 Hello, good morning, good evening, good afternoon, depending on where you are. Welcome to this insight session on developing COVID-19 vaccines. Unfortunately, COVID-19 means little introduction to anyone. The pandemic has brought the world to its knees for the best part of 2020. And while we have seen that lockdowns and distancing work, and treatments such as Dexamethasone have helped us manage the disease to some extent, overall infection rates and the death toll continue to be intolerably high. And worryingly, we continue to learn about new sequelae of the disease, some of which could be very long-lasting. Right now, all eyes are on vaccine development. Out of 300 candidates in the works, around 40 are currently being tested in humans, and nine are in phase three clinical trials. The pace of development has been unprecedented. One of these nine vaccines is being developed by AstraZeneca and the University of Oxford, another one by Johnson & Johnson. I am Magdalena Skipper, Editor-in-Chief of Nature and Weekly Journal of Science, and I am fortunate to have with me here for this COVID-19 vaccine development session, Pascal Soryo, Executive Director and CEO of AstraZeneca, and Paul Stofels, Vice Chairman of the Executive Committee and Chief Scientific Officer of Johnson & Johnson. Welcome to you both. Thank you. So let's start. Welcome. Let's start with both of your approaches to COVID-19 vaccine development rely on adenoviral delivery. Can you give us a brief overview of each of your vaccine approaches and how similar or different are they? Let's start with you, Pascal. Well, I mean, they are very, in many ways, they are similar. As you know, there are several technologies in development. One is Modified RNA, and the other one is this adenovirus vector, which both Paul and our, Paul's company and our company are using. Ours is based on a chimpanzee adenovirus, and the JNJ1 is different. So Paul, maybe you want to talk about your own vaccine. Well, it's based on adeno-26. It's a human adenovirus, and it is using the cold virus, which is not replicative anymore to carry the piece of the COVID virus into the body, the genetic information. And the genetic information is then coding for producing the spike protein in the body of the human. And that is a mechanism that we use the adenovirus as a carrier to bring a part of a genetic part into the body. And that is producing the protein to get to the vaccine. It has proven both for us, for us to be a very efficient way of doing that. And that's what we use now to develop very quickly vaccines. So as you can see, the technology is very similar. The difference is we both use an adenovirus vector that carries the spike protein, but the vector is slightly different. Yes, thank you. And then, of course, both of your companies now have gone into phase three trials. Which populations across the globe are these trials running in? And what determines your choice? I ask because, of course, we are acutely aware that different populations differ in the susceptibility to COVID-19 and then, indeed, in their disease manifestations. Paul, perhaps you can tell us first. Yeah, in the first phase, in phase one, we study in healthy volunteers to know the safety and the risk, but also the immunogenicity in, let's say, a clean situation. But in phase three now, we go very broad into and mainly targeting the populations which are most vulnerable. That means the elderly in the US, the African-American, the diverse population, but also be studying in Latin America and in Africa. So at the end of the study, we should have a very broad and diverse population into the study, which are typically the target and those people are most vulnerable to the disease. And Pascal, what about AstraZeneca? Very similar. I mean, our development program is structured a little bit differently, but fundamentally, we do the same. We have very diverse populations in America and North America, in Africa, and also we have a study in in India. So we try to go after very diverse ethnic populations, but also we need to look at different age groups. We go 18 and over. We haven't got any pediatric study yet, but essentially we try to cover different populations, ethnically, but also age-wise. And so I understand different trials are aiming for different population sizes in which the trial is ongoing. How do you determine the size of your trial? Well, the size of the trial is mainly determined also by the transmission rate, because you need to go to high-risk areas where there is a lot of transmission in order to be able to show protection. And we measure two things, is protection against disease, that's the primary endpoint, and protection against transmission. And in order to have a chance to reach a significant statistical significant endpoint and have enough data to submit for emergency use and later on for BLA for full approval, you need to have quite significant numbers. And we have done a lot of data science epidemiology to see on where and how we have to do the study to target the people most at risk. And we determined for a phase three study that will go up to 60,000 people on a global basis to be able to show the safety and the efficacy. Essentially, we follow the same approach. You have to define the size of your population based on the infection rate in the communities where you're going to run your trial. And also how fast you would like to get a response and define the size of your study. But you also need to have a sufficient safety database so you need to vaccinate sufficient number of volunteers to have enough safety. Typically, it's around 50 to 60,000 people that need to be vaccinated so you feel comfortable, you've accumulated enough data. And so I want to say that this may not be sufficient to achieve herd immunity. And how does this compare with the FDA requirement and other vaccines against other diseases? And what does it mean for transmission and indeed the need to revaccinate in the future? Well, the minimum level has been set by the authorities at 50%, but of course we aim at the most effective vaccine. We optimize for potency, you can use boosting, so there are different mechanisms for a much higher. So the expectation we have is that it is significantly higher, but we don't know at the moment we are testing. And that's where the minimum level is that, but we should aim for higher protection and hopefully we get to that. There are different numbers that are floating out there and of course that confuses people a little bit. First of all, as Paul said, you have the minimum threshold established by the regulator. So for instance, the FDA has said they need a minimum of 50% efficacy and the lower bound of the confidence interval statistically has to be 30% and above. So that's what the regulator defines. Then you have the rate of efficacy that you use as an assumption in your statistical analysis to define the size of the study and when you can do a nutrient analysis, etc. And then there is what you hope for. And we all hope for more than 60, 70% of course, but the minimum is 50. And depending on the protocol, different companies use different numbers, but I think most mostly people have used 60% efficacy as an assumption in their protocols. But we all hope for more than that, of course. And so can you comment on the second part of my question about transmission and the need to revaccinate? How are you projecting that? Will we be looking at repeated vaccinations? We have to learn that, but most probably yes. And that's also depending on how the immunity evolves in humans. We don't know if you generate antibodies and cell immunity, how long that will protect you. We know from animal models that we have studied that very extensively with all the diseases that we can get longer term protection with a single dose, but ultimately you need to boost for longer term protection. So we'll study that in several different parts of our study. We'll do a boost at two months and we'll then learn whether we do a boost at six or 12 months, but boosting will need to happen at certain points for long term protection. That's a big question. I mean, first of all, of course, we don't know whether those vaccines work, but we all hope they do. But then the next big question will be in how many people and what's the percentage of people are protected and then the next one will be how long are you protected for? And that answer we will get over time. Yes, exactly. But Paul, do I understand that correctly that the Johnson and Johnson vaccine is designed to be a single shot vaccine. Yeah, that's correct. We will test both a single shot and a booster shot, but we developed the same vector in four different indications. We did a certain development up to a certain point in Zika where we used a single shot. Also RSV now is in phase three with a single shot. But Ebola is a booster shot because Ebola is a very lethal disease. We used a prime boost, even a heterologous prime boost with two vaccines to make sure that you had one close as 100% protection because of the lethality of the virus. And so in Ebola now we are vaccinating over up to 200,000 people in the Kivu and Rwanda area to protect for Ebola. And that experience told us that if we do certain, if we developed in a certain way with certain insights and optimize that, COVID inserts, we can get to a single shot. We showed that in an animal model and now in phase one. And hopefully now we are going to study that. Hopefully yesterday when announced, we are going to study this in a phase three study. Later on in the year in October, we'll start a boost study once the phase one data will become available. Right. And so if I can just follow up on this, so is it fair to say that whether you are able to design a single shot vaccine or a booster go for the booster design is determined by a combination of the prevalence of the virus, but also your ability to target creating immunogenicity. Well, it's also determined by the factor as well as the insert. So, so there are many factors which determine the potency and the immunogenicity, but that is work of the from the scientists over many years, in our case, was the collaboration between Dan Baruch at Harvard, our team at and collaboration with NIH and the vaccine team in Leiden. So they worked on 10 already 10 years on this on this topic. Hopefully with success. We'll, we'll see soon. So, on September 6, AstraZeneca's phase three trial was paused after a person who participate in the UK trial experienced an adverse reaction. The trial was of course, we started on the September 13. We reported the day later in nature, the scientific community was not overly concerned about the pause itself, which in fact in large trials is not uncommon. But there were criticisms associated with the lack of transparency about medical confidentiality was cited as a key reason. But some have of course argued that information could be disclosed in a way that avoids individual identification. So, Pascal, could you shed some light on the decision making here isn't transparency important for public trust. We need the general public to want to receive a vaccine when they eventually arrives right. Yeah, no, absolutely. I mean, first of all, I should say that stopping a trial in a vaccine program is not uncommon. I mean, it's not not very common, either, but it happens. And if you place safety at the center of everything you do, of course, you're going to have to stop and look at events. And that's what we did. And both the independent safety committee and the regulator allowed us to restart the study. Now, the question is, how much transparency can you provide right and, and typically, you don't, you don't provide information. I mean, the guidelines, I should say the clinical guidelines recommend that you don't disclose patient level information and also you don't disclose much information at all because you could compromise the study. So that's basically what is the, the background from, from the guidelines viewpoint. Now we are actually looking at how much transparency can we provide, considering we're in a very special set of circumstances, of course. We've provided, we've disclosed our protocol, and we are looking, we're discussing with other companies as an industry, what kind of transparency could we offer, without compromising patient privacy, of course, but also without compromising the trial itself, because if you disclose the information, too much information, you can actually compromise the clinical trial itself. Excuse me, did I hear correctly, you were saying that you're discussing with other companies, so with a, with a view to arriving at some kind of a consensus. Yes, we're trying to kind of come up with a consensus to say, okay, you know, this is what we feel is reasonable to disclose that is typically not disclosed, but in this special set of circumstances where of course, people once maximum transparency, what is it that we can disclose without compromising the clinical trials and without compromising patient individual privacy. Yes, so my understanding is that the trial has restarted now in the UK, Brazil and South Africa. What about the US? The US, we're waiting to hear from the FDA that is reviewing the data we submitted. Essentially, we, the data is reviewed by an independent safety committee that is then submitted to the regulator. And because the study is actually in our case, the study is conducted by Oxford University. We are not the sponsor, they are the sponsor of the study. And they of course focused originally on providing all this information to the MHRA and to the regulators in the other countries where they are sponsored, we are the sponsor of the US study. So we then provided all this information to the FDA and we're waiting to hear their decision. Yes, and so you, you know, as we speak of transparency, you already mentioned the disclosure protocols. So of course this is very unusual. You've disclosed protocols as has Pfizer and Moderna to other companies involved in vaccine development in phase three trials and of course, yesterday in the press release, Johnson and Johnson also released the protocol. So why, why this move? It is, it is unusual, certainly unusual to disclose the protocol before the study has concluded. Paul, perhaps you can comment on that. Well, this clearly we are in very difficult, difficult, different and difficult circumstances where everyone is expecting the vaccine. It is, is having an enormous disease as an enormous impact on the world economy and people, the the political debate about this, like, are these guys doing the right work in order to get to the good information which tells that the vaccine works and is safe. And that's where when the first come back to what Pascal was saying, in normal circumstances, we are very much already scrutinized by experts. You have the independent safety, the regulatory, the ethical committees in Europe IRPs, all people with expertise and experience in, in 30 years of vaccine development. So they have an oversight of what can happen in vaccines. If you do experiments and new vaccines, they also know the very rare side effects which have appeared over the past. So they can get a good estimation of what is, what is an A, what is an adverse event, what is an unexpected adverse event and make the judgment. On top of that, we have teams which are very specialized in certain neurology teams. We have inflammation teams. We all can do the interpretation of the data. But in this case, that's, that's not enough. We, we have to be very open about what we do, the statistical designs, the endpoints, etc. And that's why we are committed to say, okay, let's, let's make it available immediately. What Pascal was also saying, we can't disclose data in a placebo controlled study on an individual level because then you debo online to study and the study becomes void. So we have to have a careful way of how we work with the regulators that give you committees, the DSMB and with the general public on making sure they trust the process. They will informed, but they don't hamper the process because that doesn't help the public either. So when we jointly are committing to significant transparency up to the point that we can continue to do our work in a very professional and scientific way. If I may add, we all want to be as transparent as possible, honestly, but the reality is, as Paul said, we have to make sure we protect patients privacy, but also importantly, protect the study integrity. And at the end of the day, I think people, people have to accept that they have to trust someone at some point, right? So you have independent safety committees, you have regulators and you don't have one regulator. You have several regulators around the world. You have the FDA, the MHRA, the EMA, Japan. I mean, so many regulators will look at this data and these results with different eyes. So I mean, at the end of the day, you get a trust that the experts whose job it is to monitor these trials and these developments are doing a good job. Medicine should be practiced for the media, it should be practiced by experts, right? Yes, you mentioned trust and of course it's a limited commodity, especially today. Do you think, just following up what you said in answer to that question, do you think there's anything more that we could be doing to ensure, reassure the public? But even though transparency is limited for reasons that you just very well explained, they ought to trust the experts that they do have safety and indeed efficacy in mind. Well, I think regulators, IRBs, DSMBs, they are not put together by just normal people. They are always the collection of experienced, independent, not connected to the company, not connected to the process as an independent review and overseeing what you do as a company. And we do that continuously in science. As you probably have heard, how you do this is you have your own process, you have an independent committee reviewing with experts what you do, giving advice. But in this case, they are the deciders and DSMB, they can decide, the FDA they can decide, so the decision is not up to the company. We give it to external experts which are very highly experienced in this matter to say whether or not there is an issue. And I think the people should trust that that process on what that that's happening, that that is understood and very well understood so that people can trust the whole situation as a whole on how we do developments in the world. And it's not different from cancer developments, inflammation developments, all this. We always do this in pharma on how we develop medicine. You know, even if people don't trust their own independent individual country regulator is also independent safety committees that are not subject to political pressure and those are independent people they don't work for the government they don't work for the company that totally independent experts. So point one and point two is, you really would have to love conspiracy theories to believe that all regulators around the world will all agree to to approve a vaccine that that is not safe and effective. I mean, it's, it's hard to believe that every country, so we would do that so you're going to have several set of eyes from different countries looking at this data. Oh, clearly we mean so absolutely point taken. Clearly there's some work to be done because some recent polls for example in the US showed that the percentage of the population who says they're prepared to take a vaccine has actually dropped since earlier to now which is paradoxical as we are perhaps getting closer to it, but speaking of timelines let's talk a little bit about time timelines. So, some still hope that there may be an approval for emergency use this year but realistically, when do you expect to have sufficient data to apply for regulatory approval. How long does that take, and assuming that the vaccine is approved, how long after that that individuals such as me, let's say, could expect to be vaccinated. I can start. We just started a phase three so we, we have to, it will take its time, which it will take to get to the endpoint on safety and efficacy. We expect that somewhere around the year and first quarter, depending on the incidents and the run of the study will be able to get to an endpoint which will show efficacy, but the endpoint in efficacy is not just the single thing. We also have put in an analysis plan that we have to have enough exposure to safety before we will stop the study because there is no use in stopping for an endpoint for efficacy if you don't have extensive safety data for example in elderly and in certain populations. So the combination of efficacy and safety data will determine when we'll there, but at the earliest towards the end of the year, but more, more reasonable I think in the first quarter, depending on the run of the study. If the vaccine is chosen for emergency use because that's done by the government, moment will be ready in January to deliver the first batches of vaccines. It will grow over the years. We have committed to a billion vaccines next year. We are pretty sure we can make that happen, but in the beginning it will be limited and it will be first going to the highest risk population, which are the health healthcare workers and elderly. Before you will get a vaccine might take some time in next year before the vaccine will reach you. That's right. So there have been actually very recently, at least a couple of recommendations as to prioritization of who in the population in the society should be first in line to receive a vaccine. But Pascal, do you want to add anything to this? I think all described it very well. I think the one thing also that people tend to forget in term of vaccination is you need results, but then you need also manufacturing. You know the day we have results doesn't mean the day after we can start vaccinating people. First of all, the regulators will have to look at it, look at the data and give approval and emergency use approval in the US for instance. But then you need to have enough quantities. And the key in this epidemic is to be able to vaccinate as many people as possible around the world, starting with those at risk of course, but covering the entire world. And it's a big population. So we will need several vaccines and we will of course have to wait a little bit until we can scale up over time as an industry to get enough doses to vaccinate everybody who wants to be vaccinated. Exactly. That's a very important point. A quick follow up to this. So I believe the day before yesterday, the Washington Post wrote about the fact that the FDA is considering tightening its standards for emergency authorization of the COVID-19 vaccine. Do you consider this would be a significant setback? I don't know yet the details. At least I might have missed it, but that's not yet communicated what that is. But the start that it will, that they want to have the follow up of two months after the cases. So that might add to the timeline or not. I have not yet looked into that. It will not be a significant setback. It might add some time to the timeline, but that is to be evaluated as the regulations come out. Okay. So I have a broad question to both of you as we come into the end. We talked about the fact that we live in a very different special circumstances. You have released your protocols of your trials. You have pledged to develop an emergency vaccine on a non-for-profit basis. We're talking about greater transparency, much more collaborative approach. Does this mean clinical trials in future will change? I think we have learned some acceleration here. When it comes to real medical emergencies, I think the companies and the FDA are now very well trained. We did this before in cancer and in HIV and in emergency circumstances to go fast. We also have more access to data science now to see where to go for clinical trials. I think the collaborative spirit in the world between companies but also between companies regulators on how to interface in order to go fast is trained by this is much better. So I see optimization of faster development of new medicines, new vaccines in the future because we went through what we went through. It's a big learning on how to work 24-7 and being able to interface with scientists all over the world as well as with regulators. It teaches us a lot. So on this very positive note, I'm afraid we're going to have to close because of just run out of time. We could spend much more time talking about it. Thank you very much to Pascal and Paul. And there will be a second session this afternoon if you want to listen more about COVID-19 vaccine development. Thank you very much.