GSK plc (GSK) Earnings Call Transcript & Summary

Good day, everyone, and welcome to GSK's RSV investor call. My name is Deborah, and I'm your event manager. [Operator Instructions] I would like to advise all parties the conference is being recorded. And now initially, I will hand on to Sarah Elton-Farr, Global Head of Investor Relations. Sarah, please go ahead. Thank you.

Thank you, Deborah. Good morning and good afternoon. Thank you for joining us to discuss the data presented at ID Week on our RSV vaccine candidates for older adults and maternal immunization. You can access the slides we are going to use in this presentation on the Investors section of GSK's website under Speeches and Presentations. I would ask you to please review our cautionary statements on Page 2. Also, please note that as we are in close period in our Q3 results next week, we will not be answering any questions on the performance of the business. And now I'll hand over to Dr. Hal Barron, Chief Scientific Officer and President of R&D at GSK.

Thank you, Sarah. And thank you, everyone, for joining this call to talk through the encouraging data on RSV we presented at ID Week. Joining me on the call, we have Dr. Emmanuel Hanon, who leads our Vaccines R&D organization. And we also have Roger Connor, the President of GSK Vaccines, who will frame up the evolving landscape within our RSV vaccines and how we think our candidate vaccine sits within this. With that, I'll make a few introductory comments and then turn it over to Manu. At Q3, I spoke to you about 3 new vaccine candidates starting Phase III studies. Two of them are for RSV. The first is for older adults, which is a very large and growing population. In the U.S. alone, there are an estimated 70 million people age 60 and above. The second RSV vaccine is for pregnant women to help pass protective antibodies to newborn infants, which in the United States represent approximately 4 million women per year and globally more than 130 million women per year. You'll see from the data that we share with you today that these vaccine candidates are well tolerated and have demonstrated a strong immune response, giving us confidence in the data and our decision to advance these programs into pivotal studies. Moving to Slide 4. As we have outlined in the past, GSK's approach to R&D is based on the multiplier effect of science times technology times culture. We define this as strengthening our R&D pipeline by focusing on science related to the immune system, the use of human genetics and the application of advanced technology such as vaccines, functional genomics, machine learning and cell therapy. As you can see on Slide 5, our focus on immunology and these advanced technologies has resulted in a world-class infectious disease portfolio, which includes 27 therapies in development, of which 18 are vaccines, and this accounts for around half of our entire pipeline. The medicines and vaccines we are developing will treat or prevent HIV, COVID, urinary tract infections, hepatitis B and many other infectious disease. This pipeline complements our existing marketed portfolio of more than 20 infectious disease therapies that together delivered almost $17 billion in revenue for GSK in 2019. And I mentioned this when I showed this slide at our Q2 results but I think it's worth repeating that analogous to the declared war on cancer, which has resulted in a marked increase in investment by the pharma biotech sector on discovery and developing important medicines for cancer patients, we're optimistic that the world's experience with COVID may lead to an increased focus on the importance and value of developing new medicines and vaccines to treat and prevent infectious diseases. And with that setup, let me tell you why we're excited about the potential for all our RSV vaccine candidates. Moving to the next slide, please. RSV is a very common respiratory virus. This infection causes acute bronchiolitis, which can lead to respiratory distress and hospitalization and even death. And it is the leading cost of hospitalization in infants under the age of 1. In addition, RSV is an important pathogen in the elderly and in high-risk adults. Although pediatricians are keenly aware that RSV may cause serious symptoms in patients, most internists are less familiar with the morbidity and even mortality associated with the virus in patients over 60. Given the lack of treatment options, this lack of awareness is understandable. In older adults, the infection can cause pneumonia, which can lead to hospitalization. And it is observed that the 1-year mortality following RSV infection in such population may be as high as 25% for these unfortunate people. In older adults, RSV is estimated to cause 177,000 hospitalizations and as many as 14,000 deaths per year in the U.S. alone. So given the significant unmet medical need and the [ high bill ] of our health care system, we're excited that we have 2 RSV vaccine candidates about to enter Phase III development. With that, now let me hand over the discussion to Dr. Manu Hanon.

Thank you, Hal. Welcome, everybody. So my name is Emmanuel Hanon. Most of the people call me Manu, and I'm responsible for the vaccine R&D pipeline in GSK. Before getting into the specifics of our RSV candidate vaccine and the data that was presented at ID Week, I would first like to talk a little about our vaccine R&D strategy. At GSK, we are looking for the multiplier effect between science, technology and culture to design and deliver groundbreaking vaccines with, for example, the strategic life cycle management of the Shingrix vaccine as well as our meningitis franchise, with key new product assets in our RSV franchise or with the -- our desire to enter new fields of vaccinology, specifically therapeutic vaccines and vaccines that target antimicrobial resistance. We do this by leveraging our portfolio of technology platform, which is literally a toolbox with the goal of addressing unmet need and improving vaccine efficacy, making manufacturing simpler and faster and speeding up development time lines. And this approach is underpinned by a special mindset and culture where we take smart risks, we ensure a single point of accountability for key decisions and we attract and retain the best talent, leveraging our presence in key geographic locations. Now on Slide 9. I believe that one of our key competitive advantage at the GSK is the strength and breadth of our technology platforms, the toolbox I was mentioning earlier. Over the last 20 years, we have been investing strategically to deliver this rich portfolio. We are the leading company in adjuvant technology, and we have a strong position in adenovirus vector as well as in bioconjugation. We are also investing heavily in messenger RNA with our SAM platform, self-amplifying messenger RNA, and with our recent CureVac partnership. Both of these platforms are highly complementary. All this means that we can uniquely select the right platform or the right combination of platform to deliver high efficacy vaccine that we can develop at pace and manufacture efficiently. Slide 10 shows the GSK vaccine pipeline. It is color coded. New products are shown in blue, strategic life cycle management in orange and global health assets in green. We have added a special category in green for our 3 COVID-19 collaborations that are at clinical phase. When looking at this pipeline, you can see the broad application of our adjuvant technology impacting all areas from life cycle management to discovery. And our pipeline is making good progress. In August, we started the Phase III of our pentavalent meningitis vaccine, which combines Bexsero, the market-leading meningitis B vaccine, with Menveo, a vaccine for A, C, W, Y meningitis strains. We have also started the Phase I/II study for our Staph vaccine, which is a great example of platform combination. The AS01 adjuvant and the bioconjugation platform have been combined to deliver a unique formulation. For COVID-19, we now have 3 clinical stage collaboration, leveraging our pandemic adjuvant which we believe has the potential to deliver strong and long-lasting immunity, which is really important for the at-risk population. With this collaboration, we have to provide an effective solution at scale. We have announced we will manufacture 1 billion of doses of the adjuvant in 2021. The preclinical data for these assets we have in-house so far are excellent, and clinical data will be available soon. Finally, and this will be the focus of the rest of my presentation. Yesterday, we reported positive clinical trial results for 2 major assets: the RSV maternal and RSV older adult vaccines, which are now progressing through stage gates and will move into Phase III. Let me now cover our approach to RSV vaccines. For 50 years, scientists have been trying to develop an RSV vaccine, but so far without success. It is only recently that science has progressed enough for us to have precise information about the identity of the antigen that should be considered to develop a successful vaccine. We know how the best antigen is likely to be the RSV fusion or F protein, and that it needs to have the right conformation to induce a sufficient quality and quantity of protective immunity. On the left of the Slide 12, you can see a 3-dimensional representation of the post-fusion conformation of the F protein. When used as a vaccine antigen, the F protein in its post-fusion conformation only triggers a moderate increase in neutralizing antibody, a maximum of threefold. We believe that the reason for this is that it does not display the most potent neutralizing epitope, which are displayed on the pre-F conformation of the protein shown in red and orange on the right-hand of the slide. If a pre-fusion conformation of the antigen is used in the vaccine, it has been showed by the NIH actually first, that it can boost neutralizing antibody by up to 15x. And this is exactly the antigen that GSK has selected. Now it is really important to highlight that the response induced by vaccine approach is polyclonal, and this is essential to get high level of protection against the virus and potentially reduce the risk of escape mutant viruses. Both these factors may mean vaccination may have advantages over monoclonal approaches. The development of a portfolio of RSV vaccine is a major area of focus for us at GSK Vaccine. Our maternal vaccine based on the pre-fusion antigen used alone is designed to protect babies during the first 6 months of life, during which 50% of hospitalization takes place. The vaccine is given during the third trimester of pregnancy with the goal protecting the baby from birth through a passive polyclonal immunization. In addition, the vaccine might also offer protection for the mother. The pediatric vaccine aims to expand protection beyond 6 months up to 2 years by raising active immunity against RSV using an adenovector, and therefore addressing the remaining medical burden associated with RSV in children. For the older adults’ vaccine, we are leveraging our adjuvant platform AS01 in the same way as we did for the Shingrix vaccine. We know that the older adults are less responsive to vaccination due to an age-related decline in immunity, specifically T-cell response. And this is why we have combined the pre-F antigen with the AS01 adjuvant to create a vaccine designed specifically for that older age group. All 3 vaccines have been designated fast track by FDA. The pediatric vaccine is in Phase II and some data will be presented as I speak next week. The maternal and the older adult vaccine are on track to start Phase III in the coming months, and this is why the next part of the presentation will focus on these 2 assets. Now let me take you through the key data from the Phase I/II trial of the maternal vaccine candidate analyzing immunogenicity and tolerability. We enrolled 500 non-pregnant women who were divided into 4 groups. One group received placebo, and 3 groups received a vaccine at different doses, 30, 60 and 120 micrograms. Now before going into the details of the results, let me give you a very important context. As you know, last year Novavax shared disappointing Phase III results for their maternal vaccine, and it did not meet the primary endpoint. Despite this, an important learning was made for the whole field. The data showed that with the vaccine able to boost neutralizing antibody by threefold, that efficacy was between 40% to 50% depending on the severity of the end point used for sick children. So this data gives an important indication of the level of immunogenicity needed that may confer protection. On the Slide 16, for our maternal vaccine, we were actually impressed by the response observed, up to a 14-fold increase in RSV neutralizing antibody using the 120-microgram dose. Clearly, this is well above the threefold impact delivered by the Novavax candidate. In addition, the response was neutralizing against RSV A subtype, but actually similar response were obtained for the RSV B subtype. And we also observed strong persistence of this response. After 3 months, there was still a six fold increase above baseline natural immunity. In terms of safety, the vaccine was well tolerated at all doses, with the most frequent adverse events being pain at injection site and headache. There was no vaccine-related safety concern. So we are just very confident in our candidate vaccine. And our Phase III is expected to start within a few weeks, with the first major results anticipated in the second half of 2022. Let me now go through the key data on immunogenicity and tolerability of the older adult vaccine candidate. On Slide 19, you can see that the trial enrolled more than 1,000 subjects. Part A involves young adults exposed to placebo of various doses of antigen, 30, 60 and 120 micrograms. This was needed to assess the safety of the vaccine but importantly to also develop a benchmark. Young adults do not develop severe RSV disease, and so that immune response can be used as a relevant benchmark to compare with the immune response of older adults. I will come back to this. Part B of the trial exposed older adults to either placebo or one of the 3 different dosage level of antigen that were combined with 2 different dose level of adjuvant. Please note that AS01B is the adjuvant used in Shingrix, and AS01E is the lower dose version of the same adjuvant optimized for tolerability. And today, I'm reporting data one month after the first dose. Data following the second dose and any subsequent analysis will be shared in due courses. On Slide 20, I'm showing you both the antibody response on the left and the T-cell response on the right. So if we look at the antibody response first, it is worth noting that after the RSV season, people who have had RSV disease generally have around a fourfold increase in antibodies. So we set the bar in our clinical trial with a six fold increase as a minimum target. And you can see the results are very clear. Using 120 microgram of antigen, we get from 8- to 9.9-fold increase in neutralizing antibody. For the T-cell response, because of the work on adjuvant and vaccines like Shingrix that we have done over the last 20 years, we have acquired a lot of experience in assessing T-cell immunity. The graph on the right represents the distribution of the T-cell response in each group before and after vaccination. And please note these are medium, upper quartile and lower quartile distribution. And this graph shows the statistically significant impact of the AS01 formulations on the distribution of T-cell response in vaccinated individuals. Both doses of AS01 were statistically superior to the non-adjuvanted formulation, which actually is in line with our expectation in this population. So when assessing the overall data including tolerability, we concluded that combining the AS01E formulation with the 120 microgram of a pre-F antigen is the optimal formulation for the older adult vaccine. Now the next critical question is, is that immune response sufficient to give incremental efficacy and efficacy for older adults? And the answer to this question -- actually to answer this question, it is important to look at the benchmark we measured in young adults. This is on the Slide 21. For the antibody response on the left of the Slide 21, it's pretty clear that vaccination stimulates the immune response in older adults to reach a similar level of neutralizing antibody to young adult. On the right-hand side of the graph looking at the T-cell response, and I want to draw your attention to the fact that the preexisting T-cell level in older adult before vaccination are much lower than the one you can observe in young adult prior to vaccination. And actually this might explain the increased susceptibility of older adults to severe infection. Now following vaccination, the level of T-cells in older adults is well above the preexisting level in young adult and is approaching the post-vaccination response of the same young adult population. I think this is pretty exciting data to see after only one dose. From a safety perspective, the first dose was well tolerated across the different doses. The most frequent adverse events were pain at the injection site, fatigue and headache, with a trend from a slightly higher rate using the AS01B adjuvant higher dose adjuvant formulation. There was no vaccine-related safety concerns. And so combining all the data, we are very confident in our candidate vaccine and are in discussion now with regulators, on track to start our Phase III within a few months. The first major result should be available during the second half of 2022. I will now hand over to Roger Connor.

Thank you, Manu, and hello, everyone. I have to say we are really excited about the opportunity for our RSV vaccines, given the severe unmet need in both older adults and babies and the very encouraging data that we have generated on our candidates. And we've been working hard to accelerate the progression of these programs and believe that they really have significant potential. In particular, I'm excited about our older adult asset because of the scale of the opportunity and the encouraging data that we are seeing on immune response from the vaccine formulations, continuing our proven adjuvant technology platform AS01, the same platform used in our Shingrix vaccine. We're also very encouraged by the Phase I/II results and look forward to seeing how these assets are going to perform in their pivotal studies. On Slide 24, we wanted to summarize the overall older adult opportunity. Hal mentioned earlier RSV creates significant and widespread health burden in older adults. And we have the opportunity here to introduce a vaccine to help protect 70 million older adults in the U.S. alone and hundreds of millions more around the world from a common and burdensome respiratory virus that can lead to pneumonia and other complications. I think a really important point is that 2/3 of older adults in the U.S. receive vaccines regularly to prevent flu and pneumococcal disease, so this is a population of health-conscious individuals. And we have a particular expertise here with tremendous consumer insights, having successfully launched Shingrix in this older adult population. Plus, we shouldn't forget GSK has a flu franchise that has a strong track record of successful execution and expansion in recent years, and there are a number of similarities between flu and RSV from an epidemiological perspective. So bottom line, an older adult vaccine for RSV represents a meaningful commercial opportunity with multibillion-dollar potential. And we believe we have the opportunity to deliver a potentially first-in-class and best-in-class differentiated asset. This is based on the knowledge we have about our adjuvant system that has delivered unprecedented efficacy in Shingrix for the same target population. So we are very excited to invest in the Phase III program, and we're on track with our plans to start early next year. Now if I move to the maternal vaccine shown on Slide 25. And the burden of RSV is also really significant in infants, and we believe the best way to protect them up to the age of 6 months is through vaccination. Now the opportunity here is the annual birth cohort, which is about 4 million in the U.S. and millions of babies more around the world. A key point here is that children are almost guaranteed to get RSV by the age of 2. It is the leading cause of hospitalization in infants less than 1 year of age. And the burden is most pronounced in the youngest of infants where half of hospitalizations occur in the first 3 months of life. Our maternal vaccine candidate is designed for routine administration during the third trimester of pregnancy, to protect the infant by conferring maternal antibodies to protect from birth through the first 6 months of life. Another benefit is that the mother may also be protected, which is good for her and potentially reduces the risk of transmission from mother to baby. Now we at GSK, we also have an existing portfolio of vaccines that are recommended for pregnant women with our pertussis and flu vaccines. And we estimate about half of moms to be in the U.S. receive those recommend vaccines already, so there's a partially built market in place and an opportunity to expand the market size. Manu also highlighted that our RSV vaccines induced a polyclonal antibody response, which we believe could help address escape mutant viruses, which is a benefit of our approach to preventing RSV infections. And by helping protect infants from birth, this program also really complements our pediatric RSV program designed for routine administration to help protect babies through to age 2. So in summary as we move to Slide 26, we are pleased to have shared these data sets for 2 of our RSV candidate vaccines to you today and look forward to initiating our Phase III studies with initial data expected for both of these large-scale programs in the second half of 2022. Those study timings are best estimates and are dependent on how RSV infections circulate during pandemic lockdowns. We'll continue to keep you updated on the progress. I want to finish by reminding you of the 3 key points I think we're making today. First, I think the opportunity is clear. There are currently no vaccines for RSV. And there is a significant market potential, in particular for older adults, but also protect -- to protect babies and children. Second, at GSK, we have a chance to introduce a first-in-class and potentially best-in-class older adult vaccine with our candidate, which includes our AS01 adjuvant system to boost the immune response. We view this as a potential multibillion-dollar opportunity. We're also competitive with our maternal vaccine with the added advantage that we could add this to our existing portfolio of maternal vaccines for flu and pertussis. Third, the data we've shared are compelling for both our older adult and maternal vaccine candidates, and like other data we have in-house, support our decision to move to Phase III studies. And finally, remember that if you add in our pediatric vaccine, we are the only company to be developing a vaccine to treat all of the at-risk populations for RSV. Now to deliver our RSV portfolio, we will continue to invest in our global manufacturing network that today already distributes almost 2 million doses per day, expanding capacity to deliver the potential for these priority assets. And with that, the team here are ready to take your questions, and I'll hand back over to the operator to start the Q&A. Thanks very much.

[Operator Instructions] But we do straight away have the first question for you. It's from Geoffrey Porges from SVB Leerink.

I appreciate all the data, and congratulations on the broad program. A few questions, if I may. First, what sort of efficacy do you believe is required in the different populations for approval of the vaccine against RSV? And could you disclose your specific endpoints, primary and secondary, for the 2 Phase IIIs that you've disclosed? Secondly, could you just give us a little bit more information about what you know about the consistency of the immune responses across different genotypes or subgroups of RSV? Specifically, you've got the NA1, ON1, BA genotypes. And it is a virus that sort of has different forms circulating from year to year. And then lastly, given the importance of the pre-f3 protein structure, why not consider an mRNA vaccine in this situation, given the success that they appear to be having in COVID?

Thanks very much for the question. Now, we're not going to disclose details of our Phase III program today, but maybe Manu, you could take those questions on [indiscernible].

Yes. So yes -- but as Roger said, we indeed we -- I'm sure you realize, we have active discussion with the regulators to agree on the final design of our Phase III, so I don't want to disclose exactly the level of efficacy. But obviously we are targeting a high level of efficacy. We have definitely a lot of -- we have accumulated a lot of data that allows us to really target high level of efficacy. To your question related to different viruses circulating, yes, I mean, RSV is an RNA virus, so it's a virus that can slightly evolve. And this is the reason why it is so critical to target that virus with what we call a polyclonal response. So a response that target multiple neutralizing epitope on the antibody side, but at the same time using for the older adult, an adjuvant to boost T-cell immunity. We all know that this T-cell immunity can be also highly cross-reactive. So this is definitely the strategy that we are pursuing. And this is why we are favoring a polyclonal approach in terms of injection of immunity in the pregnant women for the babies as well as older adults. In terms of messenger RNA, you are totally right in saying that this is definitely a disruptive technology that can accelerate the very initial phase of progression into clinical development. Now once you have reached the Phase I clinical development plan, your timings are really dependent on actually the design of the Phase III and the season that needs to be rolled out with the attack rate. So the technological advantage is less important here. But I want to acknowledge the messenger RNA technology is a very important technology. This is why GSK is heavily investing into that platform using actually 2 platforms: the self-amplification messenger RNA platform as well as the messenger RNA platform from CureVac. And I want to remind you that so we have the bridge of starting the Phase III while those that continue to use messenger RNA against RSV are just starting.

Thanks, Manu.

This is now Jo Walton from Crédit Suisse.

I wonder if you could just tell us a bit more about your degree of confidence in carrying to 6 six months in terms of efficacy from -- on the maternal side. And if you were to, let's say, give birth in April and then your -- and in the northern hemisphere, so you've got the summer. It's really only months, say, 7 to 12 that you're going to experience the RSV. Are you confident that you will have your pediatric vaccine in place for that time point? And I just wonder if you could explain a little bit more again why you think a vaccine approach is better than a mAb approach in the maternal space?

Maybe I'll start with the comparison to mAb. And Manu, you can take the 6 months question as well. I think there's a number of factors to think about. First of all, vaccines being a proven method of protection at scale is where I'd start. From a maternal immunization, GSK knows and understands maternal immunization. And this is a well-established method that utilizes that natural transmission of antibodies to the baby. So I think making sure that we make the most of the already understood methods of transmission where we use it for flu and pertussis are very, very important. I think Manu mentioned it as well, a vaccine does potentially protect the mother as well, and that can help in terms of reduced transmission. And this is important between transmission potentially of RSV from mother to the child as well. And I -- although Manu just mentioned, I think this polyclonal point is important that we know that this antigen has been designed in this way to ensure that we get that polyclonal protection. And that has the potential to reduce this risk of those escape mutant viruses, which does give us a potential for benefit over monoclonals. That's what I would point out. Manu, on the duration of protection?

Yes. So it's very clear that we will definitely measure in our Phase III efficacy a duration of 6 months. So the data needs to be generated. But when looking at the full [ impact ], [indiscernible] [ mind ] up to 14-fold increase with the selected dosage. We think actually we have pretty good margin versus the previous minimalistic benchmark that was reported in previous year. And I'm not going to repeat the comparison between monoclonal and polyclonal, but I think this is really important. Finally, I also want to insist on the notion that it's, in a way, in terms of positioning, going to be the combination of maternal and pediatric vaccine that will really ensure the protection beyond 2 -- up to 2 years. Because actually there is 50% of the medical need that needs to be addressed after 6 months, and this is actually the proposal we have with the pediatric vaccine and an active immunization.

Thanks, Manu.

And can I please just clarify your manufacturing capacity comment, in fact 2 of them? So I believe you said was it that you could make 1 billion doses of the adjuvant from a COVID perspective? And then could you clarify what sort of capacity you would have for RSV, given that presumably, if you're getting data in 2021 and 2022, you could need this in a relatively short time frame.

Yes, a great question. I think it is, just to clarify, 1 billion doses of our adjuvant available and manufactured in 2021. So that is of the AS03 adjuvant. And then for the capacity to support RSV, I won't give you the specific capacity number, but we are investing to support the significant ambition that we have for the vaccine. Thanks, Jo.

This is Tim Anderson from Wolfe Research.

Two questions, please. I'm wondering how your trial powering and timing takes into account COVID dynamics. You note on Slide 26 that the time lines for readout depends on RSV infection circulation rates during the pandemic. So are you benchmarking against past infection rates that would not have been influenced by COVID? Or has there been an adjustment made based on the best guess of what the impact of COVID could be? And then second question, with both vaccines you say, "initial data expected in second half 2022." That seems to suggest maybe that there will be some final data available at some later point. And I'm wondering if regulatory filings can be done on that initial data? Or is it going to be based on some later data? And if it's the latter, what is that later data? And what would be the filing time line for the vaccines?

Understood. Tim, thank you. Manu, maybe you take both of those.

Yes. Thanks. So it's very true that nowadays COVID-19 -- and it's not -- it's a well-known phenomenon when there is a pandemic actually, it takes -- it occupies the space, and the attack rate of other viruses can go down. And it is actually what is today being monitored in the field. So first of all, this is something we are actively monitoring very, very closely to understand what is going to be the evolution. Second point is that yes, obviously, both for the maternal and the older adult trial, we have been working on assumption adapted to the current knowledge we have on what would become the attack rates in the future, taking into consideration COVID-19. So clearly that has been taken into consideration. And thirdly, when we speak about initial data for the second half of 2022, this is definitely in the context of leveraging the data for a regulatory move. It is not an additional set of data of interest, but we will see you 2 years later with the rest of the data. No, that's not that.

So post that data point, we'll be assuming positive outcome and move through registration and regulatory process.

Exactly.

Thanks, Tim.

This is Andrew Baum from Citi.

Three questions, please. Firstly, could you talk to how you perceive the benefit of T-cell immunity, both for your COVID vaccine but also for your RSV elderly vaccine? My recollection is that even adjuvanted protein subunit vaccines don't elicit effective CD8 responses? And is that the concern here? Second, on manufacturing in relation to the RSV vaccine, how have you changed your mindset in terms of scale-up, given your experience with Shingrix where obviously demand significantly exceeds capacity? I'm just trying to gauge and put some context around your earlier comments. And then finally in relation to your COVID-19 vaccine. Could you clarify whether this will be a 1-shot or 2-shot vaccine?

Thanks, Andrew. Manu, why don't you take the first T-cell?

Yes. So as I explained during the presentation, because of the, let's say, unprecedented investment we have been doing in adjuvant platform over the last 20 years, we have to -- acquired a lot of knowledge on how do we measure this immunity, what does it mean a specific increase. And I can only -- I mean I can only -- I can definitely relate to the -- we actually made exactly the same learning for Shingrix. With Shingrix, we were measuring 15 years ago, antibody response and T-cell immunity and realized that with the adjuvant, we were able to actually impact the T-cell immunity. And we went into -- directly into Phase III as you know, translating into very high level of efficacy. So T-cell immunity in most of the viral infection plays a really important role. You are totally right mentioning CD4, CD8 T-cells. Going back to Shingrix, the Shingrix vaccine does not induce any CD8 T-cells. It actually mainly impacts the CD4 T-cell component, and it's exactly the same that we observed for the RSV older adult vaccine. And finally, on the T-cell response, I want again to point out the observation that we have consistently made between actually respiratory viruses, where in older adults both for influenza and now for RSV, you can see that the T-cell immunity is significantly lower than what you observe in young adults. And that's actually what we think really that with the use of adjuvant and with the ability to restore the T-cell immunity to levels that are comparable to young adult, we are able, like for Shingrix actually, to get again an efficient response to able to control the virus. In combination...

You're just talking -- you're just talking about CD4, right? You're not seeing any effect on CD8s, correct?

Yes. Yes.

Yes. Okay. Maybe I'll take the next question, Andrew, which is on the manufacturing scale-up. Because of the significant opportunity we are seeing, we are already working on that manufacturing scale-up plan and we'll be investing to support the assets. I think one thing to understand is that this is a subunit vaccine, which is a platform manufacturing process for us. So we're not starting from scratch as well. So we're able to scale up what we already have. But as I mentioned, we are going to be investing behind this asset because we believe it is a significant opportunity for us. On the COVID vaccine, our belief is this is most likely a partnership that is most likely to be a 2-dose vaccine. The data will obviously show that, but our working assumption is that would be 2 dose. And obviously, the AS03 plays a very important role in these vaccines from a dose sparing perspective in terms of reducing that dose. And hopefully the data will show the impact that it has both on the at-risk populations, but then hopefully as well on duration of protection as well. But our starting assumption is 2 dose. Thanks, Andrew.

This is James Gordon from JPMorgan.

James Gordon from JPMorgan. I have two questions, please. Firstly, can you contrast the 2, the RSV vaccine, the maternal and the older adult population products, to the respective Pfizer and J&J products, important differences there? And the second question on the older adults product, ultimately if it is successful, would that be something that you could try and administer alongside Shingrix? And would you then have to develop a different combo because presumably you can't have 2 adjuvanted products at the same time. So you'd have to phase it out, or could you ultimately come up with some sort of combo product?

Manu, do you want to start with the comparison with Pfizer and J&J?

So Pfizer has developed an antigen that is categorized in the same place as the GSK antigen. It is a pre-fusion conformation antigen. Pfizer has been recently communicating on their maternal vaccine. They also have an older adult vaccine presumably using the same antigen, but there is less information available on that, so I cannot say more. J&J is following a completely different strategy. They use an adenovector vaccine to immunize individuals against RSV, so it's a very different technology. We have not done a systematic comparison between what they do and what we are doing. What I can say is that we are pretty confident in the results that we have obtained on their consistency, the quality and the quantity of both antibodies and T-cell immunity. Whether we could combine the vaccine with Shingrix, that's possible. This needs to be potentially included in future life cycle management opportunities, but I cannot comment more at this stage.

I think one thing that having Shingrix on the market gives us is that, obviously, a very strong understanding of the older adult vaccination market, the channels associated with those. I think it's too soon to tell whether co-administration with Shingrix is really appropriate for RSV. That is -- Manu mentioned that's something that we could that we could look at. But we do think one of the differentiating factors here for GSK's RSV older adult vaccine is not just the adjuvant, but also our knowledge about older adult spheres as well. The other point I'd make when comparing the GSK maternal RSV to competitor activity is this point on portfolio should not be missed. Again, our maternal understanding is very high. We know this space. We have trusted vaccine in this space as well. And we know again the population through which we would administer. So I think that's a significant benefit for GSK's portfolio here to add benefit to both vaccines that we're talking about. Thanks very much.

This is Laura Sutcliffe from UBS.

I was just wondering if you could share your thoughts on the time line and maybe probability of success for your vaccine in older infants. Do you think it's more challenging than the maternal and older adult testing?

So the pediatric vaccine?

Yes, probability of success of the pediatric vaccine, maybe -- so first of all, this is one of the most challenging area. As 50 years ago, active immunization in children unfortunately led to, let's say, a completely opposite outcome of what you want to do with a vaccine. So we need to progress extremely carefully. Now the vaccine that GSK has been developing is now being assessed in RSV seronegative children, which is the ultimate target population. I think we are among the first doing that, and we will soon actually collect internally the data out of this investigation. The probability of success of that asset remains, at this stage, low. But I want to say at the same time that all the preclinical investigation, including Challenge trial that we'll do in a calf model, which is actually extremely close to the human situation, gave us extremely positive results, which give us hope that we can not only protect the first 6 months of life of these children with the polyclonal passive immunization, but we can expand beyond 2 years with this active immunization.

Thanks, Manu. Thanks, Laura.

It's Louise Pearson from Redburn.

I've got a question for Manu, and apologies if I missed it. Just on the adjuvant, could you just elaborate on the difference between the B and E formulations, what it is that makes E potentially more tolerable than B, and if these changes might sacrifice some of the adjuvant effects that were so powerful with Shingrix?

Yes. So AS01B is the adjuvant that's used with Shingrix. AS01E is a lower dose of adjuvant. It's actually a 50% dosage of adjuvant. It's actually the same adjuvant that we have been using in other program. It is definitely optimized in terms of tolerability without actually losing the impact that it can have both on antibody response as well as in T-cell immunity. But it's clear that AS01 is slightly more powerful, but we actually get already a lot of the T-cell benefits by using the AS01E adjuvant. But in the end, it's exactly the same composition. It simply adds the strength. And I think it's important to mention that as we have already exposed 20 million people with AS01B, and so we are pretty comfortable on the safety data of this adjuvant.

Thanks, Louise.

It's Graham Parry from Bank of America.

So first question on the older adults’ vaccine, will you generate any data in reduction in hospitalization or mortality prior to the outcome of the Phase II data in 2022? So is there any chance of getting any of that data out of the Phase II? Similarly, in terms of duration of response, timing of [these], et cetera, do you think you'll have that ahead of the Phase III data? Or is that going to require longer-term follow-up post the 2H '22 readout for the older adults? And then on the pediatric vaccine, could you just help us understand your thought process on timing from move to Phase III for that, what the hurdle is to move to Phase III? You're in Phase I/II in seronegative patients at the moment -- infants at the moment. Is that going to be sufficient data for a pivotal trial? And the rationale, if you could just explain it there for using A and B and not the pre-fusion design that you're using in the other vaccines?

Manu, you can take both?

Yes. So again, I'm not going to disclose the Phase III protocol, but it's very clear that we are going to target the impact of the vaccine on the severe -- on the lower respiratory tract infection RSV. So we are not going to after the mild symptoms of RSV. We are going to go after the severe symptoms. And there is obviously primary end point and secondary end point that will collect the kind of severity, such as hospitalization, as you just mentioned. We believe it's really important as the cost effectiveness assessment of the vaccines need absolutely this kind of data. I hope I captured all the questions. So I'm going -- there was a second question around the pediatric vaccine and the reason why we selected this one instead of using the pre-f. So one of the finding that we made in actually 20 years of research in that specific field is that to actively immunize children against RSV, so beyond the passive protection of contact by the mother, you absolutely need to prime T-cells. And there were different approach that were possible. And we found actually that the one that was the most effective in that specific age group and that specific population was with using an adenovirus vector that is able not only to induce T-cell response as well as antibody response. And so the question was what's going to be the next step? As I said, we will collect internally really important data by the end of this year or early next year. And this definitely will be a critical readout conditioning the next steps for that asset.

Yes. And Graham, I think your middle question was on the duration of response of the older adults? Is that right?

Oh yes.

Yes, exactly. When will you know duration response and timing of these is?

So on that, basically we need to keep all the option open in -- with that vaccine. So obviously pivotal Phase III efficacy data is going to assess the efficacy, the safety and the duration of protection. At the same time, we will also do the same on the immune response with obviously revaccination and so on. So -- but again, we are speaking here again about the Phase III protocol design and so on. So we don't want to provide more information at this stage, but we'll come back to you as soon as we can.

Graham, thank you.

The final question today from Seamus Fernandez from Guggenheim.

So just a couple of questions on the market opportunity and the level of efficacy that you believe needs to be demonstrated in the adult type population. We've seen in the adult populations the utilization, risk parameters that tends not to make for very successful market opportunities. So just wondering what the regulators, more so that the government regulators like the ACIP, are likely to be looking for in an adult vaccine to achieve the $1 billion to $2 billion market opportunity that you're talking about? And then as a follow-up question, with regard to your CoV2 strategy, you've collaborated on the CoV2 vaccine with your adjuvant, but also have the antibody effort alongside Vir. Why not have a similar type dual approach? It just seems like with a monoclonal antibody, especially one that targets a conserved epitope, you could actually have a more targeted coverage of a pediatric patient population and potentially be easier for governments to reimburse. So just trying to get a better sense of that.

Manu.

Yes, so for the first question -- you would have to remind me of the second question. So for the first question, very clear, but again I'm not going to disclose you the level of efficacy we are targeting. But it's definitely in the upper quartile that we are targeting. It's very clear also that we are going to monitor the impact of the vaccine on the severe symptoms and consequence of the infections, such as hospitalization and possibly death. But in a Phase III of this design, it's unlikely we will be able to show a difference in death, but potentially post-marketing commitment might allow us to generate that. We will obviously also evaluate the efficacy of the vaccine for all that population that is at risk of developing severe infection. Take the example of COPD patients or people treated with immunosuppressive drug. I want to remind everybody that Shingrix, we just got the approval in Europe for its use in immunocompromised patient, because, again, thanks to the adjuvant and the impact on T-cell immunity, it has the ability really to confer and restore high level of protection, even in these people that have a fragile immune response.

Thanks. And Seamus, I just want to clarify. Your last question was why are you only going after vaccines and not after a mAb also for RSV? Is that correct?

Yes. You chose a certain strategy with CoV2, which is a bit broader. Maybe it's just we were going after hospitalized patients with Vir more so than prevention. But it does seem like a prevention strategy can perhaps offer a more obvious economic return to the governments that are going to be likely paying for it significantly around the globe. So it's just more a question of yes, that choice.

I mean -- so first of all, I want to remind everybody, GSK's strategy actually is both. We have a vaccine strategy for prevention and to vaccinate the mass population, but there is also a monoclonal antibody that is being actually in Phase III today in partnership with the Vir company. And that specific monoclonal antibody is being assessed in therapeutic setting, and I think -- but maybe Hal can complete -- potentially some prophylactic setting also.

I think your question, Seamus, is about RSV though, wasn't it?

Oh, oh, sorry, sorry.

Correct?

Yes, that's correct.

Yes, yes. Like I think this is choice, and it's really around where we think we can make the biggest difference. And I won't go back through what we believe the differentiating factors are versus mAbs. But again in maternal where we have the strength and this knowledge and an established method of delivery, we really believe in it. And a key point is that vaccination through maternal protects the baby from day 0. From the moment of birth, there is protection. We think that's not fully understood yet, and that will actually be an important differentiator as well. I think we -- I think Hal, is there anything you want to add on that particular question?

Well, I would just maybe add a couple of things just really quickly. I know we're out of time. But I think the difference, to some extent, reflects the fact that there's a lot of unknowns with COVID. The first point is that we're already starting to see evidence of resistance. And one of the things that made the Vir antibody so unique was that it was found from the reverse translation of the details from patients who were infected with the SARS-CoV 1. And by identifying antibodies that would be both protective of that and COVID-19, we believe, and preclinical data supports this, that the antibody would be binding an epitope that was highly conserved. So I think when you have a situation where there's fitness advantages from different mutations, the polyclonal response may be enough, but we're already seeing resistance. So we're excited about the Vir antibody from that perspective. And as you said, the other big difference is the treatment of infected patients is a real opportunity for patients who -- where an antibody can add a [ unique thing ] from Vir. So those are the 2 rationales for doing that.

Great. Hal, Thank you. And Seamus, thanks for the questions. I think we're over time, folks. So I know there's probably more questions there. If you can e-mail those in through the IR team. We'll make sure that we get back to you. And we hope you've enjoyed this session. You got a sense for our enthusiasm and excitement for this what we think potentially very important set of vaccines. Enjoy the rest of your day. Take care and thanks very much.

Roger, everyone, all the speakers, thank you. That concludes your conference call for today. You may now disconnect. Thank you for joining, and all take care. Bye.