Sanofi (SAN) Earnings Call Transcript & Summary

So just as a reminder for everyone that this meeting is going to be recorded. I'm just waiting for my sign. Thank you. Here you go. So good morning, good afternoon, and good evening to everyone. Welcome to the Sanofi Vaccines Investor Event streaming live from the auditorium here in Paris. Thank you for joining 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 15-minute break in between. If you are following us online, you can remain connected to the same Zoom link for both sessions. I would like to start off with 2 housekeeping details. First, you can find all the slides to this event on the Investors homepage of the IR section of the website at sanofi.com, and they also have been posted in 2 parts. Second, each part will conclude with a question-and-answer session. And we would expect that you limit your questions to no more than 2. We aim to take questions from both the auditorium and from those who are following the event live on the webcast. So if you do ask a question here in the auditorium, please identify yourself and use the microphone. And to participate via the webcast, click the 'raise hand' icon at the bottom of your screen and you will be notified when your line is open to ask your question. And at that time, please make sure you unmute your microphone. So now moving to Slide 2. I would like to remind you that information presented in this call contain forward-looking statements that involve known and unknown risks, uncertainties and other factors that may cause actual results to differ materially. 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 these risk factors. Now let me take you briefly through the agenda for today. Paul Hudson, our Chief Executive Officer, will start with opening remarks; 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. Bill Averbeck, Head of Influenza Franchise; and Kimberly Tutwiler, Head of RSV franchise, will present an overview of their respective franchises and the remarkable protection of our vaccines. This will be followed by the first Q&A session. After a short break, in the second part, we will turn to R&D starting with mRNA. Frank DeRosa, Head of Research for the mRNA Center of Excellence will introduce us to his current work; followed by Jean-Francois Toussaint, Head of Vaccines R&D; and also joined by Thomas Grenier to discuss the strategic priorities and key assets. And we will close the event with a second Q&A session. With that, I'd like to hand over to Paul.

Great. Okay. Well, thank you, Eva. And thank you to everybody, and thank you for being here in person in Paris. We know that conditions can be difficult in terms of traveling. And thank you for all those that have connected online. Well, I'm delighted to be back on stage and in front of real people. It's been almost 2 years since the Capital Markets Day that we presented to you back in Boston in 2019, where we shared our long-term vision and our ambition to transform the practice of medicine. Today, we're going to provide you with deep insights into the vaccine business. Starting with Slide 5, outlining the 2 phases of our strategy, I am pleased to confirm that we remain ahead of our 6-year plan. Our strategy allowed us to make important and clear and decisive choices. Since then, quarter-after-quarter, all of the Sanofi teams have relentlessly delivered strong proof points of focus and on growth. This puts us today on a clear trajectory to deliver on our midterm financial targets and on our future pipeline execution. Our key growth drivers are performing very well, and our confidence in the choices we made is increasing. Dupixent sales nearly tripled over the last 2 years. We are currently annualizing at up to EUR 6 billion, and we've just scratched the surface with this incredible medicine. This medicine will be the cornerstone of our future leadership in immunology. Even during the most challenging times of the pandemic, we have consistently delivered on the development milestones for growth in chronic spontaneous urticaria, in eosinophilic esophagitis, in prurigo nodularis. We will continue to advance a robust clinical development program, potentially addressing a population of almost 0.5 million U.S. patients, further adding to the greater than 3 million patients currently addressable. Today, there is little doubt regarding our greater than EUR 10 billion ambition. And the only question I'm constantly asked is when we plan to increase the guidance for this amazing mega brand, and that won't be today. Vaccines will be at the core of our agenda today. We are confident it will remain a resilient and sustainable contributor to our growth and profitability. In addition to that, we're taking clear and bold steps to accelerate our R&D engine even faster. Lastly, our rich and exciting pipeline is gaining significant momentum as we continue to increase our focus on first and best-in-class science. The 7 positive pivotal readouts of this year so far speak volumes about our progress and make it clear -- and mark a clear acceleration. Nirsevimab, which we believe is the only option for all-infant protection against RSV is a perfect and impactful illustration of our renewed focus on breakthrough science. Moving on to Slide 7. I would like to say a few words on our commitment to society. Our ESG ambitions have been fully embedded in our Play to Win strategy. All of the flagship initiatives have the common objective of allowing us to mark where we can and where we are uniquely positioned to do so. That's why all of us at Sanofi are proud to be the main supplier of polio vaccines and to contribute to the global effort for eradicating this disease. We have been involved in this fight from the beginning, 30 years ago. Whilst major progress has already been made, we will continue until the disease is sustainably eradicated. We are also mindful of our obligation to do all we can to ensure a healthy planet. We are moving forward with initiatives to help improve the environmental footprint of our products, which includes the commitment that all of our vaccines will be blister free by 2027. As an industry-leading global manufacturer of hundreds of millions of vaccines every year, we have made recyclable eco-friendly product packaging a priority. Finally, just a couple of weeks ago, we were very pleased to note that the Dow Jones Sustainability Indices published annually by S&P ranked us second, and we again improved our score from 84 last year to 86 this year. Now before I hand over to Thomas, let me share a few words on the COVID-19 pandemic. Since the onset of the pandemic, our response to the crisis as a company has always been driven by 1 goal, simply to do the right thing. This purpose-driven mindset will be a critical advantage to help us win in the long term for all of our stakeholders. Today, we're focusing on our COVID-19 development efforts on the recombinant baculovirus candidate. We believe that our unique technology platform will provide a clinically relevant, meaningful option. The preliminary results we have seen from our booster study are very encouraging. As the data of our booster study keeps maturing, we look forward to seeing the first results from our Phase III efficacy study that will form the basis of our regulatory filing. We have to have the results on both primary vaccination and booster before year-end. In addition, we are leveraging our worldwide manufacturing capacity and expertise for supplying 0.5 billion doses of 3 different authorized COVID-19 vaccines over the coming months. Let me take the opportunity to express my gratitude to all of the Sanofi teams and to the leaders who have been relentlessly working on advancing science and providing our contribution to society. What's particularly impressive is that the pandemic has not given us an excuse to slow down. We have consistently delivered against all of the financial and strategic objectives we set for ourselves. A lot was said about what may be at stake for Sanofi vaccines since we were not one of the 2 companies having an mRNA COVID vaccine approved. Let's be clear, I don't see a lot of impact at this point. Yes, we may be 1 or 2 seasons later with an mRNA-based flu vaccine if it works and if it can beat the current standard of care. But beyond that, and this is what we'll talk about today, we only see opportunity. We announced the acquisition of Origimm this morning. They bring extensive knowledge in the field of skin microbiome and skin immunology. I'm excited about the potential new ground we may be breaking and here combining this with mRNA and our LNP technology. This pandemic has clearly underlined the impact that respiratory viruses can have on human health, and influenza and RSV are simply out there every year. So if not now when is the right time to protect people from it? If we had to have a silver lining from this pandemic, we would say that it has the potential to -- well, the potential to transform how we approach population health management. We can do more. In this new world, we are confident that we are perfectly positioned to play an increasingly important part. With that, I will hand over to Thomas to kick us off. Thomas?

Yes. Thank you very much, Paul. Good morning, and -- good morning or good afternoon, everyone. It's my great pleasure to present our Vaccines business in more details than ever before. Today, we will share with you how we anticipate the vaccine market will evolve, what it will take to win in that market, and finally, we will open to you the doors of our R&D labs to share with you our very exciting pipeline. Let me start with our strategy to continue to be a growth driver for Sanofi. On the next slide, please. I'm sure all of you are perfectly aware of the Sanofi Play to Win strategy, presented by Paul back in Capital Markets Day 2019. This slide shows you how we implement it in the Vaccines division. Focus on growth is clearly our top priority in Vaccines. We work relentlessly on our growth drivers, expanding of leadership, preparing the launch of nirsevimab to provide all-infant protection against RSV while continuing to grow year after year our core franchises. What you may still underappreciate though is the significant acceleration of our innovation pillar. Over the past few months, we are building at accelerated speed a second-generation mRNA platform. And we are breaking new ground with innovative targets addressing key unmet medical needs. Jean-Francois, our Head of Vaccines R&D, will describe later today these in more details. Finally, we are also bringing new ground in how we work. We are investing more in digital, including in our factories of the future. And we are embracing the speed and the agility of our new Translate Bio colleagues. Let's move on to Slide 12. For today, I went back to the quotes and comments that were made about Sanofi vaccines over the course of this year. Some of you actually may recognize some of those [ lines ]. There were for sure many questions around our flu franchise trajectory and the mRNA platform that we are building. But we've also seen commentary on our pipeline competitiveness or even the role that our COVID-19 booster may play. Now I'm sure it won't surprise you that I categorically disagree with these statements. Today, we want to show you the full picture of our business as it stands and share several elements that you may not yet be aware of. So let's get started. Next slide, please. And we'll start with COVID-19 right from the bat. You may remember that we announced in February '20 our agreement with BARDA to develop an adjuvanted recombinant COVID-19 vaccine in partnership with GSK. By then, we already clearly stated that protein-based designs will be slower off the blocks. Based on what we know now, the platform of choice for any future pandemic is mRNA. Speed wins. But in February 2020, nobody knew this. With several COVID-19 vaccines now available, BARDA continued our strong collaboration to still have a protein-based alternative in case it is needed in the future. In return, we took on the challenge to run a late, multi-country, placebo-controlled Phase III trial in a very challenging epidemic environment. And as said before, we now expect those Phase III results in the very coming few weeks. So should those results be positive, what is the role our booster against COVID-19 could play and by when? Here again, I want to be very clear. As stated multiple times, this is not a financial play for us. Why? Because preorders of the existing vaccines have already been placed for 2022 and 2023 with an abundant supply of more than 25 billion doses of authorized vaccines by mid-'22. Public information, not my estimate. And I surely believe that's completely true. So during that pandemic period, our recombinant booster may simply complement that oversupply, starting with the advanced orders from our various partners. Moving forward, in '24 and beyond for the post-pandemic phase. Should there still be a need for COVID-19 booster shots post-pandemic, we clearly estimate that the annual total market could be in the vicinity of up to 500 million doses. With a positive Phase III readout, our thermostable booster vaccine can certainly serve a good portion of this. Next slide, please. On Slide 14, the second COVID-19 question I often get is about the market potential for flu/COVID-19 combination vaccine. So better not to wait to have the question and the ability, of course, for such a combo to disrupt the flu market. Nothing new here. There is a very long history of vaccinating people against more than 1 disease simultaneously. This can either be done by combining vaccines into one single injection, that's a possibility, or by simply administering 2 injections at the very same time. On the left side of the graph, results from our co-administration study of Fluzone High-Dose with an authorized COVID-19 mRNA vaccine show that the administration of the vaccines at the same time does not deteriorate the strong immune response provided by Fluzone High-Dose. That's a good thing, ensuring seniors receive the maximum protection against influenza. So with this in mind, does a combination vaccine add significant value in this specific case of COVID-19 flu? No. No, because various critical conditions are still not met, and you can see those on the right side of the graph. First, the combination requires immunization schedule to be well aligned. Looking at the strong boosting effect from COVID-19 boosters, we do believe that the duration of protection is going to increase, and that it's very unlikely that annual boosters may be required. Instead, with many booster shots every 3 or 5 years, very similarly to what may be needed for seniors against RSV. Second criteria, to have a significant uptake any combination vaccine will have to prove that it is as effective as the best single vaccines stand-alone and that the adverse events do not increase. Otherwise, patients, health care practitioners, retailers will prefer the flexibility to choose the best vaccine against any given disease at the most convenient time, especially when these vaccines can be co-administered. So for all these reasons, we foresee a limited opportunity for a flu/COVID-19 combination vaccine in the current environment. And we do feel very confident about our differentiated flu franchise trajectory. Next slide, please. Moving beyond COVID-19, it is quite important to have in mind the strong end-to-end capabilities that we have established in vaccines. We deliver best-in-class products like our hexavalent combination vaccines that are demonstrating our unique formulation capabilities in the company. And we have a comprehensive set of in-house platforms to develop new products. All of those are required to develop new good vaccines. But once you have an excellent product, you still need another set of skills to succeed, the ones on the right. Many of those might not be yet applicable to some players, the ability to deliver at scale and to contribute to the implementation of large vaccination programs, and of course, global commercial reach. Next slide, please. But by leveraging on all those skills that you have seen that we have delivered mid- to high single-digit sales growth since 2018. Our 3 core franchises: influenza; PPH boosters; and meningitis have been the growth drivers and will remain strong contributors in the future. And now we are very glad to add RSV as our fourth core franchise. Our nirsevimab studies, as you know, have read out positively, and we are getting ready for a 2023 launch. Kimberly will, for sure, share her excitement, our excitement with this -- about this product and about the impact it will have in terms of public health. Market-wise, on the next slide, we forecast our core markets to grow significantly. Let me try to put this into perspective. Let's start with flu. We are the leader today. We'll be the leader tomorrow. And we will continue to lead in that market and grow this market. Some of you may not know that we do forecast the flu market to reach EUR 15 billion by 2030. And Sanofi flu vaccines will be the key driver of that market expansion. Beyond flu and to put things in even greater perspective, by 2030, we are going to address vaccine market segments that will total up to EUR 50 billion. On top of RSV, an important new segment that you know very well, we are going to enter the large pneumococcal market, and we aim to pioneer new frontiers. We estimate that those areas will represent EUR 10 billion in addressable market by 2030, with EUR 2 billion coming from these new frontiers alone. Next slide, please. mRNA. In June, we announced to you the creation of a dedicated center of excellence for mRNA in order to maximize the speed and the agility of our mRNA development. To invest at scale without deleting our profitability, we made prioritization choices, strong choices in order to reallocate funds to mRNA. It does not mean that our R&D budget is not going to increase over time. Science first. It does mean that it's not increasing further with the creation of this mRNA center of excellence. Today, very pleased to share with you the tremendous progress already made in a very short amount of time. The center of excellence is in place. We already have 300 employees dedicated to advancing the platform today. And among those employees are key talents from Translate Bio. The vast majority of them have chosen to join the center of excellence. The second key achievement is the positive readout of our very first mRNA clinical trial on COVID-19, which acted as a proof-of-concept, validating our mRNA platform and enabling us to move quickly to new developments. Finally, we will share today the interim results of our first mRNA flu monovalent trial, and we will show you that we are pivoting our platform to modified mRNA in a record time. Continuing to move at pace, today, we are going to introduce 4 new mRNA candidates. Frank DeRosa will elaborate on this further after the first Q&A session. And on Slide 19, our pipeline. We are building an industry-leading pipeline. We have not shared much about our future vaccines until now. But today, we are opening the door to our labs. And you get the very first tour of that exciting pipeline. On this slide, starting on the left, you will see, first, the 3 core franchises, flu, meningitis, RSV, where we will continue to enhance our pipeline. In flu, we do aim to expand the Fluzone High-Dose indication to add the younger pediatric segment where current vaccine efficacy can be further optimized. We are also actively developing the next generation flu vaccines using mRNA platform but also applying new scientific methods such as machine learning or exploring the addition of new antigens. Stay tuned. More to come in a few seconds on this. In meningitis, we are replacing Menactra, the leading ACWY vaccine by MenQuadfi, further improved vaccines that has shown a superiority against serotype C. Our main big candidate is moving in Phase II. And we plan to combine MenQuadfi with MenB to deliver our best-in-class MenPenta. In RSV, we are, of course, on track to launch the first and best-in-class product for all-infant protection against RSV. Kimberly will come back to that very soon. We will complement this with a vaccine to protect toddlers. And finally, we're planning a RSV vaccine for older adults that will ideally be combined with vaccines against other respiratory diseases. Beyond these spaces where we are already leaders, we intend to enter novel markets. That will be the significant source of growth for us moving forward, such as Pneumo for example. In partnership with SK Bioscience, our South Korean partner, we are developing a 21-component PCV vaccine. It will include serotype 9M to address broader invasive pneumococcal disease. And finally, I'm very excited by the last pillar, our new frontiers. I believe we are breaking new grounds with first-in-class vaccines against chlamydia and against acne. Chlamydia is a high-incidence disease, very often silent and undertreated. It can cause infertility in young women. We do believe our future vaccine can address this infertility. For acne, our R&D team is pioneering a new approach, developing a vaccine to treat a chronic disease associated with infectious pathogens. All these projects that you see here will address large unmet needs of large target populations. Jean-Francois, again, will present later the science behind all of those. In conclusion, our ambition is to more than double sales by the end of the decade by winning in influenza with super vaccines; by pursuing expansion in our core growth areas of PPH; meningitis and boosters; by launching nirsevimab and building the broader RSV franchise in the industry; by entering the pneumococcal market with a competitive new vaccine; and lastly, by delivering new mRNA vaccines to address strong unmet needs. So now let's move on to the flu section for which I'm very happy to welcome Bill Averbeck, our global head of the flu franchise. Over to you, Bill.

Thank you, Tim. It's always hard to follow Thomas, but it's especially hard for someone that's vertically challenged like me, so let me move these out of the way so you can actually see me today. So hi, everyone. My name is Bill Averbeck, and I'm the global head of our flu franchise. I've been here at Sanofi for over 25 years, and I've touched flu in some form or fashion for the vast majority of my career. When you work on something this long, you tend to find catch phrases or little things to get you through the day. And one of my favorite is, "Flu is only 1 letter away from fun." So with that corny analogy, let me get started and tell you why I'm excited to talk to you today about how Sanofi Pasteur is uniquely -- or Sanofi, I'm sorry, is uniquely positioned to win in flu by focusing on protection beyond flu and designing products specifically designed for the seasonal market. Now as we look to the future, we project the market to continue to grow at about an 8% compound annual growth rate from 2020 to 2030, about the same pace it has done in the previous decade. Now this means the market will reach about EUR 15 billion in 2030, which is more than some have projected. Now there are 2 main drivers for this growth. The first is an increase in immunization rates across an increasing and aging population. Now keep in mind, the coverage rates for flu vaccines remain well below the WHO goals, and this provides a strong opportunity for growth. Now the second driver is the continuous conversion to differentiated premium-priced vaccines, such as Fluzone High-Dose and Flublok. In fact, we anticipate these differentiated products will represent the majority of their overall market value in 2030. Now the question really is how much of the market will these mRNA vaccines capture? Will they have an immediate uptick? Our answer is no. In fact, we believe the mRNA products will only capture a fraction of this market by 2030. The next question is why? Why is their uptake so limited, especially when they've been so successful against COVID? My short answer is because flu is not COVID. The reality is, is that the current mRNA vaccine pandemic profile will significantly limit its uptake across the seasonal flu market. It's going to take a second-generation product to deliver on the required key success factors of a nonpandemic seasonal market. Now Frank and Jean-Francois are going to talk to you more later today about our plans for these second-generation mRNA products. So what are these key success factors? Well, we believe there are 3 that are required for this seasonal market. They are protection beyond flu; safety and tolerability; and administration. Now the first and most important key attribute is protection beyond flu. Products must demonstrate improved efficacy and effectiveness when compared to the standard of care. Consistent, high-quality data across multiple seasons that clearly demonstrates a reduction in hospitalizations is the standard. Providing immunogenicity data alone is just not enough. Payers and providers are going to continue to demand strong and consistent data across endpoints that matter. Second, safety and tolerability. Products that are administered to hundreds of millions of patients each and every year have to have an excellent safety profile to maintain a high level of patient acceptance. And lastly, administration. Now the seasonal flu market requires certain elements of administration, such as being fully liquid, being provided in a prefilled syringe and being stored in a refrigerator. These elements are a must to be successful in this market. Now one of the reasons why proving protection beyond flu is so vitally important is because of the damage this virus causes. Flu is underestimated. Many people believe that flu is just like a cold. Maybe you feel bad a couple of days. Maybe at worst, you're in bed, but you recover. The reality is the flu virus can wreak havoc across the major organ systems of the body and drive significant health care costs. For example, a person over the age of 40 is 8x more likely to have their first stroke, and even more frightening, 10x more likely to have their first heart attack within 1 to 3 days after a flu infection. Now for older adults in a nursing home setting, 9% of these patients will never fully regain their level of independence after an episode of flu, which for many is their absolute worst fear. Adults with diabetes may experience a 75% increase in abnormal glycemic events. And finally, children under the age of 14 have an eightfold risk increase for pneumonia following a flu infection. Now all of these serious and life-altering complications come at a significant cost. In the U.S. alone, these costs equate to USD 11 billion in direct and indirect health care costs each and every year. So seeing the damage that this virus can cause highlights the need for products to consistently demonstrate they can prevent these complications that we just talked about. In this environment, flu vaccines reporting immunogenicity data alone is simply not enough. Where there's no accepted immune correlative protection, as is the case for flu, a product must demonstrate protection from the actual disease. In addition, due to the devastating impact that this virus can have on patients and health systems, we believe the minimum standard for measurement of performance is how well a vaccine protects beyond flu, which means consistently demonstrating protection across a range of complications such as hospitalizations due to cardiovascular events and pneumonia. This evidence needs to include high-quality studies such as randomized controlled trials across multiple seasons, always comparing to a standard of care. This will ensure measured and consistent reductions in these costly complications. And this is exactly what we have done with Fluzone High-Dose. Our evidence generation efforts to cement Fluzone High-Dose as a superior flu vaccine didn't stop with our landmark efficacy trial, which did prove superior efficacy versus the standard dose vaccine. Fluzone is now the most studied flu vaccine on the planet. It has been studied for over 10 years and across 34 million patients. Let me say that again. This product has been studied for over 10 years. When you study a product for this long, you sometimes find things you may not have noticed at first. And that's exactly what happened here because one of the most compelling aspects of this product is the consistency of this data, which is really remarkable when you consider the variability that the flu virus can have. In a recent systematic review, Fluzone High-Dose consistently prevented more hospitalizations than a standard dose vaccine, proving its ability to provide protection beyond flu. In fact, let me highlight a couple of these data points. It demonstrated a nearly 18% reduction in cardiorespiratory hospitalizations and over 27% reduction in pneumonia hospitalizations. Now these are tremendous reductions on top of what standard dose vaccines provide. So in the U.S. alone, across a 10-year period, these reductions equated to over 800,000 medical visits and 0.5 million cardiorespiratory hospitalizations avoided, all of that resulting in USD 4.6 billion saved. And that makes Fluzone High-Dose, a highly cost-effective solution. So building this robust data package is really the only way to provide improved protection for these patients. Now to assume a product that only generates immunogenicity data can mirror Fluzone High-Dose's performance would be a mistake. As you see on the slide, Fluzone High-Dose first showed strong immunogenicity data, then demonstrated superior efficacy as well as consistent improved protection against multiple hospitalization endpoints. This is all compared to a standard dose vaccine. It has checked all of the boxes. Now Flublok. Flublok is our vaccine built on manufacturing with a recombinant technology. It has already shown strong immunogenicity and demonstrated improved efficacy in patients over the age of 50 compared to a standard dose vaccine. So we checked the first 2 boxes. Now we have 2 large, randomized Phase IV trials ongoing, both of which have hospitalizations included in their endpoints in hopes of demonstrating protection beyond flu and checking that third box. So in contrast, let me highlight 2 recent examples of flu vaccines outside of our portfolio that reported strong immunogenicity results, but later failed to demonstrate efficacy in randomized controlled trials. This slide shows data on FLUAD, manufactured by Seqirus, and GSK's adjuvanted flu vaccine in Canada. Now both of these products reported strong immunogenicity results showing high antibody levels. However, when they conducted their respective efficacy trials, both products failed their primary endpoint and did not demonstrate efficacy against flu versus their comparator. This is why proving products can prevent actual disease and then proving protection beyond flu is necessary when evaluating performance. Now these first-generation mRNA flu candidate vaccines are literally at the first step in their journey. Their first immunogenicity trials are ongoing and none have entered into trials in which efficacy we measured against the standard of care. And we believe in order for these products to be relevant, they will need to show improved efficacy versus a standard of care in randomized controlled trials and then demonstrate a consistent reduction of hospitalizations across multiple seasons. Without this efficacy and effectiveness data, these products will be challenged to be successful. Overall, the key takeaway from this slide, immunogenicity will not prove value in this market. So the reason we believe that this data will be needed for strong market adoption is that is exactly what Fluzone High-Dose has taught us. As you see on this slide, the generation of the data had a direct impact on the uptake of Fluzone High-Dose in the U.S. market. You'll notice in the beginning, we had a modest uptake when we just had immunogenicity data as payers and providers demanded more proof of performance to move away from their established standard of care. However, as data such as efficacy, cost-effectiveness and supportive high-quality real-world evidence became available, the product really started to take off. Its adoption continued to climb and now nearly 2 out of every 3 seniors in the U.S. receive Fluzone High-Dose. Generating this robust and consistent data package focused on protection beyond flu is necessary to achieve the first key success factor of the flu market. Now the second key success factor for a flu vaccine is its safety profile. For product to be used annually, patients and providers demand well-tolerated products and our flu vaccines have demonstrated consistently an excellent safety profile. And you see on the left side of this slide, the rates of adverse events seen with Fluzone High-Dose and standard dose flu vaccines are markedly lower when comparing them to a reaction profile of Moderna's mRNA COVID vaccine, and this is in patients over the age of 65. Seeing nearly half report a headache and over 80% reporting pain is just a different product profile than patients are used to experiencing with either high dose or standard dose vaccines. Now the right side of this slide shows results of the a co-administration trial involving Fluzone High-Dose and Moderna's COVID vaccine. Now this study consisted of 3 arms: one where patients received both Fluzone High-Dose and Moderna at the same time; and 2 arms where each product was given to separate patients to act as controls. Now these separate arms allowed us to make a head-to-head comparison of these reaction rates of these products. So when you look at the grade 3 reactions, which are reactions serious enough to interrupt normal activity, Fluzone High-Dose is over 12x less likely to cause a systemic grade 3 reaction and 3.5x less likely to cause a local grade 3 reaction. Patient acceptability is a key factor in a flu immunization program's ability to succeed, and to assume that patients would receive a vaccine with a 3.5 to 12x increase in serious reactions every flu season is a bit of a stretch. We speak to our customers every day, and we recently conducted market research to confirm our findings. Providers see these higher reaction rates as potential barriers to patients being immunized against flu. Now many of you may be able to relate to this research as many of you or your family members may have experienced these type of reactions after being immunized with an mRNA COVID vaccine. It's really interesting to hear about folks scheduling their COVID immunization for a time when they could spend 2 or 3 days at home after the appointment for fear of these possible reactions. This scheduling dynamic is truly unique and something we just don't see with flu immunizations. Again, flu is not COVID. So keeping all this in mind, when you consider the 3 key success factors we initially reviewed, we do not believe that the current first-generation pandemic mRNA profile platform can be successful in the flu market. Significant investments in the clinical trial work will be needed for mRNA vaccines to demonstrate improved performance against the standard of care. Randomized controlled trials, establishing efficacy and effectiveness across multiple seasons are what these products will need to demonstrate to be relevant. In addition, as we just highlighted, the current safety profile is simply not good enough to assume patients will be willing to receive a product built on this platform every single year. Patient acceptability is a huge factor in the ability for this market to continue to grow and to achieve those WHO stated immunization coverage goals. And last, but certainly not least, are the administration hurdles that these first-generation vaccines are facing. For strong adoption in a seasonal flu market, products need to be liquid, they need to be available in a prefilled syringe and they need to be stored in a refrigerator for the entire flu season. If any one of these elements are missing, it impacts an immunization program's ability to effectively deliver a large number of doses in a finite amount of time every single year. So for mRNA vaccines to be relevant in this market, they will continue to have to evolve to a second-generation product designed for seasonal routine use versus a pandemic response. This evolution is exactly what we're planning and targeting in our clinical development plans. So overall, we believe we are poised to continue to win in flu. We are actively building next-generation products, investigating multiple factors across multiple technologies designed to deliver solutions for seasonal markets across these key factors that this type of market demands. In the meantime, we will continue to expand Fluzone High-Dose and Flublok, as these products are the only 2 products that have demonstrated improved efficacy against the standard dose vaccine in randomized controlled trials. In addition, Fluzone High-Dose has also achieved a consistent demonstration of protection beyond flu for over a decade. Now having a clear path to developing the next-generation mRNA vaccines while continuing to grow our current business gives us a unique ability to win in flu. If these second-generation products can deliver on these seasonal market needs, we will be there. If for some reason, they end up missing 1 or 2 of these success factors, we will drive our current portfolio and continue to lead this market. Either way, we believe Sanofi will continue to win in flu. Thank you very much. Now I would like to bring to the stage -- or welcome to the stage Kimberly Tutwiler, who is the head of our RSV franchise, and she'll walk you through our RSV strategy. Kimberly?

Good morning, and good afternoon, everyone. I'm Kimberly Tutwiler, I lead the global RSV franchise, and I'm very happy to have a few minutes to talk with you today about RSV and nirsevimab. I'm very lucky to have been with Sanofi for the past 20 years in vaccines and very lucky to lead the RSV team. I think a discussion about RSV today is really timely because I think many of you have probably been hearing a lot about RSV in the news. And some of you have either had an experience with RSV or you know someone who has. But there are 2 things about RSV that I'd like to prove to you today. The first is that all infants need protection. And the second is that we'll accomplish this for the first time with nirsevimab. Now what we all probably know about RSV by now is that it's a significant risk for infants and it's actually the leading cause of hospitalization in this age group. But what's less known is that RSV affects all babies, especially those born at term and in good health. Now most people think of RSV as being an issue mostly for premature babies or those that are born with underlying health conditions. And the data shows that this just isn't true. What you see on the left side of the slide is a breakdown of the birth cohort and RSV hospitalizations. And you can see that 94% of babies born are healthy full-term infants. And I think we all would have expected that. But what most people don't know is that 85% of the RSV hospitalizations that happen are in those healthy full-term babies. So we know that there's a serious unmet medical need, and that's the lack of protection for all infants from RSV. And you can see on the right-hand side of the slide that infants represent a significant segment of the total RSV market with a potential value of around EUR 2.5 billion. However, unlocking this value is only possible with a strategy that addresses all infants. Now that's not possible today but let's look at how that will be possible tomorrow and what's required of a strategy to protect every single infant, and that's what's on this chart. Along the top, what you see are the requirements. First, protection of preterm or at-risk infants. Second, protection of babies regardless of the month that they're born, whether that's during the RSV season, which is November to March, just for reference like influenza, or if they're born before the season. And finally, and really importantly, duration of protection to last the entire season. And when we look at these requirements, a nirsevimab strategy is the only option that protects all infants. It can be given right before the season starts or at birth in existing routine visits, and a single dose will last for the entire season. Now that ability to protect babies who are born before the season begins is critical. Many people don't realize this, but half of the hospitalizations for RSV that occur are in babies who are born before the season begins. Now a maternal immunization strategy would only protect those babies born in season. That addresses less than half of babies born, also only half the burden of hospitalization. The protection would just not last long enough to get through the season. The easiest way to think about this is to use an example. So let's take a baby born in April. That baby would need 11 months of protection to get to and through their first RSV season, and that won't be possible with the maternal vaccine. That strategy also requires pregnant women to be vaccinated. And today, no more than half have done so for influenza, for pertussis or even COVID. The only way to address the unmet need of protecting all infants is with a strategy that delivers protection at the right time that lasts for the entire season and leverages the existing pediatric immunization framework. And the only strategy that can accomplish all of that is nirsevimab. So now that we know which strategy addresses all infants, let's take a look at how we'll make that a reality. What you see here is the clinical development program for nirsevimab. And just a reminder, this product is part of an alliance with our partners at AstraZeneca. This program centers on 3 pivotal studies to support all infant protection. The Phase IIb you've seen last year, and you may have recently seen the Phase III results, and we'll discuss those a bit today. The primary analysis of all of these studies are complete. We have some ongoing safety data to be finalized for registration, and that will begin shortly in the first quarter of 2022. But the entire goal of this development plan is to support all-infant protection, so let's take a look at the results. So the key takeaway here and what we're really excited about is that 3 out of 4 hospitalizations could be avoided with nirsevimab. Now you can see in the data on the left-hand side of the slide where nirsevimab demonstrated a very promising 74.5% reduction in medically attended RSV LRTI and that's from the Phase III MELODY study. The secondary endpoint in that study was hospitalization, and that's what you see in the middle of the slide with a 62.1% reduction. Now the Phase III study alone was not powered for that secondary endpoint, and we knew that, and we planned a prespecified pooled analysis on hospitalization. That includes subjects from the Phase IIb and from the Phase III study. And in this analysis, we're very excited about this, nirsevimab reduced RSV hospitalizations by 77.3%, 3 out of 4. And that result is very statistically significant. Now in terms of safety, we see that nirsevimab is safe and well tolerated. It has a profile-like placebo. The chart you see here is from the Phase III MELODY study. And just as a note, as you look at it, remember, the ratio of subjects recruited was 1 to 2 placebo versus nirsevimab. So please note the percentages in parentheses, if you want to make true comparisons. There are 2 points here I would emphasize. The first, the types and frequencies of adverse events were similar among nirsevimab and the placebo groups. And you can see that in the any adverse events line with placebo at 86.8% and nirsevimab at 87.4%; and the serious adverse event line, placebo is 7.3% and nirsevimab at just 6.8%. The second, and really importantly, no serious adverse events or deaths were considered by investigators to be related to nirsevimab. So now that we know with confidence that nirsevimab is highly effective and safe, we turn our attention to getting it from the clinic and into the market. And we're ready for the global launch beginning with the 2023 season. So you can see in this slide that the unmet medical need and the promise of nirsevimab is not only recognized by us, it's also recognized with priority designations from health authorities in the EU, in U.S., in U.K., China and Japan. Now we expect to begin submissions in 2022, and we anticipate our market introductions beginning in 2023. The big thing you want to know about is what are we doing now? Our prelaunch activities are already underway, and we're actively engaged with our key stakeholders for recommendations and funding, and we expect both in 2023. What I can tell you is this, there's strong interest and support from stakeholders, both medical and policy, who see the obvious need and the benefit of protecting all infants. And that's logical because protecting all infants aligns with the goals of our key partners. Take the HHS in the U.S. as an example. They have a top priority to distress disparities in health care. And it's clear from our discussions that they recognize anything short of a routine recommendation and funding for all infants could result in a situation in which lower income and potentially minority children would have fewer opportunities for RSV protection. And that's not acceptable. And that's why all infant recommendations are so important. Now to help further support the decision-making for our key stakeholders, we'll run a real-world implementation study in 2022 in Europe, and that will bring even more confirmation of the benefit of nirsevimab, particularly on its impact on hospitalizations. And finally, we're very excited to announce our Phase III study in China has been initiated just in November. So the takeaway from all of this and the thing to know is we're confident in getting nirsevimab recommended and used in all infants and we're ready to go in 2023. Now partly, that's because of the very exciting data that we see on nirsevimab. And partly, that's because the unmet need is obvious. But it's also because of our unparalleled experience in the pediatric market. This is what we do. And our next goal is routine RSV immunization for all infants. So if you haven't been able to tell by now we are very excited to be the first to deliver all-infant protection for RSV with nirsevimab. With a really promising efficacy of 74.5%, it can deliver rapid protection for the entire season with one single dose. It will also be cost effective, priced in line with other recent premium-priced vaccines, and that's to enable an all-infant use strategy. But if there's one thing that I'd like you to remember today, it's this: it's that nirsevimab is the only strategy that can address the unmet need of protecting every single infant, whether they're preterm or full term, whether they're born healthy or with underlying medical conditions, whether they're born in or out of the season. Every single baby needs to be protected against RSV because the truth is there's no way to identify which babies will be at risk. They all are. Thank you for your time today. I look forward to hearing your questions. And I'd like to welcome Eva to the stage to get us organized for the question-and-answer session. Thank you.

Thanks. So if I could invite our last 3 presenters actually back on stage, Thomas Triomphe; Bill Averbeck; Kimberly Tutwiler. We're also going to be joined by Thomas Grenier, Head of Franchise and Product Strategy; and Jon Heinrichs, Head of the RSV and R&D franchise is joining us online. Thank you. Here he goes. So for the question-and-answer session, we would like to ask you again that you limit it to 1 or 2 questions. We have around 25 minutes. I think we're right on time. We're going to take questions from the auditorium. And so if you have a question here, if you could please identify yourself and use the microphone. And then on the webcast, just reminding you, 'raise the hand' icon on the bottom of your screen and you will be notified, and then you're going to ask the question, please. At that point, please make sure you unmute your microphone. Sorry, hands up again. So we're going to start with Peter Verdult, if I could have a microphone here and if we could already have a microphone for Florent for the next question. And then maybe, Pete, if you could hand to the other Pete once you're done, and so we go quickly. So Peter ask you a question.

Peter Verdult, Citi. Two questions, one for [ Heather ]. Just can you talk a bit more about this real-world implementation study that you're setting up next year, just the scope and what you're trying to show in addition to what MEDLEY and MELODY already have shown? And then to Thomas, just on the -- just to be clear, if we see positive data, can you just remind us what commitments you have from Europe in terms of doses and what you would be fulfilling for next year and beyond?

Yes. It works. You're the queen of RSV, so you take the first one. I'll take the second one. Go ahead.

Okay. Very good. So very good question. And we're really excited about this study because we think it really helps support what our stakeholders need to make sure they recommend and fund nirsevimab. 2022 in Europe, targeted in most likely 3 countries in the U.K., France and Germany. And really the focus will be on hospitalization and the impact, sort of used in a real-world setting. But we also believe that, that will bring further confirmation because we'll target this to be a bit larger scale so that we can bring a lot more confidence to sort of go over and above the strong data set that we have today. So hopefully, that helps give a little bit of clarity.

And for the second part of the question, Pete, on COVID-19. So as you mentioned, waiting for the Phase III results in a matter of weeks. So of course, you will know immediately as soon as we have them. And in terms of commitment, we have already 75 million doses of firm commitments from European Union countries and U.K. And as you know, we have also our partnership with BARDA in which we can tap as much as they want from the 100 million doses of preorder that we have.

Florent Cespedes from Societe Generale. Two quick questions. Follow-up on RSV. Could you maybe give us an idea of what could be the ramp-up of the product, how do you see the ramp-up of this product? And could you remind us what is the -- what could be the cost because you said pretty much in line with the next-generation vaccines. And maybe, if I may, last -- another one for you, Thomas. I think you said you believe that post pandemic, you could see something like 5 million -- 500 million doses each and every year. Could you maybe give us what is behind this estimate?

So RSV COVID-19, I'm going to again, start with you, Kimberly. We don't give guidelines on specific ramp-up per year, per product, that you know very well. But I think it's important, Kimberly, that you share with the audience again, what do we think in terms of pricing, how do we want to position this product.

Sure. So good questions. One, in terms of pricing to the last question, we anticipate the product to be cost effective. I think that's a really important point first because it's our key guiding principle. And that's looking at the benefit of the product up next to what it does in the health care system and the benefit that it brings. I couldn't give you a pricing range today based on that. What I can tell you is 2 things to be confident about. It will show that it's cost effective, and that will be compelling because that's what payers and stakeholders need to see. And we're giving you that range of recent premium-priced vaccines, so that you know candidly that, that's where we're looking at it, and you can put it in a bit of a box and understand the category that it probably sits in. But that cost effectiveness is very important. We especially know for an all-infant use strategy. We don't target this product for some babies, we target it for all. And so the budget impact of that is clearly in our minds as we look at this. The only other point I would make on the ramp-up to that point is maybe just 2 things for the room. One, we anticipate going very quickly. So we're ready for 2023, and we anticipate recommendations and funding in 2023. So we don't think that, that process is going to take a long time, if that's part of the question. And we're ready to go, and we're excited about that.

And as for the second part of the question, so it's about the market size in, I would say, a post-pandemic period, so '24, '25. We all have a personal crystal ball, so I guess yours is as good as mine. A few things, though, I'd like to say on this point. First of all, what I said, and I'm happy to reiterate it, is that we foresee that market, post pandemic, to be in the vicinity of up to 500 million doses, so 'up to' is as important as the 500 million. And where it's driven from is that I look, for example, at what's the flu market size in terms of volume today. And flu market size is roughly in the 500 million to 600 million doses worldwide total market. Now that doesn't mean that it's going to be 500 million or close to that. The 'up to' is the very important part there because it's going to depend significantly about what's the remaining part of the disease, especially in terms of severe outcomes, hospitalization, death, emergency visits. Of course, that's going to be very critical. And it's very difficult to predict what it's going to be a couple of years down the road. I suspect it's going to be very low. But again, it's a crystal ball play. It may depend on where the recommendation for regular boosters are going to be. Are we talking about an age recommendation like 65 plus, for example? Or are we talking about comorbidities recommendation? That's a big role. And that's going to depend, as I was alluding to also on the frequency of those vaccination. I believe that you see a very different profile in terms of immunogenicity after a third dose of a COVID-19 vaccine. Titers are clearly going up with -- above where they were after 2 doses. I believe after 4 doses, it's going to be again, above where it is after a third dose. So I think when I look at that, the expected duration of protection and the virus becoming more and more adapted to the human host, I foresee much more need for specific booster every 3 to 5 years, as I was mentioning before.

Thank you. Okay. So then we go to Peter Welford.

Peter Welford of Jefferies. Two questions. Firstly, just on the mRNA and what you've just been talking about in terms of the dosing in the 3 to 5 years. Is that based on mRNA specifically? Or would you make that -- do you believe irrespective of what vaccine we got, I guess, speaking from an Astra person perspective, do you think this is irrespective of that? And ultimately, you think as a disease, as a respiratory disease, we should be thinking about you're going to need at least 3 to 4 doses? Or is this mRNA specific? And then the second thing I just want to bring up is related to that, again, with the comments you made regarding the immunogenicity in terms of the -- sorry, the systemic reactions that I think was made in terms of 12 times, and I think it was 3.5x. But that was, I think, versus the third dose of the COVID-19 Moderna vaccine. And obviously, those doses are given in relatively close proximity in those studies, whereas obviously, flu vaccines given annually. So just curious, relative to the first dose of the mRNA, obviously, there's a lot of smaller difference. So do you think this is because you've got the doses in close proximity? Or do you think anyway, by the time we get our fourth dose of mRNA, it's just going to get worse for all of us, i.e., is the fourth dose going to be a real issue for mRNA?

Thank you very much. A very important question. Bill be ready for the second question coming to you. On COVID-19, is it specific to mRNA or not? The comment I'm saying about the titer and the expected therefore impact in terms of frequency of vaccination, I would say, clearly, no. And the responses -- you've seen many studies, small ones, but a lot of them have been quite consistent, showing that if you have an heterologous schedule, you actually see very strong titers. So I think that goes towards saying that actually, as long as you've got 3 doses and if there is a fourth one, even further of a reasonably acceptable, good vaccines, mRNA or another technology, you will see very significant titers. And I believe that it's more linked to the virus. Let me put it another way. There is a huge number of flu strains. And the diversity of flu strains is massive compared to the diversity of COVID-19 variants. And that's why I believe with the stability of the virus, COVID moving forward, it's adaptation to human host, you will see more frequency of vaccination like 3 to 5 years, again, post pandemic, '24 and beyond. Now it's a very important question about side effects, mRNA flu, your co-administration study that you've shown. Bill, can you elaborate further? Thanks.

Absolutely. Thank you, Thomas, and thank you for the question. And certainly, if Jean-Francois or Frank want to chime in on the science side of this, please feel free. But you are correct, it is the third dose in Moderna's product that was involved in that co-administration study. I think one of the things we have to understand is that there's a lot of unknowns here. And what we do know about the flu vaccines is they can be given every single year with an excellent safety profile. There's not been an issue with any of the safety information across Fluzone High-Dose or standard dose vaccines across, again, over a decade of being studied just with Fluzone High-Dose alone. So we have a lot of known data on safety and efficacy and protection beyond flu with these products. And that's really the point I think we're making here, is that there are no quick wins here. The studies have to be done. We have to find a way to make sure these products are measured against outcomes that actually matter, both across efficacy, effectiveness and safety, to your point. And that work has to be done. And I'll offer if anybody else has any other...

Maybe if I can add one single point. So it was the third dose indeed of mRNA. It was probably the tenth dose of flu vaccine. And you still see a contrasted difference in between the adverse events. And the third dose of mRNA does not seem to be very different from an adverse event profile than the first or second dose.

Okay. So then Simon, Emmanuel and then Jean-Jacques. So if we could have a mic here.

Simon Baker from Redburn. Another flu question for Bill. You talked about the need for mRNA to demonstrate efficacy over multiple seasons. Could you therefore give us an idea, if one had started hypothetically developing an mRNA flu vaccine this year, when it could realistically be on the market? And then secondly, for Kimberly. Bill did a great job of explaining the limitations of mRNA in flu. Could you do the same in RSV given that Moderna has got mRNA-1345 in development for pediatric RSV?

Let's start with flu, Bill. Time lines?

Yes. So thank you. Very good question. I think the importance of studying across multiple seasons is because of the variability of the virus. I think you'll see different strains across different populations, require studies to be shown to actually have a consistent approach. And I think that's one of the things we're really proud of with our Fluzone High-Dose data package, is that consistency of data. In something so variable, you see ups and downs. And people think that flu vaccines are going to go up and down as you've seen in the media. But the Fluzone High-Dose, the range is really, really tight, which is really impressive. And that's why the multiple seasons are really required, especially if you're going to be asking people to switch from product that's already demonstrated that. So to do that, you need multiple seasons. You need, against the standard of care, a comparator in the study. And that makes that time line a bit further away. As I said before, there are no quick wins in flu. There's no way to do one quick immunogenicity study and take over the world. There's too much data out there across these differentiated products. We're quite proud of taking the commoditized lower-value flu market that existed 15, 20 years ago and transformed it into a growing market across differentiated products. And we've done that. We've raised the bar, not just for everybody else, but also for ourselves. And that's what we're going to be studying with our mRNA platform as well. So I think the short answer to your question around timing is we don't expect an mRNA flu vaccine before '24. And, Thomas, jump in if there's another time in your head, but certainly not before '24.

And just to add on this point. You can have a registration. You just have a registration. How do you get to convince payers? How do you get to convince people to actually receive the flu vaccine? RSV, building still on mRNA. Are there some mRNA threats you're afraid of, Kimberly?

So short answer would be no, but a good question would be why. And I'll start, and then Jean-Francois or Frank may also want to add a comment here. As you know, there have been decades of attempts at trying to get a vaccine for infants. And the thing that is very specific about RSV is that you need protection starting at birth. You just have no time to build, like you typically do pediatric combination vaccines are given in a series over those first few months to build up to that protection. And unfortunately, that critical risk period, it has to be immediately from birth. So you'll hear this from Jean-Francois a bit later today, but we've chosen deliberately our strategy of what belongs at birth in that first RSV season. And you're going to hear about what we think happens later for later populations. We don't believe that mRNA is a threat or the best option for RSV for infants because of the timing of when they need that protection. And, Frank and Jean-Francois, don't hesitate to jump in with any other points. Jean-Francois gives me the thumbs up, so I think it's okay.

That's the beauty of being a multi-platform vaccine players. You choose the platform for the best medical need. And you'll see with the potential in RSV, 3 targets in RSV, 3 different platforms to fit the best deal.

Emmanuel?

Emmanuel Papadakis, Deutsche Bank. So maybe a question on COVID. You published the Phase II recombinant data in a preprint in October. It didn't look particularly impressive in terms of GMT titers relative to convalescent sera, for example, and there was also a notable grade 3 adverse event rate. So just give us a bit color in terms of your expectations for the forthcoming Phase III data. I think, as Paul mentioned earlier, encouraging booster data. Perhaps you can give us a bit more comments in that regard. What are you hoping to show from the perspective of GMT and safety? And then a question on RSV. It's a very safety-sensitive population. We had 3 deaths in the study. They didn't appear drug-related. But to what extent do you think that's going to lend itself to regulatory scrutiny caution or you expect from ADCOM here? And also, to what extent do you think that might lend itself to -- for the foreseeable future at least, physicians preferring to stick with synergies in the preterm at-risk population?

Safety in RSV coming to you soon, Kimberly. For COVID-19 -- thank you for the question, Emmanuel. Again, Phase III results are coming very soon. So I'm not sure if I have much elaboration to make on the Phase II results that we have provided. It's really going to depend on the Phase III results. Paul was alluding to the sneak peek at interim results for the booster. We expect heterologous scheduled to be good boosters. So it's in line with the profile we expect. Now let's see. Coming soon. But again, you know very well that we need the Phase III, which we did in a very different environment. You know very well that it's a Wuhan containing vaccine in an environment, which is facing multiple diverse variants. I'm totally blind to the data, so I'm very happy to talk about it. I don't have the information. Coming very soon. And of course, as soon as we have it, we'll put it together and we share it with you. RSV, safety?

Sure. So I'll make a quick comment, and then I actually would welcome my partner in crime, Jon Heinrichs, who's here on Zoom, who's our R&D lead for nirsevimab. But let me just start with 2 things. I think it's a very good question. Babies, tiny babies, a very sensitive population. We know no issue of any of those instances being related to nirsevimab. Your question about do we anticipate hurdles from a regulatory standpoint or acceptance of the product. Short answer would be no for 2 reasons. One, some of this is just about the education of the data; and two, it's also one of the functions that our real-world implementation project will bring in Europe in 2022. Larger scale data continues to bring more confidence with that. And that's one thing we are cognizant that people need a bit of that confirmation. Jon, maybe you want to give just a little bit to reassure on the safety data there and the details around it so folks know.

Yes. Very good. Thank you for the question. I'm happy to address it. Hopefully, everybody can hear me. We are very confident with the safety profile of this antibody. We've looked at it now in the Phase III study as well as in the Phase II/III MEDLEY study. You are correct to point out that there were 3 deaths in the MELODY study. But none of those were associated with either RSV or administration of nirsevimab. In fact, the timing between administration of nirsevimab and the death was sufficiently long to really preclude the concept that it was related. Now the second part of that question is around Synagis and will providers want to stick with Synagis maybe until they get a handle on some of the safety questions that you had. What I think what we need to remember here is that Synagis is administered in a monthly manner. So those babies have to be brought in to the clinic. They have to be given an injection every month. And because of that, if you compare the profile of nirsevimab to the -- which is given one time to the profile of an antibody that's given monthly, there's an inherent advantage not only for convenience, but for safety for nirsevimab. And I think that's really going to drive the transition from Synagis to nirsevimab. So we are very confident in the safety profile, and we are very confident that none of the deaths are in any way related to nirsevimab.

Okay. Thanks. So the last question in the auditorium, from Jean-Jacques here in the middle, and then we're going to move to some questions from the webcast.

Jean-Jacques Le Fur from Bryan Garnier. First question for Thomas, perhaps. Looking at your pipeline, I saw that most of the products you presented were -- are improvement of existing vaccine. And in addition to RSV only, I would say, only and I quote "3 new diseases." And I did not see Lyme, I didn't see C. difficile, [indiscernible], CMV. So is there any reason why not hunting with these infectious diseases, sorry? And the second question is for Bill on the mRNA flu vaccine challenges you presented to us. About 3 or 4 issues for developing such a vaccine. In your view, what is the most challenging one to be solved to have competitive mRNA flu vaccine, sorry? We understand the story of having clinical trials over 3 seasons. But for example, is administration challenges or issues is one of the key challenges?

Thank you, Jean-Jacques. So on the first point, so only 3 vaccines. It's a good question. I'm very, very happy about the pipeline we are building together with the R&D team in Sanofi Vaccines. It's a big change for us. And of course, in the second part, we'll have much more explanation with Frank and with Jean-Francois. We'll talk about chlamydia. We'll talk about acne. We really believe these are very strong, nice moves. Interestingly, you mentioned CD for Lyme. We're not going there, by the way, because there are already people there. And therefore, we don't believe we'll be first-in-class, best-in-class, neither do we believe they are so interesting targets in the first place. So we spent a significant amount of time with the team since I joined to make sure that we really look at the screening of all the pathogens, where we are, where we have in our R&D tool books, differentiated tools that make us winners there and really focus on those. It's about making sure that we're really focused on winning areas. Flu, mRNA flu, what it takes to be competitive. Can you give us a bit of a reminder?

Yes. Yes, of course. Thank you. By the way, I think just to remember and to remind you, the first -- the key 3 success factors are protection beyond flu, safety and tolerability and administration. And to your point, the second 2 are sometimes overlooked. But having said that, the first and most important is protection beyond flu. You do have to find consistent results across multiple seasons versus a standard of care with endpoints that actually matter. When you look at the data, for instance, you're 10x more likely to have a heart attack within 1 to 3 days of a flu infection. Providers and payers want to see the impact of these complications in your safety -- I'm sorry, in your immunogenicity or your efficacy studies that you do. You can't just have a quick study and do that. So first and foremost, that protection beyond flu is an absolute must-have. Now the other 2 are also equally important because when you think about a seasonal vaccine, this is routinely given to hundreds of millions of patients across multiple access points, not just health care providers, not just retail pharmacies. At work, drive-in clinics, all of these different innovative ways to deliver these vaccines require incredibly safe vaccines and require thermostability. Now thermostability, Frank will talk about later, and we'll show you the platform we're having. But really, the important thing here for me to remind you is the first-generation mRNA products don't deliver on any of these 3 success factors. It will take a second-generation product, and some of these issues are going to be harder to overcome. And that's why folks like Frank and his team are going to work really hard, and it's going to take some time to get all this done.

So a very important point. So indeed, science first. So end points, you need to have a hospitalization. You need to have pneumonia. You need to have cardiorespiratory hospitalization endpoints in order to be able to drive the value. And that's very important to get this value because another element that is sometimes very forgotten is the value price versus the COGS. And we know very well that if you look at the flu market, you probably have seen Slide 23, not to remind it, where you're showing the market where it goes. There's a significant part which is about standard flu vaccine. That remain an interesting value proposition for countries that prefer a one-size-fits-all with a more moderate budget in order to be able to protect people with flu -- against flu, sorry. So standard of vaccines are at price points that are below EUR 10 a dose. And those price points are not going to be the price point of innovative vaccines coming down the road, whatever platform. So that's a pocket that is not going to be addressable there. And again, you're going back to the endpoint. What is my endpoint in terms of science? And can I do it in prefilled syringe, frozen product in prefilled syringe, challenges coming on the road? It's -- all of this is solvable. That's why we're super excited about the mRNA second generation, which is a hint to the next part of the presentation, but we are not there yet.

Okay. We will now take the question online from Wimal Kapadia at Bernstein. Wimal?

I'm Wimal Kapadia from Bernstein. So first, can I just ask about nirsevimab, please. So just looking on your slides, the guidance to 2025, it looks as though you expect nirsevimab to be around EUR 0.5 billion in '25 sales. And it seems like you believe the total infant market is worth about EUR 2.5 billion, according to Slide 34. So I guess what I'm really trying to understand is, is your EUR 2.5 billion market potential based on the assumption that this becomes a 90% penetrated vaccine market for all newborns? Because if you assume greater than 90% penetration like existing pediatric vaccines, should that number not be 2x of the EUR 2.5 billion? So I'm really just trying to understand your comments on the infant recommendations for all which you emphasized versus the EUR 2.5 billion sales potential of the infant category. That's the first question. And then my second question is just on the composition of growth regionally for influenza in terms of the EUR 15 billion by 2030. I appreciate how you segmented in the slides, but how much of the volume growth -- or sorry, the value growth is driven by EM like China where penetration is very low? And how much of it is actually driven just by a shifting mix in established markets where penetration upside is more modest?

Thank you very much, Wimal. So RSV and flu, RSV recommendation to market size. Maybe you want to specify some geographical aspect? And it's all infant protection in a given market, but maybe not for all markets and being welcoming to you for flu.

Sure. So a very good question. And you're right, in the assumption of, one, the overall market value, EUR 2.5 billion, that's what we estimate. And you're right in the assumption, right around 1.5 -- EUR 1.5 billion, EUR 1.7 billion for RSV for nirsevimab. The assumptions we've made, Thomas, made an interesting point. We don't anticipate, one, that every market will be the same in terms of all-infant protection. We want that, but we don't necessarily assume that, that will be the case. You have our key markets that you're going to see us focus first. Obviously, in the U.S. and in Europe and in Japan and China, as you saw in my presentation, we anticipate very high recommendations and penetrations there. And we'll also stage those launches and those introductions over years into other markets beyond that. We've assumed 2 things in the uptake in the penetration. One, we do give it some time to get to those typical pediatric penetration rates. Sorry, I don't think that was working for a minute. We do anticipate it takes some time to get to those rates. So we have a bit of a ramp-up. And we don't anticipate the same rate everywhere. Higher uptake rates in markets where the pediatric immunization platform is more well established, we have every reason to believe we'll be successful there. And then in some of those markets, it might not be as much. It might take some time to build. And we also have to build some awareness on RSV in some of those markets and maybe less sophisticated on that. So you're largely right in the assumption. It's just that we have a ramp up, and there's a bit of geographic diversity in it, if that makes sense.

Market -- thank you, Kimberly. Sorry. Market size, Bill, in terms of flu, some elements, qualitative elements about geography and other aspects.

Yes. Thank you for the question. I think one of the things to remember is that there's 2 factors here, and they converge a lot. So increasing immunization rates specifically across an increasing and aging population. So some of these targets are the specific targets for our differentiated products. So not only will immunization rates increase, but they'll also increase using differentiated premium-priced products. So you see a very interesting effect happened there. When you look at the immunization rates specifically, we're only projecting about 0.5 point increase per year. So we think it's pretty doable in terms of immunization rate increase overall. The real value transition is the differentiated products. As you saw on the slide, they report -- they're going to represent about the majority of the market value in 2030. So that continuous uptake of differentiated products, we continue to see in the U.S. where you see 2 out of 3 seniors immunized. We're also seeing global expansion occur, so in areas like Germany, where STIKO has a preferential recommendation for Fluzone High-Dose, Efluelda, which is called in Germany. So we're seeing that expansion happen globally, which is considerably -- driving considerable growth on the market size that we're projecting.

Okay. We'll take a final question before the break from Jo Walton at Credit Suisse. Jo?

Jo Walton from Credit Suisse. You've emphasized the need for protection data on going beyond flu, such as hospitalization. But if we look at your Slide 29, we can see that the main share conversion for high-dose flu came, where you've got just the simple efficacy data. So all other things being equal, what's changed that means that future vaccines can't also gain meaningful share from just showing initial superior efficacy assuming that safety is also acceptable? I would imagine that payers if you reduce a level of flu infection from x to y, then they would say that there would also be a similar x to y change in all of the sequelae. And following on from that, in the past, I believe that the companies that did the best in flu were those that could deliver their flu vaccine first. Now even if there isn't a change in who -- in how the strains are chosen and there's an mRNA flu vaccine out there, presumably, it could get to the market and actually be delivered earlier than the current generation just because we know that they don't take so long to get -- their manufacturing isn't so long. So isn't that also a risk in terms of market share?

Thank you so much, Jo, for those questions. Very important questions. So maybe I'll start quickly on the first one, and Bill, you complement. And the time element is going to -- something we're going to see in the second half. So Jo, you are referring to Slide 29, which is the slide showing the 10 years of performance of Fluzone High-Dose. And the big difference between now and the environment of 10 years ago is that then, it was an all commodity market. There was no Fluzone High-Dose. There was no Flublok. And that's a big difference. Because now people have new data in place that show protection beyond flu that was not there available at that time. So I think that's a very significant game-changer. The second difference, and that's what we are trying to say before is that it's not only one criteria that's going to cut it. It's the multiple criteria we've seen before. And therefore, we are back on top of what we just discussed, on the adverse events, on the ability to be prefilled -- liquid prefilled syringes available in due time. So I think that's going to be a set of different caters that will play there. The second point is very important. Bill, what about this myth that maybe we could select the trend differently or that we could produce very early and vaccinate all the elderly in the U.S. in June or in May?

So thank you, Thomas. And certainly, your second point, we're going to -- you're going to be seeing a bunch of information for Jean-Francois later in the presentation. Let me just go backwards before I go forwards and just reinforce what Thomas said. The market 10 years ago in the U.S. was an incredibly different place than it is now and there was nothing there offering any type of value proposition except for time to market. So as a speed commodity came, high-Dose came in and changed that equation with efficacy data. Now back then, that was what we needed. But I can tell you, talking to governments and health authorities now, whether it be STIKO, whether it be NACI in Canada or ECDC, all of these governing bodies and health authorities are looking well beyond efficacy in their evaluations. When you look at their evaluations, they're looking at protection beyond flu, they're looking at reductions in hospitalizations, that are the key factors that they're looking at. And I don't think you can make the jump because if you did x, you can receive y. I think the variability of flu demands proof and the level of protection that they're already getting from the -- like a product like Fluzone High-Dose, also demands proof before you make a change. And that's an element that's consistent. Back then, they wouldn't move without significant data in their minds. And now the same thing, health authorities are not going to move a market until they're completely convinced. It's as good, if not better than what they're getting now. Now in terms of time to market. I'll say one thing. Time to market was the only thing that mattered in a commodity market. However, in a differentiated market, there is allowances for time to market for the better medicine product. Medicine matters, especially in these average patients like the 65-plus. A couple of things to consider in the production process of flu, 75% of the time is on test. No matter what technology you use, no matter what platform you use, 2 weeks to really test takes 2 weeks. Also, filling prefilled syringes takes quite a lot longer than filling multiple dose -- multi-dose vials. A 10-dose vial versus [ unit dose ] presentations, literally 10x as long. So there are aspects of what the market demands across these 3 key success factors. They're going to limit their ability to deliver product and exceeding the early across any technological platform that's there. Strain selection timing, what I'll do is maybe I'll leave that to Jean-Francois for the presentation because I don't want to steal your thunder because I think what you'll see there is less than impressive impact. In fact, I think you coined it, ironically, as a coin toss. And I'll leave it at that for you to explain later.

Thank you, Bill.

Okay. So we are going to go into a very short 15-minute break. For those that are online, please just keep your Zoom link open and hopefully join us back in 15 minutes to move into our pipeline section. Thank you. [Break]

So thank you and welcome back. We are now ready to start part 2, focused on the pipeline. And for this, I would like to welcome on stage Jean-Francois Toussaint, our Head of Vaccines R&D. Jean-Francois?

Good morning, good afternoon and good evening for folks who are in Asia. I'm really delighted to meet you here today, at least the one who are in the room and the other on the screen. So actually, it's the first time that I meet you, and it's my pleasure for that. I've been in the vaccine industry for 15 years now. The last 9 months at Sanofi have certainly been the most intense in my whole career. I have to say that I have been very, very impressed by the level of energy, the sense of urgency and the world-class expertise that I could find in my R&D teams. I knew that I was joining Sanofi at a unique moment for the vaccine industry. I knew also that actually Paul and Thomas had very big ambition for Sanofi Vaccines division. But trust me, the pace of transformation and the progress that we have made already here have exceeded all my expectation. I'm excited today to share with you my vision for Sanofi Vaccines R&D and our innovative and growing pipeline. Next slide, please. So I've heard at many times that there is no room anymore to develop groundbreaking vaccines. It's done, not possible anymore. And you know what, I believe it's wrong. Today, you will see that we are opening a new chapter by entering disease areas with therapeutic vaccine, including a very first therapeutic vaccine against acne. We are doing that by leveraging our state-of-the-art capabilities in immunology and antigen design. We are also doing it by selecting exactly the right platform, the vaccine platform that is best suited for each given disease. And with strong ambition, we want to develop 10 new vaccine candidates and bring them to the clinic by 2025 and more than half of them will be based on mRNA. You will see over the next 30 minutes that we are rejuvenating our pipeline, delivering new vaccine of value with a heavy focus on vaccines that are either best-in-class or first-in-class. So you have seen that pipeline slide already with Thomas. And actually, I will use it as a menu for the discussion here. So we will present the key assets in our core franchises, but also in our growth segment. We will highlight the commercial potential, the reason to believe that it could be either first- or best-in-class, and we will share where they are in the development. There is another way to look at our pipeline. You can see that all age groups will benefit from Sanofi innovative vaccine. From the well-established pediatric segment, up to the large and growing pool of all the adult. This view also highlight how the vaccine candidates in our pipeline represents a significant growth opportunity for Sanofi. Let's talk mRNA for a minute. So you have seen over the summer that we made a very bold move in mRNA. But you should not overlook our broad set of technological platform. Have a look. No other company in the industry is levering as many technologies as Sanofi does. We developed vaccine against a large diversity of pathogens, and a broad set of technological platform allow us to pick either protein or bacterial sugar as target antigens. Our platform have demonstrated effectiveness and safety across all ages. They've been combined in multivalent vaccine, offering sustained immune response, sometimes offering lifelong protection. Of course, mRNA is an attractive technology, and we have taken the necessary action at Sanofi to have a leading mRNA platform in our toolbox. Lipid nanoparticle are sometimes overlooked, but they are equally important, and we have built a very robust position at Sanofi with the acquisition of Translate Bio, the acquisition of Tidal but also our own internal efforts. Of course, we believe strongly in mRNA and LNP. And we like that technology, especially me as head of R&D. I like it because it allows me to bring assets quicker in the clinic. It allows to reduce the technical development cost. And actually, it has a potential to facilitate the development of combination vaccine. But let's be clear, mRNA cannot be used across the board. mRNA express protein. You can only target protein antigen with mRNA, and that restricts its application to certain kind of diseases. At Sanofi, we are in the privileged situation where we can really select the technological platform that is best suited for each disease. Speaking of platform, let me introduce Frank DeRosa, the person who actually discovered and developed what is today Sanofi's mRNA platform. So Frank, maybe before you get started -- you can come on stage, please. But before you get started, can you tell me, do you believe we are competitive today with our mRNA platform?

Thank you, Jean-Francois. Yes, I believe we have a tremendous future ahead of us. Good morning, good afternoon and good evening, everyone. My name is Frank DeRosa, and it is my absolute pleasure to be here today in front of all of you and with everybody on the webcast. And it's an exciting time for us here for the team at Sanofi as well as the team at Translate Bio. Today, I'm going to share with you some of the progress that we've made in a short period of time since coming together and our ambitious plans for where we want to take this platform. But before I get into all that, I want to share a personal note. For most of the world, mRNA became a household word maybe a little over a year ago. For me, personally, it's been my life's focus for over a decade since the beginning of this platform and having helped build the original team, helping create the foundation, the mRNA and LNP capabilities of large-scale manufacturing. And now to see the potential of this technology and the opportunity to take what we have built and scale it an unprecedented level for me is truly exciting. I have to say I've been fortunate enough to have the opportunity to have visited multiple sites within Sanofi seeing the last 2 months, actually, the teams in Cambridge, in Orlando and in France here in Paris and Marcy-l'Etoile and Lyon. It was actually my third trip in the last 2 months to France. So it's been unbelievable, to be honest. And what I see here, the experience within this organization, the dedication of these teams and the capabilities that this company brings with respect to everything, state-of-the-art analytics, formulation, process and manufacturing, fill/finish, you name it, these are things that we at Translate Bio always wanted to build over time, and we hope that we got to. It's present right here, right now in full force. So as we go to Slide 9, what are we doing with all of this? Well, we're moving fast. We're putting these strengths together, and we're forming an mRNA Center of Excellence, as Thomas had mentioned earlier. And this center is designed to be flexible and agile with a biotech mindset, but we're combining those strengths, the expertise, the know-how, the capabilities of both entities. So we're aiming for the center to have at least 400 dedicated resources. And I'm happy to say that we've had a high retention rate with our TBIO employees, many of which are part of the original team when we started this years back. And we all know how hot this market is for talent, specifically in this space. So we're really encouraged by that. We've expanded our capabilities, both internally and externally in many different areas, such as delivery capabilities and even our recent announcement with our partnership with Baidu to expand our computational capabilities. And we generated encouraging clinical results from our first 2 clinical programs, which I will share in a moment, and you'll hear about our adaptation and evolution of this platform as we push into clinical trials for next year and beyond. All right. So let's begin with a snapshot overview of our first clinical trial with this technology as we move to the next slide. So we've successfully entered our first Phase I/II clinical trial. And this is to screen our technology for COVID in particular, utilizing one of our proprietary LNPs in unmodified messenger RNA. Now the study design is shown here on the right side of the slide, the 3 dose levels, there were 2 injections at 3 weeks apart. So as we move to the next slide, you'll see some early positive interim results that we obtained from our first sentinel cohorts. Now what we're looking at here are data representing both seroconversion with neutralizing antibody titers as well as tolerability. And we observed a very nice immune response, 100% seroconversion at our top 2 dose levels, that's 15 and 45 micrograms. The neutralizing antibody titers that we measured are represented as a ratio to that of convalescent sera. And again, we see a dose-dependent increase in the neutralizing antibody titers. And these titers are exceeding those seen from the CureVac vaccine, which I believe was around 0.5 at their top dose. So these results confirm the potential of our platform. Now as we look at the graph on the right side, we see reactogenicity profiles at each dose level. And we see elevated reactogenicity for our upper 2 dose levels. This result is in line with the profile that has been reported previously for unmodified COVID mRNA vaccines. Notably, we see a drop in reactogenicity after the second dose, which is interesting and potentially differentiating, and we'll be further characterizing this as we move forward with this platform. So we continue to progress this platform in additional clinical trials, this time for influenza, and the clinical trial study design is shown on the next slide as we move forward. So in this Phase I clinical trial, we're continuing to explore the platform, this time for seasonal flu. And this is the first time this has been assessed in the clinic. It's through the application of a monovalent flu vaccine, looking at unmodified H3 hemagglutinin mRNA as our antigen. And this time, it's in 2 different LNPs. So the dose levels, again, are depicted at the right side, similar to the previous trial design that we just showed, but this time, it's only a single dose. Now the early interim results of this trial are captured on the next slide as we move forward. We're very encouraged by these results thus far. As before, we're looking at both seroconversion as well as tolerability in this first set of data here. In the first LNP, we see good tolerability across-the-board at all dose levels. However, we did not see a dose response with respect to seroconversion. This is in contrast to our second LNP where we see a very nice dose response. And we're achieving equivalent titers to recombinant HA at 15 micrograms and superior titers at 45 micrograms. This is encouraging, although the reactogenicity of this particular formulation was elevated at that top dose level. But when we look at that mid-dose level, we're on par with Flublok immunogenicity, and we're presenting a reactogenicity profile very similar to the Moderna COVID vaccine. So these data collectively prove that mRNA works for influenza with respect to generating titers. Now there are differences between these 2 LNPs, but we are very encouraged at the overall performance. And we do recognize key areas for improvement, and we're already quickly moving forward to try and address all those with solutions. So as we go to Slide 14, the first way to address this is with a rapid and successful pivot to modified messenger RNA, and this is to help with the reactogenicity observations that we see. This platform is 100% amenable to modified technology. And we've looked at a lot of these different modifications over the years. So we know this switch is very straightforward and readily applicable. And we've been able to generate extensive preclinical data in multiple models. For example, shown here on this slide. These graphs, they're representing neutralizing antibody titers, robust titers in nonhuman primates for both unmodified and modified HA vaccines. And this is over a wide dose range. We've already generated GMP material that's modified mRNA that we anticipate utilizing in multiple clinical trials next year, including for both monovalent and quadrivalent flu vaccines in 2022. And our first modified mRNA clinical readout will also be in '22. And you'll hear more about this approach in a few moments with Jean-Francois. So as we go to the next slide, we understand there are multiple factors in creating an optimal mRNA vaccine. And we, of course, want to keep reactogenicity to a minimum. And this evolution of our platform is providing us with enhanced properties for potentially lowering reactogenicity, not only through the use of modified mRNA, but also through designing more optimal delivery systems. The graphs here, they represent 2 selected cytokines that we're using as biomarkers with which we can represent stimulation. And we're looking at both the type of mRNA as well as the delivery system used using our proprietary MIMIC system assay. And as we've evolved on both the mRNA front as well as the delivery front, we see a progressive reduction in these biomarkers, which we expect to reduce reactogenicity as we move into the clinic. As you've heard earlier from Bill, there are challenges which need to be addressed, other ones besides this when we think about creating those optimal messenger RNA vaccines. Next slide, please. Thermostability, certainly, a big factor here when it comes to creating competitive vaccines outside of a pandemic setting. And looking on this graph at the left -- I like this graph a lot. There's a nice comparison of where the current state of stability for various vaccine technologies, and this is under pharmacy-friendly conditions, 2 to 8 degrees Celsius or refrigerated conditions. You can see that mRNA-based vaccines have minimal stability under these conditions as a liquid suspension. And you compare that to Sanofi's Fluzone with stability of 1 year under these conditions and even Hexaxim with 4-year stability at 2 to 8 degrees Celsius, very impressive. And what do I mean when I say this word thermostability? It's about the integrity of your drug product over a period of time at a given temperature. So for mRNA and LNPs, we always think about particle size, aggregation. But the critical issue is mRNA integrity, critical. Many people think about mRNA integrity, and they think nucleases, RNases. I like to describe this with my team as ghosts that you can't see, but they are everywhere, and they're about to true up your RNA, which is all true. But what we are referring to here is hydrolysis. Water cleaving your mRNA, and it only takes 1 break in that phosphate chain to lose all of your activity. So it's very important. This is a critical fundamental parameter that we are looking at and we're taking multiple approaches to addressing. First of which is represented in the middle slide -- excuse me, the middle graph on this slide. And that's through lyophilization, a process to remove water. We've already achieved 1-year stability at 2 to 8 degrees under lyophilized conditions. And you can see that we're measuring mRNA integrity there. That line is very nicely holding steady across that graph over 12 months. And you compare that directly to its liquid form, the same formulation, which shows extensive degradation by 1 month and completely degraded by 3 months. So we are ready to go with lyophilized mRNA formulations with our proprietary process, and we can use those for specific programs. Now some may have told you that lyophilized formulations for vaccines will solve everything. It won't. You need a stable, fully liquid formulation to meet or exceed the standard of care, as Bill had mentioned earlier. And so we're moving towards exactly that. And that's what's represented on this graph on the right side of this slide. Now we know this takes time, and it's not easy. But we've made a lot of progress on this front. And represented here in this graph is a novel proprietary prototype lipid nanoparticle formulation that's showing -- demonstrating stability at 2 to 8 degrees as a liquid in the presence of water. And the way we're measuring that on this graph is actually through in-vivo potency over the course of 6 months, looking at reported protein production from that mRNA. And so while this is still a prototype, we are extremely encouraged by these data, and we're looking to apply these learnings to our lead next-generation formulations as we develop a more optimal stability profile and direct application to wider vaccine markets. So we can summarize these parameters on the following slide. All right. So how do we view this platform? We have a fantastic foundation for this platform. And that's through its comprehensive development for over a decade. We recognize the barriers that we have to face. And these are faced by all companies in this field, and we are rapidly addressing each one of them. So as you go through this table, we've classified each of these stages of progression as generations, first generation, second generation and so on. These generations are classified based on their properties and the resulting markets with which they can address. For example, first-generation mRNA, this is where our current COVID vaccines are. We can all agree they've had a tremendous benefit to everyone. They demonstrate high immunogenicity, but they also demonstrate moderate to high reactogenicity. And these properties are further complicated by poor thermostability profiles. And so as we've all seen, these have worked well under pandemic situations, but we do not believe that this will be acceptable for established vaccine markets. For those markets, we look towards second-generation mRNA vaccines. And this is whether reactogenicity profiles are dramatically improved and the thermostability is greatly enhanced, either through lyophilization as we've already demonstrated and we have our process for or even better, a fully liquid vaccine for a minimum of 9 months, preferably 1 year at 2 to 8 degrees Celsius, and this will be the case for flu applications. So as we continue to evolve the platform and make innovative steps forward, we're adding to these beneficial properties and creating ways or perhaps finding ways to extend the duration of expression or even tailor our delivery systems for organ and cell specificity. And we've got efforts continuing and making progress along all these fronts. And this really begins to allow you to think more broadly to allow for further applications outside of vaccines and into multiple therapeutic areas. And this is one of the things that I love about this technology, it's potential for broad applicability. For the last 12 years, I've been focused on using mRNA for therapeutic applications, using mRNA to treat rare chronic disease in other areas. And what excites me again with the teams and the capabilities here at Sanofi is the scientific expertise and their novel approaches to medicine. So in the short 2 months that we've been together, since this acquisition, not only have we pushed deeper into vaccines, we've also been working very closely with groups across the greater organization to try and apply this platform in areas such as CAR-T therapies in collaboration with the Tidal team and technology in areas such as genome editing and even looking at our delivery capabilities and applying them towards other nucleic acid-based therapies. We have established a platform which works, and we recognize the challenges ahead, and we're already moving full speed towards solutions for those. We have an extremely competitive team, and now we are weaponized. This is why I'm truly excited about the future here and the establishment of this mRNA Center of Excellence. And now you'll hear about our pipeline deploying multiple technologies, including how we are applying our next-generation mRNA technology across multiple disease targets. Jean-Francois?

Thank you so much, Frank. Thank you also for bringing such a robust mRNA platform in Sanofi and such wonderful team, by the way. Thank you very much. So now let's start the deep dive into our pipeline. And this is something that I will do with my partner in crime, Thomas Grenier, that you have already seen on the stage for the Q&A. Actually, together with Thomas, we are shaping the pipeline in the vaccine division to win not only in science, but also on the marketplace. We'll start with the next-generation influenza vaccines. I feel it's a very good segue because of the heavy role that the mRNA is playing in our strategy. But you will see in a couple of slide that we will go through that mRNA won't be sufficient and that it is a unique science and the data that we have accumulated over the last decades that will keep us ahead of this -- in the space of influenza vaccine. So the influenza vaccine market is growing, and we predict that it will reach 15 billion by 2030. As a flu vaccine leader, we are building the next generation of influenza vaccine by incorporating multiple layers of innovation. You will see in the next slide our development plan with the mRNA platform in flu. But I will also share with you the ongoing work in R&D with machine learning and neuraminidase. So Frank has shown you the encouraging result with a monovalent flu trial. Now let me share the next step here on this slide. Actually, you see that we have conducted preclinical evaluation of a quadrivalent mRNA vaccine. And we're pleased to see that this mRNA vaccine was at par or slightly better than recombinant HA, which is used in Flublok as you know. We know that thermostability and tolerability or the profile of the influenza vaccine will be important and that it must exceed the one that we have now in mRNA and it must match the one that we have in today's vaccine. That's why we've pivoted. We have pivoted to modified mRNA, and we are testing multiple lipid nanoparticle. The progress that we've achieved so far is very encouraging, and it's completely aligned with our expectations when we started it. Next year, we're going to start our Phase I/II trial with quadrivalent modified mRNA HA-based vaccine. It will benchmark mRNA versus standard of care, looking at immunogenicity and safety. And it will also allow us to select the formulation that we will bring in Phase III. And if everything goes well, we're going to start the Phase III actually 1 year later in 2023. The objective of the Phase III will be to demonstrate safety, but also efficacy of our vaccine and compare it to the standard of care. Remember that our goal with the next generation of influenza vaccine is to improve the efficacy. And so we need to demonstrate it. Demonstrating also the protection beyond flu is very important. Protecting against the severe consequences of flu is something that is valued by payers. And this is something that we will embed in our development plan. Actually, we are convinced at Sanofi that raising the efficacy of influenza vaccine may also require new strain selection, building a little bit on the question that came earlier during the former session. But let's face it, we don't believe that it is going to be a simple journey, and we don't believe that just delaying the strain selection by 2 or 3 months will make the difference. We don't believe it's going to be the solution. Why? Let's look at some fact. So on this slide, on the left, you see that we have analyzed the main circulating strains over the last 10 years. As you can see in yellow here, there are only 2 years where there was a significant mismatch that occurred between the vaccine strain and the WHO-selected strain. This highlights that the impact of a mismatch on the overall efficacy of flu vaccine is not so dramatic and we need to do something different. The graph on the right illustrate the circulation of one [ strain ] of H3N2 virus between '13 and '15. WHO selection take place in February, which is highlighted in gray here. Vaccination start in September, that you see in blue. And actually, the epidemic happens from December onwards, highlighted in pink. And as you can see, the strain evolution is very dynamic and the strain that predominates right before the season may collapse as soon as we start vaccination or even when we are in the season. So if you look at that pattern, really selecting the strain of flu to include in the vaccine later would not have helped at all. By the way, we are December 1. Who can bet here that we won't have a mismatch this year or if we have a mismatch, that mismatch will last the whole season? I bet nobody can do it today. Just highlighting that selecting later will not help. So of course, we believe we need to select a better strain. How are we going to do that? With us, it's with machine learning. You know everybody talks machine learning these days. At Sanofi, we just didn't talk about it, but we also took our leadership role into full play. And actually, we piloted the selection of flu strain by machine learning. What did we do? We have actually leveraged thousands of sequences available in the public domain. We have also included data generated in our own laboratories. We applied machine learning, selected 4 strains and the prototype of them that we included in a clinical trial and compared to the standard of care, the strain that is recommended by WHO. We then evaluated the level of functional antibody that these prototypes were eliciting. And as you can see on the left-hand side, the strains that were picked by machine learning sometime matched but usually induced higher titers against a variety of strain, representing the diversity of flu H3N2. This is important. This is an important slide, guys. These are data that we actually have never shared so far. So if you want to look also at another way we could represent our data, we looked at seroconversion. In flu GMT seroconversion, both are important. And you can see on the right-hand side of the slide that actually 2 out of the 4 machine learning-selected strain induced a better seroconversion, a broader seroconversion against more strains. The other 2 were not better, but they were matching the WHO standard of care. Instead of being theoretical and simplistic, we have in our hands here at Sanofi the very first data suggesting that machine learning can help selecting better strain. Of course, our algorithm is not perfect. I told you these were a prototype strain. But we keep obviously improving it and going to the clinic and generating data, feeding them in the algorithm is what matters to really win in that space. So we spoke about mRNA. We spoke about machine learning. So the third layer of innovation that we are incorporating in our flu vaccine is about including novel antigens. At Sanofi, we've been looking at neuraminidase for years because of the Fluzone High-Dose vaccine contains higher amount of neuraminidase. It induced higher seroconversion, as you can see on the left from -- of this slide. And we even have some preliminary evidence that the antibodies against neuraminidase contribute to the higher efficacy of Fluzone High-Dose. What did we do? We have generated so far data with neuraminidase in an mRNA format, and we have shown that we can include it in the QIV mRNA HA-based vaccine without any interference. You can see, of course, that the titers against neuraminidase were very nice as well. So I trust now that this short overview gave you an idea of our determination here at Sanofi to keep innovating in flu. mRNA will be a fantastic tool to advance the next generation of influenza vaccine, but innovation beyond mRNA will be required to deliver the high efficacy that everybody is expecting actually. RSV is another area of focus in our pipeline. This is also a franchise that is very close to my heart because I've been spending thousand of hours, shaping and leading various RSV vaccine programs prior to joining Sanofi. So this is a field I know well. We actually estimate that RSV market would exceed EUR 8 billion by 2030. And it's a market spread across 3 age groups. We at Sanofi will play in the 3 segment, but we have made the educated choice, as already primed by Kimberly, to leverage different platforms, different technologies, different vaccine candidates to make sure we deliver the optimal protection for each age group. As Kimberly explained, we are very pleased by nirsevimab Phase III data, multiple Phase III all going in the same direction, and we are confident we'll take a significant share of the infant market. For toddlers, we are developing a live attenuated virus vaccine as a follow-on to nirsevimab. And for older adult, we are leveraging our mRNA platform, starting first with RSV stand-alone vaccine and then moving forward with potential respiratory combo vaccine. This slide actually shows the burden of RSV in toddlers, and it is a burden that is often underestimated. But hospitals, general practitioners and RSV expert are very clear, the RSV burden doesn't stop after the first season. And you can see it from this slide actually. RSV remains a significant driver of hospitalization in children between 4 -- 1 and 4 year of age. You can also see that it's a much -- a significant driver of outpatient visit and actually exceeding that in the infants below 1 year. And all of these visits, these hospitalization are triggering a significant health care usage but actually also causing a loss of productivity for parents. We are convinced at Sanofi that we have the very first RSV vaccine toddler that has the potential to deliver both a very strong safety profile but also a strong efficacy against upper and lower respiratory tract infection, preventing outpatient visits and hospitalization. Our vaccine candidate is a live attenuated virus that we have in-licensed from the NIH. NIH has actually rationally designed a vaccine candidate to achieve the fine balance as it is already the case with live attenuated vaccine between underattenuation and overattenuation. But to say differently, to achieve the very sweet spot where the virus can still replicate, elicit a protective immune response while remaining safe. And it took actually 7 candidates evaluated in clinical trials in toddlers and 2 decades for NIH to identify that specific live attenuated virus that we are talking here about. We currently have an ongoing Phase I/II trial with that candidate, and we expect to have a readout on safety and immunogenicity in 2022. Actually, we already have exciting data with that vaccine candidate. And these are data that have been generated by the John Hopkins University (sic) [ Johns Hopkins University. ] This graph shows the 2 most promising live attenuated viruses that they developed. And you can see from the left graph that both candidates here were eliciting a very strong immune response, strong neutralizing antibodies. But we decided to go with the delta NS2, the ones with a square around it, because we prefer its shedding profile and its safety profile as well. Interestingly, the John Hopkin Institutes (sic) [ Johns Hopkins Institute ] conducted a meta-analysis, [ pooling ] these 2 live attenuated viruses. And they could already show a significant reduction of medically attended acute respiratory infection. As the vaccine is given intranasally, we are confident that it has the potential to actually prevent the large burden of RSV outpatient visits in addition to the hospitalization. And given this only promising result, we have decided in Sanofi to accelerate the development of this vaccine that would be the first-in-class for sure. Let's now have a look at the other end of the age spectrum. You can see on this slide that influenza, RSV and other respiratory viruses continue to import a large disease burden in the older adults. But the epidemiology of these viruses is quite different from each other. Flu is changing very quickly and mandates yearly adaptation of the vaccine composition. On the other hand, you see RSV, hMPV and PIV are different. They show a very slow, very limited actually, evolution, which will not require adjusting the vaccine every year and which will not require seasonal administration of the vaccine. So we are convinced at Sanofi that the burden of RSV is sufficient to justify the development of RSV stand-alone vaccine. But as a second step, we expect the RSV vaccine to be part of a broader combination vaccine for older adult. So the next question is, okay, you start an RSV program, nice. You go in the clinic in 2022 with that, but how are you going to differentiate from competition? Here, again, we have leveraged our core competencies to design a superior antigen based on the RSV fusion protein. The preclinical data that we generated show that our proprietary antigen focuses the immune response on the most important antigenic site on the virus. This is the site 0, the same site that is targeted by nirsevimab that Kimberly likes so much. Our antigen is increase -- is associated with an increased immunogenicity over our competitor antigen that you can recognize in the middle panel. And we have shown that this antigen is compatible to be used in an mRNA format or as you can see on the right. This smart design has actually been under the spotlight when it has been selected by the prestigious journal, Science Immunology, to become the cover of one of their edition. And with that antigen in our hand, yes, we're going to start a Phase I/II trial next year in 2022. As I mentioned earlier, we are not going to stop there. And we have already initiated the first step to develop a respiratory combination vaccine for older adult. We have actually conducted several round of immunization of the hMPV, human metapneumovirus, fusion protein antigen. This has led to a design with improved immunogenicity and improved stability. And we have shown again on the right graph that this antigen is compatible and works under mRNA format. The work continues. We are not stopping here. We are working on other targets, and we plan actually to advance a respiratory combo virus vaccine by 2023, again, Phase I/II. So overall, I guess, you grasp my excitement for [indiscernible]. This is my life. This has been my life for quite a few years. And our end-to-end pipeline is really exciting. Actually, my ambition is for Sanofi to be quoted as the RSV company in the future, and Kimberly will like that, and she will pioneer that with nirsevimab. Now let's switch topic and let's -- next slide, please. May I have the next slide? No, the former one. Yes, the former one. Seems I'm missing a slide here. No worries. That's fine. So actually, I wanted to transition now -- sorry for that. I wanted to transition to other assets in our pipeline, assets that I will actually cover with Thomas, and Thomas will show us the progress we're making on pneumococcal and meningitis. Thomas, the floor is yours.

That's right, Jean-Francois, exciting news. Discussing 2 areas today: pneumococcal, a new field for us; and meningitis, an area where we are winning today and we plan to keep winning in the future. My name is Thomas Grenier. I'm in charge of franchises and product strategy for Sanofi vaccines. I'm delighted to be here today to share with you our ambition for these 2 key franchises. Let's start with pneumococcal on the next slide, Slide 32. It's a disease, it's a market that you know pretty well. I'm very excited to share with you today for the first time the unique features of our program and why we are convinced that we have everything it takes to become a key player here. First, why would we want to go in this arena? We see 3 compelling reasons: first, the size of the market, more than EUR 6 billion, with growth expected; second, we see strong synergies with our existing and future product portfolio, both in pediatrics and adults; third, the science. The science is fairly mature. One of the biggest challenges we see is in formulation with more than 20 serotypes in a single syringe. It's a great opportunity to leverage our formulation expertise that Thomas shared earlier today. Entering the pneumococcal serotype race is not a light commitment. That's why we have set up a strategic partnership with SK bioscience, which help us bring together the right capabilities and a good way to share the significant investment and risk of such an ambitious program. Now why should anyone believe that there's room for us on this market? Well, we are convinced that there's an opportunity for us to keep raising the bar here. The race to expand strain coverage is not over. You have certainly seen the latest ACIP recommendation, recognizing the value of both PCV20 and PCV15 combined with PPSV23 in adults to replace current standard. More strain coverage is a clear expectation from health authorities. What's our approach here? We decided to enter the field with a 21-component vaccine, including the serotype 9N that will be adding up to 7 points of coverage in older adults. We're in this field for good, and we will continue to monitor the epidemiology and keep adding new serotypes over the long term. Now where are we with the development of the program? We are conducting an extensive Phase II program: first, in infants and toddlers, where we are testing the product as a primary series, followed by a booster dose; and in adults and older adults where we are studying it as a single dose. In each population, we are evaluating 3 formulations that we benchmark against competitors. The goal is to identify the best composition to deliver competitive assets. We plan to have Phase II results in all 3 population by the end of next year and to progress into Phase III as early as 2023. We are truly excited to enter this market by bringing enhanced protection to patients of all age groups. Let's face it, we are going after some of our competitors' bread and butter. But for us, it's on the upside. Now meningitis. This is an area that we know extremely well because we pioneered it. The market is worth north of EUR 2 billion with still a large growth potential. As you know, we are the leader with men quadrivalent and Menactra in the U.S. with 65% market share. Now we are setting a new standard with MenQuadfi, and I will share more about it in the next slide. Moving forward, we want to complement our portfolio with a competitive MenB, offering broader strain coverage. So what does it do? Well, it paves the way to our ultimate goal, a best-in-class, fully liquid pentavalent vaccine based on MenQuadfi, proven best-in-class backbone, and our new MenB component with increased coverage. We see this as a very exciting perspective. Now let's have a look at the reason why MenQuadfi is setting the new standard in the quadrivalent space. First, MenQuadfi offers a superior immune response against monovalent MenC and quad vaccines in naive toddlers. Second, MenQuadfi provides the best convenience to health care providers with a fully liquid formulation requiring no reconstitution, much simpler for providers. Finally, MenQuadfi is becoming the vaccine with the broadest age indication. It's the only vaccine that fully matches both the U.S. and European schedule, allowing us to participate in all markets with one truly global product. And our indication in older adults with no upper age limit worldwide is key for international markets. Now let me tell you why superior immune response against MenC matters so much for public health authorities, especially in Europe. So far, no MenQuad conjugate vaccines has demonstrated noninferiority against serotype C. To maintain uncompromised protection against MenC, several European countries have decided to stick to monovalent MenC and not switch to quadrivalent. MenQuadfi brings the solution. We have brand-new data, and we can see them on the graph. MenQuadfi has demonstrated superior immune response against MenC in naive toddlers. We believe this will clear the switch to quadrivalent, providing enhanced protection to children. As you remember, we first entered Europe, we spent quite a fee this year in '21, and we see growth opportunities for the future with upcoming conversions. Moving forward, we are convinced that MenQuadfi gives us an edge for the development of our best-in-class pentavalent vaccine. Starting with higher MenC titers will help counterbalance potential immune interference between serotypes should that happen. Our competitors do not have this advantage with their [ quiet backbones. ] Now regarding MenB, we have a competitive MenB candidate currently in Phase II. With this candidate, we target broader strain coverage, broader than current standard. So Jean-Francois, please, would you tell us a bit more on the exciting science beyond this improved MenB we're looking for?

Yes. Sure, Thomas. So actually, we have designed a vaccine that address all the limitations that we have seen in the field over the last decade. And we have selected a cocktail of antigens and specific design actually that offer a broad MenB strain coverage and that has the potential also to have a reduced reactogenicity. So have a look at them. So we first selected to include 2 fHbp proteins. We have decided to use mutated version of them, version that actually nonlipidated to reduce reactogenicity. We included NadA. NadA is very important, adhesin that actually we find in most hypervirulent strains of MenB. And finally, we have included an outer membrane vesicle to broaden further the coverage and also provide a slight adjuvant potential. This is a vaccine composition that actually we have tested in preclinical models. And we're -- actually, you can see the data here on the right, and we have been very pleased to observe that our composition was actually eliciting antibodies with a bactericidal activity against all the representative strains. And as you can also detect the outer circles represent our competitor, and they could not do that. This vaccine is actually in Phase I/II nowadays, and we expect an immunogenicity and safety readout in 2022. In addition, as Thomas mentioned, we plan to leverage MenACWY, so MenQuadfi, bring MenB together and start the development of a men penta vaccine as soon as 2023. By the way, Frank, we just completed 2 important projects, 2 projects that are not based on mRNA. So could you tell us why mRNA is not used there and why potentially it could -- it will never get there? Can you tell me?

Yes. Well, I would say, first, mRNA can do a lot of things. But with respect to this target, if you want to be competitive and effective, it's going to take a little more than that and mRNA can't really address some of these approaches such as polyconjugates and outer membrane vesicles that you have listed up there. So I would imagine for some of our mRNA peers out there with a singular technology that they would not have a competitive early-stage program in their pipeline for this target in particular.

Thank you so much, Frank. No, I think, guys, it's very important. These are fields that are not reached by mRNA. And actually, you saw it. To succeed in men penta, we needed to leverage glycoconjugate, recombinant protein, but also bacterial fermentation and outer membrane vesicles. So that is something that not everybody can do certainly. And this is what it takes to lead in a field like meningitis. So now let's move on with the 2 new field that actually we're pioneering. So I want to complete the chapter of our pipeline here by opening the discussion on 2 new targets. I want to share with you how we are pioneering science to open new growth areas for Sanofi with 2 best-in-class vaccine. Thomas already mentioned them, chlamydia vaccine and acne vaccine. Actually, with acne, we are opening a chapter where vaccines are used to treat chronic conditions of infectious origin. And the program, of course, that I'm going to discuss are early. Yes, they are not yet in Phase I/II, and we still have some uncertainty. But despite being conservative, we are very much convinced that these 2 program have the potential to bring sales above EUR 2 billion every year. Let's start with chlamydia, the silent cause of infertility in women. Actually, chlamydia is associated with a very high incidence globally. Not only here, everywhere in the world, you see chlamydia. And in the U.S. only, it's estimated that 2 million women experience a chlamydia infection every year. Actually, those who get diagnosed get treated with antibiotic and don't develop the severe condition of the disease. But as you can see from this slide, 800,000 of them are never diagnosed, and 300,000 of them are developing a severe complication like pelvic inflammatory disease. That results at the end in more than 20,000 cases of infertility every year. As such, the most dramatic consequences of chlamydia infection are for young women. And like for HPV, we anticipate that the vaccine would be first implemented in adolescent girls and in young women. But potentially afterwards, this will also go to men because men also suffer from chlamydia infection. The protection against chlamydia require very strong T cell immunity. And more specifically, the induction of CD4 T cell-expressing interferon gamma. We have been screening multiple T cell antigen, and we could find 2 with the superior immunogenicity. You can see them on the graph here. We have also compared this antigen in an mRNA format and recombinant format. And actually, we could see that the mRNA was superior to recombinant protein plus adjuvant. We also implemented in the lab breakthrough innovation that allows us to measure the entry of Chlamydia trachomatis bacteria into endocervical cell line. And this is a tool that our scientists are using today in the lab to screen and identify new antigens that can elicit neutralizing antibody response. The research is on track to support the initiation of the first Phase I/II with our chlamydia vaccine candidate by 2023. Of course, you can see the need is very large, and we're really thrilled to have the potential to deliver a solution for millions of women globally. Moving to Slide 42 now. And today, we are extremely pleased to bring, to welcome actually into the Sanofi family the biotech from Austria called Origimm. I'll talk about that. So it's a small biotech that has been pioneering acne for a decade now. Origimm will actually accelerate our effort to develop the very first acne vaccine candidate. Acne is probably the most visible and widespread disease in adolescent. It's estimated that more than 200 million adolescents suffer from acne. And up to 40% of them develop moderate to severe acne, the form of the disease that is associated with the largest and most significant psychological impact on our adolescent. And you are not without knowing for sure that acne is associated with an increase in suicidal thought in adolescent, right? So the standard of care in acne, as you know, is largely insufficient. On one hand, you have a lot of over-the-counter product and antibiotics that have limited efficacy. On the other hand, you have isotretinoin, actually a drug that display some efficacy but that can be associated with very severe adverse event and that is barely used for that same reason. Needless to say that, and I guess, we have a couple of parents in the room and on the web, the financial burden for acne is pretty significant. Actually, you see also that the bacteria causing acne is associated with other severe disease. You can see that on the bottom right of the slide. And these targets, while not today in our portfolio, are potential future target for us as we move forward. Now let's move to the science. And actually, most people ignore that acne is a result of 2 opposing forces, 2 forces, 2 players that we know extremely well in vaccines R&D. On one hand, you have a bacteria. And the bacteria in acne is called Cutibacterium acnes. It's a bacteria that invades the pilosebaceous unit in our skin. On the other hand, you have the immune system and the immune system gets excited by this bacteria. It overreacts and triggers a very significant inflammatory response. The good thing is that we do vaccines, and vaccines actually modulate the immune system and keep bacteria under control. And that's why we are confident we can succeed in that field. With Origimm, we are acquiring a set of antigens that are inducing functional antibodies against the virulent strains that are responsible for acne. You can see some results on the right-hand side here. Origimm also brings a decade of expertise in acne. And combining their expertise together with our science and our technological platform, we are very confident we can start Phase I/II by 2023. As we conclude this session, I think we noted that we have been on a journey, a journey to rejuvenate our pipeline and build an industry-leading vaccine pipeline. We have added exciting assets in Phase I. You saw RSV toddlers, my favorite for sure. You saw PCV1 -- PCV21 and you saw also meningitis, MenB, to be followed by men penta. Now we are looking forward to bring 10 new candidates in the clinic by 2025. So remember, at Sanofi, we are a leader in vaccine. We have a broad technology toolbox and state-of-the-art capabilities in antigen design and immunology. We have been delivering innovative vaccine to fight infectious disease in endemic and epidemic setting for decades. And we will continue to do so. But today, we're also opening a new chapter with vaccines to prevent and treat chronic diseases of infectious origin. We think that it is an underappreciated field with significant untapped potential. The first asset there is a vaccine candidate to treat acne. And we had a jump start in that field with the acquisition of the dynamic biotech Origimm. Altogether, that brings us with a very balanced and promising pipeline that has been designed to improve public health globally while contributing to the sustainable growth of Sanofi. Now let me hand over to Thomas for the conclusion.

Thank you very much, Jean-Francois. I have the feeling soon you will have 10 favorite projects, not just one. It's been great. I'm conscious of time. So it's been really great to share with all of you our strategy, our capabilities and our industry-leading pipeline. A few words of conclusion though, for today. I want to summarize what is probably a significant amount of new information. Number one, we will continue to deliver according to our 2025 guidance and expect to more than double our sales by 2030, thanks to our 3 core franchises, influenza leadership, strong manage, PPH and booster performances and, of course, the upcoming launch of all infant protection solution against RSV with nirsevimab. Number two, our mRNA Center of Excellence is progressing at record speed. And we really want to share with you we're excited to deliver the second generation of vaccines that will truly unlock the potential of mRNA. Number three, we are building together a highly innovative pipeline, addressing unmet medical needs that are of significant size and providing new solutions to patients suffering from very severe disease. We really hope that you enjoyed this session as much as we have. We are a bit of a passionate team, but it's now time to open the second Q&A.

Okay, yes. So if I could just ask our presenters back on stage and we again are joined by Jon. I probably don't have to go through the procedures again. So we're going to start again with some questions here, but I also want to take the opportunity to take some questions from the web. So who wants to take 1 or 2 questions here? Maybe we go to [ Eric ] this time.

Yes. [indiscernible], Stifel. Two questions. One, R&D related, the other not. On R&D, in terms of flu, I was expecting, in terms of challenges, you to address mRNA. You did, and pretty in-depth, and thanks for that. But also maybe universal flu vaccine to some extent. So now moving. This could be additive and not a direct threat to what you're doing, but still what are you thinking about that? Are you conducting anything internal? Or are you just looking at what the others are doing and having more time to think about it? And the second question that is not R&D related, just to understand to what extent nirsevimab can impact the P&L of the GBU of vaccines because it's kind of a mab priced as a vaccine? And so just to better understand the push and pulls about how this might impact us, [ good ] and maybe SG&A as well. And given the size of the drug, what we may expect, although we cannot expect to get specific answers about profitability of the drug itself.

Thank you very much, [ Eric ]. For the first question, I'll bring this to you, Jean-Francois. Flu universal, it's something that's been discussed for many, many times. You know that we had some programs in the past around this. A very, very challenging time lines. The big list of companies have stopped their programs for complicated reasons. Jean-Francois, please answer, what do you think about universal flu?

Yes. So thank you for the question. I think it's a fascinating one for sure in science. We have been active in the field. We've been looking at what is happening there. Honestly, so far, we have not been convinced by the approaches that are used. We believe all of them have flaws and will not lead to a product. We believe that machine learning will help us to actually develop better vaccine, vaccine for offering a better protection. So that's always very pragmatic. But the way to deliver it, and there are also some T-cell-based approaches that have been failing over the last 2 years. So again, not an area where we believe we can win. Finally, demonstrating the value of universal vaccine needs a lot of data over a long time. And you cannot fail on a single year. So again, here, we believe we have the winning strategy with machine learning and improvement of the vaccine with neuraminidase and the other approaches I described.

On nirsevimab financials, it's a partnership with AstraZeneca that we are 50-50 sharing. What we are foreseeing is, of course, nirsevimab is a significant growth driver for us. Profitability-wise, we're going to be in the ballpark of the profitability of the GBU, but really, it's a growth driver for us.

Okay. So we would now move to some questions on the web, please, and then we can come back to the auditorium.

Okay. And so we'll start with Richard Vosser from JPMorgan. Richard?

Richard Vosser from JPMorgan. Just a question on RSV to start with. Just on the vaccine toddler approach, just if you could give us more details why you're using a live attenuated approach for the pediatric rather than focusing on the [ pre-F ] candidate that is looking at 0 antibodies for older adults, just the reason behind those 2 different approaches. And then maybe coming back to flu and then thinking about the benefit of standard-dose flu on hospitalizations and high-dose flu on hospitalizations. Could you give us an idea of the absolute reduction in hospitalizations for both those approaches? You've had the relative reduction on the slide. And therefore, what level of hospitalization protection you think we'd need to see from a new candidate such as mRNA here to really make a difference?

Thank you, Richard. For the second one, I might come to you Bill in a second, so you might be ready to take a mic and jump on the scene. For the first one, on RSV toddler program, a very exciting program. and first-in-class, best-in-class, as mentioned before. Jon Heinrichs was also with us by Zoom and was the scientific head behind our RSV programs. Please tell us what you think about the different approaches.

Yes. Thanks, Thomas. Very exciting program, you're right, and it's an interesting question. Thank you for that. I would answer it by saying that since RSV's natural route of infection is through mucosal infection that a live attenuated RSV vaccine that targets that same route is likely to produce the best response, both mucosally and systemically to prevent disease. On top of that, we have several decades of experience from the field with live attenuated RSV vaccines to show that they're safe, that they're well tolerated. And as Jean-Francois showed you, preliminary evidence indicate that they are protective against both upper respiratory and lower respiratory tract disease. So we think that this has the best chance of being successful for an infant vaccine approach. Whether or not an injectable vaccine could do the same, really, in toddlers is something that will have to be addressed preclinically and clinically. But for us, the best approach is to target the same route of infection as seen by natural disease.

Thank you, Jon. Bill, hospitalizations, again through high dose and standard dose, relative efficacy versus absolute numbers?

Absolutely. Okay. Thank you for the question. I think one of the things that we have to continue to remember is that standard of care in the baseline is a standard dose vaccine. So one of the things we've done with our programs is we've always compared to that baseline and showed a relative performance and a relative efficacy advantage. And we think that's really the way to go. And it's why it's important that these clinical trials upcoming continue to reference the standard of care and show the benefit. For health authorities and governments to make informed decisions, the question they ask is how much better is this product I'm giving. And you really can't do that with absolute efficacy or absolute reductions, you have to do it in incremental gains or relative efficacy. You have to do it across multiple seasons across the endpoints that we talked about. So that's really the advantage of relative efficacy and why we've chosen that path and why we would encourage all the health authorities continue to use that and all of these new candidate vaccines, including ours, to maintain their relative efficacy advantage.

Saying it differently, Richard. Flu is pretty much recommended every single where -- every single place, every single country in the world, above 65 and above. So ethically, you have to provide a flu vaccine. The standard dose or high dose, that could be discussed. We have our opinion, you know that. But definitely, when you want to study with a new vaccine, flu is not COVID-19, not [ a pandemic ] flu, you will have to do a relative efficacy.

The next question is from Graham Parry from Bank of America.

So firstly, could you clarify a few things on the mRNA flu Phase I data that you showed, just to help us understand it better. So the age of patients in the trial, the definition of seroconversion being used, is that a fourfold increase in titers? And what the absolute geometric mean titer ratios translate to -- sorry, ratio translates to in terms of absolute levels? So how does this compare versus products that are out there on the market already? And then secondly, on time lines, you highlighted first half of next year for modified mRNA monovalent to enter the clinic and second half for quadrivalent. Is the start of the latter contingent on the former? And is LNP optimization a rate limiting step for both of those progressions to take place?

Thank you very much, Graham. I'll go to you, Frank, first on flu mRNA Phase I, different elements. And Jean-Francois, you can complete.

Thank you very much. I can actually start on the second part of the question, which is the timing for the monovalent versus quadrivalent certainly. This is not dependent on the monovalent being done first. So the result of that going into the quadrivalent. What we're doing is we're taking a platform approach to this. As you saw with this first Phase I clinical trial, we had multiple LNP candidates there, and we're assessing those. We're very happy with the performance of LNP. Number two, certainly, we have other additional LNPs actually that we're screening and we plan on screening in the clinic across flu and other targets as well. So we anticipate learning as much as we can from that monovalent approach and hopefully applying that into the quadrivalent approach as we go forward, not just for Phase I, but then, of course, into Phase III.

Yes. So on flu, to address the question. So can you hear me okay? Okay. It's coming now. So on flu, just for the rest of your question. So the age was a young adult, so 18-45. This is the target group that we have in the trial here. And actually, in terms of translating the GMT ratio into titers, this is something that we did not want to provide today. And for a very specific reason is that we know some people attempted to extrapolate efficacy from GMT titers. But we have shown here that you can have very high GMT and still fail in efficacy. So we believe it is a wrong benchmark actually. So that's the reason why we didn't go there really and did not want to provide that. On the top, we have generated data with different labs and different labs testing different -- the same samples with apparently the same assay can have the result that differs by sevenfold. So again, telling you our GMT titers and trying to compare versus prior trials or trials from competitors that are coming, we believe, is not relevant. Again, the GMT ratio show where it starts from, how much of a seroconversion you have, how much of an increase you have. Seroconversion was defined as a fourfold increase indeed.

Time lines for the monovalent and quadrivalent, did we answer that?

I think Frank answered saying that, indeed, we're going to test the monovalent in first half. We will test multiple parameters. And yes, we will bring quadrivalent formulation in the second half of next year.

Okay. So we'll take the next questions from Geoff Porges at Leerink. Geoff? So we will move to Tim Anderson at Wolfe. Tim?

A couple of questions, please. On RSV older adult opportunity, you've described this as about a EUR 4.5 billion opportunity. I'm wondering if it could actually be much less than this using the experience with pneumococcal conjugate vaccines in adults as a proxy. To me, there's a lot of similarities between pneumococcal pneumonia and RSV pneumonia in terms of things like incidence, morbidity and disease awareness among the population. Prevnar has been on the market in adults for a number of years. Of the EUR 6 billion annually that it sells, only 25% of that's in adults, so it's about EUR 1.5 billion. And that EUR 1.5 billion adult segment is not exactly growing. So why would RSV be any different? And the second question, just earlier, you made the comment, you didn't think a combination mRNA COVID plus mRNA flu vaccine is really a risk. But if we assume that patients are going to need both shots annually, how can it not be a risk to have one product that can offer 2 diseases with just 1 shot? And competitors like Pfizer and Moderna are obviously ahead in mRNA understanding and ahead in terms of having a COVID product on the market.

Thank you very much, Tim. I'll be happy to take the second point on combination, which I believe we have addressed, but we can go back to it. But before we go there, Thomas, maybe you want to take the one on RSV older, the market size with perspective on it versus an elderly [indiscernible] market, which is around EUR 1.5 billion?

Sure. Thanks for the question. And yes, there is a connection between the 2 populations, the 2 disease. Now on PCV, as you said, there is 20%, 25% of the market is with adults. The rest is with infants. We see some growth in the adult segments. That's one of the drivers we see. So we think the market here can still grow. Specifically on RSV, I mean, contrary to PCV, it won't be one shot for the rest of the life, it would be a shot that would happen every 3 to 5 years, we believe. So that's more recurring administration. And that's why we're looking as well on adding other serotypes. And I think a combination vaccines adding potentially other diseases in a combo to bring even more value and impact public health. So I think we see nice potential. We need the right product, first monovalent and then a combination vaccines. We're convinced we can be competitive there.

Yes. Maybe building on Thomas' answer. So I think it's very important you guys understand. Yes, the 2 most advanced candidate in RSV older adult. They are more advanced than we are, but they are using a technology that will make it difficult for them to have a combo vaccine that will take an awful amount of time. That's why we decided to go with mRNA. And with mRNA, we can bring additional viruses. And by bringing them we will also improve the economics of this vaccine.

Which is a great segue to the second question from Tim. If that's true Jean-Francois, why aren't we smart enough to do a COVID-19 through combo and why are we scared about it on the flu market? And great question, Tim. To come back to it. For a combo to be successful, you need a few very important successful criteria. First of all, you need to be able to have them at the same immunization schedule. We do not believe that annual vaccination, postpandemic, so from '24 and beyond, will be required against COVID-19. Second, even if you believe the immunization schedule will be the same, every single year, then you need to have the same level of protection than the best vaccine stand-alone on each disease. And here, we believe, back to the section we had on flu, that protection beyond flu was demonstrated with Flublok and with Fluzone High-Dose. We are very far from that with Phase I through mRNA candidate. Thirdly, you need to show that you're not deteriorating in a combination vaccine, the actual adverse event profile. And you've seen that you get from the study we've done head-to-head 12.3x more Grade 3 adverse events with mRNA COVID-19 shot versus Fluzone High-Dose Grade 3 adverse events. And last but not least, all the convenience factors that we've mentioned on mRNA will make it very practical for a combo. And I'm not saying that because it's a discovery. I want to be very clear. We, at Sanofi Pasteur, we add a combination through vaccine. For many years, we have sold in France a flu tetanus vaccine. When I was the head of the franchise, that's the first thing I stopped because it was a great loss maker every single year in this company because there are not enough people that are ready to take a combination vaccine with flu when the immunization schedule just don't match.

Thanks. So the last 2, 3 questions in the auditorium, the gentlemen in row #3, yes, and then we can go to -- nothing.

Dominic Lunn from Crédit Suisse. So 2 on R&D and 1 on costs, if I can. And potentially a bit of focus on some of the assets or areas that we didn't talk about today. So before going into today, I think there was a bit of focus in the investor community on potentially combining mRNA and oncology, but we didn't see that today. Is that just because it's not in the scope of today's Vaccines Day? Or could that be something else you look at? Secondly, on viral vectors vaccines, you listed them in your toolbox, but there doesn't seem to be much talk about them. Do you see much opportunity here going forward? Or do you see these more as maybe a less good version of the mRNA approach? And then finally, on costs. clearly, you're setting up the mRNA Center of Excellence. So you'd hope to have a greater mix shift towards mRNA therapeutics going forward. Due to the kind of the highly fungible nature of manufacturing in this mechanism of action, is there an opportunity to drive down COGS maybe in the longer term as you get a higher mix of mRNA?

Thank you very much. Great questions. On the first one, I'll simply take the easy one. So it's indeed a Vaccines Day. So that's why we didn't make the focus on it. However, it's a very important part, and we'll come back to this in a later stage. The second point was about viral vector, how do we see it position in our toolbox. Jean-Francois?

Yes. So fairly easy that one. I think if we need it, we're going to use it. Today, we don't see really an application of our vectors for the new candidates that we have in the pipe, but we master that technology. And if it's needed, we're going to use it. As simple as that.

For the mRNA and the cost of goods, going to depend on the innovation you bring with your mRNA product. It starts by having the right product and the right target. That's why I was talking about the flu mRNA. And I was mentioning before the standard dose market versus the differentiated flu vaccine market. Yes, you can definitely work on the COGS. But as I said before, also, standard-dose, egg-based vaccines will remain cheaper in terms of cost of goods than any mRNA. And definitely, when we go to flu, we're not going to be in multi-dose [ whilst filling ]. You have to look at what will be the cost of goods where raw materials is the important part of the cost of goods in mRNA and when you start doing this fill and pack into syringes. So overall, in the very long term with new vaccines and the right product, it could be an interesting COGS play. In the short term for flu no, it's not really addressing that.

So I think we have another question from Simon.

Simon Baker from Redburn. A couple of slightly bigger picture questions on mRNA. Firstly, you gave a few examples where you've pivoted from unmodified to modified mRNA. Is there any role left for unmodified? And if so, what are they? And then secondly, on lipid nanoparticles. There was a paper out in early November, suggesting that the lipid nanoparticles are having an adjuvant effect. I just wondering what your thoughts were on that and if that's a tunable and selectable property. And related to the question about lyophilization, I think it was Moderna said the reason they didn't produce their vaccine as a dry powder was a lack of global capacity for lyophilization. Where do we sit in normal times for capacity to produce these sorts of lyophilized powders on a sufficient scale?

Thank you very much, Simon. Just on the last point. That's one of the advantages of having multiple vaccines because we have a few vaccines that are already lyophilized within our portfolio, and that's how we can play with different platforms. Back to you guys for the first 2 questions. Frank, do you want to take the one on modified versus unmodified? Any role for unmodified? And I come to you, Jean-Francois, for the other one.

Certainly. So thank you very much. We have made the switch to modified. We've generated data, as I mentioned earlier, with both. Of course, we've got a long history with unmodified and modified actually on this platform. We're leaving the door open because we have the ability to work with both. So right now our direction is with modified. But where we see an application for unmodified, we know we can play there immediately.

Yes. On the adjuvant effect of lipid nanoparticles, I think you are completely right. Yes, we know they stimulate the immune system on their own. I think there was a slide that Frank shown actually on the biomarkers where we see that with the same mRNA when we change LNP, we see a different reduction in the inflammatory cytokine. Two things. So yes, that's why you need to play with multiple LNP. And actually, one LNP that works well in one population may not work in the other because -- or the adults who may need something a bit more potent. Important, and that's why we're looking at multiple of them. Second point is about biomarkers. It's important we do what we do here. We generate biomarkers that will allow us to understand what LNP do so that we can really educate the next-generation, mRNA 2.0, mRNA 3.0.

And if I could just build a little bit on that also with the LNPs. So there's a lot of components associated when you design an LNP. And one thing that we're really fortunate, we've developed very large libraries with very diverse chemical structured ionizable lipids for different applications, not just intramuscular but other ones as well. And then you take those and you combine those with your [indiscernible] your cholesterol, et cetera, in different ratios. All of those things play a role in the effect of adjuvancy and potency and ultimately efficacy. And so we've got a lot of experience on this team both in terms of materials that we can utilize and employ right away, but also in terms of how to combine those to have the desired effect.

Let's try the last question from the web.

So we'll try again with Geoff Porges at Leerink. Geoff?

First question, just on investment. You're doing a lot, lots of different programs. I'm just wondering if you could share with us a little bit about the amount of CapEx that you're going to have to make in vaccines in the next couple of years and whether vaccines is going to be a net positive contributor to return on invested capital for the company or whether this is sort of an investment period for vaccines? And then secondly, I just want to go back to the question of tolerability of mRNA vaccines. Should -- could you give us a sense of whether you believe the tolerability issues that we're seeing with these first generation are due to the -- principally the LNP or principally to the mRNA? And do you believe that those tolerability issues are dose related? Because it would seem to be a potential limitation to these combinations, whether you can put 5 or 6 different antigens all containing their own mRNAs into 1 syringe and achieve better tolerability.

Thank you very much, Geoff. On the first one, it's always dangerous to respond to a group financial question in front of your CFO. So I'll go to J-B on the first one.

Thank you, Thomas. Yes, Geoff, you're right that it will take a bit of CapEx. But the new thing is that we are investing in new technologies in terms of manufacturing with our EVF, Evolutive facility, which brings a real possibility to change very quickly from one manufacturing output to another. So yes, we will invest in those. And it's quite timely that we are really boosting our free cash flow generation, as you can see, quarter-after-quarter. So that will not dent our capacity to go on investing in science. But yes, there will be some investment. Because also to get to the growth level we are committed to and to double our presence in vaccine by 2030, we will need this capacity.

Thank you, J-B. mRNA tolerability, short response?

Yes. So again, here, yes, we are very much convinced that both mRNA and LNP contribute to reactogenicity of mRNA vaccines. That's why we are making so many efforts in optimizing mRNA in having a large library of LNP and identifying biomarkers. We believe this is a winning equation, and that's why we're putting so much effort now. That's also why it will take a bit of time, and that's why we believe we are really in the race and will be competitive for sure.

So thank you. I'm now asking, Paul, back on stage just for a few concluding remarks. Thank you.

Great. Thank you. So very conscious that we are a little bit over, mainly driven by the great questions, I should point out. We set upfront that we're going to more than double the overall size of the business in vaccines, more than. It's important for you to remember that. We are building a reputation for delivering on our commitments. Whether it's Dupixent, whether it's the market growth -- it's the 8.5% or high single-digit growth in vaccines, we are going to deliver on our commitments. Whether you enjoy the urban myths and legends that have been propelling around on mRNA, whether it's the booster market, combinations, whether it's -- whatever is being fed into the marketplace on any given day, if you take a dispassionate look at the hyper transparency of today, it is our first time to address this audience since mRNAs were first approved at the end of last year. So you have to pause and reflect on that because there's one thing operating in a pandemic, as it's been said, with government support, government distribution, easy price negotiations, no policies, no procedures, no standard of care. It's a very different thing operating in established markets where payers need more convincing than they've ever done before. And whilst it may be possible to pivot to new platforms, and we're going to try it too in mRNA very quickly, it takes decades to build a global capability to execute flawlessly on all aspects of accessing markets and bringing value to patients. We will be the market leader in RSV. We will be absolutely one of the winners in flu. We will bring 10 news candidates forward. More than half of them will be an mRNA. we will make the CapEx investments. We won't get off our commitments that we've made through '22 and '25. And you should at least understand that I believe that the capabilities in our vaccine business are truly extraordinary and are still underappreciated, and we'll see that. I want to thank my team, our team and their teams, for the truly excellent work today in sharing that. Look forward to outperforming and surprising everybody, and we'd encourage just a dispassionate reflection on some of the fundamentals of what drives these markets, particularly influenza, when you're sitting back and deciding what to write. So thank you for your attention today. Thanks to the team, and thanks to everybody. I think there may be for those on Zoom, I'm sorry, but for anybody here, there may be a drink available. So we look forward to join you there for a few more minutes. So thanks to all.

With this, we are concluding our event. Thank you for joining.