Okay, thanks everyone. I think we're gonna get started. Hello, thank you for joining us for Valneva's Investor Day. I'm Joshua Drumm, Vice President of Investor Relations, it's my pleasure to welcome you this morning, as well as those listening on the webcast. Today you're going to hear from Valneva's management and senior leaders about the company's near and midterm value drivers, including its late-stage development pipeline, commercialized vaccines, and select preclinical vaccine candidates. In a few moments, I'll introduce CEO Thomas Lingelbach to provide a brief overview of Valneva and our late-stage development pipeline. Thomas will hand it over to Katrin Dubischar, Director of our Chikungunya Vaccine Program, to provide an overview of VLA1553, including recently reported data. Ooh. Katrin will welcome John Kanaras, General Manager of our U.S. subsidiary, to discuss the commercial outlook for our Chikungunya Vaccine candidate.
This will be followed by a discussion from Thomas on Valneva and Pfizer's phase III vaccine candidate for Lyme disease, VLA15, also including recently reported follow-up data from an ongoing phase II study. Thomas will introduce our preclinical pipeline and welcome Anders Lilja, Valneva's Director of Preclinical R&D, to provide some additional detail on select preclinical programs. Our CFO, Peter Buhler, will then provide an overview of our commercialized vaccine products as well as a brief financial overview before opening the floor for the panel to take your questions. For those of you participating via webcast, you may submit questions using the Q&A text box at the bottom of the webcast player or by emailing your questions to questions@lifesciadvisors.com.
Before we kick things off, I'd like to remind listeners quickly that during this presentation we will be making forward-looking statements, which are subject to certain risks and uncertainties that could cause actual results to differ materially from those expressed or implied by these forward-looking statements. You can find additional information about these risks and uncertainties in our periodic filings with the Securities and Exchange Commission and with the French Financial Markets Authority, which are listed on our company website, www.valneva.com. Please note that today's presentation includes information provided as of today, December 6th, 2022, and Valneva undertakes no obligation to revise or update forward-looking statements except as required by applicable law. With that, it's my pleasure to introduce Thomas to begin today's presentations.
Many thanks, Josh. Good day, everyone. Great pleasure to have you here and those also on the webcast. Valneva. As you know, Valneva is a fully integrated specialty vaccine company. We are focusing on the development, manufacturing, and commercialization of prophylactic vaccines for infectious diseases in areas of high unmet medical need. We take a highly specialized and targeted approach to the development of our vaccines. What does it really mean? It means that we are technology agnostic. Which means we go by indication. We pick an indication where we believe that there is value in generating a vaccine-preventable solution, and then we pick the best possible technology for it. We are not a technology company. We are a disease company that focuses really on where we can make a change to people's life.
We have a very high, highly experienced team at Valneva. Some of my colleagues are with us here today. We have shown something that not many biotech companies can say. We have brought products from the bench to global licensure. Of course, we have an infrastructure around our manufacturing operations, which especially in the world of biologics is key. We decided a few years ago to build a strong position in travel vaccines. As such, we built our own commercial infrastructure. I'm glad that we have the representative of our single largest commercial subsidiary today with us, John, in order to really best position our travelers vaccines in the market. Our ambition is to grow the travel franchise further.
When you look at our value proposition today, you know, there are basically four key pillars. You know that the company has been going through quite, I would say, a momentous period over the past 18 months, you know, going into COVID, out of COVID, and respective development activities. We have kind of reshaped our strategy towards, you know, continuing with our advanced clinical development programs and clearly focus here on chik launch globally and with Pfizer to progress our Lyme program as quickly as we can. To rebuild the pipeline. We positioned, you know, quite a significant number of our R&D staff and allocated them to our COVID vaccine development activities, which resulted in a kind of a delay in bringing preclinical candidates into the clinic and towards the clinic.
We have, of course, now reactivated this engine and go full steam towards preparing the next clinical candidates. We are also, and this is part of our strategy, evaluating assets for potential in-licensing. I mentioned already our commercial products. We're gonna hear more about it, but it's very clear that we are focusing on maximizing the opportunity around travel, around travel vaccination, which is an exciting field in vaccines. With regards to COVID, we are still sitting on a bunch of inventory doses, and we are trying to deploy this inventory into international markets. Of course, having gone out of COVID meant also for the company to resize its operations, and we are in the middle of this process right now as we speak, and expect a saving of approximately EUR 12 million in annualized basis.
Looking at the pipeline, you will hear about our chikungunya program, our Lyme disease vaccine program. We used to work on Clostridioides difficile. We were one of the companies that brought a Clostridioides difficile program to end of phase II. We shelved it at that point in time, and we are now looking for potential partners following, I would say, some ambivalent results that others kind of presented around Clostridioides difficile. We are in the process of evaluating our Zika vaccine candidate for reactivation in the clinical development, which is again, a very important point, given that Zika got now on the blueprint by WHO. There is a clear demand for a Zika vaccine.
We follow 100% the WHO target product profile, having used an inactivated whole virus based approach for our Zika vaccine. We will talk more about the commercial products. You will hear that from Peter later. We will then wrap up also with an outlook around what's next, including our COVID activities. With this introduction, I would like to hand over to Katrin.
Good morning. Good morning. It's a pleasure to be here today and talk about our chikungunya vaccine candidate, I wanna start off with talking a little bit about the disease itself. Chikungunya isn't a very well-known disease, but it's actually a major public health concern. The disease is often described as associated with low mortality, but with very high morbidity. This is owed due to the fact that, in contrast to some other arboviral diseases, chikungunya is very highly symptomatic, up to 97% of people who get bitten by an infected mosquito will develop symptoms of chikungunya. Those symptoms are primarily high fever, that has a very acute onset and pain, joint pain. The joint pain for chikungunya has been described to be really severe, very painful.
Actually, the name of the disease comes from an African word for, from a Kimakonde word for, meaning to be contorted or to be bent up because of the painful experiences of those people. They aren't able to stand upright anymore. Chikungunya doesn't only have an acute phase. It progresses to a chronic phase in around 43% of the individuals and that chronic phase can last months to years and can also be associated with severe joint pain. There is a high burden of disease owed both to the very high symptomatic acute phase and the chronic symptoms. That can really be a debilitating disease. People are sometimes unable to work, and so there is a high economic burden also associated with the disease.
Outbreaks of chikungunya have been described on many continents, including on the Americas, and there is a potential for outbreaks to also happen in Southern Europe or in Southern United States, where the vector mosquitoes that can transmit the chikungunya virus are residing. That has already happened. For example, we've seen chikungunya outbreaks in Italy. These outbreaks in the regions that I just described can take place if an infected traveler returns and is still in the viremic phase of the disease. Therefore, they can spark a local transmission if they return home and are bitten by a mosquito, which will then be able to pass the infection on. At present, there's only symptomatic treatment against chikungunya, no targeted antivirals, and there is also no vaccine available to date.
With that clear unmet medical need, we've set out to develop our chikungunya vaccine candidate. We're using a live attenuated technology for our candidate, targeting to induce a long-lasting immunity with a single dose. As I'll speak more to later, we've completed our clinical program that will be supporting our BLA filing with the FDA. We've been able to achieve a number of important regulatory milestones over the last years, including the start of our BLA submission as the first chikungunya vaccine program globally, Fast Track and Breakthrough Designation, the PRIME designations. When we think about the target populations for our chikungunya vaccine candidate, on the one hand, we're seeing the use of this in Western countries, in travelers, in military to support troop readiness and also for outbreak preparedness reasons.
We also, of course, have a medical need in endemic regions. Many of those are in low, middle-income countries, therefore, we've partnered with Instituto Butantan and CEPI. I'll briefly introduce the licensure pathway for chikungunya vaccines. Owed to the specific epidemiology, which includes short-lived, very explosive, but short-lived outbreaks, classical efficacy studies are not considered feasible for chikungunya vaccines, and therefore, regulators have agreed to license chikungunya vaccines based on serological endpoints. In the U.S., this pathway is referred to as the accelerated approval pathway. That's a brief overview of our clinical trial profile supporting our BLA submission. We've conducted a phase I clinical study in 120 adults. We've tested three dose levels of our vaccine candidate, and also included a revaccination in that study.
In terms of results, we've seen that the vaccine was highly immunogenic with a single immunization. We haven't seen an anamnestic response after the revaccination, confirming that this is truly a single-dose vaccine candidate. We've seen a supportive safety profile with those data and since we didn't need to confirm any further schedule optimization in a phase II clinical study, we've been able to advance directly into phase III trials. We've conducted a pivotal phase III trial that was a placebo-controlled, randomized controlled study looking at safety and immunogenicity data and a lot-to-lot consistency clinical study. I also want to briefly mention the way we determined our primary endpoint for those studies. We've determined this surrogate of protection using sera from individuals immunized in our phase I clinical trial and transferred those sera to non-human primates.
We were able to transfer the antibodies built by immunization to non-human primates and have then challenged those non-human primates with wild-type chikungunya virus. When we monitored the animals for development of disease and for viral titers, we were able to determine which antibody level pre-challenge was resulting in a non-detectable viral load after the challenge. This cutoff titer has been agreed with the FDA as our definition for seroresponse. Just in brief, that's the design of our phase III clinical trial. We ran that study in the United States. We included adults, 18 years and above with no upper age limit. We've been enrolling around 4,100 individuals. About 3,080 received the VLA1553 vaccine, and about 1,000 received a placebo immunization.
The primary endpoint was on day 29 following the immunization. Everybody was followed until month six in the trial. We looked at immunogenicity in a subgroup of about 460 participants. We've been able to report results from that study in the past. What I'd like to focus on here for today is some new data that we've been able to generate in the October ACIP meeting on our vaccine candidate. There was considerable interest in data in older adults. We've been looking at a new analysis population, a secondary analysis population from our trial, where we were able to bring the number of elderly participants with immunogenicity data up to 107. What we've seen there in terms of results is actually matching very nicely what we've seen in the primary analysis of that study.
We see 99% of those aged 65 and older develop a seroresponse in our study, and we also saw good persistence in that population. This slide is coming back to the results from our pivotal trial, but it's also highlighting the very exciting findings we've been able to publish on Monday on antibody persistence with our candidate. I just wanna walk you through the graph quickly. What you can see here to the left in the blue columns is results for the per protocol population in our pivotal trial, with around 99% seroresponse seen on day 29, so the primary endpoint. And if you look to the far right here, the purple column presents the seroresponse observed after 12 months in the recent data.
As you can see nicely, seroresponse persists at 99% after 12 months, which is a really encouraging finding. This slide now shows you the development of neutralizing antibody titers over time, so the kinetics. The population we're looking at here is the whole sample population of our antibody persistence study. That's roughly around 360 individuals we were monitoring. What we can see here is that, as observed in the past, we see a peak neutralizing antibody titer at day 29 in our vaccine recipients. We see a slight decline up until month six, but the titers stay comfortably above this level determined for seroresponse with the FDA.
Very importantly now, throughout the follow-up phase from month six to month 12, we see that the titers remain absolutely stable, which very nicely supports our prospects of inducing long-lasting immunity with a single dose. The other point I'd like to mention on that slide is, you see actually two lines here. The blue color one is for younger adults below 65 years of age. The darker maroon color represents adults 65 years and above. As you can see, the lines are basically superimposed, confirming that we see comparable titer levels in older adults and younger adults.
The reason why I'm highlighting that is not only because it's something that's not commonly observed with the vaccines, oftentimes you see lower immune responses in elderly individuals, but in our case, chikungunya also has a higher rate of causing severe disease in older adults. Just to round our clinical data up, these are results from the lot-to-lot consistency trial. Lot-to-lot consistency trials are studies that are routinely asked from the FDA for development of vaccines. To demonstrate that the vaccine can be manufactured consistently from lot to lot, and we've met the primary endpoint in that study. It's about 408 participants. The GMT values for the three lots tested match nicely and also the seroresponse rates observed in that study, 98% approximately, match very nicely with the data we've seen in the pivotal clinical trial.
That's a quick summary of our key clinical data highlights. I'm not going to work through all the points on immunogenicity because we mentioned most of those now. Just to briefly point out that we have seen also in our phase I clinical study, at an earlier time point of day 14, that neutralizing antibody titers had already developed in all the vaccinees at that point in time. In terms of safety throughout our program, the vaccine has shown to be generally well-tolerated. We see about 50% of the individuals will develop solicited systemic adverse events. The most common ones are headache, fatigue, and myalgia. Most of the adverse events are mild or moderate in intensity. A handful of severe adverse events have been reported, about 2%, and that's most commonly fever.
Moving forward to more forward-looking slides. The first thing I want to highlight briefly is our collaboration with CEPI and Instituto Butantan. CEPI has recognized the large unmet medical need around chikungunya vaccines and has therefore installed funding of chikungunya vaccines. In the framework of that CEPI funding, we have also entered a collaboration with Instituto Butantan, who are an important Brazilian vaccine manufacturer. This collaboration will entail that Butantan will make the vaccine available, manufacture, and also commercialize worldwide in LMIC markets, and we will also do some joint development steps. What will be our next development steps? In terms of ongoing clinical trials, the antibody persistence study that I've showed data with you previously will continue with annual readouts for at least five years after immunization.
The second study that we've currently ongoing is a trial in Brazil in adolescents. This study is carried out in collaboration with Instituto Butantan. The study will on the one-hand side, support an additional label expansion with the travelers markets for chikungunya, for our chikungunya vaccine. On the other hand, we expect that the data from that study will be supportive for local licensure in Brazil. In terms of future clinical trials, we are considering co-vaccination studies of this vaccine candidate. We will further expand into other pediatric age subsets and potentially look to studies in special populations. We also expect that under the Accelerated Approval pathway agreed with the FDA, we will be doing post-marketing effectiveness clinical trials in the form of phase IV observational studies.
On a regulatory outlook, we've been able to start submission of our BLA with the FDA in August of this year. We're looking forward to completing the rolling BLA submission in December. After we've completed our filing, there will be the FDA's review phase and, at the end of the filing acceptance review phase, they will determine whether we are eligible for a Priority Review. We should be eligible based on the fact that we've been granted the Breakthrough Designation, and if they grant Priority Review, that will put us on a six-month review clock. The FDA will also determine the action due date at the end of their filing acceptance period.
We may also see a Vaccines and Related Biological Products Advisory Committee meeting come up, and the timing of such a meeting would be also determined in dependence of the action due date. Last not least, chikungunya has been a neglected tropical disease for a while, and hence the FDA has included chikungunya on their neglected tropical diseases Priority Review Voucher list, meaning the first, the sponsor who will get the first approved BLA for a chikungunya vaccine is eligible to receive a Priority Review Voucher. Should we receive the PRV, the intention of the company is to monetize that. Apart from our regulatory processes with the FDA, we've also received the Priority Medicines designation from the EMA, we expect to commence further regulatory processes, including with the EMA at the second half of next year. So thank you very much.
With that, I'll hand it over to John.
Good morning. My name is John Kanaras, I'm the General Manager for Valneva here in the U.S., I'll be providing an update on our thinking and planning regarding the commercialization of VLA 1553. Simply stated, it comes down to where we see this vaccine addressing the unmet medical need created by chikungunya. The COVID-19 pandemic has taught us how. Whoops. Sorry, has taught us how vulnerable we are to emerging infectious disease threats, especially those that originate outside our borders. The WHO, along with many other public health organizations, have begun launching initiatives to mitigate the risk of diseases with outbreak and pandemic potential. The Global Arbovirus Initiative that was launched back in March of this year, lists chikungunya as one of these diseases that has outbreak and outbreak potential, not pandemic, because... Well, we won't go there.
The frequency and magnitude of outbreaks has been increasing globally over the past 20 years, and many times that spark of an outbreak is initiated by a traveler, either within region of a country or across borders. As shared by my colleague, chikungunya has two distinct phases and is associated with significant morbidity and has both an acute and chronic phase. Of particular note, the chronic phase can last months and years and is often associated with chronic rheumatism that can be considerably disabling. While there's no seminal estimate of the cost, both human and economic cost of chikungunya globally, there is one recent estimate by researchers out of Yale University that estimate the burden of chikungunya in the Americas.
These researchers attempted to estimate the underreporting that happens with chikungunya during the outbreak and expansion of chikungunya between 2013 and 2015. Through their estimates accounting for that underreporting, they projected that there were 39.9 million cases of chikungunya, 23.8 million disability-adjusted life years lost at a cost of EUR 185 billion to society. The reason for this is the cycle of transmission. Unlike respiratory diseases, where the cycle of transmission is primarily human to human, the cycle of transmission for chikungunya is almost exclusively vector to host. As described previously, an infected mosquito, this is the urban cycle, an infected mosquito will bite a naive host. That host will become viremic. Another mosquito bites that viremic host, ingests the virus, and then transmits that virus to another naive human, continuing the cycle.
That's what causes these acute and abrupt outbreaks. There are two primary vectors, and the geography for these vectors has expanded considerably over the past two decades. The Aedes aegypti vector was the original vector. You see on this graph, the vectors and their habitat. In green, those geographies are not suitable for either vector. In yellow is suitable for Aedes aegypti, in blue for albopictus, and then red suitable for both. The Aedes aegypti mosquito was the originating mosquito, primarily habitat in tropical and subtropical regions. It originated in Africa, and then in the early 2000s spread to Asia.
At the same time, there was a mutation in the virus that allowed it to then be able to be carried by the albopictus, and that's important because the habitat for the albopictus is broader, goes into temperate climates and even colder climates. About 2013, the virus was introduced into the Americas, specifically the Caribbean, and spread from there. At this point, there are over 100 countries where chikungunya has either been reported or is endemic, and that impacts about 3.9 billion inhabitants. Those inhabitants are clearly at risk for the disease, but equally importantly, travelers to those endemic areas are at risk for the disease. Given the cycle of transmission that we just described, what has happened and can happen is that an infected traveler can unwittingly come back and start local transmission in their geography.
If we can zoom in on the U.S. and Europe right now, I'll share with you kind of, you know, what the habitat for these vectors are in the U.S. and Europe specifically. The top half of the slide looks at albopictus and where it's currently endemic. On my far right, your left is the U.S. obviously, if you look at the, your right in red is where albopictus has been established within Europe. The bottom half of the slide looks at Aedes aegypti and where it's endemic in the U.S. and also in Europe, and very limited establishment of aegypti within Europe at this point. Again, the risk of outbreak is really linked to infected travelers coming back.
You know, what we're advocating for and what we believe is an opportunity is to help protect the domestic public health security of each country by routinely vaccinating appropriate patients before they travel abroad, so they do not unwittingly bring back the virus and start local transmission. Both the U.S. CDC and ECDC monitor both imported cases and locally transmitted cases. On your left, my right, is data from the U.S. CDC. You see a spike in cases in 2013, 2014 following the introduction into, in the Caribbean, and then a pretty consistent trend of case reporting leading up into the pandemic when things kind of shut down. Similarly, in Europe, you see a spike in cases during an outbreak in Italy and France, but a consistent flow of cases being observed within Europe. Mainly imported cases.
Fortunately, there haven't been many locally transmitted cases, there's always the potential for that. Again, the rationale for advocating for policy to proactively vaccinate outbound travelers who are at risk for chikungunya. That naturally flows to where we see the opportunities for this vaccine and where we think we can have an impact on the medical need of this disease. Specifically within travelers, both civilian travelers going to chik endemic markets, military people who are deployed, active duty personnel and dependents deployed to chik endemic markets, and then local procurement opportunities with governments who are preparing for potential outbreaks. Those are varied and a lot of competing priorities within government budgets for that, those are discussions that are being had.
On the left side, your left side, my right, is the opportunity for having a big impact on the markets where chikungunya is currently endemic, working with Instituto Butantan and CEPI to commercialize the vaccine in those endemic markets. Fortunately, VLA1553 fits perfectly within our existing commercial infrastructure. We have an experienced team of professionals who have tremendous depth of experience commercializing vaccines generally and travel vaccines specifically. This is pretty much a plug-and-play vaccine for us within our existing infrastructure. At the same time, there may be some additional resources needed depending on the market to fully capitalize on the opportunity for Chikungunya. In the grand scheme of our overall plan, it's relatively modest in terms of the additional resources needed. One of the key issues with respect to the opportunity is how many outbound travelers are going to these chik endemic markets.
These data are from IATA, and they look at outbound passenger data from Valneva markets to chik endemic markets. Now, these are passengers, not unique travelers. The easiest way to think about unique travelers is divide by two. That's a factor that we usually get from IATA that accounts for unique travelers. What you see, two key points on this slide. Number one is the global travel recovery is beginning. We see it clearly in our commercial data. We see it in the IATA data. IATA is projecting that the global travel recovery will be fully in place by 2025. That's point number one. Point number two is a small percentage of a large number is still a large number. We're not saying that every outbound unique traveler is appropriate for our vaccine.
Even if we get just a small percentage of outbound travelers protected, that yields significantly doses sold and significant patients protected. This is new data regarding understanding the customer perspective on chikungunya disease and their likelihood to recommend or prescribe a vaccine for the HCP or for the traveler to accept the vaccine. Let me orient you to the data. First, we did two large-scale quantitative internet-based survey studies about a year ago, first with healthcare professionals globally and then with travelers globally. What you see on this slide are strictly the U.S. respondents. We asked them questions in a five-point Likert scale. What these data show for the HCPs is we exposed both the HCPs and the travelers to a general summary of the chikungunya disease and the map of where it's endemic. Then we asked them these two questions.
For HCPs, we asked, what is your likelihood of recommending a chikungunya vaccine if recommended by the ACIP? This was a generic chikungunya vaccine. This was not our target product profile. Just trying to understand what the interest is in a chikungunya vaccine candidate, period. What you can see is 15% of HCPs said they were very likely to recommend or prescribe, and 73% said they were somewhat likely. Top two box score of 78%. For the travelers, we similarly asked them, if your doctor recommended a chikungunya vaccine, again, a generic vaccine, not specifically our vaccine candidate, how likely are you to get vaccinated? 52%, top box score is 52% in the top box score. Somewhat likely, the second highest box was 29%. Combined 79% top two box score.
What we take this as is that there's considerable interest in the disease and the vaccine if educated properly. We also know that awareness is really low, and we've got a lot of work to do to educate both physicians and travelers. We've started that work this year with presence at many international congresses, and we'll continue that work into 2023. This is also new information. The market access environment for travel vaccines has historically been primarily an out-of-pocket market where patients pay out of pocket and there's limited access due to affordability issues by patients. That landscape is changing specifically in the U.S. with the passage of the Inflation Reduction Act this summer. There was a component of the Inflation Reduction Act that requires that all ACIP-recommended vaccines for patients enrolled in Part D plans will be covered without cost-sharing.
Even if used in limited populations, zero cost-sharing, the industry lingo is first dollar coverage. It's covered at $1 . This is new. In the U.S., there's 49 million Americans 65 and older. An estimated 10,000 Americans turn 65 every day with the aging in of the baby boomer population. We're really encouraged by this policy change because it clearly demonstrates the importance of vaccines, not just routine vaccines, but all vaccines in protecting individuals. This policy is not only good for the individual, but again, it's important and good for our domestic public health security given the outbreak potential of chikungunya. Another really key point on this slide is that it anchors to an ACIP recommendation. For coverage to be in place, it has to be recommended by the ACIP.
That transitions to this next slide, which is the number one priority we have in the U.S., is to work with the CDC to get a recommendation for this vaccine in appropriate individuals. The ACIP process is well known to us. We've, we've been through it with IXIARO. As you all know, the CDC established the work group in May of this year. We had a joint presentation to the ACIP in October, and the CDC has declared an estimated date for a recommendation vote to be February 2024. The bottom half of the slide it comes from a CDC slide deck with their timeline. Superimposed over that is our expected regulatory timeline.
We're working really closely with the CDC to give them all the data they need to help them integrate the information so that they can make an appropriate recommendation for whom this vaccine should be recommended and in what circumstances. Should that recommendation come to be, then the information shown on the previous slide would fall into place where individuals would have first-dollar coverage for our chikungunya vaccine who are Medicare Part D. In closing, just to summarize, chikungunya is a significant public health threat with significant morbidity. The habitat for the vectors has continued to expand, and there's a very real threat and potential for further expansion and even local transmission within markets like the U.S. We believe vaccinating travelers is a really important consideration for policymakers.
This vaccine is fits in perfectly to our existing commercial infrastructure. We believe that we've got the capability and expertise to maximize its potential and help to protect patients, support HCPs and stakeholders, and deliver value for our shareholders as well. With that, I will turn it over to Thomas to talk to you about Lyme.
Thank you so much, John. Yeah, let's turn over to Lyme disease. You know that we are very excited about our Lyme vaccine program. In our collaboration with Pfizer, you know that this program is the only vaccine development program targeting Lyme disease in the world on the planet today. We have gone through numerous clinical studies, phase I, phase II, and we are right now in phase III with active enrollment ongoing. I mentioned the partnership with Pfizer. I'm going to explain more what the terms and conditions of this partnership look like. We have developed here a very modern recombinant subunit-based vaccine approach, covering through a multivalent, six-valent to be precise, the main serotypes prevalent in the northern hemisphere. Again, I'm going to go through those in detail.
This vaccine follows a proven mode of action. There used to be a Lyme vaccine back in the 90s here in the United States. This vaccine was a, you know, I would say a development success, but a public fiasco. Basically, we follow a similar scientific mode of action and therefore, you know, have a high probability to reproduce also the respective effectiveness numbers that you're going to see. The program got Fast Track designation by FDA back in 2017. Our partnership with Pfizer at a glance here. We established a strategic alliance with Pfizer back in April 2020. We amended and updated the agreement earlier this year in the summer.
We adjusted a couple of points due to the evolution of the partnership and also the evolution of, let's say, the development plan as part of the continuous regulatory interactions. We changed the cost-sharing split from 30/70 to 40/60. Pfizer invested EUR 95 million into Valneva and became one of our top five shareholders. Of course, this is a deal that gives Pfizer the full responsibility for late-stage development as well as control over global commercialization. We are eligible to receive a bit more than EUR 400 million in milestone payments. We received already EUR 165 million.
We have later tiered royalties starting at 14%-22%, combined also with, as I mentioned earlier, you know, cumulative sales milestones as part of the EUR 400 million bucket. We have a wonderful co-development structure in place, excellent working relationship, and I would say the best possible partner for this program you could find. Lyme disease, I mean, we are here in New York City. I don't think that I need to talk a lot about Lyme disease. It is a very severe, tick-transmitted infection. We see this really at a rise because we learned earlier about chikungunya vectors. Here we are also talking about a vector-transmitted disease.
Of course, due to global warming and other, you know, implications, the tick population is at a rise, and because the tick population is at a rise, the disease is at a rise. We see here in the U.S., for example, you know, a clear, you know, distribution. Lyme is everywhere. You can even find Lyme cases in California, but you see a distribution from north to south, from east to west. You have in Europe, you have some countries with high incidence rates of Lyme.
You know, it started all off in the so-called Alpine belt, you now see that it's spreading and even countries where there was no Lyme disease in the past, like France, you know, have a quite significant number of Lyme disease cases today. It is very important to note that Lyme borreliosis can progress to serious life-altering symptoms. You know, it starts with an early localized disease, you know, the famous bull's-eye, called erythema migrans, then the nonspecific flu-like symptoms. It then progresses towards disseminated disease. This can take days, weeks, or even months after the initial infection, and this includes things like neuroborreliosis, carditis, arthritis, and other, you know, severe clinical manifestations.
It's also important that the world has learned a lot about the clinical manifestations about Lyme disease and what was considered a rather, you know, a need for. Back in the nineties, there was a paper, people saying, you know, the vaccine against Lyme disease is a vaccine for yuppies, right? I mean, nowadays, I mean, we have all learned that this is very, very different, and Lyme is very, very serious. Yeah, and then there are persistent symptoms, and there is, you know, no, literally no response to treatment, and very long-lasting, sometimes up to lifelong clinical manifestations. The clearly vaccination is a solution, and the prevention by a vaccine would be a significant improvement over current preventative and treatment strategies.
You know, the physical prevention strategies have limited effectiveness, as we all know. The antibody, the antibiotic prophylaxis after the tick bite is effective for a certain period of time, but the bite is often unnoted. The early disease may be missed and, you know, the diagnosis still today is a challenge. The potential for severe clinical manifestations is really huge. When it comes to the mode of action, we are using and targeting the so-called outer surface protein A of Lyme borreliosis, called OspA. This mechanism is basically a mechanism that takes place in the midgut of the tick.
Basically, when the tick sucks the blood from the human host, this blood contains anti-OspA antibodies, and those anti-OspA antibodies do the job in the midgut of the tick. Some of the mechanisms that really take place in the midgut of the tick are understood, others not yet fully, right? We know that clearly the antibody to OspA neutralizes the bacteria in the midgut of the tick and blocking therefore the transmission to the host back with the secretes that the tick gives, you know, after it attached to the human host. However, there are also mediated effector functions in the tick, and those are, as I said, not fully understood at this point in time. When we talk about our vaccine design and the way we have structured this vaccine, I would call it modern protein engineering.
What you see here is truncated, stabilized, lipidated, you know, so-called heterodimers. What does it all mean? It means that you target primarily the C-terminal of the region containing the pro-protective antibodies, the epitopes, and then you combine it pairwise, you know, serotype one with serotype two, serotype three with serotype four, five with six. You use a linker, which is basically derived from a certain number of amino acids from serotype two, and stabilize it with a disulfide bond. You lipidate it, so the lipidation together with alum has an improvement, an effect on positive immunogenicity, so it's a sort of an additional adjuvantation.
The interesting feature that we did, and we talk more about the old Lyme history, is that we have replaced a region in serotype 1 that had, you know, when they sequenced back in the 90s, they saw that there was a region that had an homology to a human T-cell epitope. This is called hLFA-1, and we replaced that, which exists only in serotype 1, with a similar region from serotype 2. The old vaccines that were in development back in the 90s were OspA full lengths, not only the C-terminal, full- length serotype 1 only. One licensed LYMErix by GSK, ImuLyme, Sanofi successfully conducted phase III. After three immunizations, they showed 76% or 92% efficacy in a placebo-controlled setting.
You know, we worked, of course, before spending a lot of money together with Pfizer in late-stage development, we looked at proof of concept. Is there an animal model that can help us to predict where we're gonna land on the effectiveness of the vaccine? We had only one data point, and the one data point was that the old vaccines, OspA serotype 1 full lengths worked. We re-cooked it. When you see here, the lipOspA A is basically the native full-length OspA serotype 1, in a way, the old LYMErix construct.
We did an active immunization through the tick challenge model in mice, which mimics very nicely the overall mode of action because it takes place in the midgut of the tick, right? We showed that VLA15 was as efficacious as the native full-length OspA, looking at serotype 1 only. We did also a passive transfer model, showed also there that the human sera from people immunized with VLA15 were protective. When we look at the development plan, I mentioned already one phase I study, three phase II studies, including pediatrics. More than 1,000 people pre-phase III had received the vaccine candidate. We are now in phase III, enrollment is ongoing.
I'm gonna talk more about the VALOR study in a minute. When we look at the key immunogenicity data that we obtained over the course of the last years, this is a very interesting and important slide. When you develop a multivalent vaccine, there are a couple of things that you wanna have. Number one is you want to have a balanced immune response across the different serotypes. This is something that we achieved through the various phase II studies. You see a very nice and balanced immunological profile against the six serotypes. Second, you wanna see that, of course, you have an antibody uptake, you see the immune response going up and staying up for the protection targeted across the tick season.
Since we know from the old Lyme vaccines that a booster will be necessary, you wanna see the anamnestic response. What happens if you give a booster shot? This is shown here on the red bar, and you see that after a booster shot, the immune response goes significantly higher as compared to primary immunization. Fantastic anamnestic response. Whether a booster every year is needed or a booster every other year or every third year, this is something that we have to show as part of the further development. Safety, not a lot to say. Bottom line message, generally well-tolerated and very, very consistent with other licensed lipidated vaccines.
When we look at the at the six-month antibody persistence results that we recently kind of presented, this was another very important point because also here, we saw that the antibody levels remained above the baseline six months after completion of the three-dose priming. We saw that the higher antibody levels observed in the three-dose versus the two-dose, which again gave us a validation of our decision to go for the three-dose priming, and we confirmed the safety profile that we saw in the past. How does the current study look like that we are currently running? 6,000 people, U.S./Europe. Randomized 1-to-1 placebo against VIRUM, randomized 2-to-1 U.S. versus Europe.
Primary endpoint, this was something that we had to change after regulatory, you know, consultations. Primary endpoint, efficacy after three plus one, so three-dose priming plus a booster for the second season. This, the study goes over two seasons, then we look at the primary endpoint efficacy after booster in the second season, and as a secondary endpoint, the efficacy number after the 1st season. This study is called VALOR, currently actively recruiting, we are targeting completion, of course, in time for the tick season 2023. With that, I close the part on Lyme. With just one word on Lyme, we are very excited about the fact that we are working towards finding a vaccine-preventable solution for such a devastating disease.
We really hope that we will be able to successfully complete this program on time with hopefully, you know, a positive data readout at the end of the tick season 2024, and then a submission for licensure in 2025. Yeah, with two very exciting programs like our Lyme and tick programs in late-stage development or even in the licensure process already in the case of tick, and with COVID that has been a great development success for Valneva, but unfortunately not turned into a commercial success. We have to ask ourselves, you know, what's next in the pipeline? We consider ourselves a vaccine powerhouse that is able to bring products from bench to licensure. Therefore, the key question is: How do we, you know, generate more programs in our clinical pipeline?
As I mentioned at the beginning, due to the fact that we redirected resources to COVID, we had kind of slowed down our preclinical activity, so we ramped it up, and we are trying to do a combination of, you know, bringing our preclinical programs forward, reprioritizing our resources onto preclinical activities. At the same time, we will continue, as we have done in the past, to look for outside opportunities to potentially, you know, even in-license earlier-stage clinical assets. When we look at our own pipeline, the important thing to note here is that we have four programs in our preclinical pipeline, and I'm not counting here what we discussed earlier, for example, with regards to Zika. Yeah. Zika was already in the clinic.
We may reactivate, bring it back into the clinic. Here we are talking about really things that we developed from bench onwards. The most advanced program that we have is a program targeting the human metapneumovirus, you know, commercially and very glad that Anders is here today, who is heading up our preclinical activities to present this more. Especially the potential combination hMPV and RSV is expected to really tackle a very significant unmet medical need. EBV vaccine candidate against the Epstein-Barr virus, very recently, again, a significant learning around EBV and, you know, primary and secondary mechanisms that vaccination against EBV could result in.
We have been working on parvovirus and on Campylobacter, and to some of the questions that I received earlier, and I think we had, with Peter, I had the conversation outside over coffee. No, we are not targeting only travel vaccines in our development. We are targeting areas of high unmet medical need. With the exception of mRNA, this company has R&D capability and expertise across all different vaccine technologies that are out there. I think this is a very important point to consider when we also look about, you know, into our preclinical activities. With that, little introduction to our future pipeline development, I would like to hand over to Anders.
Good morning, everyone. I'd like to start to talk about respiratory infections in general for a minute. Respiratory infections of course affect all of us, right? On a fairly regular basis, at least annually, the severity ranges from just a simple, you know, annoyance to, you know, being in bed for a few days. For the most part, we don't care which virus infects us, right? Because it's not really that important. For some patient populations or some populations, you know, the very, very young, the immunocompromised or the elderly, some of these infections can be fatal threats. One of the most well-known, which is in the news currently, is RSV. RSV has been the plague for, you know, for decades, or been a known plague for decades.
This is an especially bad season, which you might have seen in the news. There are several states where no, you know, pediatric emergency or pediatric intensive care unit beds available because of RSV. Good news is that after a very long journey towards an RSV vaccine, there were a couple of top-line results reported by GSK and Pfizer in the past couple of months. It seems, you know, of course, I'm not privy to the details, but it seems from the top-line data that RSV vaccines are on the way and will soon be available to prevent this terrible infection. This begs the question: what comes next in the respiratory infection space? Also what lessons were learned from the long RSV development that we can apply to other infections.
The answer to the first question, we believe is human metapneumovirus, as Thomas mentioned, hMPV for short. hMPV is very similar to RSV, both on the virological level as well as in terms of epidemiology and disease burden. It might be a touch less severe, but it's nevertheless a significant threat to the same populations as RSV is for the very young and for the elderly. It puts a great number of people in the hospital every year. There is, of course, no hMPV vaccine, and we are planning to develop a vaccine based on a protein subunit, which I'll talk about in a minute. It has a large market potential, and as Thomas mentioned, it has a potential for combining with RSV or other vaccines.
This is the current development landscape. Moderna has actually completed a phase I. Icosavax have just started the phase I, ourselves and the NIH have preclinical or programs in advanced preclinical stage, I would say. There's a few things worth noting here, and that is that both Moderna and Icosavax candidates are already bivalent. They are combining either hMPV with the parainfluenza virus in the case of Moderna, or hMPV and RSV in the case of Icosavax, which shows the great potential for pairing these up. Another important fact to note is that Moderna has chosen a full-length F protein, and I'll get back to that in a minute why this is important.
Just say, suffice it to say for now that Moderna's is not an engineered stabilized antigen, which I will talk about a lot in a minute. The other three approaches, including ours, are stabilized. Moderna has posted their data or published their data, and they reported a six-fold boost in previously exposed adults. This was not dose-dependent. It was constant over the dose range they tested. It is of course, very hard to know without the correlative protection what the six-fold boost really means, whether this is a significant, you know, increase or not.
Again, comparing to RSV, a similar virus, albeit different virus, the NIH and Pfizer have posted higher boosts for their RSV vaccines, and take it for what it's worth, but it's hinting that there's a room for improvement for this, compared to the Moderna vaccine candidate. The other question I posed in the first slide was what lessons can we learn from the RSV success and apply it to hMPV ? The clear answer is structure-based antigen design.
The RSV vaccine, what really truly enabled the RSV vaccine and got this to the finish line most likely was the application of structure-based design, and the discovery first of the RSV-F prefusion structure, which allowed scientists to stabilize it and use this as an antigen in the vaccines where the previous postfusion structures had failed. Why this is important is shown in this cartoon. From left to right, you have first the prefusion structure, which is sitting on the virus surface. When the virus comes in contact with receptors on the cell surface for entering the host cell, it goes through a large conformational change. First, it inserts two fusion peptides, it's into the cell membrane.
This conformational change continues as a giant engine, if you will, and brings the two membranes together, fuses the lipid membranes, so the virus can enter the cell. The end result is that you have a postfusion structure, which is basically the spent molecules. It's, you know, not, no longer active. Whether you have epitopes exposed on a prefusion, postfusion structure or not is sort of irrelevant because they just bind, but it doesn't prevent anything. What you really want is antibodies that target the prefusion structure and can prevent either the attachment to the cell or this conformational change. And this is what was enabled with the RSV vaccine and brought this to the goal line. Our hMPV vaccine is based on these principles.
We have a stabilized prefusion F antigen. F is immunodominant and highly conserved as it is for RSV. The desired immune response is an high level of neutralizing antibodies biased towards TH2. This is a type of T cells. Oh, sorry. You want to avoid TH2s. Biased towards TH1. You want to avoid TH2 because TH2 T cells or TH2-biased responses have been shown to lead to increased risk of vaccine-enhanced disease for RSV and also for SARS-CoV-1, but not for 2. Just like RSV, there are two subtypes of hMPV , A and B, and of course, you want the vaccine to protect against both. The approach we have taken is the same as for the two RSV vaccines I mentioned, subunit protein.
We will, and we are looking at adding an adjuvant. Whether that's needed in the end, we will see, but we are at least assuming this is the case. Again, there is potential for combining this vaccine because it's the same technology with other RSV or with RSV vaccines. This slide outlines how we came to our prefusion antigen, and I can't go into details because the method I think is a trade secret, and the details of the design are not yet public. In a simple way, you start with the structure information available, so the RSV prefusion structure. At the time, there was, of course, a sequence for the hMPV , and you can do simulations to model the hMPV structure.
Based on these simulations, you can then design modifications to stabilize this protein or fix it in a prefusion form. You test these experimentally, and you use the data that comes from these experiments to feed back and go over this a few times, and in the end, you have, in our case, a prefusion F protein. There is now an hMPV prefusion structure known. It was not at the time. Characterization on the right-hand side. It's fairly simple. You know, in this research stage, you look at purity and yield by standard methods. You look at the trimer composition. The native F protein is a trimer, which is of course important for have the right conformations. You look at the high trimer content.
The most, of course, important is you can use pre- and post-fusion specific antibodies to show that it's, you know, it's binding pre-fusion specific antibodies, but not post-fusion specific antibodies to have a high likelihood that this is in the, in the right conformation. We're currently determining the cryo-EM and crystal structures of our F antigen. The data is not yet available, but that is something that's ongoing, and will be the final proof that we have the real thing. Of course, we've also shown immunogenicity, and this is also something we did in these iterations. For the final candidate, we have done mouse immunogenicity and challenge studies.
Mice were immunized with either a prefusion F protein based on the A1 strain or the B1 strain, or A1 strain or a B1 strain. There are several. Challenged with a subgroup A2 virus. We determined neutralizing titers against A1 and B1, we also challenged the animals with the A2 virus and looked at the viral loads in lungs of these animals after challenge. The left-hand panel, you see the neutralization of an A1 subtype virus, as you can see, the A1 vaccine, it not surprisingly induced higher titers against the A1 virus than the B1 strain vaccine. What was surprising was in a different experiment, we showed that the A1 vaccine also induced higher titers against B1 virus for neutralization.
Finally, in the right-hand panel, you see the challenge study. Here, small bars are good. You can see that for the A1 virus, we have at really small dose, low dose levels already complete protection against viral replication in the lung. The A1 strain is, you know, better than the B1 strain as a vaccine antigen also against heterologous subtypes. To summarize the hMPV part, our proprietary hMPV vaccine candidate is based on an adjuvanted subunit stabilized prefusion F protein. The stabilized prefusion F candidate is ours. We have developed it from scratch, and I would say it's cutting-edge in terms of being innovative. It is produced in CHO cells, which is a standard vaccine production platform, so there's nothing, there's no challenges there.
The purification process is also based on standard methods, and we have production yields that are suitable for larger- scale production and upscaling. Immunization with the prefusion A1 F protein generated superior neutralizing antibody responses against both homologous and heterologous strains, and also the challenge, it protected well against challenge all at low doses. As I mentioned, adjuvant evaluation is in progress, and we have some promising results. Switching now to the other program that Thomas mentioned, EBV, Epstein-Barr virus. This is not a respiratory infection. This is a herpes virus. Most of us are infected with it when we get to adulthood, 95% or so, by the age of 25. It stays with the host for life.
You most likely know EBV for its as being the causative agent of infectious mononucleosis, also known as mono or kissing disease. It's a fairly, you know, severe febrile infection that puts you out of commission for a few weeks at minimum. It has a big impact on, you know, job time lost, students being out of school for a long time, and for the armed services. What is actually, in the long run, probably more significant from a medical perspective and from a public health perspective is that it's a causative agent for multiple sclerosis. This was a landmark paper that was published earlier this year, although there had been interim analyses previously, this was not a great surprise.
The paper this year from Bjørnevik et al. made a very, very strong link between multiple sclerosis and prior EBV infection and mononucleosis. Also it's been known for decades that EBV is associated with human cancers of several different kinds. EBV was first isolated from a cancer cell. It was the first isolated oncovirus, as a matter of fact. A few words about the infectious cycle of EBV because this will become important in understanding where we are thinking of our vaccine development. EBV enters the host usually through the mouth and infects epithelial cells in the oropharynx. From there's a secondary spread to B cells. Then, you know, they can, of course.
They set up latency in B cells. The virus can then reactivate periodically and reinfect epithelials, et cetera. The B cells are required for the B cell infection is required for infectious mononucleosis as well as likely for multiple sclerosis. The epithelial cells are important if you want to have sterilizing immunity. You need to prevent the initial infection, and of course, epithelial cells is also important in several of the human cancers. The reason I'm telling you this is that the different antigens we're looking at for EBV elicit antibodies that block either infection of epithelial cells or infection of B cells or both. This is where this becomes important.
Similar to Lyme, there has been a significant clinical trial made in the past by GSK that kind of guides our thinking on this and also provides a proof of concept to an extent. GSK had a GP350 subunit protein vaccine adjuvanted with AS04, which went to a phase II in the early 2000s. Shown in this table, you can see a protection data, and it shows that you had a statistically significant 78% reduction of mononucleosis in this patient population, but no protection against infection itself. In hindsight, this was not surprising because the GP350 protein elicits antibodies that only block B cell infection. In a sense, this vaccine did exactly what it did.
It elicited these antibodies that prevented a B cell infection, which prevented the mononucleosis disease, but it was not a sterilizing immunity because the host could still get infected through the epithelial cells. For second-generation EBV vaccines, ourselves and other developers are including additional antigens, which will elicit antibodies that also block infection of epithelial cell infection. This is a look at the landscape for EBV. Moderna, again, it's always Moderna, are already in phase I. They have two antigens called GP220 and gH/gL GP42. GP220 is a variant of GP350. The name is a bit misleading, but it's a splice variant, so it has the same epitopes as GP350. gH/gL GP42 is, of course, a tripartite complex that's a variation of gH/gL.
NIH have their own program, which is based on ferritin nanoparticles, which is one of their platform technologies. They are actually in the clinic already with only GP350, which, as I just told you, will likely not work as well as is needed. They have also outlicensed the technology to a company called ModeX. ModeX have published non-human primate data where they have also this gH/gL with and without GP42. It seems likely this is what will become, you know, from NIH and ModeX, the final formulation. They have published a guidance that they will enter the clinic next year. There's our own program. We are looking at three antigens, the GP350 again, gH/gL, and GB. GB is the EBV version of F, so it's the fusion protein.
We think that antibodies to GB has the potential to block infection of any cell type, which we find highly intriguing. We have two paths. We're doing our own development with our own designs, and we also have an exclusive evaluation of a third party of third-party designs. A few words. This ties back again to the RSV story. We have taken a rational approach in this. There is structural information for all of these three antigens. From left to right is GP350, gH/gL, and GB. Not shown here, there's also a gH/gL GP42 structure available. We have all the information, and we have already designed a large number of antigens we are currently testing. Of course, this is very confidential, so I cannot go into the details.
They range from minor tweaks that will help with productivity, increased production yields, et cetera, to the other end of the spectrum, where we have more significant innovation, where we think we were able to improve the immunogenicity of these proteins compared to the wild- type version. As I mentioned, we have. This is our own internal design process. We have also an exclusive license agreement where we are evaluating designs that are of a slightly different nature in parallel. This, these two programs are complementary, but in the end, we will basically pick the best antigen combination from either of the programs to take to the clinic. To summarize here, neutralizing antibodies block EBV infection of B cells and epithelial cells.
Our vaccine candidate will be based on adjuvanted subunit viral glycoproteins, that will elicit high titers of EBV-neutralizing antibodies, and neutralizing both B cells and epithelial cells. We are evaluating both external and internal designs. We will again combine the best antigens from either of these approaches. This is again, subunit protein technology, can be easily produced in CHO cells and scalable to whatever, you know, quantity we need and purified using standard methods. We will use modern or novel adjuvant technologies, to maximize the immune response to these antigens. This is also plans that are drawn out, but this has to come after the antigen selection. With that, hand over to Peter.
Thank you, Anders Lilja. Now let's look a bit at our commercial product proposition. Right now, we're selling two of our proprietary products, and we have a couple of products that we in-license from third parties. The first proprietary product is IXIARO, a product against Japanese encephalitis that we sell in the markets where we have a direct presence. You see them listed here, USA, Canada, U.K., France, Nordics, the Benelux countries, and Austria. We also sell it through partners in specific other key markets, for instance, Germany. IXIARO generated about EUR 100 million revenues prior to the pandemic, and they actually delivered double-digit sales growth, at least for the last three years prior to the pandemic. Second product we distribute is DUKORAL.
DUKORAL is a product against cholera and against ETEC in certain countries, which delivered about EUR 30 million in sales prior to COVID. Again, we distribute it in the markets where we have a direct presence. Here the key difference is to IXIARO is that we do not sell DUKORAL currently in the United States. Those are the two products, two of our own products. As you see at the bottom of the slide, we have a number of products we in-licensed from third parties in specific markets. It started in 2016 when we in-licensed a product against flu for the Austrian market, followed in 2018 by a rabies product for Canada.
In 2020, two products that we in-licensed from Bavarian Nordic. Finally, we announced earlier this year a deal for distribution of VBI's hepatitis B product in European markets. You see we have a really good track record here, where from 2016 to date, we in-licensed quite a number of products. In the first nine months of the current year, we generated approximately EUR 18 million in revenues. Looking at the commercial performance and the sales performance, and how it developed once the pandemic hit. What you see here is we sold approximately EUR 130 million of products pre-pandemic, which of course dramatically collapsed as the pandemic hit, and it was basically divided by two in 2020 and 2021.
Looking at 2022, we actually see a nice recovery of the travel market, in particular for IXIARO but also for DUKORAL. What you see also here in the chart very nicely illustrated is the significant growth, of course, of the third-party products. We announced earlier this year that we expect to achieve EUR 70 million-EUR 80 million product sales this year for our existing travel franchise. Of course, you know, significantly driven by the third-party products as well. We clearly see a significant recovery again in 2023, and by 2024, we expect to be back at pre-COVID levels. Of course always provided there is not again a major wave of COVID-19 pandemic.
Actually, as we ramped up sales in the current year, we also experienced some supply shortages with both IXIARO and DUKORAL, and we expect to recover these shortages in 2023. Looking at our first nine months' performance, and we presented these to the market about a month ago. We see IXIARO, you know, delivering EUR 19.4 million growth sales, sorry, significant growth over last year, about 4x the revenues of 2021, and that is the travel market, so excluding the DoD. We see cholera, the cholera product, DUKORAL, as well nicely growing to EUR 9.2 million, where in the prior year we had almost no sales, half a million sales only. As I already mentioned, third-party products, increasing significantly.
You see the U.S. Department of Defense sales are down, that was expected based on the delivery schedule. Here we expect a new supply contract in 2023. A few words on our COVID-19 vaccine sales. As Thomas already mentioned, we really think it was a huge development success, unfortunately it did not result in a commercial success. We generated year-to-date sales of EUR 23.9 million at the end of September, and that was driven by shipments to the EU member states that maintained a certain number of doses, and also to the Kingdom of Bahrain. How do we expect to execute on our commercial strategy?
We basically identified three key levers to accelerate commercial performance again. The first pillar here is the recovery of the travel health market. As people start traveling again, we will continue to build on our brand identity and our reputation as a company that's really committed to collaborate and partner with health, healthcare practitioners and travelers to provide vaccines to travelers. We are providing tools and services to the healthcare practitioners. We'll of course, support the customers as we see the market recovering. The second pillar is expanding our vaccine portfolio, and here it's of course, you know, as I alluded to, adding third-party distribution products. We are of course continuously looking for complementary partnerships.
Then the third pillar and John talked quite a bit about that, is the launch of our chikungunya vaccine expected in the United States in 2023. We are right now, of course, building our commercial capabilities and infrastructure to really make that launch a success. We invested in market access capabilities also in-house, and we develop, of course, the brand and are continue to invest into better understanding the market. On this slide, you see an illustration how we roll out our new travel health campaign. This is basically what we will provide, you know, to the doctors, to support our unique travel vaccine range. It basically highlights our strong R&D capabilities and our commitment to the travel market.
Before we move on to the financials, I need to spend a few words, I think, on our COVID-19 vaccine. Again, given the lack of commercial success, we decided to suspend the manufacturing in the third quarter of 2022. We will continue to execute on certain clinical trials that had started previously, and some of those will run also into 2023. As Thomas mentioned, we have quite significant stock of 8-10 million doses that are available for sales, and we of course, continue our efforts to try and deploy those into international markets. We have discussions with various governments around the world, but right now we do not include anything in our internal forecasts related to that product, so anything we would sell would come as an upside.
We have some time of course, because right now we have a shelf life of 18 months, and we expect to be able to extend that to 24 months. Spending a few minutes on financial overview. As you know, we listed the company on Nasdaq in May of last year, then we did two successful follow-on offerings that actually generated good cash inflows. As previously explained, Pfizer invested EUR 95 million into Valneva to support actually our contribution to the Lyme trial. At the end of September, we had a cash position of EUR 260 million, and through the global offering, we added close to EUR 100 million net to that position.
The way we look at it is we're really well-financed at least to 2024 to execute on our current business. Given the COVID wind down, we also went into a program that we call Reshape, which is really looking into how we optimize our company to ensure our continued growth and deliver on our programs. We are reducing our workforce because we significantly increased the workforce because of the COVID program. The way we look at it is we will decrease by about 20%-25% our number of FTEs, and that will be done through a combination of natural attrition, but there will also be layoffs in 2022, but also again in 2023 as we wind down the programs. We expect an annual saving of approximately EUR 12 million.
As we focus on the future, we will clearly be a more nimble company post-restructuring, but we'll still be our headcounts will still be about 25% above pre-COVID, which really positions us well to retain our talents and deliver on our programs. With the resizing of the company, we will of course continue to advance our chikungunya vaccine, invest in our Lyme disease vaccine together with Pfizer, of course also as Anders alluded to, progress our preclinical assets. When we look at the equity story and how we expect to generate value over the coming years, as you see illustrated on this slide, today our revenues are basically composed by IXIARO, DUKORAL, and the third-party products.
In 2023 and 2024, we will add our chikungunya program VLA1553 to that which we expect to significantly add to our top line. Of course, not so much in 2023 because this will be the Eur-year of launch in the U.S., but from 2024. After that, the next step will be VLA15. Once it's launched into the market, we will get significant milestones for the first initial sales and then of course, also that generate, as discussed previously, double-digit royalties with basically no spend attached to it. We really see here a clear trajectory for growth and dramatically increase our top line.
Before I conclude, I just remind you the guidance we issued or we reconfirmed when we released our Q3 financials. We expect total revenues for the year to be in the range of EUR 340 million-EUR 360 million, composed of EUR 30 million-EUR 40 million revenues related to our COVID vaccine product sales, EUR 70 million-EUR 80 million of our travel vaccines, and then approximately EUR 240 million of revenues that are primarily driven by revenues recognized from the EC and the U.K. COVID contracts. In terms of R&D spend, we expect quite a bit lower spend than we initially planned for. Basically what we guided is EUR 95 million-EUR 110 million, and we maintain that for now.
This concludes my section, and I think we're gonna hand, pass into Q&A, and I would ask my colleagues to join me up here. Josh, you will moderate the Q&A, right?
While the panel is assembling, I'll just remind our webcast listeners that if you wanna ask a question, you can submit your question via the text box in the webcast player or by emailing questions to questions@lifesciadvisors.com. Yeah, we can take our first question.
Hi, Evan Wang from Guggenheim. Thank you for the presentation. Very helpful. In terms of the chikungunya program, you highlighted potential for a VRBPAC meeting. Is that based on any recent feedback from FDA? If so, any additional info FDA is looking for?
Does the microphone work?
Yeah. Yes.
Yes. Excellent. Indeed that expectation is based on FDA communications that we have had. As I mentioned in the presentation, we're looking forward to receive more information from the FDA, including a potential date for an advisory committee meeting. We believe that this will be determined only later once we're clear on the actual due date from the FDA's side.
Got it. Then you've talked about some potential for in-licensing deals. Can you help us think about how Valneva is thinking about the type of deal, in terms of, you know, staging, what kind of validation you guys are looking for, size? Thanks.
I think you are referring to the, to what I mentioned around pipeline. Am I right? Yeah. Yes. I mean, you have seen that we have really strong R&D capabilities from early research all the way to bringing products to licensure. We have capacity in, I would say, earlier clinical stage programs. We have a very good, very solid and extremely strong preclinical pipeline, but we lack a little bit the earlier stage clinical part. We are currently looking into, you know, potentially augmenting this clinical pipeline. We have a process ongoing. We have a dedicated team ongoing that is screening the market at this point in time. Please keep in mind that the principles of what I explained around Valneva's basic mission will apply.
All of our assets, whether you look at the commercial assets or whether you look at our development assets, are highly differentiated assets. First in class, only in class, best in class. This is clearly the direction of travel we're gonna take. We're not gonna go into the me-too space. We're not gonna work on the 20th pneumo program or flu program. We're not gonna go into the ring with the big gorillas. Which means we're gonna screen for programs today, we have not limited ourselves to how we're gonna finance it or. We believe that science will win and we will look at the quality of the respective asset, and then we will take a decision how to bring it on board.
We have a very strong shareholder base. We have extremely strong financial partners with whom we are working together for a long time. We are convinced that if the asset is right, we will be able to finance it.
Other questions?
I can take one question.
Yeah.
Just curious on the Lyme vaccine. Obviously I live just north of Manhattan in the countryside, and Lyme is rife there. I know the population that surrounds me, and persuading them to take three doses of a Lyme vaccine, I know would be difficult. They'd probably do one, they may do two, but three would be difficult for them. Then if it was annual, that also probably would be difficult for them. They, you know, would say, "Why do I need to get it?" I'm just wondering whether you've thought about starting some kind of program on an oral version of the Lyme vaccine, which would persuade them to do it because it's much easier and. Is that not possible?
No, it's an excellent question, and the answer is not yet. I think, on the one hand side, you are right. You know, the more doses you have for priming, the more issues you are facing with compliance, on the second or third dose in particular. Having said that, we have many vaccines in the market today, which are based on a three-dose priming and which are very successfully being, I would say applied, in the market field. Of course, it all depends around the balance of severity of the disease, the, the power of protection, and therefore, you know, the recommendation will be key. The final efficacy number will be key.
We are less concerned about a booster after the first season, especially since we have all experienced the COVID situation. There was a reason for why actually the FDA also wanted to see, you know, the efficacy data post-booster because we all understand that, you know, there was a clear lack of evidence for COVID, for example, you know, what really happens effective is from a efficacy perspective post-COVID. We are less concerned about this booster and whether then an annual booster will be needed or not, we have to see.
Because right now you have seen that there is a very high anamnestic response, and whether the, I would say, the antibody persistence will be good enough after the first booster to potentially last for another two or three years, as it was the case initially for tick-borne encephalitis when it was introduced. We have to examine, and then, you know, as part of life cycle management in vaccines, I mean, we talked about this before, you know that. I mean, routes of application, routes of delivery, different ways of, I would say applying the vaccine antigen is certainly something that all vaccine companies constantly are working on. But mostly in as part of life cycle management, and this is also how we look at it.
Thank you. Alex Osipov, Cowen. Thanks for the presentation. Also had a question about the Lyme vaccine. Was wondering if you think in theory there's an avenue for this mechanism of action to be, you know, efficacious against Borrelia already in the patients, so in other words, for existing Lyme patients.
Mm. Yeah. It's an interesting question. It's currently not in our focus.
Yep, appreciate it.
Hey, guys. Kyle from Oppenheimer. Congrats on the data yesterday again. Do you mind sharing more color on sort of the launch plan of chikungunya considering both at the FDA approval process and also ACIP?
John, you want to take it?
Just a quick follow-up question. When you say the launch plan, can you?
Second one. You know, sort of the timeline, also, markets that you want to focus on. Thanks.
Yes. Following FDA approval, we would really need to wait for an ACIP vote in February before there's really broad commercialization. Between FDA approval and an ACIP recommendation, we would be educating clinicians primarily on the continue informing about the disease, but more specifically around the vaccine efficacy. They would vaccinate whoever they deem appropriate, but many physicians will wait until an ACIP recommendation so they understand for whom the CDC thinks is appropriate before they go broadly and vaccinate a lot of people. Between FDA approval and ACIP recommendation, you should see some adoption, but most of the adoption would follow the ACIP recommendation if and when it happens.
Hi, this is Kevin Strang from Jefferies, congrats on the updates as well. Just talking about the ACIP timeline figure that you had there for 2023, when do you anticipate that you would have all the data that you need to bring to ACIP prior to that 2024 vote, in terms of the, you know, adolescent data, co-vaccination or anything else? When it comes to the co-vaccination data, or data in subjects who are previously infected, how important are our data around those topics as well?
On the ACIP process, we are in a continuous exchange on data. We're also looking to provide them with certain sub-analysis from the data we've generated in our phase III studies. Those are continuously evaluated by the CDC. The adolescent data, we're going to work with ACIP as soon as those data are available. Just to mention that in principle, the ACIP will issue recommendations on within the indication of the vaccine, and our BLA submission will focus on data in adults, so our approved indications would also focus on data in adults. Adolescent clinical data are of interest to the ACIP working group. They may analyze and comment on them. In principle, the recommendations would focus on adult populations at the moment. It's a continuous dialogue, and we'll
We anticipate to be able to share all of the necessary information with the ACIP working group well in advance of them concluding their considerations and their grade evaluation. Around the other trials and the concomitant vaccination, I think the same applies. We do not anticipate at this stage that the ACIP working group would review any data from potential future co-vaccination studies that would be coming at a later stage whenever such data would be generated and submitted to the FDA.
Great. Thanks. Just a quick follow-up for the Lyme phase III, you know, now that that is enrolling, is there anything that you're able to speak about in terms of enrollment pace or enthusiasm around the trial, and, you know, your confidence that the study could get enrolled by the second quarter of next year?
You know that for the phase III study VALOR, the clinical operations or the conduct is in the hands of Pfizer with a very professional team that is very used to run large- scale clinical studies. Based on the recruitment pace that we are seeing today, we are very confident that we will meet the timeline, which means having all the subjects included that we need in the for the tick season 2023. You know that the tick season is peaking around, you know, June, July, and you have, I mean, most of you know it starts March, April, and goes all the way to September, October.
That's basically, you know, we are looking, you know, into a very good, kind of execution performance at this point in time. Of course, we have to see now with the younger ones getting into the trial. This is typically more difficult than the adults, right? Remember, we want to do, the efficacy study in everyone above five years of age. But even if we had a lower recruitment number there are, you know, potential strategies to complement that.
Thank you.
Hi. Evan Wang, Guggenheim. just following up on Lyme. in terms of the recruitment by the, you know, the peak tick season, does that mean fully dosed or enrolled in the trial? I have a follow-up in terms of the antibody persistence data. You know, I guess how does that six-month data compare to your modeling and any kind of extrapolation we can take in terms of durability?
Okay. First of all, of course, when you want to run an efficacy study, you want to be to have as much people as possible at your peak titer. Yeah. Which means full priming completed, and ideally then, you know, two, let's say, weeks later, you know, approaching the peak. The more you get into this peak and high incidence, the better the signal that you're gonna get, because you are assuming a certain attack rate, you are assuming a certain number of Lyme cases. Of course, given the seasonality, you have a very strong peak in the middle, right?
Of course, there is not a lot you can do to optimize that, clearly you want to make sure that you have as many people as possible, you know, fully vaccinated and at peak antibody titers, around the peak area of your Lyme, you know, incidence. That's clearly the point. What's the follow-up question again?
How does the antibody persistence?
Yeah, I think the antibody persistence data that we have been seeing recently on the six months, confirm basically what we had expected to see. Basically, in the old days of the OspA vaccines, there was very, very little, you know, follow-up data really generated and published. Based on, you know, the profile of the antibodies, meaning caused by or generated with the outer surface protein A, one could have expected this kind of profile over time. The good news is that also we don't have an immunological threshold that we can correlate with efficacy at this point in time.
We have an indication based on all of our preclinical supportive work, in vivo work that we have been doing, bridging that to old data that was generated with LYMErix or ImuLyme at the time. We believe that we are, at the six months time point, still above or at this protective threshold, which is exactly what you want. You want people to be protected over the tick season, and then for the next tick season, have a booster shot, which hopefully is gonna last for more than, just a single season.
Okay. I apologize for running a bit over, but I wanna get to some of the questions that are coming in online. This is also from your colleague at Jefferies. Wanting to know what are the gating factors for combining the hMPV vaccine with an RSV vaccine, and what are the plan and next steps for doing so?
Then a follow-up question about what, if we can say anything about the IP strategy for our prefusion F protein modifications?
I'm gonna talk to the first one and let Anders talk about the second one. Basically, at this point in time, we are developing in our preclinical chop an hMPV candidate. We have no own RSV program, and we have no intention to start an own RSV program at this point in time. Which means we will, of course, test the waters with potential partners who are working on RSV, and we'll see whether there is an interest at which point, ideally, to combine approaches. This might be at an early clinical point. This may be at a mid, you know, clinical point, like a phase II stage. There could even be a possibility to develop it all the way through.
This is, these are all the options that we are currently evaluating, on the, more on the business side. I think from a technological perspective, with a subunit prefusion, you know, I do not see any technical challenge to co-formulate in with another protein-based vaccine candidate. Therefore, you know, it's just a matter of, you know, more the business side, I would say of things to determine the strategy than the scientific one. Yeah.
Is this on? Yes. IP strategy. I had a slide on this actually. I took it out because I wasn't sure if anybody would want to know this. Of course, for the designs, IP is filed. We have priority. They're not yet granted, I believe. Everything should be covered. There are, of course, more than one way to make these. You know, there are other players as well that likely have their own filings and how that all plays out, I think we have to find out over time. We have our portfolio secure.
Okay. Just a few more. Also from Jefferies, wanting to dig a little bit more into the market for chikungunya and some of the key assumptions behind the EUR 500 million annual potential. Essentially, is this, are we talking about the total market or specifically for our product candidate? If there's anything we can say in terms of our expectations for penetration for each market segment and pricing?
e last question would have been, do me please an Excel sheet. But no, I mean, look, I mean, the point of the... When we talk about the EUR 500 million, you know, market potential, I mean, this is not something that we just took out of the blue. We engaged a couple of years ago, L.E.K. Consulting, to help us doing a market study. We have other data points that we generated within certain countries. I think John presented a couple of key, I would say, market research data that we did also from a U.S. perspective. And the EUR 500 million is the total market. It's not necessarily only our product, but depends on the market share, of course.
We have to see whether there will be a competing chik program reaching the market or not, right. I mean, when we started chik, there were five programs ongoing. Right now, there are only two that are in phase III or, you know, ours then in the, as one of the two on the way to licensure. The EUR 500 million is based on that. We have currently reviewed and updated the whole plan. We believe that the number is still okay. It is important to note that this number excludes, and all the studies that we have done in the past excludes an opportunity for potential outbreak preparedness/stockpiling, right. Because this is impossible to quantify, I mean, for travelers, for endemic markets, it's relatively straightforward.
You just use a classical waterfall model starting from your actual travelers data and from the people who are actually getting the vaccine all the way down what John presented. As much as we can say, we will not talk about price today because we are in the middle of an ACIP process, health economic analysis, and pricing is a key component to that. When it comes to, you know, what should a modern vaccine cost in today's environment, I would kindly refer to one of the statements that the Pfizer CEO on that matter made very recently.
Sure. Maybe one more, and then we'll have to answer the rest by email. Samir from Rx Securities asked if considering that IXIARO is also an ACIP-recommended vaccine, what impact do you think the Inflation Reduction Act could have on travel sales, and when would you expect this to have an effect?
It's a wonderful question for John.
It's a great question. We're looking at that actively right now. We do expect to have a positive impact in 2023. That provision.
Goes into effect January 1st, 2023. There, there'll be an education process educating providers on this new information, educating patients on this new information. Part of the dynamic is that many of our travel health professionals do not accept insurance. It's, you know, kind of a concierge-type medicine approach. The patients would have to pay the provider and then seek reimbursement from their plan. There's an education process that we'll go through with both providers and patients, but we do expect a positive impact in 2023, and we expect that impact to grow over time and also impact our VLA1553 candidate. All right. Well, thank you everyone for a productive Q&A. I apologize again for going over. I'll just invite Thomas back up to give some concluding remarks.
Yes. First and foremost, I would like to thank my fellow colleagues, who have not only, you know, joined me yesterday for our wonderful bell-ringing ceremony, which also it was 18 months after the initial IPO and Nasdaq listing, was a fantastic event that I will personally never forget. It was great to have the entire team with us. Yeah, Our objective for today has really been to present to you the, you know, where we are with the company, where we wanna go, on our vision to really become a leading specialty vaccine company. We really want to, you know, I know that many people, you know, call us, in the investor community a niche play. At the same time, investors don't like the word niche, right?
Specialty is the way we position ourselves. We want to make a change to people's life with differentiated solutions, addressing new and significant unmet medical needs. We do that by staying focused. We stay focused on our key competencies. We not go out of our, you know, key area of expertise, and this is prophylactic vaccines, across all the technological platforms. At this point in time, excluding mRNA, and really advance those programs and make wherever possible, those programs also a commercial success through our own infrastructure.
From a basic, I would say, overall news flow perspective, which is important for all of you, let me focus here in this slide, which is a pretty detailed summary of the expected news flow and catalysts that we expect over the course of the next, let's say, two years. This helps you a little bit also seeing, you know, the evolution of the company and the different steps. You see that we on Lyme, we have, of course, we presented antibody persistence data. Both Pfizer and us, we were very pleased because the antibody persistence data fully confirmed what we had expected. Of course, we will follow up with additional antibody persistence data also next year. The enrollment completion, we discussed it, is a very important point.
The efficacy readout after the second season, once the season has been completed in 2024, is of course the big data readout for Lyme. Followed in the earlier part of 2025 with the respective, you know, submissions, which are currently contemplated to take place in parallel, MAA, so Europe, EMA, as well as U.S. FDA. On chikungunya, you know, Katrin explained very nicely that we're gonna follow up the antibody persistence on chik. Why are we doing that? Because we are assuming that this is the only chik vaccine in the world that will provide long-term protection with a single shot, full stop. That's basically the reason why we are following up on the respective, you know, antibody persistence time points.
We expect the rolling submission with the FDA to be completed imminently. We have the adolescent study enrollment completion that we are currently, you know, doing in Brazil. The data coming thereafter. The ex-U.S. regulatory submissions, which, you know, we have all put into the second half of 2023, and for which we will include adolescence data. You see the FDA approval, the potential PRV sale. I mean, Katrin explained the, let's say, the breakthrough and how it's interlinked with the six-month review cycle, which you can translate into when we are anticipating PDUFA date. Of course, ACIP recommendation, the ACIP vote, which is already set for February 24, 2024.
Basically then the ex-U.S. approvals, which we can kick in. Also we expect, of course, at least from a traveler's perspective, United States to be the single largest market for chikungunya. We haven't talked a lot about COVID, but we have, of course, still, you know, as we are facing down our COVID activities, we are still expecting some data points. These data points may help us to sell the inventory. You will see when we guide for next year's financials, we're gonna consider, you know, COVID as a pure upside. And I hope that we've made it clear today, we are not basing our fate into COVID at this point in time. We are really seeing COVID as an upside case going forward. We have the hMPV activities.
You see some of the decision points that we're gonna take. Zika potential clinical entry. I mentioned that, you know, now with only two companies, namely Takeda and us, really fulfilling the WHO target product profile with regards to inactivated vaccines. We believe that there is a significant possibility for our program to be reactivated into the clinic. You know, the EBV preclinical initial POC that we just so nicely achieved for hMPV , and these are the things that we are currently expecting. A very news flow rich, you know, short-term future for Valneva on our way to really become one of the leading pure- play vaccine companies that are out there.
My last word on that is, many of you know I'm 33 years in vaccines. I've never done anything else in my life than vaccines. When I started back, more than 30 years ago, there were more than a dozen of fully dedicated vaccine companies, with market caps above EUR 1 billion at the time. Today, you know, there are very, very few left. The big companies, the big vaccine businesses are part of large pharma corporations. If, an investor wants to invest in a pure- play vaccine story, there are not many out there. This is our case, I would like to thank you for your attendance, for all your support, I wish you already now happy holidays. Thank you.