Sanofi (SAN) Earnings Call Transcript & Summary

All right. Okay. Wow. Yes, it's really lovely to see such a crowded room. And if I could ask all of you, if you could just try to really put all your luggage a little bit under the chair or something. We just want to make sure that we have aisle free. All right. Good morning, good afternoon and good evening to everyone. Welcome to the Sanofi Vaccines Investor Event, streaming live from London. Thank you for joining us and spending the next 3 hours with us to discuss our Vaccines business. We have divided the event in 2 parts and have planned for a 20-minute break in between. If you're following us online, you can remain connected to the same Zoom link for both sessions. I would like to start off with 2 more housekeeping details. First, you can find all the slides to this event on the Investors page of the IR section of the website at sanofi.com. And second, each part will conclude with a question-and-answer session. And for that, we would like to ask you that you limit your questions to no more than 2. We aim to take questions from the room here in London and also from those who are following us live on the webcast. So if you do ask your question here, please identify yourself and use a microphone. And to participate via the webcast, please click the Raise Hand icon at the bottom of your screen. And you will be notified when your line is open to ask a question. And at that time, please make sure you unmute your microphone. Now moving to Slide 2. I would like to remind you that information presented in this call contains forward-looking statements that involve known and unknown risks, uncertainties and other factors that may cause actual results to differ materially. So I refer you to our Form 20-F document on file with the SEC and also our Document d'Enregistrement Universel for a description of those risk factors. So now let me take you briefly through the agenda for today. Paul Hudson, our Chief Executive Officer, will start with opening remarks; and followed by Thomas Triomphe, Head of Vaccines Business Unit, who will share the Sanofi vaccine strategy and the road map to deliver the guidance up to 2025 and our ambitions up to 2030 with a focus on our pipeline. And then Thomas will be joined by his vaccines team to present an overview of the RSV and Influenza Franchises and the remarkable protection of our vaccines. This will be followed by the first Q&A session. And after a short break in the second part, we will turn to our new growth areas. The vaccines team will present our pneumococcal and meningococcal programs, and we'll share the work in progress on mRNA. Now for the New Frontier section, we will welcome an external speaker, Dr. Geisler, Professor of Medicine and Epidemiology from the University of Alabama at Birmingham, who will provide his perspective on chlamydia and its consequences. Then the Sanofi Vaccines team will present our chlamydia program as well as our active program, and then we will close the event with a second Q&A session. And with that, I would like to hand over the call to Paul.

Thank you -- well thank you, Eva. One of our best forward-looking statements I've seen to date. Thank you to everybody for coming today. For those not in the room, thank you for connecting. It's a small room, and you can see the money has been invested in R&D. Thank you for the organizers for the fish and chips to make me feel like it's home. So we're already a great start to the day. I'm really excited about what the team will share with you. I'm really excited for those that were studious enough to go back and look at 2021 and to read the transcript and to see whether what we said would come true would come true did actually come true. What we predicted would happen in the markets, particularly with mRNA, whether it did in fact turned out that way. We like to believe it will and you should hold us accountable today for the comments that we made in '21. And therefore, you should have confidence in what we share with you today is also something bankable about what we think about the future. So please bear that in mind with straight, and we believe in what we're saying, and you should be able to bank it. They gave me 4 minutes to be able to tee up the entire company and the excitement. And that's okay. We're making tremendous progress. Back in '19, we highlighted some very important moments for the company. We said that in the future we'll be EUR 10 billion -- greater than EUR 10 billion for Dupixent. And in fact, this year will be greater than EUR 10 billion in a single calendar year. Incredible progress. We raised eyebrows then. As you know, and now people raise their eyebrows when we don't announce an even bigger number. But we'll get to that, I'm sure, in good time. We said that we'd deliver outstanding vaccine performance and high mid-single-digit growth, we did and are. And we said that we'd prioritize the pipeline. We've redistributed more than EUR 2.7 billion so the pipeline, and the business reallocated it over these future years alone. So our transformation is underway. As it goes, we laid out sort of what we thought we would do. I mentioned some of this already, including the BD and M&A deals, the things we're exceptionally proud of, improving the profitability. And more recently, I shared more publicly our commitment to AI. While you may or may not be interested, while you may or may not understand AI, you should know at least that it unlocks significant productivity and resource reallocation opportunities for us in our company to go to the next level. It's perhaps the next big disruptor to be able to allow us to, a, target better in R&D, but to reallocate resources to do that more efficiently with a higher probability of success. So it's not just optics, it's not just vanity, it's real work. 22,000 people out of our 91,000 have access to AI on a daily basis. 9,000 make better decisions, we believe, every day because of AI-enabled opportunities in our company. I think we're the biggest AI-scaled company outside of tech anywhere in the world, any sector. So we made tremendous progress. And whilst the finances are very important, the progress in the pipeline is probably something that I'm most proud of, already 3 first-in-class, best-in-class launches this year. Remember the last time this great company did that. Beyfortus, strong AdCom, complete lockout, if you like. The guidelines pretty much in hand and the launch in time for the season. We're really, really in a very strong place. And given that it's pioneering the opportunity, it's pretty incredible what this team has done, and most of them are here and will get their moment. For Altuviiio, we're off to a really strong start. And while you may or may not be interested, we'll share more through the quarters and later this year. We're ahead of where we thought we would be. And 10% of our patients are switched from Hemlibra. Again, that's remained consistent. That's interesting in itself because that tells us we have a slightly bigger opportunity than perhaps people thought. And for Tzield, which we manage just to put into our pocket nicely not that long ago, we have a chance to do something significant to protect beta-cell function in type 1, and we have perhaps even a decade's worth of being on our own to do it. So it's going to do something very special. We'll earn the right. You may have seen from the American Diabetes Association last weekend, they put it in the guidelines. And if you've been around our industry a long time, it takes years to get into guidelines, years. And they proactively put it into the guidelines. So not only are we doing some deals, we're doing them late, we're doing them in immunology, but we're doing them where they are appreciated by the specialists, the professions, those who care for patients. It's really extraordinary, actually. A couple of quick comments. If I draw your attention to tolebrutinib. Yes, we still need to find a path forward, but we're really actively engaged. More that we'll share with you at Q2 probably. But the relapsing/remitting data ahead of us and not far behind that, we hope the secondary progressive data, which still leaves us differentiated. Nobody else is doing a secondary aggressive study. You know that. Nobody else probably will. It will be us. And so while we don't get the chance to talk about it too often, nothing has changed for us. It's still a tremendous belief and a real opportunity. And then finally, fitusiran, which perhaps isn't even in people's models. For those that were less eagle-eyed and missed that, just remind of the Lancet article, the publication that showed you the 7-year extension. Buried within that was a small cohort of patients that went on to the new regime, which was a longer into the lower dose. And that's fascinating because they were stable and had maintained efficacy. Will that be a leading indicator for what happens with the Phase III readout? If it is, then we've ended up with the longest interval for fitusiran, and we've ended up with the most effective treatment in Altuviiio with gene therapy step back. Let's be honest. So we could end up with the most important franchise in the entire industry in hemophilia. Maybe we just go to, I think, the last slide, which is the pipeline news. I sat with a bus tour that passed through Paris earlier this year. And I said, how many readouts do we need, albeit they're at different stages, for you to believe that this company has started to reassert itself scientifically? Remember, 3 first-in-class, best-in-class launches already. You know the PDUFA for CSU will be later this year, I think, in November. You know COPD, not many people gave us a prayer of pulling that off. And then, of course, we get to disrupt, not really everybody is fully understood that itepekimab is a different patient population entirely. And it's for the former smokers and indeed had a positive pass-through of its interim. So we're getting much closer to having the only 2 advanced therapies in COPD. Imagine that. And then amlitelimab, we told you a long time ago that in the hope of launching early something that would compete with Dupixent that would perhaps be longer interval and have the same, if not better, efficacy. Dupixent will grow until it's very end of its life. It is foundational. But you know from experience in biologics that there is something extraordinary going to happen in the OX40-ligand for us, which we specifically chose and then developed, will now enter Phase III. It's a different game. Imagine Skyrizi was launched 4 or 5 years ago. This is what this will be for us. This is a big deal. And then frexalimab, which was presented at a conference, which not many of you, I think, attended, but the CD40-ligand approach, the -- had greater than 9% lesion reduction, extraordinary efficacy, of course, going into Phase III. And maybe we get to take on [indiscernible] in that setting but with no downside risk on side effects and safety. So really a moment for us. Lastly, and I have the pleasure of being at the American Thoracic Society meeting for the [ TB ] COPD, itepekimab, IA, but also to talk about the IL-13/TSLP, which from the pheno data, as you know, puts us as perhaps the new efficacy bar in asthma. Nanobody out of the Ablynx agreement or acquisition and really could be totally extraordinary. So we're advancing those. And then the very last one, I mentioned more like in passing but really something pretty special is the oral TNF. So you will see that we have a huge opportunity to do something. And with the IRA like it is and it's a small molecule, we will have to be brave enough to go forward and all the indications we think we can do, and we're brave enough. So you will see what we do. So an extraordinary list. And I said to a bus tour in January, how many does it take for you to be excited? They said, if you get 2 or 3 of those, Paul, this means you're back. And of course, by the time you run into some of those people, even at the lunch, they said, well, we really meant 4 or 5. Okay. So we're at 5, and we have a couple of more here. I think just think about it from our perspective, more than 10 consecutive quarters of growth; complete reallocation of resource to do what we need to do; 3 first-in-class, best-in-class launches; 5 first and best data readouts, one or two more to come; and our last LOE of Aubagio this year, imagine where this company has moved itself in a short period of time. We're a different company, different management, different expectations, and we are making sure that by the end of this year that people understand what a great proposition that we are. I'll leave you with this last comment, perhaps, we will launch 3 to 5 mega-blockbusters between '26 and the end of the decade, potentially more than that, let's be honest, and not including the 3 that we launched this year. So think about the scale of what we're doing and who we are without a bathtub that is leaking because we don't have the major LOEs that everybody else has. Different proposition for us, and this is all without the magic of vaccines and for the magic of vaccines, the magician himself, Thomas Triomphe. Thomas?

Thank you very much, Paul. Great to start bioscience and definitely, it deserves more than 4 minutes. Very glad you took them. Good morning, good afternoon, everyone. It's my great, great pleasure to host our second vaccines investor even after the first one in December 2021. Today, the Vaccines team is going to share with you the progress that we've made since Q4 2021 with a focus on our vaccines pipeline and our R&D engine is finally delivering very exciting journey to discover with you today. Let me start first with our ambition, exactly as it was laid out at our vaccines event in December 2021, the exact same slide. And I'm delighted to share that we are well on track on every single of those 3 pillars that we identified back then. First, on our sales trajectory. We delivered mid- to high single-digit growth over the past 2 years driven by our core franchises, well in line with our 2018-2025 guidance. Second, and definitely, we're going to talk about it today on mRNA. Only 24 months after the creation of our mRNA Center of Excellence, we have now established a competitive platform at the forefront of mRNA Science. Our team will share with you today our clinical data, but also what we are doing in research, where we are pushing the boundary of this technology. Overall, I'm really thrilled by the progress made by the team over the past couple of years, a very short amount of time, great results. Lastly, in the next 3 hours, we are going to deep dive into our exciting pipeline and share with you our innovative products can really address unmet medical need, all over the vaccine space and change the life of millions of people. But before we look into our future, let's reflect for a moment where we are on the execution of our Play-to-Win road map. Over the past 3 years, this organization went through a massive transformation and has been impressed day after day by the energy, by the passion that our employees have put together to make sure that we deliver tangible results. You can see on this slide some of our main achievements along the 4 pillars of our Play-to-Win strategy. So just to name a few, when it comes to focus on growth, I was before mentioning the first 2 years, we actually delivered an 8% CAGR on our top line since 2018, well in line with our guidance, with 2 of our vaccines reaching blockbuster status. Our innovation engine is delivering very strongly with Beyfortus already licensed in not 1, 2, 3, but 32 countries and ready to launch for 2023 season now. On accelerated efficiencies, we have improved significantly the Vaccines business profitability by 6 percentage points between 2018 and 2022. Finally, on reinventing how we work every single day, you know very well that we strive to create a unique culture at Sanofi, an environment where everyone, every employee can bring his best or her best self at work. I'm proud to see that in this unique environment, 2 years after the acquisition of Translate Bio, more than 90% of our mRNA experts have embraced that culture and chose to continue to work with us. Put simply, great progress on the execution of our road map. In the past 2 years, the Vaccines R&D organization has also been through a major transformation of its own under the leadership of Jean-Francois Toussaint. But instead of me, maybe Jean-Francois, can you tell us more about that transformation.

Yes, sure. Thank you. Thank you very much, Thomas. Before going there, I got to say that I still have a hard time believing that I joined your team only 2 years ago because we've done so much already together. It's really an exciting journey, and thanks for the trust here. So of course, today, we're going to share many new data. You have seen that in the deck. But before that, let me say a few words about the major transformation of our R&D organization. You saw it, our major -- transformation was based on 3 pillars, and it was designed to reinforce and to modernize the key enablers for us to win in Vaccines. First, we continue to strengthen our capabilities in immunology and in antigen design. On that front, I'm very pleased to share with you that actually we have scaled up and validated for the MIMIC. MIMIC is our proprietary technology that recapitulate the immune system of humans just in a tube. I'm also excited by the progress that we've made in antigen design. I'm sure that you have heard many people questioning the ability of mRNA to express bacterial antigens. Not only we never doubted it, but actually, we have done it. And we're going to show a couple of examples today -- later in the day. The second pillar of our transformation is about vaccines platform. You know we invested massively in mRNA 2 years ago, first, with the creation of our mRNA Center of Excellence, then by welcoming Frank and our TBio colleagues within the Sanofi Vaccines R&D organization. I'll cover that in a minute, the very exciting progress we've made, but what is important at this stage for you to remember is that Sanofi is a deep expertise in multiple vaccine technologies and that we use the best platform for each given target. This will obviously come through the day when you will see the progress that we have made across our pipeline. The third pillar of our transformation is our renewed research and discovery pipeline, expanding into new diseases. More than ever, we are convinced that viral and bacterial infection trigger or accelerate chronic diseases. While we have initiated multiple programs in this area, we're going to share with you today the significant progress we've made on acne and chlamydia vaccines. Along with the transformation, we have also successfully rebuilt and advanced our Vaccine pipeline, showing strong execution across all development stages. We have seen the approval of 3 new products. Of course, Beyfortus, our first and best-in-class product for the prevention of RSV in infants. We have seen our COVID Beta booster vaccine that was registered in Europe. But we have also seen our Chinese version of vaccine [ VidPrevtyn], so our first quadrivalent influenza vaccine made in China for China. We obviously also moved significantly the early pipeline. And by the end of this year, we'll have progressed 6 new programs into Phase I/II. These include programs on flu, on RSV, on acne and also meningitis pentavalent vaccine. Last but not least, our ambition is very clear and very realistic. It's actually to bring at least 5 new programs into pivotal trial by 2025. Of course, a significant part of our early pipeline relies on the mRNA technology, but it takes a team to do that. And we are very proud of the scientists but also the technologies that we have attracted in the mRNA center of excellence, including the Translate Bio people that have been working in mRNA for more than 10 years. We obviously complemented their skills with employee coming from Sanofi but also from diverse external groups. And among them, we attracted several top-notch expert in AI and machine learning that have already developed proprietary generative modeling for mRNA design and LNP design. On the technological front, you will see that later today, we are very pleased and proud to see that our first generation of mRNA already has a competitive profile. But we don't want to stop there, and we have anticipated it. Our stated ambition is to develop the next-generation mRNA. That's why we kept innovating, bringing as many as 5 lipids in clinical trials. Likewise, we have identified 4 mRNA enhancement features, and we also progressed very significantly on thermostability, going beyond 9 months of stability at 4 degrees in a liquid formulation. So finally, the journey was also very exciting when it went to execution and the deployment of mRNA across the pipeline. We pivoted to modified mRNA and validate it clinically. So everything the pivot, the GMP and the clinic in 9 months. And in 2022, we also initiated no less than 7 clinical trials based on mRNA. So I hope you will agree with me that we are really on a winning track here. Thomas, back to you.

Thanks a lot. What I like a lot, the at least 5 in Phase III by 2025. Very impressive acceleration, indeed, Jean-Francois, thank you very much. When developing new vaccines, our scientists can now choose from 9 distinct platforms, probably the largest number in the industry. And while it all starts with R&D, let me remind everyone that our Vaccine business is also built on very strong foundations, reliably supplying massive number of doses all over the world every single year, generating convincing evidence that support the cost effectiveness of our product and the best recommendation and the strong commercial workforce dedicated to Vaccines. It may seem obvious on this slide, but we have seen recently various players in this industry, some new ones, failing on 1 or 2 of these elements. Mastering these end-to-end capabilities is exactly what ensures that the vaccines that we discover in the lab will actually get used and do protect people. On the next few slides, I'd like to share with you and take a moment to really look at how we operate at Sanofi Vaccines. More specifically, our societal commitments are embedded into our business decisions every single day. You can see on this slide the 4 pillars of the Sanofi CSR strategy: affordable access, R&D for unmet needs, planet care and in and beyond the workplace. Today I selected to share 2 cases that I believe do exemplify our ESG influences, the choices that we are making in terms of vaccine development. First, a case under the affordable access pillar and another one under the planet care pillar. We rarely discuss with financial investors, especially our traveler and endemic franchise. That includes vaccines against rabies, hepatitis A, typhoid fever, yellow fever, probably because these vaccines do not play into the EUR 1 billion markets. However, those vaccines are of utmost importance, addressing diseases mostly prevalent in low- and middle-income countries. Have a look at yellow fever. Despite spending millions of dollars every single year in attempting to decrease the population of mosquitoes, the ones that transmit -- transmit the yellow fever virus. These mosquito populations and the yellow fever cases continue to increase every single year. And global warming is just making things worse. Finally, vaccination is now regarded as being the most important means to help prevent those outbreaks. Sanofi is one of the key few companies to supply yellow fever vaccines. We've been partnering with UNICEF and with other players for decades now, ensuring supply and readiness to respond to outbreaks. We are committed into this fight. And from an R&D standpoint, we continue to invest in yellow fever. We want to develop the next-generation yellow fever vaccine that will replace the current 2 yellow fever vaccines that we have in our portfolio. I'm glad to report today only on this slide that the recent Phase II results on our new yellow fever vaccines are very positive and we are moving the program immediately to Phase III. From an operational standpoint, on top of that, of course, replacing 2 yellow fever vaccine from a previous generation with one single new yellow fever vaccines will clearly rationalize our manufacturing footprint and simplify our operations. Last but not least, you know that our new yellow fever vaccine will, of course, be embedded into our global access plan. Turning to planet care. On our second example, at Sanofi, we are constantly working to optimize the environment performance of our product. And you have seen but we have decided to make sure that all new vaccines will be eco-designed by 2025. Concretely, what does that mean? For decades now, the standard packaging for syringe presentation was to provide those syringe into a plastic blister. Plastic takes hundreds of years to degrade, can break down in microplastics, contaminate the food chain, harm human health. Reducing plastic use is critical. We can help protect the environment and reduce the impact of the plastic pollution. We want to do our part, which is why we decided we target to reach 100% blister-free packaging by 2027, even if it means potentially accelerating our industrial CapEx. And we're well on our way. By the end of 2023, 40% of our syringes will be plastic blister-free, while, of course, 100% of our vial presentation already is. Moving away from plastic is not just for us. It's also about making sure that we set up the right standard as we do believe that many countries around the planet will start adding into the vaccine standards this requirement, a high request for nonplastic-containing packaging moving forward, and we'll be at the forefront of it. Now let's come back to our vaccines pipeline to wrap up this introduction. At our Vaccines Day in 2021, we shared early information about our pipeline with many early-stage trials that were going on at that time. As explained by Jean-Francois before, we have transformed the R&D organization in this company, enabling us to move fast and progress at speed. Today, we're going to share with you some results that are about the 12 key areas that you see here highlighted in this peak area. We will actually start with a deep dive into RSV in the middle of the chart. And you receive calls right now on RSV, I can see, where we are the only company to offer protection to infants, to toddlers and to other adults with specific products developed with 3 different technologies that are best suited to deliver the targeted results with both the targeted profile products that we have. Then we'll go to influenza. We have a comprehensive mRNA program, focusing on next-generation vaccines so not -- not just give me to -- but actually improve versus current on health care, bill will lead us there. We will then turn to our exciting entry into multibillion pneumococcal field with a strong PCV21 Phase II data, I'm sure you have seen it this morning, and how we are also building in parallel a best-in-class meningitis franchise. Lastly, we're going to uncover the progress that we made in the search of novel vaccines in the unchartered territory of acne and chlamydia. So let's move on to the RSV section. We received the calls. It means we need to get there. I'd like to welcome Kimberly Tutwiler, our Global Head of RSV Franchise. Kimberly, floor is yours.

All right. Good afternoon, good morning. I'm Kimberly Tutwiler. I lead the global RSV franchise. I'm happy I'll be joined later by Jean-Francois, our Vaccines Head of R&D. And I'm really happy to have a chance to talk with all of you about how we will deliver a best-in-class franchise for RSV. So since we last talked in 2021, a few things have happened. First, there was an unprecedented RSV season last year that unfortunately impacted many thousands of families around the world. Second, there are now a number of RSV immunizations coming to the market after decades of waiting. And finally, there's a lot of momentum for the first RSV immunization designed for all infants, and that's Beyfortus. So we're excited to show you today the progress of Beyfortus and our entire RSV franchise, but most importantly, how we'll benefit patients. So our ambition is to lead in RSV across all critical target populations, and that ambition starts with Beyfortus in infants. This is a best-in-class immunization designed for all infant protection for infants in their first RSV season. Now we'll follow Beyfortus with RSV Toddler. This is a first-in-class, live-attenuated intranasal vaccine, and it's designed for toddlers in their second RSV season. And then finally, our target in the older adult market is an mRNA combination vaccine with RSV, human metapneumovirus and parainfluenza virus. You can see the total RSV market valued at just around EUR 8 billion. And our foundation of our RSV Franchise starts in just a few months during this upcoming season with Beyfortus where the need for all infants is so critical. So let's start there, and let's start with what's new with this product. And we start with fantastic news, where the FDA Advisory Committee voted unanimously in favor of nirsevimab for infants in their first RSV season. They also voted in favor of nirsevimab for high-risk infants in their second season. So this outcome reinforces the very strong efficacy and safety of nirsevimab. This is probably the most popular question I heard from many of you at lunch, what are our next steps? So I can tell you, license and an ACIP recommendation anticipated in the coming weeks before the RSV season. So the question, will we be ready to launch in 2023? The answer is yes, we will. So we had more good news recently for Beyfortus from our results in the HARMONIE study, where its strong efficacy was confirmed in the real-world setting. So you may remember the study, we discussed it in 2021. This is a Phase IIIb study. It was conducted in France, Germany and here in the U.K. during this last RSV season in more than 8,000 infants, greater than or equal to 29 weeks of gestational age. So we conducted the study for a few reasons: certainly to further reinforce the very strong data that we had in the pivotal Phase III MELODY study; also, to further enrich our hospitalization data. We wanted to demonstrate as well the implementation of Beyfortus in the real-world setting. And finally, we wanted to confirm the safety profile in a large population. So you'll see the design of the study on this slide. Infants were randomized and allocated to receive either Beyfortus or no intervention during the first-and-only visit of this trial, and then they were followed up each month electronically throughout the season. These results were presented recently at the SP Congress. So let's take a look at this data. Starting with safety. We see that Beyfortus has an excellent safety and tolerability profile. You can see that the percentage of adverse events is similar to no intervention, and there are no serious adverse events that are determined to be related to Beyfortus. Now these results are consistent with what's been seen in our previous studies. So the big question you probably want to know is what about the efficacy. So let's take a look at that. And this is absolutely exciting. Beyfortus demonstrated an impressive 83% reduction of hospitalizations due to RSV LRTI. Now given that RSV is the leading cause of hospitalization in infants, this efficacy is so important for health care providers, but even more so for infants and their families. These results are also consistent with what's been demonstrated by Beyfortus in other studies. Importantly, the efficacy here of Beyfortus in HARMONIE and in all of its studies is maintained for the entire RSV season. That's typically 5 months. And that's critical for providing the protection that all infants need, and it's a massive advantage for Beyfortus. But we know that in addition to efficacy, health care providers, health authorities and payers and maybe many of you also want to know the impact of a product when it's implemented, primarily in the health care events that are prevented. And because there's a lot happening in this market with new entrants, it's important to evaluate that impact comparatively. So let's take a look at that data. When we look at the real-life impact of nirsevimab, the result is that it's expected to prevent 3x as many RSV events than a maternal vaccine. Now that's a significant impact, and it's due to its strong efficacy, expected higher immunization coverage rates and the fact that nirsevimab is designed for all infants. So let me walk you through the slide and orient you with the data that's here. This slide shows the results of a model comparing nirsevimab and maternal immunization in the U.S. And it leverages recent clinical trial data for each product, not from a head-to-head study. The assumptions that are here are sourced from the CDC, the University of Michigan model on efficacy, health events and RSV circulation. And you may have seen this at the ACIP meeting last week. The efficacy included here is that 5 months or greater to represent the duration of the RSV season, which nirsevimab is 79.5% and for maternal vaccine is 51.3%. The immunization coverage rates here are 80% for nirsevimab aligned with the pediatric series; 50% from maternal immunization, aligned with current maternal immunization rates. Now you may notice there's something else that's exciting on this slide and that's new, and that's new data. That's the efficacy against all-cause LRTI hospitalization. This is from the HARMONIE study, where nirsevimab demonstrated an impressive 58% reduction of all-cause LRTI hospitalization. It's significant. It's also unique as only nirsevimab has been proven to impact this important end point. And I'll pause for a minute on this to be clear because 58% is a very high number for an all-cause endpoint. So we are very excited to see this efficacy for Beyfortus. So what does all this mean? The bottom line with all this data and all this information is this: whether it's efficacy, the ability to protect all infants regardless of the month they're born or immunization coverage rates, the data shows that nirsevimab is the more complete, and frankly, the better option to protect all infants. As I mentioned earlier, we are ready to launch in the 2023 season. Stakeholders are fully engaged on this topic. We already have licenses in Europe and Canada and here in Great Britain, and we expect broad population programs in Spain and in France. We expect, I mentioned earlier, the license and the ACIP recommendation coming soon in time for the RSV season in the U.S. And we're already preparing there with contracting and reimbursement milestones and implementation on track. If you saw the ACIP meeting last week, you also saw a high level of support and excitement for all infant protection but also for nirsevimab from some of the comments that were shared. We also had exciting news recently outside of North America and Europe, in China, where Beyfortus has been granted priority review. And finally, a really important element. We're not waiting to produce doses. That's already underway, as you can see in this picture on this slide, and we expect to fulfill the demand for this first season. So leading up to this launch, we've engaged with a lot of physicians and public health stakeholders, and most of them have had the same reflection that they've been waiting for decades for a solution for RSV that they could offer to the broad infant population and that they've desperately needed something to stem the tide of the RSV season every year as we were reminded last fall, when a universal health emergency was declared in the U.S. and hospital beds around the world were full of sick infants from RSV. This season, we'll have the opportunity to protect all infants for the very first time with Beyfortus. So we've been discussing Beyfortus, which addresses the need for RSV protection in the first season, and I could talk about Beyfortus all day, but I'm going to move on. And I want to talk about the fact that the burden of RSV doesn't end there. RSV is a significant burden in the second season and beyond as well, impacting toddlers. So the data you see on this slide on the left is the RSV burden in hospitalizations, pediatric office visits and emergency room visits in infants 6 to 11 and 12 to 23 months of age. On the right, the key diagnoses of GP visits in kids up to 5 years of age. And what you see is that RSV is a core driver for bronchiolitis, antibiotic prescriptions, respiratory and acute respiratory disease. So while we certainly hear the most about the burden of RSV to the youngest infants in the first season, and that's where it's the highest, the truth is that burden continues into the second season and needs to be addressed. The good news is, we have a solution here, and Jean-Francois will tell us about the exciting assets we have to finish the job, which is to protect toddlers in their second RSV season and then as well to protect older adults with our respiratory combination vaccine. Jean-Francois?

Thanks, Kimberly. And congratulations again on the outstanding ACIP outcomes - every outcome, that's brilliant. Starting with Toddlers, as the first of the 2 program I will cover. It's very important for you to understand that the needs, as Kimberly explained, but also the immunization opportunities are quite different in toddlers versus infant. In toddlers, we actually have some time in between the first and the second season to come with an active immunization, immunization that will amount an active immune response in the toddler. We plan to do it with a unique vaccine approach that is based on the live-attenuated virus that will be given intranasally. This candidate because it's given intranasally is expected to protect both the upper but also the lower respiratory tract, cutting visit to the GP, to the emergency unit, cutting hospitalization, but also potentially impacting transmission as well. The vaccine that we use has been rationally designed by the NIH to remain immunogenic while offering an optimal safety profile. And here is how we see it working in practice. So let's take the example of a baby born in the U.S. in June, for example, this cute toddler at the top of this slide. If she is born in June, she will receive Beyfortus at the age of 3 to 4 months, and she will be protected for the whole season. At the end of the first RSV season when she turns 9 to 10 months, she will be offered 2 doses of our RSV Toddler vaccine and that will protect her for the second RSV season. So as you can see, combining nirsevimab and our RSV Toddler vaccine is expected to offer a continued protection of all infants across the whole first few seasons and the first few years of life. And here is how we have developed this product. So following a Phase I safety dose escalation study that I'm not going to show you today, we have enrolled toddlers 6 to 18 months of age and administered them 2 doses of either a low dose or a high dose of the vaccine candidate. We've measured endpoints that are pretty classical for Phase I, so safety, immunogenicity and vaccine response rate. Let's start with the safety. Actually, there is really not much to be seen here. We are very pleased with the safety profile of this vaccine candidate, which was similar to the placebo, whatever the dose that was tested. We have defined vaccine response rate as a composite endpoint based on immunological response but also the detection of the live-attenuated virus replicating at day 7. As you can see from this graph, the difference between the 2 doses was marginal. And that's extremely important because that gives us some space to develop this product to define its potency but also to define it's shelf life. The difference between a single dose and the 2-dose regimen was also fairly limited. But at the end, if you look closely at the data, it's still the 2-dose schedule that offer the most attractive profile with a very good 93% vaccine response rate. With a note that immunogenicity, and we're equally pleased to see that both formulation induced a very robust immune response. So the way the data are presented here is actually a classical reverse cumulative curves, where you have on the X-axis the neutralizing antibody titers and on the Y-axis the percentage of volunteers. What is key here is that the 2 formulation induced a nice shift of the curve to the right, reflecting a substantial increase of neutralizing antibody titers in most volunteers. So overall, we are very encouraged by the data gathered in this program, and we are actively preparing for a pivotal phase III trial. And we expect to start pivotal phase III trial in the first half of 2024. If this reached positively in phase III, there is no doubt that we will deliver the first-in-class RSV vaccine for toddlers and that we will set a high bar for competitors that are at least 2 years behind us. Shifting gears, let's go to our RSV Older Adult program. And as you know, we have been following the field and there have been quite a few or a couple actually of RSV vaccine approved recently. But our ambition at Sanofi goes beyond that as we aim to come with a vaccine combination that will protect against multiple viruses of the same family and it's important of the same family. Why? Because we believe that the winning combination for all the adults need to include viruses that are associated with the medical -- high-medical burden that's obvious but also virus that don't evolve over time so that we can keep the vaccine composition stable year-on-year. If you look at the chart on this slide, you will see that the combination vaccine, including RSV, hMPV is standing for human Metapneumovirus and PIV standing for parainfluenza virus. Such a combination vaccine will address a similar medical need as influenza vaccines. You remember December '21, at least the ones who were with us at that time. And you remember that we are predictive that RSV vaccine for older adult would not need to be given every year. And this is exactly what ACIP has confirmed last week. We expect it will be the same for hMPV, the same for PIV, supporting again while other combo vaccine combining RSV, hMPV and PIV is the one that makes sense. So RSV is obviously stepping stone of our program. So end of last year, we initiated a Phase I/II trials with multiple formulations in a small cohort of young adults, so adult below 50 years of age, and a larger cohort of adults above 60 years of age. We tested 3 dosages of mRNA and 2 different lipid nanoparticles. This was a classical Phase I/II where the objectives were to assess safety and immunogenicity. Here again, we were very pleased with the profile of a vaccine candidate, and we have identified the formulation that was both potent and well tolerated. On the left part of this slide, you can see the reactogenicity. And yes, the vaccine was extremely well tolerated with self-resolving adverse event of mild to moderate intensity and over short duration. On the right, you see the vaccine -- sorry for that, you see that the vaccine was also very immunogenic with 11.5 fold increase in neutralizing antibody titers in the young adults and a 5.4-fold increase in the older adult. We believe this is particularly strong because remember, we have faced a very intense RSV season in the year that preceded, [indiscernible] which was conducted in January, February. Also, our safety data show that we have room to increase further dose in older adults if we need to. So based on this result, we are very confident about moving forward a couple of combination vaccine formulations in the Phase I/II trial by the end of this year. Looking at the competitive environment now, we believe that our combo vaccine has the real potential to be a first in class, and we expect that its superior medical value combining these 3 viruses, superior medical value compared to RSV, will provide a more compelling case to recommending body, leading to a better recommendation than the one that was provided to GSK and Pfizer by the ACIP last week. Kimberly, would you like to wrap up the session for us, please.

Thank you, Jean-Francois. So hopefully, you can tell we're really excited about our ambition to protect all targeted ages from RSV. And we're the only company to offer this. You'll see on this slide our strong portfolio of products and our next steps. And you'll see that we're advancing the development of our products in toddlers and older adults quickly, moving forward in the next few months. Our products, combined with our commercial expertise in introducing pediatric and adult immunizations, is what will secure our RSV leadership. But if there's one thing that you should take away today about our RSV Franchise, it's this: it's the first and best in class is what we will do, and that begins in a few short months in the infant market where we will address a critical need with Beyfortus, and we will win for all infants and their families. Thank you for your time today. I look forward to hearing your questions later. And now I'm happy to welcome Bill Averbeck to the stage to talk about our exciting Flu Franchise.

All right. Thank you, Kimberly. Well done. Hi. I'm Bill Averbeck. I'm the head of our Flu Franchise. Right before this event started, one of you came up to me and said, "Are you that guy that said, flu is only one letter away from fun?" And I said, "Yes." And he said, "You put it on and saying that again today?" I said, "No." So Peter, there you are. The next question was, "Anything else witty to say today?" And I said, "Witty, no. Something, sure." I was hoping this event will be on Friday because everybody knows, you can't spell Friday without IR. However, this is on Thursday, so we can't spell Thursday day without U, so thank you for coming to our event. And that's the pity side that I was looking for. Yes, I'm going to stop before I get the hook. So why am I here? Not just for bad, bad jokes, but I am here actually to talk to you because I'm excited to speak to you today about why we believe we are uniquely positioned to win in flu by delivering on protection beyond flu and by designing a vaccine specifically built for seasonal markets. Now the one thing I'd like to reinforce as we begin the flu section is the leadership that we hold in this market. We have been part of the flu ecosystem for over 70 years, and I'm happy to announce that reports of our demise have been greatly exaggerated. We have been, we are and we will continue to be the leader in flu. Now we have a rich history in flu, and I've continued this leadership via the pioneering of the transition of quadrivalent vaccines beginning in 2014. And we've continuously driven the value of the flu market higher, while maintaining our overall leadership position, reaching EUR 3 billion in annual sales. Now a cornerstone of this increased value is our differentiated product offering with products like Fluzone High-Dose and Flublok. We have defined a new class of differentiated flu vaccines and now set a new benchmark of protection beyond flu as these standard of evaluating these vaccines. Now we will continue to lead this market through our pursuit of the next chapter in flu prevention with mRNA technology. And we hear more about our progress with our flu program from Saranya. However, before we get there, I want to take a second to remind us that this is not a technology story, but rather this is about preventing the most serious outcomes in the most vulnerable patients regardless of the platform utilized. Now as many of you may recall on December 2021, we made the point that mRNA vaccines would not have immediate impact for the simple reasons that flu is not COVID and that the vaccine profile -- the pandemic vaccine profile will significantly limit its uptake in the seasonal market. In fact, we stated that mRNA vaccines would only capture a fraction of this market by 2030. Now when we stated this position, I'm willing to bet some of you folks listening and weren't so sure this is how things are going to play out. However, since then, we have seen data has only reinforced the reality that first-generation vaccines simply cannot deliver on the key success factors of this market. Essentially, we told you that the road to the first-generation mRNA vaccines will be long and difficult and without significant improvements, they simply will not be commercially viable. Now let me remind you of these 3 key success factors that have only been reinforced over the last 18 months. So the first factor is protection beyond flu, and it remains the most important. Products must demonstrate improved efficacy and effectiveness when compared to the standard of care. Payers and providers demand consistent, strong data across endpoints that matter like hospitalizations from pneumonia and cardiovascular complications. Now the second is tolerability. Products that are administered to hundreds of millions of patients each and every year must have an excellent tolerability profile to maintain a high level of patient acceptance. Lastly, administration. The seasonal flu market requires certain elements of administration, such as having a liquid formulation in a prefilled syringe that can be stored in a refrigerator. These elements are half to half to be successful in this market. So what has changed in the last 18 months? I'll offer 2 points. One, protection beyond flu has been established as the true measurement of flu vaccine performance, and we have new data that shows flus on high dose has increased its leading position and continues to be the benchmark that all other products will be compared to. Secondly, we went out and spoke to both providers and consumers, and we have new market research that clearly reinforces that products with increased reactogenicity and limited thermostability will not be accepted by either providers or patients. So I'm not here to share our hopes or opinions. I'm here to show you new data that clearly proves our position is correct. First-generation mRNA flu vaccines will not win. So let me start with protection beyond flu and Fluzone High-Dose. As you can see, delivering protection beyond flu to the older adult population has allowed Fluzone High-Dose to continue to be the strong and consistent market leader in the U.S., significantly contributing to us delivering about USD 1.7 billion overall in 2022. Demonstrating protection beyond flu was a key factor when the product was evaluated by the ACIP and led to their conclusion that Fluzone High-Dose has the most data for the most outcomes. So as an organization, we are committed to continually add to this robust data package of Fluzone High-Dose. So we set the bar for protection in this age group of Fluzone High-Dose with data from 12 years and over 45 million patients. However, it's not just about the sheer volume of data, which is unparalleled, but it's also about the quality of this data. Randomization is such a critical element of study design that we are investing in novel ways to randomize large number of subjects to further prove the impact of Fluzone High-Dose has in a population in real-world settings. Within flu studies, we aim to measure the impact of Fluzone High-Dose versus standard dose vaccines on protection beyond flu endpoints, like pneumonia and influenza hospitalizations. In our first study, creatively named DANFLU-1, Fluzone High-Dose has showed an impressive 64% reduction in pneumonia and influenza hospitalizations versus standard-dose vaccines across 12,000 subjects. Now we're aiming to further validate these results in DANFLU-2 where we randomized over 200,000 subjects to add to the unprecedented body of evidence that we have for Fluzone High-Dose. And it's not just us saying this. The impact of Fluzone High-Dose has been recognized worldwide with the recommendations or favorable reimbursement in over 10 key markets. So the bottom line is that for older adults, the highest level of evidence of proven performance against flu-related complications is required, and only Fluzone High-Dose has demonstrated this across both randomized controlled trials and randomized real-world studies. Any product attempting to be commercially viable in its older adult segment has to replicate the sustained, well-documented performance to the same level as Fluzone High-Dose. Essentially, we will continue to raise this benchmark as others are trying to reach it. So my second point is across tolerability and thermostability. As you may recall, that second key success factor is tolerability, which is important for both older and younger adults at a particular concern for younger adults where coverage rates are much lower. Flu vaccination rates have been increasing for years as a result of global efforts to build consumer confidence. So introducing a product with an unfavorable reaction profile risk upsetting this delicate balance. And that's exactly what health care providers and consumers reinforce in recent market research. In fact, introducing a product with 3x the severe reactions versus the standard of care could decrease health care workers' willingness to administer by almost 70%. Even an increase in 2x in reactions will result in a decrease of up to 40%. And consumers share the same pattern with again an almost 70% decrease and willingness to accept a vaccine with 3x the severe reactions versus what they're currently accustomed to. So the final key success factor is administration. And here, again, I remind you of the delegate seasonal flu ecosystem that has been established over decades. This ecosystem was set up to maximize access at every opportunity, whether it's a doctor's office, the pharmacy, the workplace or drive-through types of clinics. What these networks were not set up to do was manage ultra-cold change like what we saw in mRNA COVID vaccines. So not only does a pandemic profile introduce complexity, it again risks decreasing uptake, something made evident in our recent research with health care professionals. So we found that a lack of a refrigerator stable flu vaccine lasting throughout the season could decrease health care workers' willingness to use it by 40%. So overall, we continue to maintain that the first-generation mRNA vaccine candidates will not be successful in the flu market as they have not even come close to the proven protective patient benefits of Fluzone High-dose and have significant work to do across reactogenicity and thermostability compared to any of the currently licensed-flu vaccines. For mRNA vaccines to be relevant in this market, they will have to continue to evolve to a next generation of product design for seasonal routine use. Now to further discuss our efforts in developing these next-generation products, I'd like to turn it over to Saranya to walk you through the progress we're making on our mRNA flu program. Saranya?

Good morning, good afternoon. My name is Saranya Sridhar. I'm the Head of Translational Medicine, and it's my pleasure to be here today to share the progress on our mRNA flu program. Bill, thanks for the jokes, but also thank you for the target product profile that you've made very clear that we need to achieve for future influenza mRNA vaccines. Last year, we started 4 trials as part of our program with quadrivalent hemagglutinin-based and neuraminidase-based vaccines. In our first 3 trials, we evaluated multiple formulations of a quadrivalent hemagglutinin-based mRNA vaccine. And in these trials, we tested 3 different lipid nanoparticles and different dosages. We are very clear about the benchmark that mRNA flu vaccines have to meet. And therefore, in each trial, we compared them to the standard of care in each population, so Fluzone Standard-Dose and Flublok in the young adults and Fluzone High-Dose in the older adults. We also started our first pilot trial with neuraminidase, a different antigen to Hemagglutinin. We are adding this additional antigen because we had previously shown that neuraminidase antibodies play an important role in the superior efficacy of Fluzone High-Dose. So we started a pilot trial to see whether mRNA vaccine candidate could induce antibody titers in the same range as Fluzone High-Dose. So let me share some data with you from these trials, which gives us confidence that we do have a very competitive mRNA platform. So let's start with the quadrivalent hemagglutinin-based trials. And here are the immunogenicity results from our lead lipid nanoparticle in the young adults. We present a very typical endpoints for flu. So on the left-hand graph, you can see the forward increase in antibody titers compared to the baseline. And on the right, you see the seroconversion rate. As you can see in the first 2 sets of columns representing the responses to the flu A strains, our mRNA vaccine shown here in purple induces a very strong immune response, trending superior to Fluzone Standard-Dose and in the same range as Flublok for both endpoints. And as reported with the other mRNA flu vaccine candidates, the immune response against flu B, shown in the last 2 sets of columns here, was trending lower than the standard-of-care vaccines, more evident when you compare to Flublok. So the immune response we observed with our platform is very similar to that observed with other mRNA vaccines. And what that tells us is that improving on the standard of care, the minimum bar against which all mRNA vaccines need to be compared, is difficult. If we compare the data from our platform on the left to another mRNA candidate vaccine, we can see the same pattern of strong immune responses for the A strains and lower B strain responses. And what that's suggesting to us is that low flu B responses are probably a class effect across mRNA platforms and that we do need to find a more comprehensive solution to ensure a strong B strain performance year-on-year with mRNA. Now as Bill mentioned earlier, reactogenicity is as important as immunogenicity. So let's look at our reactogenicity compared to the competition. We measured the Grade 3 local adverse reactions shown here on the left and the systemic adverse reactions on the right. And our candidate performed better than reported with other mRNA vaccines. However, compared to Fluzone Standard-Dose and Flublok which wasn't associated with any Grade 3 events in this trial, our mRNA vaccine was more reactogenic. So while we're on the right track to improve tolerability of mRNA vaccines, we continue to work to bring them to the levels observed with standard-of-care vaccines. Taken together, I think the strong immune responses against the A strains, our platforms lower reactogenicity profile compared to the competition, confirms that we do have a competitive mRNA platform. And as Frank will detail much later today, we will continue to evolve the platform in step with the competition to improve reactogenicity and tolerability and thermostability. Let us be clear that mRNA technology is only a means to deliver improved flu vaccines. As we said in December 2021, the mRNA technology alone won't be sufficient to achieve these goals. So next couple of slides, I want to give you an update on the progress we've made on machine learning for better strain selection and on the inclusion of neuraminidase antigens. Let me first remind you of the concept of our innovative machine learning-based approach. As shown on the left-hand figure of this slide, every year, the WHO collaborating centers generate large data sets, leading to a recommendation of the strains to include in the vaccine, which provides a coverage as indicated here by the small black circle. Despite the rigorous framework used, influenza is so unpredictable that new strains sometimes emerge right before or even within the season, as shown by the red cluster at the top of this graph, leading to suboptimal vaccine performance. At our last Investor Day, we had shared how we designed algorithms to select strains offering a broader coverage, as shown here by the largest circle in blue. And this has the potential to make vaccines more resilient against viral evolutions during the season. We also shared data from the clinical trials we have conducted with H3 strains that validated this approach. Today, we are pleased to share with you how we've extended this concept to H1 strains. And as you can see on the right-hand side of this graph, machine learning strains, the solid lines, offered a stronger immune response against a broad panel of strains compared to the WHO-selected strains, the dotted lines. And what this does is it brings us much closer to entering this improvement in our development pipeline. Let me finish with the data from the pilot trial I've mentioned earlier, where we have tested different doses of unmodified mRNA-encoding neuraminidase and compare it to Fluzone High-Dose. We're very pleased with the data from this trial. These graphs show the response to neuraminidase with [ 4-fold ] rise of antibody titers on the left and seroconversion on the right. And we know that the minimum bar to be used as a reference when including neuraminidase in your vaccine composition is Fluzone High-Dose, which contains about 2.5 to 3x higher neuraminidase content than standard flu vaccines. Our mRNA neuraminidase vaccine met this benchmark. In using antibody titers and seroconversion rates have at least equal to those induced by Fluzone High-Dose. And of note, we also observed a good reactogenicity profile with this vaccine despite the use of unmodified mRNA. So Bill, we've got through a lot of data here that underlines the strength of our flu portfolio. Why don't you come up and summarize it for everyone.

Thank you, Saranya. So overall, we believe we're continued to be poised to win in flu. We are actively building; next-generation flu vaccines, investigating multiple factors across multiple technologies designed to deliver solutions for seasonal markets across the key factors that this type of market demands. And we've made great progress on our mRNA flu vaccines, clearly closing the gap with our competitors. However, further work is required because even if it were to be licensed, this first generation mRNA vaccine will not be commercially successful for all the reasons we outlined today. In the meantime, we are focused on expanding both Fluzone High-Dose and Flublok, as these products are the only 2 products that have proven a demonstrated performance of efficacy against a standard-dose vaccine in randomized controlled trials. In addition, Fluzone High-Dose has achieved a consistent demonstration of protection beyond flu for over 12 years. So having a clear path to developing the next-generation flu vaccine while continuing to grow our current business gives us that unique ability to continue to win in flu. Thank you very much.

So now we have around 20 minutes for our first Q&A session. So I'd like to invite all our presenters back on stage, and we're going to start here in the room. And why don't we just start from the side, if we start with Florent. If you could please wait for the mic, just identify yourself quickly and then off we go.

Florent Cespedes from Societe Generale. A question for Thomas. You usually where you are guiding, you are cautious, but you are also ambitious. With a EUR 10 billion target for 2030, could you give us -- share with us what -- which are the plus and minus or the moving parts that could lead to a potential increase or maybe the challenges?

Thanks, Florent. Great question. So it's all about the ambition. And the way you phrase the question is very important. Yes, we're reasonably cautious, which I will translate as we see what we're going to do, and we do it and we deliver it back to '21 and '23 but with ambition. And I think the important part of the ambition is greater or EUR 10 billion sales by 2030 doesn't mean we are shooting for EUR 10.00 billion. Now how we're going to get there, which is being your questions, we don't exactly provide numbers and not going to change our habit, an exact split product by product. I still need more -- a few more quarterly earnings to get there one day. But of course, if you think what we are seeing in the pipeline today and the data we have, it's going to be clearly more confident in what we're building RSV. I think RSV Toddler is going to be great. I'm sure there might be some questions there. Beyfortus is not if, it's a now, it's a reality. RSV Older Adult, it's not about an RSV flu combo. And I'm happy to come back to this. It's about having the right RSV combo, and that creates a lot of certainty. And of course, you can talk about PCV21 and put a number. But when you don't have Phase II data, it's different when you have Phase II data. So all of this together is going to be greater or equal than EUR 10 billion.

Then we'll go to Pete.

Pete Verdult, Citi. Three quick ones. Paul, firstly for you, I enjoyed your rousing call to arms comments at the start. With that in mind and if you do get a fair wind with the upcoming data readouts. Just what's your appetite like to move midterm targets away from BOI and free cash flow to actually grow growth-based targets. Thomas, just you've given us your revenue expectations. I realize you no longer disclose the Vaccines margins. But just aspirationally, would the idea from a profitability perspective be to maintain already high levels or can you do better? And then lastly, one for you, Thomas, would you consider inorganic opportunities in adult RSV if opportunities came up? Or is it very much about you want to go down the path of combination vaccines with non-evolving viruses?

You want me to start in and -- I'll start with the vaccines one, profitability. Well, you know we don't provide any more specific targets, but it doesn't mean that the goal is to decrease profitability. So you know a road map of Play-to Win, 3 pillars efficiency, the third one, efficiency is going to remain there. However, what I think is very exciting is that we have more and more proof points of the R&D delivery. So each time -- our R&D philosophy is pretty simple, and I'm sure I'll come back to it today. It starts by looking what's the need in the marketplace. Therefore, what's the target profile we want to have? Therefore, what's the science requirement to get there? And if we have the science, then we got speed there. So we are making good proof points on the science. For sure, we're going to keep investing in R&D science in vaccines, but of course, with the right level of efficiency. On the other part, inorganic opportunity, like everyone, we're looking into it. It needs to make sense. It needs to fit with our commercial footprint. It needs to fit with what we know and are able to. When it comes, I think you had something specific in mind about our RSV Older Adult. It goes back to the philosophy, and that's why I started by that first, what's the need. The need -- and that's exactly what we mentioned in December 2021. The need is to add the right respiratory combo that makes sense. And in December 2021, then we said, okay, I understand and I hear the hype, but we do believe variably that RSV flu combination vaccines will have a very low opportunity because RSV will not be an annual vaccination because the RSV virus is very stable, which is not the case of flu. Turned out to be much more interesting when it's ACIP saying it than just on the figures, I fully understand that part. We also said and we talk about our combination, but same thing, they will have limited opportunities because burden of disease is going to shift. Requirements in this year are going to shift. So the way we're looking at it is actually what you had in your question is what's the need? RSV-based combination that answer a multi-annual protection on stable respiratory viruses. hMPV, PIV, are just in that space, and there are two problems for hospitalization of the elderly. If externally, to come back to your question, there was a great opportunity in that space. We will look into it. Right now, the science is very good in our camp, and we're going full speed on this one.

Thanks, Thomas, and thanks to the team. By the way, I don't often get a chance to say this upfront during the session, but a great job, really strong. Rousing is what you said, right? I think we're getting ahead of ourselves to talk about the areas you want to go. You can see that moment right? You can see it in our future. But I think my energy this morning was more towards this afternoon, was more to try and help people understand that we've reached such an accumulation of positive news flow, but I'm not sure it's fully appreciated, calculated, included. And I think there's some work to do on that. And when I feel like it's been properly included in the thinking of where we are, there's just too much for it to be ignored, and we can talk about how best to look longer term as a company.

Move to Graham.

It's Graham Parry from Bank of America. A question on Toddler RSV. So what is the intended Phase III trial design in terms of endpoints? And what do you think you need to show in a Phase III trial to stimulate same broad uptake there? Is it just lower respiratory tract disease? Is it hospitalization data that you're going to need to really get an ACIP recommendation there? And then do you have any sort of sense of the size of the market there? Is this a pneumococcal-size market, for example, in your minds? Or is it something smaller? And then second question on flu, can you just clarify whether the quadrivalents that you've been showing today -- shown today are already thermostable? And -- or is that still [ GDC ] in further development? And how do you intend to improve the serotype immunogenicity?

Great questions. I'm very pleased to have some RSV Toddler questions. Jean-Francois, I give this one to you. RSV Toddler end points, do you see the clinical design? Maybe just on the marketplace and the size of the opportunity, do we see it as a pneumococcal opportunity just for RSV Toddler. No, and it would be a lie if I were saying so. Why? Because it's not for shots and it's the burden of disease of RSV between 1 and 5 years of age not IPD, invasive pneumococcal disease, from birth. But it's -- you saw the market, it's a EUR 1 billion-plus marketplace. We're going to be first, best in class, and I don't think there's going to be much competition at all with the product profile we have. So it's a potential blockbuster for sure, not a clinical -- pneumococcal area. And design...

Yes. And I think the last question, Graham, I think we rather -- in the interest of time, we park for the second half because we have some...

You have the answer in the second half, and you can ask about thermostability we're going to show you with Frank what we're doing in mRNA thermostability.

Yes. Thank you, Thomas, and thank you, Graham, for the question. So for sure, in RSV Toddler, we're going to develop it as we have done for nirsevimab, meaning we're going to look at all the endpoints that matter from a public health point of view. It's clear that we are discussing now the endpoints with the regulatory agency, and it's still early. But for sure, no doubt that we will have lower respiratory tract as an endpoint. Yes, we're going to look at upper respiratory tract because we believe there is a need there and we believe that will be a differentiator from us -- for us compared to competition. Of course, these are 2 endpoints only that I'm sharing with you today. There will be others in the Phase III or post-licensure. So for sure, as nirsevimab documentation, I would say.

So Matthew?

It's Matthew Weston from Credit Suisse. Two RSV questions, if I can. The first just on capacity. You made it clear that you felt you had capacity for the upcoming season. I realize it's biologics are very different from what we see with normal vaccine scalability. But can I just check that you don't see any issues in terms of multiyear scalability of supply for that product? And then secondly, just back to RSV Toddler, I might be wrong. I thought the ACIP recommendation was a majority vote that for high-risk patients, they should get it -- they could get nirsevimab in their second season. So other than the economics of being wholly owned versus not wholly owned, what's the advantage of going for all toddlers with a novel vaccine versus just sticking with nirsevimab in the second season for high risk?

Thanks for the clarifying questions. I get to you, Kimberly, for the second question. The first one I can handle quickly. supply, do we feel good? We feel very good. And no issue on ramp up. We have a great partner that has strong manufacturing capabilities for monoclonal antibody. We're able to scale, and we feel very strong when we look at next year. Compared to monoclonal antibody this year, so yes.

Sure. And good question for Toddler on nirsevimab, just to clarify for high-risk babies in the second season. So why would we go for a toddler vaccine versus nirsevimab for all babies in the second season? Probably it wouldn't make sense, one, from the total health economics of nirsevimab for all babies in second season probably would not make a lot of sense. But I would also say, remember, in the first season, we're giving the antibodies passively because babies are too vulnerable, too little to develop their own. The value of giving a live-attenuated intranasal vaccine in the second season is they're going to build their own antibody response. And we hope that, that's going to last a little bit of time because kids are at risk until age 5. So it's about sizing what is necessary based on the problem at hand. When they're so little in the first season, they can't do this on their own. But when I get to the second season, that's the right time to let them develop their own antibodies, and hopefully, those are going to last. And so that's a bit the rationale.

Maybe just clarify, Matthew, the ACIP warning may be -- or the FDA AdCom wording, maybe a bit confusing. When they're taking babies at risk, it doesn't mean all the babies or the second season. It's a very tiny proportion.

Okay. Luisa?

Luisa Hector from Berenberg. So again, RSV questions, maybe the older adults this time. So you didn't say a lot about the Phase IIb. And what is the reason for that trial rather than Phase III? I think you mentioned possibly trying a higher dose. And would you perhaps compare to the new vaccines that are launching now? And when we think about the mono or the combo RSV, is there a role perhaps to look at booster Phase III is there eventually? Or would that be the focus being on the unvaccinated still?

I like R&D creativity popping up. Great question. The second one. Jean-Francois, I'll give you the floor for those 2 questions. First one, on the design of the next stage for RSV toddler and what about combo for vaccination?

Yes. So the reason why we designed the Phase IIb is fairly simple. And the reason it's changing a little bit following the outcome of last week, the HCP from last week. So for sure, we are convinced we have a great vaccine, no doubt. But we were fearing that actually the window to show the efficacy would win. And that's why we designed a Phase IIb to show the efficacy against placebo before the vaccine is widely implemented. I must say now that Pfizer and GSK have received a pretty poor recommendation with a shared decision-making. We believe the uptake of the RSV older adult vaccine from these Pfizer will be much slower than anticipated. That means the window might remain open longer. We may demonstrate efficacy in the Phase IIb and potentially in the Phase III with a combo with where the space is going. But that's the reason for that trial actually. Allow me to..

The vaccination handle.

No, I think it's a brilliant question. I love it. For sure, again, another set of data that was apparent last week is that when you revaccinate with a protein-based vaccine, you cannot boost at least when you're a vaccine after the -- after 1 year. This might be true for all the RSV vaccine for all the adults or it might be a class effect of protein-based vaccine, in which case, our vaccine could have a profile for primary vaccination but also a profile for booster dose. And at the end, we expect that booster dose will be needed. You saw the efficacy dropping in RSV toddler. It's not that you will be immune for the rest of your life. The markets will not disappear. You saw the efficacy waning both with a adjuvanted vaccine and a non-adjuvanted vaccine. So everybody will have to reboost at some point. That's our view.

And if you need to boost after 3 to 5 years, and the market has been built by their colleagues. And if mRNA technology is the right one to boost, it will not be a bad put to build.

Peter?

Peter Welford, Jefferies. Two questions. Firstly, just coming back to the RSV toddlers. Just wondering, we've seen great antibody immunogenicity data many times before in RSV, and then Phase III trials have failed. This is obviously intranasal. Any thoughts on doing a challenge trial before you go into Phase III given the route and given everything else? And equally, do you have to some make sense, enrich for the 1-year and the 2-year olds? I guess what's the risk? By the time you get 4- and 5-year olds, they're actually natural immunity, mutes the response you're going to be able to get in a Phase III trial when you're trying to actually show hard endpoints. And then if I could just ask on flu. Is the only way you can beat Flu, Flublok in terms of real endpoints to go with more antigens, more strains, more -- and I guess the question is, do you realistically think you can ever beat Fluzone High-Dose with just a quadrivalent mRNA vaccine? Is there any point?

Before go to flu RSV toddler, maybe explaining a bit what we have in mind, challenge or the challenge and how we do see maybe the product profile because it could be used for toddlers, as the name says, but the intent is not to provide protection just for the second season. The idea will be to protect for more seasons without new doses of the RSV toddler product. But challenge?

Yes. Challenge is usually something that you do when you are not sure that your vaccine will work in Phase III and you want to discharge the risk. If we don't have confidence, it's a reasonable option to consider. We are confident in the performance of our vaccine. It's building on decades of research at the NIH and that's why we believe with the safety, the immunogenicity, the vaccine response rate. The next logical way for us is go straight in Phase III.

I think that's a really interesting question. I mean clearly, I think you're convinced, thankfully that Fluzone High-dose is a really high bar. So that's the important message, I think, you should take away. Fluzone High-dose are very interesting. So it's really an evolution of technology. And I think what you see in Fluzone High-Dose is a combination of different antigens. You do have hemagglutinin there, but you also have neuraminidase in them. In fact, you have some other antigens like nuclear protein. So I think you're right, it is a high bar to meet there. And that's why I think what we're trying to do in R&D is really look at multiple parallel approaches that include both neuraminidase but also this machine learning approach, optimizing the B strain. And I think as we get the data next year about all these different approaches, I think we get a much better indication of where we need to go.

Okay. Let's try to take one question from the webcast, if we could have David. David, can you hear us?

Yes. Great. Can you hear me as well?

David from Leerink?

Yes. Can you hear me as well?

Are you unmuted?

All right. Can you hear me?

Yes, fantastic.

I have 2. First, could you discuss your hypothesis why mRNA vaccines for flu underperform on the B strains consistently? And then second, with respect to PCV21, if you could just comment on what happened with the adult Phase II results.

Okay. Thanks. Let's park the PCV for the second one. We can come back to that. But yes, let's talk about mRNA and the B strains.

Yes. And I'm sorry, I may disappoint you a little bit. We have a fairly good idea of what is happening. Of course, it's also a very highly competitive field. So -- and you have seen that our competitors have not really disclosed what they were working on to fix it. We are working on a couple of opportunities. We believe we have the solution in one of the streams that we're not going to share that for the reason I mentioned.

And Bill will have given you the answer that flu is not COVID, i.e. it's not only population, but it has multiple strains of flu before. And therefore, the real space trying to go is much more complicated. Science will tell the right pathway.

Okay. Let's take one quick last one here in the room, if we have Simon. And yes, we have a second Q&A session also after the second part.

Simon Baker from Redburn. Just going back to RSV, just one question. On the hospitalization data, that's changed quite a bit since the December '21 presentation as of 177,000 this time. It was [ 105,000 ] last time. Is that just a different data source or has things changed post pandemic and there's a bigger disease burden [indiscernible] ?

Hospitalization, Kimberly, you want to take this one?

So we continue to look for the best hospitalization data that we can find, right? We're always getting new sources because RSV is also a space where we continue to get more and more information through surveillance and [ Epidemiology ]. So I think that's the first thing. I think the trend of what you see on the impact in hospitalization, but how much of it there is and then the impact from a product perspective on what we can reduce, I don't think that's changed. I do think we have some new data sources that you're seeing. So that's absolutely true.

Surveillance system, that we used to be. And when you look, you're fine.

Okay. We're going to go for a short break. For those that are following us online, we're going to shorten the break to 10 minutes. So as planned, we're going to be back now at 3:40. Please stay on the same link. For those here in the room, we're just going to take a short bio break, get some air into the room. For the ladies, if you need to go, you have to go right and then immediately left, left. And for the gents, if you need a restroom, just go straight past the elevators into the hall and then it's on the right side. So let's see you all back again here with fresh air, hopefully, in 10 minutes. Thank you. [Break]

And I would like to acknowledge the presence of SK CEO, Mr. Jaeyong Ahn, and here with us today on the second row. We have a very productive partnership on this ambitious program, and we are sharing together this significant promising investment. As a reminder, we are codeveloping together our PCV21. SK is in charge of manufacturing and retains commercial right in Korea, while we are leading the commercial launch globally. I'd like to come back on the medical improvement we are bringing by adding a 21st serotypes standard of care. With our PCV21, we do have the opportunity to extend protection against pneumococcal disease and raise the bar by adding coverage. This matters. Additional serotype coverage matters in the PCV pediatric field. Indeed, there is still a significant residual burden of pneumococcal disease, especially in the pediatric segment. As an illustration in the U.S. alone, [indiscernible] disease accounts for 1,500 invasive pneumococcal disease cases as well as 1.5 billion cases of acute otitis media in the population less than 5 years old. Despite major progress, this is still out there. Our additional serotype 9N will provide an additional 5 to 7 percentage points gain in IPD coverage across all ages. In addition, beyond direct protection to children, PCV vaccination offers a positive indirect impact on the other age segment through herd protection, which does help reduce the residual burden of disease in the overall population. Now let's hear from Jean-Francois on the exciting results from the Phase II trial of our PCV21 vaccine. Jean-Francois, the floor is yours.

Thank you very much, Thomas. So as you explained, we are focusing on accelerating on the pediatric segment. So I'm going to share with you today the data observed in the pediatric trial. So we designed our Phase I/II trial actually to select the formulation that could be progressed into pivotal trial. And we tested multiple formulations, compared them to PCV13. PCV13 was obviously the standard of care at the time when we started the trial. So the vaccine was tested in influenza according to classical schedule based on 3 administration at 0 -- at 2, 4 and 6 months of age and then a booster between 12 and 15 months. And the endpoint were very typical for Phase II trials, so safety, reactogenicity and immunogenicity, of course. So for immunogenicity, please note that we have used the endpoints that are mandated by regulatory authorities for licensure. These are the IgG concentration and the response rate post those 3 as well as the IgG concentration of those 4. So let's have a look at the reactogenicity profile first. And here, I'm showing only the lead formulation in purple. As you can see, the vaccine was very well tolerated with a similar level of local and systemic reactions compared to the PCV13. Now let's deep dive in the first part of the section and have a look at the immune response induced by a lead formulation. So the graph on this slide, I acknowledge, are fairly complicated. So let me walk you through the data that they contain. So first, it's important to note that this graph -- this slide is focusing on the serotypes that are in common with PCV13. The different serotypes will be covered on the next slide. And in each slide, the different lines represent different serotypes. Second, you see that the graph contains 2 sets of information. The purple dots represent our PCV21 vaccine candidate, whereas the gray dots are reported by our competitor with the PCV20 vaccine that was recently approved in the pediatric population. Third, I want to remind you that the data are expressed in relative value compared to PCV13. So it's either as a concentration ratio or at the seroconversion rate difference. Now that we are all on the same page, at least I hope that we are on the same page. And if it's not the case, there is a break afterwards to discuss that. Let's have a look at the data. So the fourth graph here on the left part shows the strong immune response induced by a PCV21 vaccine candidate after the third dose. You will note that all the serotypes are in line with PCV20, but that we actually have a really, really favorable profile for serotypes 3, 5 and 23F. And you know that serotype 3 is a critical one. So we are very pleased to see that our deliberate efforts to improve it are really paying off. The graph in the middle looks at the seroresponse rate as those 3 and the graph on the right represent the IgG concentration for those 4. And both of them through the same picture and they confirm a favorable profile of our candidate comport to PCV20. So this slide now shows under the same format, the results that have been absorbed with A serotype that are not contained in PCV13. And again, we were pleased to see that we are vaccine induced a strong immune response, which results in line or favorable with PCV20. So if you combine these 2 slides together, I'm sure that you now understand why we're excited about this candidate and why we're excited about the way it compares to PCV20. We believe that this result that you just saw create a strong path for us into Phase III and then to licensure. Now let me share with you for the very first time how we plan to stay ahead of the pack today with PCV21 but also in future generation containing more than 21 components. So we actually introduced a new carrier to improve the performance of the 4 serotype: 1, 5, 15B and 22F. And we do that to improve performance of performance but also to avoid overloading the immune system with a creme carrier. The graph on the right show that these 4 conjugates induced a strong immune response. And as we have seen before, including this carrier did not increase teratogenicity or the tolerability profile of our product. So the last piece of exciting data with this product was gathered in an additional Phase II trial that was designed to support the interchangeability of our product with PCV13. We actually administered PCV21 or PCV13 to toddlers who have been primed with 3 doses of PCV13. As you can see on the left graph, both candidates were equally capable of boosting the immune response primed by PCV13. As shown on the right graph, a single dose of our PCV21 candidate induced a strong immune response against the serotype not covered by PCV13. What does it mean in practice? It means that baby will see 3 dose of PCV13 or PCV20 in the future would be eligible to receive our PCV21 vaccine as a fourth dose, making it easier for the practitioner to switch from one product to the other while offering the benefit of the additional serotypes. So I hope that you appreciate that we have developed an ambitious program and that our Phase II results have convinced you that we are really well positioned at Sanofi to deliver the first PCV vaccine covering more than 20 serotype in infants. Together with our excellent partner, SK Bioscience, we will initiate the pivotal Phase III trials in the first half of '24. And we will target regulatory submission in '27. So if you look at the size of the market and you look at the profile of our product, we really believe that our PCV21 pediatric candidate will become a blockbuster and that very quickly after launch. As I said, we will not stop at 21. That's not the end of the race, and we have already initiated the preclinical development of a higher-valance product. So just summarizing it, if you put it all together, we are convinced that we can make a strong entry in the PCV market, and we intend to remain highly competitive on the long run. Now let's move to meningitis and other exciting prevention area. So Thomas, floor is yours.

Thank you, Jean-Francois. Now meningitis. I am very excited to report that we are consolidating our leadership in meningitis with MenQuadfi. MenQuadfi is setting a new standard in the quadrivalent meningitis prevention space. Its best-in-class profile is defined by several features that do matter in the daily practice. First, higher immune response against C, which we know is key in many markets that are switching from C standalone to ACWY and do not tolerate any compromises on C protection. Second, MenQuadfi is available in a fully liquid presentation that eases administration for the health care providers. Third, MenQuadfi age indication is broad, giving administration flexibility and ability to match multiple schedules in the U.S. and in the rest of the world. Lastly, we now have up to 7 years persistence in different age groups, which is now documented in our label. MenQuadfi is the U.S. market leader with more than 60% market share. And I am very happy to share that we have converted all our U.S. customers from an atop to MenQuadfi. Beyond the U.S., MenQuadfi is now registered in more than 53 countries, including all the major European countries and key international markets. Now I'd like to share new groundbreaking evidence on the improvement MenQuadfi brings to the meningitis field reinforcing its best-in-class profile. You certainly remember data we provided in December '21, showing that MenQuadfi induces a superior immune response against MenC compared to competitors' products. Since that time, we have generated additional impactful data demonstrating yet again MenQuadfi's best-in-class profile. On the left part of the slide, you can see the immune response induced by MenQuadfi versus Pfizer protien vaccines in adolescent population. This graph is pretty self-explanatory and shows the improved performance of MenQuadfi across all 4 ACWY components and particularly for serogroup C, which is fully consistent with what we showed last time. The graph on the right shows the immune response induced by MenQuadfi this time with GSK's quadrivalent vaccine in infants and toddlers. Here, it shows that 3 doses of MenQuadfi is similar, if not a better, immune response than 2 doses of GSK vaccine. These are obviously important for MenQuadfi. But on top, as you can imagine, they also give us a lot of confidence when using MenQuadfi as our backbone to develop a best-in-class pentavalent MenACWY vaccine. Now let me tell you something that's really exciting. Next year, in '24, MenQuadfi will be the only product available in the presentation preferred by 80% of HCPs ready-to-use pre-filled syringe, which is so much more practical. Due to the use of silicon pre-filled syringes, no manufacturer had succeeded to achieve this to date. After considerable process development and through the right exclusive collaboration, we resolved this CMC challenge. As you realize, this is another major improvement for our customers, enabling seamless administration. We have high confidence that this new feature will become a significant differentiator as we observed with several other syringe products in multiple markets. To say the least, meningitis schemes are quite complex and highly heterogeneous, which means that you absolutely need the most complete profile to be able to play and win globally in this market. With its most complete product profile, MenQuadfi is best positioned to address current and future immunization schedules for meningitis vaccines. As administration here, age groups. As you can see on the left part of the slide, recommendations vary greatly between countries. Here again, MenQuadfi broad indication is a key advantage to sustain growth over the coming years. Now the elephant in the room. It's a small room. Some believe that the pentavalent is going to take over and the quadrivalent is going to be replaced. In reality, that transition will not be immediate at all. In fact, a quadrivalent vaccine will be relevant in the market still for quite some time. Why is that? Well, I think the pentavalent will not be effortless for health authorities and will depend on multiple factors. Immunization schedule compatibility is one. Epidemiological trends by age and serotype is another one. And last but not least, cost effectiveness and impact on public budgets does matter. Let's illustrate this with the U.S. market. As you know, ACIP gathered last week to discuss potential schedule evolution. And they can for it's not going to be a walk in the park for the pentavalent. It will take time and the right product profile, which, by the way, could be one of the reasons why GSK is planning to come with the second-generation pentavalent in a few years from now. Let me remind you here, the current schedule in the U.S., meningitis ACWY vaccine is given in routine 2 doses: at age 11, 16, and that's where MenQuadfi leads. Meningitis B vaccine is optional. And it's given with the first dose at [indiscernible] then a second one, 3 months later with limited coverage rates because of the recommendation shared clinical decision-making from ACIP due to the value perceived of this vaccination. So that means the first doses, the 11 years old doses, is on the table for pentavalent just to start with. And then the only change ACIP actually opened the door to last week is for the second dose at age 16 to be optionally combined with the first quite dose however, still with the same optional scheme, which means that the schedule essentially remains the same. And under such recommendation, we know that the ramp-up of the pentavalent will only be slow. So to sum it up, MenQuadfi with its best-in-class profile is poised for continued success. Now as leader in meningitis vaccines, we continue to innovate and we are building the future based on our best-in-class MenQuadfi backbone. Saranya, do you want to share with us the exciting set of data that we have and you bought for us today on our meningitis portfolio, please?

Thank you, Thomas. We've indeed made significant progress in our portfolio. So let me start with our meningitis B program and the data from our Phase I/II trial in adults and adolescents. And as a reminder, this vaccine candidate is based on multiple components selected to offer broad protection against circulating strains of meningitis B. We tested different formulations in order to find the sweet spot between reactogenicity and immunogenicity, and we compared them to 2 licensed vaccines: Bexsero and Trumenba. And today, I'll share with you the data from the adolescent cohort, and we are very pleased with the outcome. What you can see here are the data from 2 formulations that we intend to progress to the next trial. And the data presented here are the functional serum bactericidal responses against different MenB strains. The left part includes the strains that we use to design our vaccine, and the right part refers to strains not in our vaccine. The color code in forms of the immune response rate observed with our vaccine compared to Bexsero and Trumenba. The green cell indicates the strains for which we observed the seroresponse rate at least 15x higher than the competitive vaccine. The dashed green cells represent the strains where we saw a similar immune response to the competition, meaning within minus 15% to plus 15% seroresponse rate range. And the yellow cells represent the strains against which we had a lower response than the competition, noting that this includes the strains that were used by our competitor to develop their own vaccine. So what did we observe? First, very pleased that our vaccine candidate was well tolerated, in line with competitors' vaccine in this population. Second, all components of the vaccine were immunogenic, induced a functional bactericidal immune response. Finally, the breadth of the immune response that we observed and the coverage of the different strains were completely aligned with our prediction. And this data gives us the confidence to proceed to the next stage. Our next stage includes progressing our MenB vaccine to toddlers and infants, but it also includes the development of a men penta vaccine building on our best-in-class MenQuadfi vaccine. The preparation of our Phase I/II trial for our men Penta is underway, and we have significant reasons to believe that this vaccine perform well. And let me share some preclinical data that will give you the same confidence. On the left side of this slide, you see the stability of the different components when mixed in our pentavalent formulation. The upper graph shows the amount of free polysaccharide across all 4 ACWY conjugates, which doesn't increase over time. And on the bottom part, you can see that the MenB components also remained very stable over time. On the right side of this graph, you can see that the different components did not interfere with each other in a rapid preclinical model. This data greenlights our advance of this program to a Phase I/II study planned to start in the second half of this year. So overall, we are in a very strong position with our meningitis portfolio. We are setting new standards with our best-in-class MenACWY vaccine, MenQuadfi. Our Phase I/II readout for our novel MenB formulation demonstrates strong potential for cross-protection across B strains and a very competitive product profile, thanks to its specific design. We will be able to put these together to achieve our goal of a best-in-class, fully liquid pentavalent vaccine. Again, we expect this to be available in ready-to-use syringes, a real differentiator in this market, and we expect to file for registration in 2027. Thanks. With that, let me hand over to Jean-Francois and Frank to walk you through the progress with our very exciting mRNA platform. Jean-Francois?

Yes. We need traffic light in this room at some point. So thanks very much, Saranya. Thank you for walking us through these exciting data, but also thank you very much for all the work that you and your team are doing on delivery. It's really much appreciated. Now for this session, I'm delighted to share the stage with you, Frank, Frank DeRosa, our mRNA Chief Technological Officer and also the Head of our biomarker and research group in the mRNA center of excellence. So together with Frank, we will give you an overview of the great progress that we have made with mRNA since we last talked in December '21. So I trust that by now, the RSV and the flu data have convinced you that we already have a leading mRNA platform. We now share our robust innovation pipeline that will lead us to the next generation of mRNA. To achieve this stage, we have doubled down both on execution on one side but also on innovation. As we speak and I already mentioned, we already have in our pocket the result of 7 trials based on mRNA candidates. We've also assessed the clinical performance of 3LNP, and we'll have 2 more by the end of this year. But the pace, the breadth and the depth of our research would not be possible without our people. There as well, we've exceeded our ambition with more than 600 top-notch MRNA experts dedicated to mRNA science and technology. Increasingly important into this world are the collaboration that we have forged across academia, with example, our expanded collaboration with Dan Anderson at MIT; across industry with multiple innovative companies, for example, Baidu or Inceptive; but also with government, such as the vibrant partnership that we forged with the Queensland state in Australia. Innovation is happening everywhere in our Harmony Center of Excellence, and you're going to review with Frank the elements covered on the right of this slide. But before going there, I'd like to emphasize the importance of the end-to-end approach that we are pursuing in our mRNA center of excellence and the role played by artificial intelligence and machine learning. As we all know, it takes an aligned and committed organization to generate but also to structure the massive data set supporting the development of predictive and generative modeling. And as we know as well, the performance of mRNA depends on multiple parameters, and all of them need to be optimized. That's why we've built an organization where data scientists are working very closely with experts in antigen design, mRNA science, LNP science, biomarker and transactional medicine. With that, they develop proprietary models across the full spectrum, learning from CMC, learning from preclinical in-vitro, preclinical in-vivo but also from transactional trials. And it's actually these iterative loops that propel us with a high confidence towards the next generation of mRNA. I'd like to also highlight the expansion of our mRNA technology to bacterial target. We all know that mRNA is particularly suited to express viral antigens. And our data here on the left confirm that again. But the chart on the right illustrates our mRNA vaccine candidate against acne and chlamydia can induce equivalent or even superior level of functional antibody levels compared to the recombinant protein equivalent antigen. I'll leave it to Sally to cover that a little bit later when we go through the early pipeline. And for now, Frank, time has come for you to go a little bit deeper in our mRNA science. Frank?

Thank you very much, Jean-Francois. Good morning and good afternoon, everybody. As we just saw, the versatility of our mRNA platform is an essential pillar to our ambition to create first-in-class and best-in-class vaccines and therapeutics. And although we're focusing on vaccines today, we understand the power of this technology and believe in the use of mRNA beyond vaccines, and we're currently exploring this further in other therapeutic areas in close collaboration with our pharma colleagues within the company. But vaccines are not perfect. As you've heard today, they require additional innovation. So I want to begin with some key topics that you've heard today regarding areas of intense focus for us in research as we push into our next-generation platform. Potency, reactogenicity, thermal stability, you've heard this several times today, you see it on the screen. These are recurring themes that are critical to an mRNA vaccine's success. Solving these will certainly open the doors dramatically for broader applications that I mentioned here today. And I'd like to begin with potency and how we are approaching this parameter. And there's many ways to approach this. You can look at the mRNA side of the puzzle, you can look at the LNP side of the puzzle. For mRNA, think about how you can do this to increase the potency. You can increase it through antigen expression. You can increase this through increasing the stability or increasing the purity of the quality of the mRNA. Shown here is an example of how we are doing early efforts here to improve the amount of antigen produced per molecule of mRNA. That's what you're seeing on the right here, to improve the instructions that we want to deliver to our bodies. This is through sequence specific changes where we computationally design hundreds of thousands of these sequences, narrowed down to multi-hundred, synthesize them and test them. And we can see just by optimizing the sequence in this way, you can see a significant increase in the amount of antigen produced per given mRNA molecule. And when we dive a little deeper, we can attribute this increase to an increase in translational efficiencies. It's what's shown in the center here of the slide, what's known as ribosomal engagement. That's the machinery in our cells that recognizes the mRNA, recognizes those instructions and can read them easier. And that's what's affording more antigen per mRNA delivery. When we go one step further, we can visualize this increase in antigen expression through cell imaging. That's what's shown on the right there. Much more orange fluorescence results in much more antigen produced at a given dose. So I mentioned we can approach potency through the mRNA side of things. This is just one example. It can also be approached through the delivery system. And in our case, we're talking about lipid nanoparticles or LNP. So I just want to give a little refresher here to briefly reintroduce LNPs and what they're typically made on. Now typically, they're made of 4 components that are listed here. I would say the vast majority of focus in the field is on one component on that first guy up there. The INIs will lipid no doubt we have focused there as well, and there's a good reason for that. It can drive the potency. It can drive cell distribution. It can drive the tolerability. And we've made extensive progress creating a vast and differentiated chemical space around these lipid families. And what you're seeing here in the upper left-hand corner are multiple different lipid families chemically defined, chemically unique from one another that are showing superior potency over benchmark lipids there. But we're not stopping at that one component. We're innovating around the second component as well where we designed novel proprietary helper lipids here, a space largely unexplored in the field. And we've looked at the third component as well, where we've identified novel sterile derivatives. And when we add these 2 already potent INIs liquids, we begin to see double, triple, even quadruple the amount of protein produced at the same dose, really boosting that potency. And so again, we continue to innovate, and we move to that fourth and final component there, where we're swapping out that PEG lipid for alternative lipids there that maintain that activity and could have beneficial properties there. So we're not just looking at one component. We're optimizing around the entire LNP, all 4 components. And actually, we've pushed further than that because we've identified and developed novel proprietary excipients. That can act as a fifth component here, and we're seeing some really nice activity from some of these, again, up to 4x the amount of protein when we just add this fifth component into our delivery systems. So why is this so important? Higher potency can provide a potentially lower efficacious dose and better tolerability. And that leads us to our second key focus here, which is reactogenicity. And we're taking a comprehensive approach to building our understanding of what causes the reactogenicity that we observe with these vaccines. And we're doing this by generating clinical data across a large number of platform variables. Now you may recall the graphic that Jean-Francois just showed, that cycle of preclinical to clinical, in vitro to in vivo to human and how these data relate to one another and how we can feed that back into the platform. This is the clinical piece of that cycle. This is where we're interrogating platform features clinically to allow us to build a predictive model that will hopefully allow us to increase our speed for candidate selection and also our probability for success. That's the goal. And some of those platform variables include the type of mRNA. They include different disease targets. They include single versus multivalent approaches as well as a variety of different LNPs. And all of these studies, including ongoing ones help us to rank these different vaccines, these different variables. And we can show this in a plot shown here, a very simple high-level plot where we can -- immunogenic versus reactogenic performance here, very cool stuff and allows us to visualize that quite easily how they're performing. So I just want to go a little bit deeper here, and I want to share with you a snapshot of the approaches that we're taking to help link our preclinical observations with our clinical ones, utilizing our proprietary MIMIC system. This is an ex vivo system looking at immune cells and how they respond to any external variable we want to test. So the figure on the left is detailing cytokinin responses following an in vitro vaccination of this MIMIC system with various LNPs. And the improvements that we're seeing in the reduction of inflammatory cytokines can clearly be observed when we move from one mRNA to the next LNP iteration that we've selected for clinical development over time. These reductions that we see preclinically in the MIMIC system can be similarly observed clinically as we progress on the right side of the slide here, where we see a marked decline in the frequency as well as the severity of adverse events as we move from unmodified to modified. This is the type of mRNA. Other variables include different LNPs, as I mentioned before. And we've explored that in the clinic as well. And what we're seeing here is a comparison of 2 different LNPs. And first, I would note the low percentages of Grade 3 across the board in these 2 first-generation formulations with LNP showing clear differences from LNP 2, LNP 3 to LNP 2 there with a number of different readouts. This is a trend that we observe in our MIMIC system preclinically as well. And we're taking this even further. We started to identify key cytokines and genetic signatures that we're trying to correlate and link to adverse events that we see and assign pathways associated with that from what we're seeing preclinically to what we're seeing clinically in humans again. So we're very excited about this progress. We're continuing to build rapidly to develop this further. All right. So I've touched upon 2 of those topics, potency and reactogenicity. The third one that we've talked about and you've heard a little bit about, thermo stability, and it is a tough nut to crack, no doubt. You heard from Bill earlier the need for this in established markets such as flu or a minimum of 9-month stability, preferably 12 months plus, as a liquid under refrigerated conditions. And I'd like to begin here just to explain how we see the pathway for success as there are multiple challenges associated with this and many factors involved. The LNP plays a role, mRNA plays a role, scale plays a role, and handling across the entire industrial chain plays a big role in this. And if you think about what we mean when we say thermal stability, it's about your product being stable at a given temperature over a given period of time. It's not just about the LNP, but it's the mRNA inside of it. That's actually the real challenge there. So when a product is scaled up to large scale, early-clinical phase, late-clinical phase, commercial stage, when you have to perform fill finish, when you have to pack and ship, all of these processes ship away at your integrity because they involve either refrigerated conditions or even ambient or room temperature conditions sometimes. So a lot of work has gone into understanding what drives this and how we can prevent it. So I first want to begin by saying it is possible. It is possible to have an mRNA LNP stable for 12 months as a liquid unrefrigerated conditions. Now I want to point out here, this is a prototype LNP with specific features that are resulting in this. And we've learned a lot through this prototype as well as through additional endeavors on factors that can have a beneficial effect. The key is how can you incorporate this knowledge into your leading product. And we've made significant gains there. And here in this example, we've shown up to 9 months relative stability with our QIV LNP candidate. This is a flu candidate. This is a quadrivalent flu candidate in particular. So progress is certainly being made, and we continue to drive, we continue to improve, we continue to learn and develop our expertise in this. So as we move into the last slide here, I'm very excited at the progress we've made on so many fronts. We have firmly established a competitive platform, and it's been an incredibly productive 18 months since we last spoke. And we're addressing all of those critical areas that we feel are required for success through technological advancement as well as biological innovation through antigen design. And all of that together is putting us in a strong position to cross new frontiers. And to expand on these new frontiers, I'd like to welcome Sally Mossman to the stage, our Head of Research Portfolio Strategy. Sally?

Thank you so much, Frank. So hi, everyone. It's delightful to be here. And for this next section in our event, I have the great pleasure to spend some time talking with you about the earlier programs in our pipeline. And these are both programs that I'm particularly excited about. In each case, we're working to address as yet significant unmet medical needs and pushing the frontiers of science in vaccinology. So for today, we're going to be updating you on our chlamydia vaccine program. We'll be joined by Dr. William Geisler, who is going to share his significant expertise in the chlamydia field by educating us on the burden of disease there. This will be followed by a view on the data that has enabled selecting our final vaccine candidate to progress the clinical evaluation. Then secondly, we're going to cover our highly innovative therapeutic acne vaccine program. We'll be sharing our encouraging preclinical data, which has allowed us to embark on preparations towards a clinical study start later this year. So without further ado, let's move on to chlamydia. And it's my absolute pleasure to welcome Dr. William Geisler to the stage. Dr. Geisler is a Professor of Medicine in epidemiology in the division of infectious diseases at the University of Alabama at Birmingham. His expertise is in adult infectious disease, particularly sexually transmitted infections. And in this capacity, he has served as an expert consultants for the CDC and the WHO. So with that, Dr. Geisler, the floor is yours.

Okay. Thank you for the introduction, Sally, and welcome, everyone, to this presentation. I'll be discussing the continued high burden of chlamydia as a justification for why we need a chlamydia vaccine. If you've not heard chlamydia before, it is a sexually transmitted infection. It is due to a bacteria called chlamydia trachomatis. This is a bacteria that bacteria that infects humans actually inside human cells. That picture on the right is a fluorescent image showing you chlamydia bodies in the red impacting a host cell, which is shown in green there. Okay. So the World Health Organization monitors 4 curable STIs. One of those 4 is Chlamydia. The other ones are gonorrhea, syphilis and trichomoniasis. This global map here shows you how common these 4 curable STI are worldwide. But you start to break down the actual numbers and you look at chlamydia within the bacteria, there are about 129 million new cases of chlamydia each year, which is more than gonorrhea and syphilis, the other 2 bacteria, put together. So this is the most common -- chlamydia is the most common bacterial STI worldwide. Why is it so common? Well, it's common because it's a chronic infection, and most people who have this infection actually don't know that they have it. And so if you look at some of the earlier studies, they showed that women to have chlamydia, over 75% had no sign or symptoms of infection. And for men, that's over 50%. Some of the more recent studies using some of the newer molecular technology show that actually the asymptomatic rate probably exceeds 80% in both men and women. Now once you get infected with chlamydia, it lasts for at least weeks to months in pretty much most individuals. But there have been 2 studies in women that show that at least 50% of women are infected for 1 year or longer when they have chlamydia. On the figure and you're right, there is 1 of those 2 studies. This started as a natural history HPV study. As part of that study, they collected specimen about every 6 months and then later on went back and tested all these specimens for chlamydia. And what they found is that if you look at women at the beginning of the study who had asymptomatic chlamydia, and if you follow the figure to right and you look at 1 year, about 50% still have chlamydia if they're not treated about 1 year later. If you go out to about 3 years, they're still about 5% with persisting chlamydia even during that time. Despite the asymptomatic nature of chlamydia, don't let that fool you. Even in its asymptomatic state, it causes significant health consequences, particularly in women. Okay? So in women, when this infection gets to their gentle tract, it can spread to the upper gentle tract, something we call pelvic inflammatory disease or PID, for short. And that occurs in about 10% to 15% of women who have chlamydia. Once you have PID, about 1 and every 5 women or so can get infertility. About 1 in 3 women can get chronic pelvic pain lasting weeks to months. And then there's about a threefold increased risk for one of PID to get something called ectopic pregnancy. That is a nonviable pregnancy where basically the fertilized embryo plant in the wrong place, and that can lead to hemorrhaging and other complications in women. Now men do get chlamydia, of course. And they can have symptoms from chlamydia, they can have decreased fertility. But one of the greatest burden of chlamydia, men is simply that men transmit it to women. And then women get the reproductive morbidity that we just talked about. Now women who are pregnant and get chlamydia, they can lose the baby during pregnancy. They can lose the baby right before birth. They can have a premature delivery, and that baby can be low birthweight and have other complications because of its low birthweight. When a mother has a vaginal birth and that baby passes through the birth canal if the mother has chlamydia, baby can get an infection in his eyes or in this respiratory tract from the mother when that happens. And then the other thing that many people forget about, that's very important is that when you have chlamydia, it recruits inflammatory cells to your genital tracts, such as CD4 T cells. CD4 T cells are the target cells for HIV. So you have an increased risk to get HIV if you are chlamydia-infected. So I've just told you that committee is very common and it has these important health consequence. So of course, there are control programs in place to try to prevent chlamydia. And so pretty much most higher-resource settings as well as many lower-resource settings have these control programs in place. And they're quite comprehensive. You can see here there are chlamydia prevention measures, including recommending accidents, which as you can imagine, that doesn't work so well; promoting sexual health education; promoting use of bearing methods like condoms. But what we don't have is a vaccine for chlamydia prevention, the ultimate form of prevention. Now we do, of course, try to identify people to have a chlamydia. We certainly test them. And what's recommended for asymptomatic young women minimize sex with men and higher-risk individuals is that you get tested for chlamydia using very sensitive molecular tests once a year and then if you have signs or symptoms suggesting chlamydia that you get tested with these same types of tests. And if we find chlamydia in you, we have very good treatments for the patient and for the partner, either a 7-day antibiotic course of antibiotic called doxycycline or a single-dose treatment right there when a patient is sitting in front of you give them a single-dose treatment of azithromycin. And these 2 antibiotics cure over 95% of genital infections with Chlamydia, and we have no antibiotic resistance concerns with these antibiotics despite using them for over 40 years. So you would think, gosh, right, these control program sounds great. We've got these prevention measures. We've got really accurate test. We have very good treatments. We can control chlamydia in the world, right? Wrong, okay? So our chlamydia control program, pretty much everywhere in the world, have been ineffective in controlling chlamydia rates. This CDC surveillance data shown here on the left, I think illustrates us quite nicely. So CDC has been tracking chlamydia since 1984. And it became a notifiable condition in 1995, the most reported infection actually in the U.S. prior to COVID. And you can see the rates have gone essentially every year, except for perhaps 2020. But that was a false decline at that time because the highest-risk people are not getting the testing done during COVID. So it looked like the rates were going down, but they weren't going down. They were going up. If you want to look at specific numbers, in the U.S., over 1.6 million cases of chlamydia get reported to CDC because it's required to report to CDC. Those are the ones we actually know about. Research suggests there's actually about 4 million cases -- new cases each year of chlamydia in the U.S. alone, okay? So then you're probably going, why aren't these control programs actually working? Well, earlier, I kind of mentioned that basically, most chlamydia is asymptomatic and it's chronic. So we simply -- many chlamydia cases go undetected and untreated. We simply don't know about them. So either patients don't go to get testing done or they go see doctors and doctors don't do the testing. It just doesn't happen. But very important to this discussion that you've been hearing today is something regarding immunity to chlamydia. And so it turned out that most individuals when they have chlamydia, they do not develop good, long-lasting protective immunity to natural infection with the whole bacteria itself. So basically, if they develop any immunity, it's pretty short-lived within a matter of just a few months, and then they just get re-infected over and over again. And about 20% of people are re-infected again within about a 1-year period after they are infected. And what's really kind of crazy is that we had these control programs, right? Our goal is to decrease chlamydia and the complications, but what animal models show in some limited human studies is actually that the more aggressive we get in trying to find chlamydia and treat it and treat it earlier in the course of infection, we are actually taking away one's ability to mount a protective immune response. They actually become more vulnerable to chlamydia than if you didn't treat it at all, and then they just get re-infected over and over and over, okay? So that's just to kind of summarize the points I've been making here is that chlamydia became the most prevalent bacterial STI worldwide. Infections are chronic. Infections are mostly asymptomatic. We have these great control programs in place. They do a lot of different things. What they don't do is actually decrease chlamydia itself, okay? And so really, there's nothing else out there from a prevention perspective right now that's going to decrease chlamydia except for a vaccine. And that's really the strong justification for why we need a chlamydia vaccine. Thank you.

Thank you so much, Dr. Geisler. We really appreciate that. And we welcome you back on stage for the Q&A afterwards. I'm sure there's many questions and interest on chlamydia. So we heard from Dr. Geisler about the burden of disease and the impact on patients. But then I wanted to supplement that by sharing this slide with you as I find it really quite striking. So these are CDC data from a study highlighting the significant direct costs associated with sexually transmitted infections in the U.S. And as you can see from the graphic, a significant portion of those is actually attributed to chlamydia. It's lower only than HIV and HPV, in fact. Now the Queensland government in Australia is well aware of this burden, and this is why they have elected to support our chlamydia vaccine development program through our Translational Science Hub in Queensland. So now let's take a look at the science behind chlamydia and what we know about protective immunity. Chlamydia is a complex pathogen, as you can see from the left-hand side of this slide. It's actually unusual in that it's a bacterium. But as Dr. Geisler told us, it spends a part of its life cycle inside human cells. In fact, it's almost like a virus in that regard. It has 2 different stages in the life cycle, the intracellular reticulate body and the extracellular infectious particle, which is the elementary body. Now for the intracellular reticulate body, there is a wealth of evidence to support a role for CD4 T cells secreting interferon gamma in mediating protective immune responses. In addition, it's likely that antibodies that recognize the extracellular elementary bodies will also be important in infection. So putting this together, our targeted immune profile constitutes both antibodies and CD4 T cells. In addition, genital chlamydia disease is caused by a few different serovars or serotypes, if you will. And it's, therefore, important to design our vaccine and to demonstrate broad recognition across the relevant serovars. Finally, we need to show that the T cell-inducing properties of the vaccine have broad population coverage in terms of HLA recognition. Now our preclinical data show that through our innovative multivalent antigen design, we are indeed meeting this targeted immune profile. So let's be clear. We did not achieve this overnight. In fact, we had to screen 89 different antigen designs and 100 different mRNA constructs to come up with this final vaccine composition. So the graph on the left shows that with our antigen A design, we are able to induce CD4 T cells secreting interferon gamma that recognized broadly across relevant serovars. The remaining data illustrates that antigens B, C and D each induce cross-reactive antibodies capable of binding native elementary bodies of diverse serovars, further enhancing our vaccine candidate composition. And I'm delighted to announce that we are progressing this vaccine into the clinic for a Phase I/II in 2024. So let's move on to acne now. So acne is a chronic inflammatory skin disease, and I'm sure everyone is very familiar with acne as a disease. And in fact, I'm sure almost all of you know someone who has suffered from this. In fact, acne is the eighth most common chronic disease globally, and it's increasing. The chronic nature of acne disease really places a heavy burden on sufferers and it can cause major psychosocial impact. The long-term use of antibiotics in treatment regimens is not ideal and it's likely contributing to increased global antimicrobial resistance. And yes, acne medicines do exist, but they're not checking all the boxes for patients. And on top of this, they bring significant economic costs. So recent market research that we conducted highlights the treatment gaps that I just referred to, signaling the need really for better solutions across all dimensions: Reliable long-term efficacy, ease of implementation and lack of serious side effects. That's really key. And the quotes on the left side of this slide really highlight that gap. So we heard from a dermatologist in Germany, "Isotretinoin has the efficacy, but it's complicated and has risks. None of the options we have give us everything we need in one treatment." And a dermatologist from the U.S. told us, "Acne is very hard on patients because it's a disease everyone can see. I don't take it lightly because I know it can have psychological and social ramifications." Those powerful messages speak for themselves, I believe. So our approach in the acne immunotherapeutic space is an ambitious one. The targeted approach is designed to restore a healthy microbiome balance. Our strategy leverages the antigens we acquired through the Origimm deal. And the graph on the right illustrates how the proof of mechanism for those Origimm antigens has been validated by the generation of robust antibacterial antibodies with antigens delivered in the form of proteins in this case. In addition to the Origimm antigens, we further combined with one that we developed internally. We've honed what is generally very challenging antibacterial functional assays, and we're leveraging this critical know-how to move at full speed with our vaccine candidate. And then importantly, due to the inflammatory nature of this chronic disease, we clearly benefit from Sanofi's significant expertise and prowess in the field of immunology and inflammation across the company. So the disease, acne vulgarum, is a result of dysbiosis of the skin microbiome and it's driven by the outgrowth of pathogenic Cutibacterium acnes strains. The vaccine is, therefore, specifically targeting this bacterium and its mediators. Our mRNA vaccine candidate is designed for therapeutic use in patients and it addresses multiple mechanisms of action to enhance the probability to succeed. So let me walk you through those mechanisms now. The Origimm antigens are overexpressed on the surface of pathogenic bacterial strains and, therefore, are included in the vaccine to induce antibodies capable of killing those strains. In addition to that, there's the additional potential functionality to block essential bacterial mechanisms such as iron uptake and cellular adhesion. And then the final antigen in the vaccine is designed to block inflammatory mediators that interrupt -- to interrupt the cascade of inflammation that is so characteristic of acne disease. Our preclinical data on the mRNA vaccine candidate have shown proof of concept for the vaccine design and allowed us to engage in the GMP production and readiness for Phase I/II. So let's walk through the data. On the left side of the slide, mRNA constructs expressing the Origimm antigens, antigens 1 and 2, are able to induce antibodies capable of killing C. acnes bacteria to a degree at least equivalent to what we've seen with recombinant proteins. So reiterating the point that we heard from Jean-Francois earlier. The antigen 3 construct induces antibodies that successfully neutralize C. acne inflammatory factor and, again, it's to an equivalent or even superior in this case for mRNA compared to recombinant protein. Now furthermore, when we add the 3 antigens together as mRNAs, we see no interference in overall functional response, and these data are shown on the right side panel of this slide. So collectively, these data support moving ahead with this multivalent mRNA vaccine candidate, and we initiate our Phase I/II in the patient population already in 2023. And I have to say we eagerly await the data from that trial. So let me just end by saying that we are incredibly excited by our early pipeline. I really look forward to being able to disclose more with you at a future date. We're moving rapidly into new areas. We're supremely focused on addressing so far unmet medical needs and importantly, being open to leverage the right technological solution to meet the challenge, be it mRNA, being it recombinant proteins, being it monoclonal antibodies or beyond. Science leads the way. As we move into fields of therapeutic vaccines, the association of infectious agents with chronic diseases and interventions to address microbiome imbalance, we're strongly enabled by our state-of-the-art immunology and our world-class antigen design. So I thank you for your attention today. And with that, I'm going to hand the floor back to Thomas, who is going to close out our session today. Thomas, the floor is yours.

Thank you. Thank you very much, Dr. Geisler. Thank you very much, Sally. Great, great science progress. It's been fantastic to share with all of you our strategy, our capabilities and our vaccine industry-leading pipeline. Before we move to Q&A, sorry, allow me a few words of conclusion, giving a lot of time for Q&A, I understand, to summarize the data you've seen today. As shared through the presentation, we strive to deliver a pipeline of best-in-class or first-in-class vaccine to improve people life. We intend to do so at pace, like we've done over the past 18 months. Since we last met in December '21, we received 3 significant new product approvals, the latest being Beyfortus, which addresses a major unmet medical need. We are building a leading-edge mRNA platform, and our teams are exploring new ways to further improve that technology. And we are moving at speed with 6 new vaccine candidates having entered or will enter Phase I/II trial over 2022 and 2023. As mentioned before, we intend to bring at least, that's the important part, at least 5 first-in-class/best-in-class vaccine candidates into Phase III by 2025. To conclude, we confirm that our ambition is to deliver annual sales exceeding EUR 10 billion by the end of the decade, that is well within our reach. To get there, our major strongholds will remain differentiated flu vaccines, complex pediatric combination and meningitis immunizations. They will remain a key part of our growth journey. On top of the strong foundation for our business, our R&D transformation and acceleration is now enabling us to add key new franchises, a best-in-class R&D franchise starting by the launch of Beyfortus in 2023 and covering all the unmet needs in terms of RSV protection; a very competitive PCV21 to enter a multibillion pneumococcal market with our partner, has a first product [indiscernible] segment; and finally, new mRNA vaccine such as chlamydia or acne that you've just seen. Those are not just me-too or me-better. We expect them to be truly transformative products, first-in-class immunization. That's pretty simple. We're building exciting assets. We have the team and we have the fundamentals. We're now 100% focused on the execution. With this, let's now turn on to our second Q&A.

Thank you. Yes. So maybe we can squeeze you all on stage. And so we're now going to get to our second round of questions. [Operator Instructions]

Zain Ebrahim, JPMorgan. So 2 for me, please. The first was just on PCV21. So the Phase II data that you showed, again, on those 3 showed strong sero response data versus registration hurdle on I think every strain except for maybe strain 6B. So I just wanted to understand how important that strain is for overall efficacy you think against invasive pneumococcal disease. And maybe bigger picture, how important do you think more functional endpoints in terms of efficacy against IPD or hospitalization would be needed for your PCV programs to drive approval, but also uptake ultimately? And then my second question, if I may, just going back to the first session. It's very clear that Fluzone High-Dose is the bar. Just wondering if you could provide us with an update on your expectations for Fluzone High-Dose this year.

While the team is preparing the answer on PCV21, I can take the first question quite easily. We're really focused even today on the pipeline or R&D. We have the pleasure and the chance to have quarterly earnings every quarter. So I'm sure we'll talk about that very soon, probably in 1 month from now. We're in the prebooking season. And what we discussed before at the last quarterly earnings is still there, but we'll have more discussions in 1 month from now. PCV21, I'm turning to you and if you want to confirm...

Yes. So indeed, this might be the weakest point in PCV21. We believe it's very much manageable. Actually, we [indiscernible] what would be the outcome of the Phase III if we were to run it based on the Phase II data. I'm very confident that it will pass the bar. So let's be clear about that. Yes, every serotype might be important. If it's not important today, it might be important tomorrow because you know the serotype evolution in PCV is important. That's why the 9N is extremely important. Finally, also just to clarify that for you in terms of regulatory acceptance. Clearly, the regulators look at the totality of the data. And for example, in the Pfizer pediatric trial, they missed on 6 serotypes and still looking at the totality of the data, got the approval and recommendation for this vaccine, so that I would say at this stage.

And maybe in terms of uptake, we don't see any preferential recommendation in the PCV pediatric market. So it's going to be about the [indiscernible] of the product. We know we are going to come with a competitive product, which is going to make a difference for Pfizer. We have the portfolio. We have the connection in the U.S., in the different countries, the contract in play to foray into this market and have a ramp-up when we get approved. So let's deliver this product profile, and we are convinced that it's a hot profile that will help us make a difference.

Evan Wang from Guggenheim. Two questions on PCV. With respect -- have you shared updates -- or can you provide an update on adult Phase II data? And will you have a direct comparisons to PCV20, or do you plan that in peds and adults? Second, on the next gen approaches in PCV, the data on the [indiscernible] interesting. So can you talk about how you're thinking about using that to expand on additional serotypes and how far you think you can go with the [indiscernible]?

I think we may link that question to the question that we had from David before. So definitely. So new models will stop.

Yes. So for sure, for the new model to -- as you have seen today, we are sharing quite a few data. So we needed to be selective on what we share. As you heard, we are also very conscious about where we allocate our capital and we are looking for first-in-class/best-in-class vaccine. When we look at the competitive environment in the old adult space, but also when we look at the epidemiology and some of the avenues that our competitors are taking, we're thinking maybe it's not a good idea to allocate capital to the old adults at this stage. And yes, we are considering potentially 2 different options. As you see, there are 2 options in the field. Either going for a vaccine that is specifically designed for the older adult or adding more serotypes. Now I can take the question on how many serotypes we can put on the new carriers. And actually, I will take the question by not taking it because, obviously, the field is very competitive. We know that others are using -- also considering using other carriers when we are doing it. And actually, we're not going to share that information at this stage.

But glad that you understood that the new carrier is also very important.

We go to Richard.

Yes. Richard Parkes from BNP Paribas Exane. A couple of questions around the same topic really, on the technology platforms and mRNA. I think you mentioned 9 different technology platforms within vaccines, but the 2 true leads of novel new vaccines chlamydia and acne are both based on the mRNA technology. So could you talk about the reasons for going with that platform for those 2 vaccines? Is it based on being able to do something that you can't do with other technologies? Or is it that you can just move more quickly in assessing new antigens and combinations, et cetera? And then the related question is just related to that, now you've had an mRNA in-house for some time. How do you feel that's going to impact R&D productivity within vaccines and the benefits longer term?

I think it will be great on R&D productivity because, of course, we can go [indiscernible] into multiple spaces. And especially once you have your library of LNPs, you've built all the preclinical data, and that gives you an ability to go very fast into Phase I/II and move on. To the first question, I'm transferring the mic to you in a second on this. On the first question, how do we select the platform? It needs to be what the best platform for the target profile. On the 2 examples you've seen, on chlamydia and on acne, we're looking at different technologies. And then we are selecting based on what we see in the early stage of research. And you've seen that we are able to express more antigens with the mRNA platform than with the protein platform. Both of them are immunogenic. Both of them expand the proteins of interest. But it's really about making sure that when you look at the ability to evolve the platform, sometimes you have to go back to normal words -- as well as the trade-off between ability to generate the right amount of antigen and the [indiscernible] profile, then we find the sweet spot.

Yes. So broader toolbox across the vaccine industry. Important to note, nothing is missing. So we have everything we need to deliver the vaccine we need. That's 1 important piece. As Sally was saying, science is leading us and data are leading us. And I also want to add here. So you could see how we use the different platforms across the portfolio. We have made substantial progress on expression of bacterial antigen with mRNA. We don't say that all the bacterial protein can be expressed in mRNA. And that's why, again, generating the right piece of data, having the right antigen design team, having the right immunology is going to help us narrow down and select the platform we want to have. Sally?

Yes. Just a quick point to add on to that. So for chlamydia, in particular, there's a very -- one of the major antigens that most people use in their vaccine is a highly complex molecule that has multiple transmembrane spanning regions. And we believe that mRNA is actually uniquely suited to presenting that antigen with appropriate native confirmation. And the other thing, I think, is in both cases, we're looking at multivalent vaccines, right? And mRNA, of course, is particularly flexible and well suited to multivalent.

Next we go to Jo.

My questions go back to the first presentation. I think it was on Slide 38, where it showed the amount of increase in antibodies you got with your RSV in older adults, and it was only about 5x. And vaccine in older adults is a higher number than that. So how competitive -- is that relevant? Is that in itself predictive of ultimately how successful a vaccine might be? How do you think that you're going to compare? And are you confident that the other 2 components that you're putting with it have got an equal sort of decay rate such that you're going to get a vaccine that you're going to use every 2 or 3 years because if one of the other components needed to be re-vaccinated every year, then it wouldn't work. I think we're all quite surprised at how the RSV one turned out. So it's just your degree of confidence that the 2 other ones you've put it with are going to make a great every-3-year vaccine, whatever it is. And my second question is on machine learning. We heard about that a lot in 2021. We're hearing about it again. It enables you to choose the best possible antigens and get the best possible vaccine. And yet, you have it and the CDC doesn't have it. So if the CDC says do A, B, C and D, and your little generator says, "Oh, I should actually be doing 4 other ones," do you go, well, we're going to be better and then not be an approved vaccine -- how do you actually get the world to benefit from this extra knowledge? How do you benefit from having this knowledge, which nobody else appears to have?

So I go to Sanjay for machine learning, and I do see machine learning coming into flu, especially with CDC WHO. Is it [indiscernible]? On RSV, although I come to you on the competitiveness and the data where does it come from, what does it say and what do we do for the Phase IIb, just 1 point before we go there. As we said, and it's very personal as you can imagine. As we've seen on this number, I don't think it will be every 2 years neither, maybe every 3 to 5 years.

I think it's a very valid question with machine learning flu. I mean I think what we -- I think the concept we're trying to make sure we're talking about is the fact that there are companies who believe that keep adding more strains might get you greater benefits. And I think what we're basically trying to argue is that perhaps the selection of the strain is a better way to look at this. People have talked about selecting later. People have talked about time to manufacture. And in essence, what we believe is, I think the selection of the strain is probably the biggest choice you can make in demonstrating value in terms of efficacy. I think we are clearly in discussions with many different people, both academics, government organizations about how to move this forward. I just want to take a step back and say we're very confident where we are with machine learning approach. But we need to demonstrate in the clinic that, that approach demonstrates some clinical benefit, and we'll get there. But it's going to take some time. And that's where the confidence is going to come from for the CDC, for the WHO work with us in making that approach more feasible in the long term. So I think there's some way to go, but we're getting there.

Thank you, Saranya. And building on that, you understood there are 2 words. We can replace, but we can also add new strains selected by machine learning to create that difference. We're still being compliant with CDC, WHO recommendation while offering the benefit that people are looking for. So back to the question on RSV on the adult. Of course, if we measure it because we believe that it has some relevance, is there a [ creative ] protection? No, there is no [ creative ] protection in RSV. We are very confident with the 5.4 fold increase vaccine in older adults. Indeed, it's trending lower in the older adult compared to GSK and Pfizer. We explained it with 2 main reasons. So the first one is really about the season. This year, after 2 years of COVID, we had an unprecedented heavy RSV season, meaning more people have been infected, more people have seen their antibody level boosted. And actually, when they are high, you cannot push them further. That's why our vaccine could not move everybody and reach that 5.4. I take an example, a company called [indiscernible] that you may know or may not know. Last year, they reported with the vaccine a sixfold increase. This year, they've already reached fourfold increase. Why? Because the season was particularly heavy. Another example, you know J&J has discontinued its program, but they've published the efficacy data of the vaccine season 2, season 3. The antibody doesn't [indiscernible] season 2 season 3, and they still have efficacy. So do you need to reach a ninefold increase? We believe we might be there if we are in the right season. If we are not there, is it an issue, we believe we can protect with what we have. So honestly, we feel good about the data we have, and that's why we're moving forward with the Phase I/II combo and with the Phase IIb. [Technical Difficulty] Yes. Really interesting. Of course, we selected these viruses because they are the cousin, if I may speak like that, of the RSV. They are viruses of exactly the same family. They are viruses -- or the target antigen is the same, it's the fusion protein. So we are very confident that what is valid for RSV will be transposable to what is happening for HMPV and PIV. And it's totally different from the people who think flu and RSV virus that change every year that change even within the season compared to RSV, HMPV, PIV that are very stable.

But Jo, you're right. We need to see it in the clinic also.

Okay. I would like to try another one from the web. So I know we have Steve Scala raised his hand. Steve, can you hear us?

Yes, I can hear you. Can you hear me?

Yes. All good.

Two questions. Aren't potential COVID flu combinations a risk to your flu business? And if not, then why not? And then secondly, at Sanofi's Vaccine Day in December 2021, the company projected the influenza market would grow to EUR 15 billion in 2030. Does Sanofi still believe that, that's a good estimate?

I will go on the second one to our worldwide expert of flu, Mr. Bill Averbeck, because it's a question from the first one, you have time to come quietly. On the COVID-19 flu combo, great question. Not exactly the first time it's been asked. I think between 2021, and please go back to the transcript, where we said COVID-19 flu combo could play a role. But if it happens, it's going to be very limited and it's going to take a lot of time to get there. I think since that time, how should I put it, flu vaccine development has been a humbling story for many companies because flu is not COVID and flu is not RSV, which is the same statement about RSV. So why do I say that? Right now -- COVID-19 in 2021 was the high level of disease. Fast forward 18 months down the road, what's the burden of disease to date, not of '21 and '22, today of COVID-19? What's the actual vaccination rate in the U.S. against COVID-19? And why is that? Is it because people don't care anymore about COVID-19? Is it because they're fatigued about the COVID-19 vaccination? Or is it because it's not the right product profile because it's still the first generation mRNA? So I think there's a lot of questions to answer on that now for '23. There's also a lot of questions to think about where is COVID-19, following that same trend, going to be in 2025? And as we predicted in '21, I reiterate that the flu burden of disease is going to be way higher than the COVID-19 going to be and, therefore, put yourselves in the shoes of the U.S. [indiscernible] recommending body. Are you going to say, "Oh, it's great to go for a combination vaccine" for the 10% of the population that might still, at that time, maybe want a COVID-19 booster if it's still recommended. To go for a combination, if it actually degrades negatively, the medical service provides on flu, i.e., the biggest burden of disease for the most fragile population on this planet and you say every year, I'm going to reduce their protection and I'm going to increase the reactogenicity of the product? I don't think so. So it will take a second generation of mRNA. Is it impossible? No, that's why we're searching hard on it. We are still investing big into flu next step because we are leading into now, we'll be leading into tomorrow. But it's not the first generation and, therefore, it's not in the coming years. Next generation, we're all at it. We are all starting on same ground. We have all reached the same level, if you wish, of average standard flu like with higher reactogenicity on strength in the first generation of mRNA, thanks, but no thanks. Not making it for the customer. Now it's on to the races for the next generation. We believe we have a very good change.

So I'll talk about the outlook, if it's okay. So I think our guidance is consistent with what we provided to you last 18 months ago for a couple of reasons, actually 3. One, the elderly population continues to grow, right? They're the most growing population in the next 10-year span. In that population, immunization rates still have a ways to go. In fact, some countries are less than half of where the WHO gold immunization really is. So there's a growing population, immunization rate -- immunization opportunities still exist. And we're growing differentiated vaccines at a higher price point. So the vast majority of these products, we believe, are going to be used in the elderly population at a higher price point. So these 3 factors, plus we see an incremental VCR of about 0.5 point a year, gets you to the guidance that we provided you last time.

We take 1 last question.

And we take many more during the drink afterwards.

So who should I pick, Simon?

Simon Baker from Redburn. A couple of quick ones. Just on chlamydia, the data looks -- the emerging data looks very interesting. But as you showed, the direct cost is less than $1 billion in the U.S. So just thinking how we should think about the price and target population for vaccination? And then a quick one on LNPs and the optimization you've been doing there. A lot of the focus on LNPs tends to be on temperature stability and protection of the mRNA itself, but there's been work done on the potential role of LNPs actually as adjuvants and also single-component LNPs for tissue targeting. I'm just wondering if you could give us your thoughts on both of those as a potential in LNP research.

For the LNPs, I'll go to Frank and Jean-Francois to complement Frank later on. Do you want to start on chlamydia, Thomas and Sally?

Sure. On chlamydia, I think you see the figure close to $700 million in direct costs, which is very close to the running cost of HPV, you see just next, and you see the business size in the U.S. of HPV is billions. So that's one part of the answer. And the other part is you had the indirect cost, the [indiscernible] cost. It will go easily to the $2 billion, $3 billion per year in the U.S. in terms of cost. And that's based on the data we have today, and we see the trends are going up. And the more we look, the more we find. So is it the next HPV? I'll let you think about it. We see a lot of parallel with that market and a lot of potential for public health as well as in terms of economics with these vaccines.

LNPs. Go Frank.

All right. Sure. So great question on that. With LNPs with adjuvant in certainly familiar with the data that's been out there. And look, we're looking at a lot of different approaches for immune modulation up or down with various different entities, whether it be an LNP or whether it be another type of excipient for that. What you want to be careful, though, is the reactogenicity. So you've already got an LNP there. You've got mRNA there. You see the reactogenicity already. Adding an empty LNP or exploding the lipid from that regard, it's a fine balance. And we're very aware of that and we're looking into it. With respect to targeting and using LNPs as target and there's 2 different ways to do this. I feel like you're referring to the types that are past the targeting. Based on the lipid composition, it can go to different organs. We certainly have that capability, and we've generated a lot of data around that. There's also active targeting where you can put an active targeting agent, which we're exploring as well, not just from a vaccine standpoint, but also from a therapeutic area standpoint also. So we've got the expertise in-house. In fact, we've got that through a bunch of different technological platforms within Sanofi. So it's actually quite powerful. I think we're pretty unique in that regard. And so the technology capabilities that we have and the goal that we're doing and what we're exploring right now is synergizing those technologies within our company, which we think gives us much better advantage over other people.

Yes. Just to complement very quickly. Yes, we have all the technology we need in Sanofi. And for example, we added Tidal via M&A in our portfolio about 2 years ago exactly for that purpose, which is targeting of the LNP not only to the organs, as someone are doing, but to the particular cell that you need to transform. So really, we have the toolbox we need to transform the course of medicine.

I just want to add a little bit more about the cost, which is in the billions of dollars each year. The cost for chlamydia is really driven by its complications: ectopic pregnancy, PID and infertility. Infertility, in particular, is very expensive. Those costs continue to climb. So -- because ideally, what [indiscernible] having done is something called assisted reproductive technology, but you have to go see a specialist for that. It's very expensive. Those costs continue to decline. When many people don't appreciate it because there's a huge gap in the world, a lot of people can't access that infertility technology. And so we have a lot of people who need a vaccine because they're not going to have access to these complications once they happen.

So we're going to close the event now. We're already over time. A big thank you to my Sanofi colleagues from vaccines, special thanks to Dr. Geisler, for all of you sharing your expertise, but also your passion. And for those that still have time, you're very welcome to stay with us a little more, ask more questions. We're going to be back in the other room. Thank you very much. And hope to see you soon at another R&D event. We're going to send out an invite shortly for an R&D day at the second half of the year.

And the drinks room is fresh.