, and launching next year. None of the others would likely accelerate that launch for the fall of 2024.
For RSV, just want to confirm, you have not observed any serious adverse events in your trial. Sorry, I know you don't have the GBS. Have you observed any other immune-mediated demyelinating conditions in the trial?
Maybe just to clarify what Christi was reporting to you. This is a trial in adults over the age of 60. We did see serious adverse events in both the mRNA-1345 and the placebo group. Rates were balanced, frankly, I think we'd have some concerns about our safety monitoring if in that age population we hadn't seen some serious adverse events when there are 37,000 individuals that we've enrolled. In terms of acute demyelinating events, yes, we have not seen Guillain-Barré, we have not seen other demyelinating events, including ADEM, or Acute Disseminated Encephalomyelitis.
Thank you.
Thank you. Simon Baker from Redburn. I've got a lot of questions, but I'll try and restrain myself. Going back to the mRNA-1283 data, you pointed out that the reactogenicity was comparable. In the past there's been a feeling that reactogenicity was linked to chain length, and that would suggest that's not the case here. Your thoughts on that and the relevance, and the reason I'm asking it is if there isn't a clear link between chain length and reactogenicity, and in light of the science paper that was published in January, what are your thoughts on a universal flu vaccine encoding for 20 A and B subtypes? Moving on to the financials. The outlook for 2027 you gave Jim is really helpful.
The COGS range of 20%-25% makes a lot of sense. In that context, the COGS for guidance for 2023 of 35%-40% or 30%-35% ex royalty seems a little bit high. I just wonder if you could give us a bit more insight into the moving parts for 2023 relative to that 2027 outlook. Thank you.
I have to say, it's like you're a plant sitting next to Raphael with that 20-valent flu vaccine. I'm sure he's... I can see him grinning, thinking like, "Of course, why not?" Look, I think on the, on the point of, react to Jackie, I'll invite you to comment, but as it relates to the platform science on it, you know, we have, we have generally seen that reactogenicity isn't related necessarily to construct length or even dose level as you look at a massive mRNA, but more to the on target immune response that you're seeing against the antigen. In that sense, you know, it maybe isn't, as surprising.
As it relates to how many antigens you can get in there on, you know, Raphael already talked about the fact that he's got an 8 valent, if you count the neuraminidase antigens, an 8 valent flu vaccine. We will look to continue to explore that. At this point, you know, we haven't yet hit a limit when it comes to antigens that are well-tolerated that we can get in there. At some point, we of course will. We can't go all the way up to 20 without some risk, I'm sure. Jackie, anything you'd add in terms of the reactogenicity data for mRNA-1283?
I think you've basically covered it. Maybe the one thing I will say is that in mRNA-1273, we did make an attempt to look at whether reactogenicity was linked to the level of immune response. I will say that link was actually there, but it was really weak. I think, again, people are complicated and respond to things differently. The vaccine platform has been consistent in the reactogenicity pattern we see. The magnitude actually does vary between programs. I mean, with all of the caveats about comparing cross studies and so forth. I think the antigens and as Stéphane said, the on target immunity is also playing a role there. We'll continue to research and look.
In terms of the COGS question, it's a great question. Maybe to make it super simple, I'll point you to 2022. If you look at 2022, our COGS as a percent of revenue was 29%. Let's round it to 30%. Half of that was waste. If you look at what we wrote off from an inventory perspective, we wrote off $1.7 billion of inventory. We had $800 million of unutilized capacity out there. When we say as we transition from a pandemic to an endemic, that basically means we have to get through that waste. What we provided for in this year's forecast is a little bit more of that. We still have a substantial amount of inventory that we assess all the time and believe we can utilize.
Should we not be able to utilize because of any kind of demand issues or otherwise, we provided for a little bit, an excess amount of waste remaining in 2023. We would hope that starts to drop in 2024 and 2025, and that by 2027, we're through all that. Waste should be 1% or 2% of COGS, not 15% of revenue, not 15% of revenue. That's why 2023 is still elevated.
Hi, this is Alex Hammond on for Geoff Meacham from Bank of America. Thank you for taking my question. How does Moderna weigh capital allocation and clinical investments versus profitability? Should we expect any near-term M&A, and have your interest changed in this space? Thank you.
You wanna. If I heard the question, it's on capital allocation versus profitability, and then has our outlook changed? Maybe I'll start with the latter. Our outlook hasn't changed. We still have the same capital allocation priorities. We've been very disciplined about them. First is to reinvest back into the business, as evidenced by our R&D, investment into R&D, as well as capital expenditure. We laid out what the investment that we're gonna have to make over the next three years. The second is business development. Most of that comes through collaborations. You asked about acquisitions. We had our first small one that Stéphane just mentioned in OriCiro. That was less than $100 million. We don't anticipate or foresee any substantial acquisitions out there right now.
I think if there's any, it's probably more in that smaller range. We are seeing a good pipeline for collaborations. I think we've announced four or five in the last, you know, three or four months actually. That's number two. The third is to return any excess capital to shareholders, which we've been very disciplined about. As we came into the year, we had $2.8 billion of remaining authorization on our $3 billion for share buyback. We continue to look at what our forecasts are and what our excess capital is, to the extent that we believe it's there, we will return to shareholders. That's the prioritization hasn't changed. As it pertains to versus profitability, obviously a very difficult question for us. We don't take losing money lightly.
That is not hopefully our base case. Our base case is to hopefully make money. That said, the market is relatively unpredictable, to Michael's question earlier, particularly on COVID as it's sitting right now. We talked about the $5 billion floor we have in terms of assigned APAs, and we hope to win on top of that. We believe it's the right thing to do for long-term value creation. If that means, I've said this before to people, that if that means that we have to use, I'll say $2 billion, $1 billion in loss plus $1 billion in capital expenditures, that's $2 billion on $18 billion of cash, we think that's the right move. That's the fortunate position that we're in right now, and we hope to continue to be in in 2024.
If the same situation presents itself and we still get the same excellent results that come out of RSV, PCV, PA, COVID, I mean, we've got a lot of success here. I think we think that the best thing to do is invest that back into the business.
Yeah. Maybe just to add to Jamey's answer, if you can hear me. I think 2023 is a very odd year because we have only one product
We are expecting to have RSV and flu in 2024, such mean more sales. The $5 billion is not our guidance. It's, as our past quarter, the floor. Those are the signed contracts. As you know, this number assumes nothing in the U.S., like we don't sell a $0.01 in the U.S., which we think we will sell product in the U.S. in the fall. It assumes no new contract in Europe and assumes no new contract in Japan. That's the $5 billion just to calibrate it. As Jamey said, we're comfortable with $2 billion for the first half of the year. I think 2023 was really the situation whereas we had to understand the move to endemic. You know, I've never managed a business going from pandemic to endemic in my life. I don't think anybody in the room has before.
We just wanna be cautious 'cause we don't want to not make our numbers. There was the PCV data. When the PCV data came, you guys will see some of it on Sunday, we look at it with the team, we look at it with Merck and with the board, we're like, "This is not the moment to be shy." We have $18 billion in the bank. We believe, I think KEYTRUDA is a great example of value creation. We believe we can do something very important with PCV for patients and for investors. We say we're gonna invest what is required to maximize the value of PCV to patients and investors starting this year. We are investing a lot.
We have to scale up manufacturing, which goes into R&D costs for when it's for phase III. As you recall, we had only made 200 worth, 200 patients worth of product in the phase II. For just melanoma and two phase III, we're talking thousands of patients, and we want to do many more studies than that. We're also ramping up manufacturing, which is part of the R&D investment. We think, as Jimmy said, it's the right thing to create value. Our goal here is to create return for shareholders by creating value. 2023 might not be a great year in terms of how our P&L look like, but we think it's the right thing to do to create a lot of value in the mid to long term.
Yeah, Hartaj Singh with Oppenheimer. Just got two quick questions. One is, just Jamey talking about, you know, your assumption in 2027. You know, your competitors, for example, in COVID-19 vaccine space, they mentioned that they have a majority market share in the U.S., ex-U.S. Some people, many studies might argue that you might have a slightly better COVID-19 vaccine, right? How do you think of market share going forward, even with all the other vaccines that you're hopefully gonna be launching? You planning on being first to market, best to market, combination of both? How to think about that? How does that play into your assumptions? I just got a very quick follow-up on reactogenicity question from earlier.
Yeah. I can take a stab at this one. You're correct. As far as I'm aware, most, if not all the real-world evidence data have shown that consistently the Moderna vaccine performed better in terms of hospitalization and deaths. There are some countries where we have a leading share today, take the U.K., take Switzerland. Some countries have wanted to use that differentiation to drive clinical outcome, and they have pushed nationally. I've heard from, for example, Swiss investors, them being at pharmacy and the pharmacy spending half an hour switching somebody who was on Pfizer to use Moderna. This is an anecdote, but it shows in the market share. In some countries, health officials have decided during the pandemic that they did not want to differentiate the vaccines. You guys read scientific papers, some doctors read scientific papers, not all of them.
One of the work we're gonna be doing in the commercial team and the medical team is to continue to get the message out as we can do that as we move into commercial markets.
Thanks, Stéphane. Just a quick question on reactogenicity. on just the absolute amount, you know, that you're giving to patients. You know, 25 micrograms versus 50 versus 150. Thinking forward to the combination vaccines, Stephen and Jackie, is the goal to bring that absolute amount down while getting the combination vaccines in? I mean, how much does that matter to the reactogenicity profile? Just the absolute amount of product you're giving. Thank you.
I'll take a stab and then let Jackie actually build. Look, I would caution us to think too much about the mass of the dose. Our goal is for sure to optimize the overall profile of combination vaccine. You wanna make sure that you maintain the expectations for efficacy, and you wanna make sure that you have a really good tolerability profile and obviously always safety. You know, the RSV data that was shared, if you look at it, that's a 50-microgram dose, right? That's the same dose that we're talking about with COVID boosters or other things. It's clearly not the mass because at that level we're seeing really good efficacy, but a very different reactogenicity profile, one that really is quite comparable to placebo, maybe 1% or 2% on the grade three is different.
That's why I think it's probably not just mass, Hartaj. I think it is about actually interrogating biologically how those antigens form together. What's the optimal reactogenicity profile from a clinical perspective? I don't know, Jackie, if you'd build on that.
I really have nothing to add other than, I think each program has its own unique facets. I mean, there is a certain contribution of dose. We know that, in the COVID program, for example, we studied a 250 microgram dose level. We stopped it. In CMV, for example, we were able to go up to 300 micrograms and didn't have to stop the dose level. To the extent that there is some degree of dose ranging, yes, things like mRNA-1283 that we can potentially give at a lower dose are desirable because they may be able to allow us to put additional antigens in the vaccine.
It's not really the only determinant of reactogenicity, and that's why I think the data that we generate are so important 'cause each product is slightly different.
Hi, Evan Wang from Guggenheim. Just a question for Stéphane. I know you said in three to five years you may be known as a cancer company.
You've laid out some pretty big goals for vaccines. I guess longer term, could we see the cancer opportunity being larger than this vaccines opportunity?
I mean, you guys can do math much better than I can in terms of the size of the oncology market, how the aging population and immunotherapy, it's growing. We believe the way our product works from a mechanistic standpoint in terms of educating T-cell is very, very powerful. We believe that we're going to build a great vaccine franchise in terms of a cancer vaccine franchise in terms of oncology. When you look at the just the size of immunotherapy market today and what is projected to be in five or 10 years, those are pretty big numbers. Some products are going to go generic in the meantime. Could we end up having a material share of oncology markets? We believe so.
Hi. Thank you. This is Serena, of Wells Fargo here from Mohit Bansal's team. I wanted to ask about the RSV vaccine. kind of given how differently each company has defined, their endpoints based on signs and symptoms, can you help us think about how to compare the reported vaccine efficacies and what differentiates, mRNA-1345? Also on safety, kind of given the delta from placebo, just how you would compare 1345 versus GSK and Pfizer's? Thank you.
Right. Well, again, I want to really caveat taking different studies, different populations, and comparing them, especially when Reacto is measured differently. Different companies not only look for different endpoints, they look at different scales for the same endpoint. I would really caution against direct comparisons overall. That said, I would say that the way we addressed vaccine efficacy was more similar to the way Pfizer has addressed vaccine efficacy. The strength, I think, of that kind of case definition is that, first and foremost, it relies on RT-PCR, so identification of the pathogen. Secondly, it clearly defines symptoms that we know are statistically associated with RSV and the presence or absence of those symptoms there.
I think, what's exciting about our data, is the ability to protect against the lower respiratory tract disease and, you know, as was presented at the recent RSV Congress, we had one hospitalization in the study. It was in the placebo group. We're going to expand on those data, coming up. I'm not going to steal my thunder on Sunday when we present in Copenhagen. Just to say that I think, the maintenance of high levels of protection, so, 83 and 84%, regardless of 2+ or 3+, really implies that we're achieving the high level of protection even in subjects that have fewer numbers of symptoms. I think that, protection, severe, more severe and milder disease actually, really speaks to the strength of maintenance of efficacy.
You'll see more about even milder disease on Sunday. I hope you pay attention there. I don't know if there's anything anyone else wants to add about it.
That's well said. I think we're really optimistic about our profile, but we'll wait for the data in return.
I think that's it for questions.
Great.
Thank you very much to the.
Super. Well, thank you very much, everybody, for joining in person or live. We look forward to continuing the dialogue. Thank you. Have a great day.
Thank you.