On Vaccines and Vaccinology, in COVID and Beyond

with @rvenkayya @jorgecondebio WHEN are we going to have a COVID-19 vaccine, and how the heck are we going from 12 years of vaccine development compressed into 12 months or so? What will and won’t be compromised here, and where do new technologies (like mRNA) come in? Where will vaccines likely be distributed first; who will and won't get them initially; how do we maintain not just safety and efficacy of vaccines but trust and transparency when it comes to mis/information? We may actually see the emergence of a "Neo Anti-Vaxxer"... but we may also be entering a renaissance for vaccinology after this pandemic.

Speaker names marked ? are inferred from speaking time and the show’s known hosts — they are not voice-verified.

• 0:00Sonal?

  Hi, everyone. Welcome to the A6 and Z Podcast. I'm Sonal and today's episode is all about vaccines. When exactly will we get one for COVID-19? How, where, and why? And while it's a super timely question and concern, this episode covers a wide range of topics all about vaccines and vaccinology well beyond the current pandemic. Beginning with the quick primer on vaccine development to what we'll have to give up to shrink development from a typical 12 years or so to 12 months or so, what modern technologies are being applied to this current development, some for the very first time, including mRNA vaccines, where manufacturing and scale up comes in, and by the way, why have we traditionally used eggs in growing vaccines? The conversation also touches on business models, opportunities

• 0:45Sonal?

  for all kinds of different players, and tough public policy questions around public transparency, who gets the vaccines first when they arrive, and inequalities, possible impacts on different populations, risks, and much more. How does the question of vaccines impact school reopenings? Where does misinformation come in? These are both topics, by the way, that we're diving deep on in upcoming episodes. And will we see the emergence of a different kind of anti-vaxxer movement here? A6 and Z general partner Jorge Conde interviews Rajiv Venkaya, president of the Global Vaccine Business Unit at Takeda Pharmaceutical Company, where he leads vaccine development for Dengue norovirus and Zika and is co-leading their response to the COVID-19 outbreak. Venkaya also formerly served in the White House as Special Assistant

• 1:30Sonal?

  to the President for Biod Defense, where, among other things, he was a principal author of the National Strategy for Pandemic Influenza Plan. So they cover a lot of ground in this episode. For past podcasts and pieces in our ongoing coronavirus series, be sure to check out a6andz.com/coronavirus.

• 1:48Speaker 01

  So obviously, this is in the news every moment of every day. One of the best hopes for getting life back to normal is the introduction of the vaccine. It's become a very hot topic. It's become a very political topic as it relates to COVID. So one of the things I want to start with is get your take on where are we? Where are we in terms of developing a vaccine against this novel coronavirus? What is the state of the state?

• 2:13Speaker 02

  I have to say that of all the things that have transpired in this pandemic, the speed of our vaccine development efforts globally are one of the things that gives me the greatest hope that we'll be able to manage. Through this and get to a much better day relatively soon. This is a situation we've never been in in the past because it takes such a long time to develop vaccines. If companies know that there are a lot of other companies that are developing a certain vaccine, then they're likely to not pursue the program because it takes so long, it's capital intensive, it's risky. Why go through all that if there is a chance that you could get through the entire 10 to 15 year process and then there's nobody that wants to take your vaccine? In this case, however, we have a lot of programs moving forward in parallel.

• 2:56Speaker 02

  Back in January, an organization called the Coalition for Epidemic Preparedness Innovations, SEPI, which I happen to sit on the board of, was monitoring the events quite carefully and actually in late January announced that they were going to invest in three vaccine development programs for the virus that we now call SARS-CoV-2 that causes COVID-19. Since then, there have been announced over 200 programs in vaccine development for SARS-CoV-2 across universities, small biotechs, big pharma. There is no shortage of effort going into developing a vaccine. That, of course, isn't enough, having a lot of people working on this. You need to have processes and systems and governmental and regulatory commitment to

• 3:41Speaker 02

  make things happen quickly. And here again, I would say that vaccine development is moving at what we would call light speed relative to the standard timelines. So when we think about normal vaccine development prior to the pandemic, we would estimate between 10 and 15 years, potentially much longer, to go from discovering a potential vaccine all the way through to making that vaccine available to a lot of people. That entire process is being compressed down to 12 to 18 months.

• 4:12Speaker 01

  The conventional wisdom always was it takes nine months to make a baby, it takes about 10 years to make a vaccine.

• 4:18Speaker 02

  Let me just confirm that the conventional wisdom that it takes nine months to develop a baby still holds, that hasn't changed. With regard to vaccine development, however, we have found ways to massively reduce the time to evaluations of efficacy and safety and hopefully licensure. To give you a sense for what goes into developing a vaccine, you have to start with an understanding of what proteins in the virus are more likely to generate the immune response that will protect a person from an infection. And we do that in what we call preclinical research, where we're looking at different parts of the virus and testing it in the laboratory to see whether it can interfere with the replication of the virus in a person.

• 5:01Speaker 02

  We then go into animal testing, where we get an initial sense as to the safety and effectiveness of the vaccine and protecting against the actual virus. And then we go into phase one testing, where we look at the dose of the vaccine as well as the initial safety assessment of the vaccine. And if we can get through phase one and two with a good understanding of safety and efficacy and deem the vaccine suitable for large-scale testing, then we go into what we call large phase three clinical efficacy evaluations. And this is where we give the vaccine or a placebo to tens of thousands of individuals, assume that some of them are going to be exposed to the virus, and then compare how

• 5:44Speaker 02

  many people in the placebo group get the infection versus how many in the vaccine group get the infection. And we can do a statistical analysis to determine whether and to what degree the vaccine is protective against the virus.

• 5:56Speaker 01

  We're working furiously to get to a vaccine in something like 12 to 18 months, which is obviously a lot shorter than 12 years. If you look from start to hopefully finish, what is driving so much of that compression? Some of it, let's argue, is perhaps some novel vaccine technologies have allowed us to discover and develop a vaccine candidate much more quickly than we could in the past. So so many different technologies that are being brought to bear to get us a vaccine against SARS-CoV-2.

• 6:28Speaker 01

  Some of these are new technologies, some of these are old technologies. So let's just take a second to go through that because to me, one of the things that's been stunning is how some very novel technologies are being essentially debuted for the first time against this virus. Specifically, I'm thinking about the work that's happening with mRNA vaccines. Can you take a minute just to walk us through what is different from an mRNA vaccine standpoint as a technology platform versus, say, a attenuated live vaccine versus, say, a subunit vaccine, the latter two of which have been used many times for many different types of viruses?

• 7:06Speaker 02

  Sure. This is a really important concept. So the underlying principle is that if you expose the human body to a protein that is on the surface of a virus or in the virus, that you can train the body to recognize that component and by extension, the virus and develop antibodies and T cells, cell-mediated immunity that will protect you if you happen to be exposed to that virus in the future. And as you mentioned, there are some well-proven approaches to developing these types of vaccines. One approach is to take the virus itself and activate it or kill it and purify it and give that to people. That's a way to train the immune system and we've done

• 7:46Speaker 02

  that for decades. Another way is to take a virus and then do what we call attenuation, meaning that you get a version of it that doesn't cause disease, but it does give exposure to the immune system so you can train it. That's been used over decades successfully in vaccines like the measles and Mumps and Rebele vaccine. We have these newer platforms that you referenced that are really interesting because they allow you to work out many of the specifics around the actual vaccine manufacturing in advance. And then, once you identify the specific virus that is causing the problem, you can plug in the sequence of the proteins that you think are most likely to be important

• 8:29Speaker 02

  in immunity and very quickly produce candidate vaccines that you can take into clinical trials and then ideally scale up into large quantities. mRNA vaccine as a concept has been around for quite some time. And in fact, there have been efforts to take platforms like that and apply them to emerging pathogens like SARS and MERS, two other coronaviruses, and even pathogens like Ebola. But they've never gone as far as they have with COVID-19. And in this case, so far, those platforms have really demonstrated that you can go from identification of the pathogen to clinical trials in absolute record time.

• 9:14Speaker 01

  It took Moderna famously like 40 some odd days, right?

• 9:17Speaker 02

  Before they had a candidate vaccine that they were ready to take into clinical trials, that's what the company has said. And it's exactly what people had hoped would be the case for these new platforms. Now, let's be clear, there is not yet any vaccine based on an mRNA platform that is licensed. And so this is the debut, if you will, for this kind of vaccine, not to go into clinical trials, because that's been done before with these types of vaccines, but to go all the way through to efficacy trial, efficacy that the vaccine can actually reduce disease. And that is exactly what is happening now in the first phase three clinical trial of an mRNA vaccine, the one that's produced by Moderna.

• 9:56Speaker 01

  We still have to go through the entire process to prove that they're safe and effective, as you laid out. So what do we give up in terms of knowledge or safety and efficacy of a vaccine when we compress from 10 to 12 years to 12 to 18 months? Like, what are we sacrificing?

• 10:14Speaker 02

  Yeah, it's a really, really important question. There are some administrative things that have been done to reduce the amount of time that it takes to prepare for clinical trials, go through the paperwork, the data analysis, what have you. There's some other very important concepts that allow this shortening. Number one is that a lot of things are being done in parallel, as opposed to traditional vaccine development where things happen in sequence. You go through your initial trials in animals, those preclinical studies, then you go into phase one, two, and three. And oftentimes, each of those phases can take one, two, three, or more years to get through them. And so instead of doing all of that in sequence, because we're doing them in parallel, we're able to get to phase three, these large-scale efficacy trials, very quickly. Another thing that we're doing

• 10:59Speaker 02

  in parallel is to begin scaling up the manufacturing process for these vaccines and even producing

• 11:06Speaker 02

  Large volumes of what we call commercial material, meaning material that could be used for the launch of a vaccine before we even have the data to support safety and efficacy. With an understanding that if the data doesn't prove that this vaccine is safe and effective, then we will write off all of that inventory. We'll throw it away. We'll scrap it. So a lot of money is being put at risk to shorten the time between when we have the data and we can actually make large volumes of vaccine available to large numbers of people. You asked a key question. What are we giving up? Well, one thing that gives me a lot of confidence in this process is that the size of the clinical trials that are being conducted for these vaccines are about the same size of trials

• 11:51Speaker 02

  that we would normally conduct to demonstrate efficacy and safety of any vaccine. So the bar hasn't changed there. What will be different is that at the time we launched these first licensed vaccines, we will not have many years of follow-up on the vaccine to know, for example, what's the duration of protection? Do we find that over time the immunity wanes and so a person has to have a booster? The other thing we won't know is whether there are some very rare side effects that can happen but further out from the time of vaccination, say two, three, four years later, maybe only once a person is exposed to the virus itself. We've seen that this can happen with some other vaccines. These events tend to be very rare

• 12:36Speaker 02

  and because they're rare, you might not pick them up in a 30,000 or 50,000 person clinical trial. It's not until you actually go into large numbers of people before you'll pick them up. And this is where it is very important that the scientific community and the biopharmaceutical industry be extremely transparent about the data that they're generating. That supports licensure and then after they license their vaccines that they share on an ongoing basis the safety information on these vaccines so the public is aware.

• 13:05Speaker 01

  And are the rare events that occur presumably these are immune driven events? Some sort of a catastrophic immune reaction that happens like you say rarely but happens on say reexposure to a virus or something similar?

• 13:18Speaker 02

  They could be. To give you a couple of examples, there was a vaccine for rotavirus a long time ago that was pulled off of the market because after it was given to children, you could see a complication in the small intestine called intussusception. There was a finding with a dengue vaccine in the past that individuals that received the vaccine who had never been exposed to dengue previously, once they were then exposed to the virus, had a risk of having more severe disease than had they not received the vaccine at all. And then there was a question around an association between a flu vaccine with an adjuvant and narcolepsy, which was completely unexpected and rare, very rare, but it is a potential association.

• 14:01Speaker 02

  So they aren't all necessarily catastrophic, in fact, most are not. But it's important that when we talk to people about vaccinations, we give them a full understanding of the efficacy and safety profile. And I can tell you that amongst the scientific and the public health and the medical and the communities and the industry, this is of paramount concern, the concept of vaccine confidence. When we launched the first COVID vaccines, the public needs to know that they have been rigorously evaluated for safety and efficacy and that they can trust in those vaccines. Because if people lose trust in vaccines, then that jeopardizes trust in all vaccines, which we've worked so hard to build over time.

• 14:44Speaker 01

  Yeah, and it's interesting because we've already seen some of the effects of losing trust in vaccines, right? With the anti-vaxxer movement that exists today with a lot of the disinformation that accompanies that. Obviously, you've had your fair share of exposure to the world of anti-vaxxers. And to me, one of the fascinating things about anti-vaxxers is they're so concerned about vaccines based on bad information. In the case of what's happening with the COVID vaccine and how quickly we're going to get a vaccine in our hands, one of the interesting things here is that we're likely to see the emergence of something that I would call a neo-anti-vaxxer. It's not someone who's against a vaccine based on bad information, it's someone who's concerned about a vaccine because we don't have enough information. This is a new thing, right?

• 15:29Speaker 01

  Because it's a new technology being used to go after a new threat, and we're doing it as quickly as we can for the benefit of everyone. And by the way, I think one of the interesting things is that these neo-anti-vaxxers probably look at anti-vaxxers and think they're crazy, but at the same time, the neo-anti-vaxxers are also going to be ones that are hesitant to take a vaccine that is probably in their benefit to do. I think this is going to be a very big challenge for us to make sure that we don't have sort of COVID vaccine denialism that impacts how much uptake there is for something like this.

• 16:00Speaker 02

  So this is a really important issue. In fact, a recent survey suggested that half the population here in the US would be hesitant about taking a coronavirus vaccine when it becomes available. I think it would be a mistake to think of this population as being an expanded version of the group that was hesitant about vaccines before the pandemic. That group has had a range of concerns. I would say that there are a spectrum of reasons why some people have questions about vaccines. Now, in some cases, their concerns are based on completely unproven, even fraudulent information that has been put out there, and it's been hard to remove from people's memories.

• 16:42Speaker 02

  The Andrew Wakefield experience of the flawed connection between a measles monkey reveller vaccine and autism is the best example of that. However, there are a lot of parents who have children with autism who have reasonable questions about why does my child have autism? And in the absence of a good medical or scientific explanation for that, they're trying to understand whether there is something that they could have done differently to change that, and for their children that haven't been vaccinated, they're asking whether they should think about vaccines differently. And here, I think... The data is very much in favor of the safety of vaccines. There is not a connection to autism. That's been looked at extensively. On the other end of the spectrum are people in the context of COVID who are saying,

• 17:27Speaker 02

  what you said earlier, wait a minute, it only takes 10 to 15 years to develop the vaccine. You're going to do this in 12 to 18 months. Come on, how did you shrink those timelines down to about a year or 18 months without compromising somewhere? And did that compromise happen on your assessments of safety? I want to see that this thing is really safe before I give it to myself, before I take it or give it to my kids. And these are very reasonable questions because we have not done this before. And while we do have good answers for that, we don't actually have data in front of us right now to show what we're basing licensure of vaccines on. And we also are going to need more time to understand the long-term profile of the vaccines after their launch.

• 18:11Speaker 02

  So these are reasonable questions. I think the way they need to be addressed is by extreme transparency, by biopharmaceutical companies that are developing vaccines, by regulatory authorities and governments before the vaccines are licensed. And then after those vaccines are available, we have to be very transparent about the data we're collecting around long-term safety. And while I think that the likelihood of significant events showing up two, three years down the line are small, very small, we do still need to collect that data and report it out so that everyone maintains their confidence in the vaccines that we're using to stop this pandemic.

• 18:50Speaker 01

  So a question for you, what does the vaccine uptake need to be in the population for it to be effective?

• 18:58Speaker 02

  Well, this is something that is debated and it depends on a number of things, including what you consider to be effective. But generally speaking, people have said that you want to have close to 70% of the population taking up a vaccine in order to get a level of immunity that protects the population against the virus and easy transmission through the population. That number could be lower and still be significantly effective.

• 19:22Speaker 01

  Are we going to have, and should we have a COVID vaccine? Are we going to have many COVID vaccines? Because if we look at childhood immunizations, et cetera, there's an MMR vaccine, right? There's the full schedule that our children get. I don't know which one the child is getting. They're getting the one that's recommended by the doctor. So if we have one vaccine approved and licensed, is that it? Or do you expect that we will have many COVID vaccines? And how would we expect individuals to choose if we have multiple choices?

• 19:51Speaker 02

  I think there are going to be multiple COVID-19 vaccines, and they are going to have very different attributes. And it will be the job of recommending bodies that are groups of experts that look at, in this case, what vaccines are available, to make recommendations on what the best vaccines are on a population by population basis. We know that in older adults, some vaccines don't work as well. We may find that certain types of vaccines are suitable for older adults, whereas others are not. The same could apply for women who are pregnant. And there will be differences in efficacy, meaning the degree of the likelihood of protection. There might be differences in the safety profile,

• 20:32Speaker 02

  meaning some might have more fever at the time of immunization or local pain, say, in the arm. There might be differences in duration of protection, where some vaccines require more frequent boosters than others, which may not even require a booster at all. The healthy adult population tends to be the place where the vaccines are getting their initial data. But most vaccines will also eventually, if not in the near term, be tested in older adult populations. The special examples will all be a part of the follow-on data collection plan to see how the vaccine performs for those individual groups. In most cases, companies have a platform at hand that is promising for vaccine development.

• 21:17Speaker 02

  The goal is to get something that is safe and effective and can help us to address this pandemic as quickly as possible, and then to figure out what the populations are that it will be most suitable for.

• 21:28Speaker 01

  You know, one of the arguments here is if you make real investment in developing the technology where you could essentially print up the mRNA that you think is likely to code for the bits of protein that will train the immune system to recognize and attack the virus. How much of this has been a with upfront investment as new threats emerge? It'll be as simple as sequencing the virus, predicting what's likely to be the bits of the virus that are likely to generate an immune response, print those up, the mRNA, and then very quickly, like we saw in the case of Moderna, get to a development candidate, manufacture it, and get it out to the masses. In other words, are we just entering a new world now where we can have vaccines developed on demand as threats emerge?

• 22:13Speaker 02

  We're moving in that direction, and I can tell you that this is something close to the promised land in vaccines, that if you have a brand-new bug that emerges that no one ever thought of, that you could very quickly go from identifying the virus, the genetic sequence, the proteins that are most important for protection, and then produce large volumes of vaccines. That platform approach, which some have called plug-and-play, would be very, very helpful for many reasons. One is this disease X concept, the idea that nature might throw something to us that we've never seen before that requires a brand-new vaccine to be developed very, very quickly. That kind of platform approach could be really helpful there.

• 22:55Speaker 02

  In my past life, when I worked in the biodefense arena at the White House, we thought about this as a way to protect against biodefense threats, where there was a concern that a scientist in a lab somewhere could take a virus that was either harmless or one against which we had a vaccine, and then genetically modify it so it could evade the vaccine protection. That's another example where you might need the ability to quickly produce a vaccine against a brand-new agent. Now, this is the hope. I wouldn't say that we're there yet, but we have made massive progress toward understanding whether that will be feasible in this pandemic. We will know very, very soon whether vaccines produced on the mRNA platform are effective

• 23:40Speaker 02

  against this virus, and if that can be shown, that will be a huge advance for public health, for science. Now, there are some real challenges that still need to be overcome. First of all, we need to see if these vaccines can be scaled up from a manufacturing standpoint very, very quickly, and Not just be produced at scale, but also be produced with reproducible high quality. This is one of the biggest challenges that you run into when making biologics at large scale, particularly when we're talking about hundreds of millions or even billions of doses. The other question is, what is the durability of protection going to be? And will it be comparable to what we see with other vaccines? And then, of course, the level of efficacy.

• 24:23Speaker 02

  Is this a vaccine that will protect 70 to 80% of the population against COVID? Or is it something significantly less than that that isn't as attractive when you compare to theoretically other vaccines that are better? So there are some pretty big unknowns there.

• 24:37Speaker 01

  Vaccine production is not a trivial thing. I mean, we grow vaccines. Sometimes we grow them in eggs, right? And literally in chicken eggs. There are some very, very sort of painstaking, difficult ways to make vaccines, to make them at scale, to have quality control, all of the things you point out. How do the novel vaccine platforms compare to sort of the traditional ways of producing vaccines? Because it's not plug and play in that regard, I get that. But is it a market improvement over the current way of doing things?

• 25:08Speaker 02

  Depending on the platform, it's a marked improvement over what we've been doing. The worst-case examples are producing vaccines in eggs like the traditional way of producing influenza vaccines, where lots of things can interfere with the yield of your production process, how much vaccine is coming out of an individual egg.

• 25:26Speaker 01

  By the way, why do we need to make vaccines in chicken eggs?

• 25:29Speaker 02

  Well, we're trying to move away from that. The good thing about eggs is that they're a platform that's been around for decades. We kind of know what we're doing and because we've seen all the bad things happen that can happen from a manufacturing standpoint, a lot of troubleshooting has happened. So it's reliable. There are lots of problems, though, with eggs. We know that for certain flu viruses that are bird viruses, they can actually infect your egg, your chickens, and that can result in problems with egg production. And some of those viruses don't grow as well in eggs. So. Lots of challenges there. We're now moving to cell culture based vaccines and other manufacturing technologies that are less unpredictable because the reagents are basically all within our control. It's really just a matter of getting enough reagents and

• 26:12Speaker 02

  then having bioreactors and other infrastructure that's big enough to be able to produce these things at scale. You do still have to demonstrate that as you scale up production from, for example, a tabletop 10-liter bioreactor to a 50 to 500 to 1,000-liter bioreactor or bigger, that you have the exact same production parameters and characteristics of the product. And that is not an insignificant thing. That can take a lot of time. In fact, that's one of the big bottlenecks to vaccine manufacturing is that scale up process.

• 26:45Speaker 01

  What's interesting is all of the technological infrastructure that comes to play when we think about things like future pandemics.

• 26:51Speaker 02

  If we can do it for COVID, that doesn't necessarily mean that the same approach is going to work with other viruses, but it will certainly be a big vote of confidence for the community. And certainly, we will then be doing a lot more work to make those platforms robust enough to prepare us for the next pandemic.

• 27:09Speaker 01

  Yeah, we're not there yet, but I think we're well on the way there. And I think that's very promising. So in the case of COVID, and obviously COVID wasn't the first example of this, but I think it's a very notable one, where within arguably what days of when the virus was identified, it had been sequenced and the sequence had been distributed around the world. So the digital version of the virus traveled around the world much faster than the biological version of the virus did, which is a remarkable thing.

• 27:35Speaker 02

  That's right.

• 27:36Speaker 01

  If you couple that with the ability to have the potential for plug and play type vaccine development, then all of a sudden, the ability to respond to novel biological threats is so incredibly enhanced from what we had before.

• 27:50Speaker 02

  I actually think that we are going to see a renaissance in vaccinology after this pandemic. Partially because so many new platforms are actually being evaluated in clinical trials, something that was previously very, very difficult to do because of the time and risk and investment needed to make that happen. Second is that we're evaluating some new adjuvants, which are immune boosting substances that allow you to do a couple of things. Number one, get away with smaller doses of protein or the antigen that allows you to immunize more people. And the second is that adjuvants can also broaden the immune response so that if the

• 28:30Speaker 02

  virus goes through a mutational change that modifies the proteins on its surface, your immune response is better prepared to deal with that evolution. The other is that we're discovering more efficient, smarter ways to develop vaccines. And while I don't think we're going to be developing any other vaccines in less than a year in the absence of an emergency, I have to believe that there's a middle ground between one year and the previous 10 to 15 years that is going to make it faster to develop vaccines. And by doing all of these things, by reducing the time, by reducing the investment necessary and reducing the risk, we're going to see, I think, more in the investment community,

• 29:12Speaker 02

  more in the biopharmaceutical company, see vaccines as a really interesting place to get involved and to tackle some infectious disease threats that we just didn't think we could tackle in the past because there was, for example, not enough market certainty to go after that. Yes. So that, to me, is a really exciting opportunity. By the way, I do want to say, the other big learning coming out of this pandemic, before January of this year, we had spent decades thinking that the next pandemic was going to be caused by influenza. It wasn't. It was caused by a coronavirus. And guess what? The last two epidemics of concern were caused by coronaviruses, MERS and SARS.

• 29:56Speaker 02

  So I would say that the world has now been put on notice that in all likelihood, the next pandemic will be caused by either a coronavirus or a flu virus. And this is the reason why we need to take advantage of this renaissance in vaccinology to tackle those two classes of virus across the board. We need diagnostics, we need treatments, we need vaccines that will protect us so that we have a kitchen cabinet of stuff ready to go when the next pandemic happens.

• 30:25Speaker 01

  I love hearing you talk about a renaissance in vaccinology. One of the challenges historically, and I think this is related to the long timelines and a lot of the other things that you've mentioned. One of the challenges in this space from an investment standpoint has been market uncertainty. The challenges to the business model, right? Because your buyer tends to be nations, your buying window tends to be emergencies. When the emergency goes away, the nations lose interest, the market goes away. And at least historically, a lot of the pharma companies that have leaned in with vaccine efforts, especially in response to an emergency, have felt like they've been left holding the bag. How does the market reset given this pandemic? And do you think it'll be a sustained reset in terms of how the market functions?

• 31:09Speaker 02

  Well, people have a short memory, as you said. I think the memory will be less short coming out of this crisis of a generation than it has been for other crises. And so I think that's going to carry us for some time. The traditional way you de-risk these types of activities is to have governments or philanthropies come in and fund the R and D. So the company at least isn't having to take the risk with its own capital and justify that to its board and to its shareholders. I think we'll see a lot more of that, I hope so, that de-risking that happens after this pandemic. But I also think that there are business models that could make a lot of sense for companies here. Let me take the example of antivirals. So I just mentioned that I think flu or a coronavirus is going to cause the next pandemic.

• 31:54Speaker 02

  There's no reason why we couldn't have A, I won't call it a moonshot because it's overused, I'll call it a Mars shot, to develop antivirals for coronaviruses and flu, both of which, by the way, cause disease on an ongoing basis. And if you can come up with a great antiviral for flu or a great antiviral for coronaviruses that have a good shot at being effective against the next novel pathogen that causes a pandemic, there's a product you can sell today to make your business sustainable that's going to reap you a windfall if a pandemic happens, which probably won't happen for quite some time, we hope. But at least you've got that sustainability that comes from having the ongoing use of the product. The same applies with diagnostic technologies.

• 32:36Speaker 02

  We need diagnostics for countless diseases today. If you're working in diagnostics, hopefully we'll be able to develop better diagnostics coming out of this pandemic. And then we've already talked about vaccines and the opportunity there.

• 32:48Speaker 01

  So, given the vaccines landscape, how challenging it is to discover, develop, to produce, manufacture, to get approved, to negotiate with nations and other large organizations. But also, given the fact that there's so much new technology moving into this space of vaccine development. Rajiv, do you think there is any unique role for emerging startups to play in this ecosystem? Or is this an ecosystem that just by nature of it tends to be dominated by incumbents?

• 33:14Speaker 02

  I think there absolutely is an opportunity for startups. It is a complicated landscape, I recognize. But if you have a good idea, let me use the example of diagnostic tests. I mean, we've heard a lot about testing, but an element of testing that people haven't talked a lot about is, what is it going to take to get to a low-cost, home-based, say, almost pregnancy script-like test that can let you know whether or not you have the virus within a few minutes? I mean, if we could have this and have it be rapidly deployed across the world, that would have a massive impact on disease transmission. And that kind of idea where there is a clear Public health response need as well as a policy need should see the light of day. You should be able to find investors.

• 33:59Speaker 02

  Ideally, you would be designing your technology in such a way that it will be applicable in peacetime, meaning that once the pandemic is over, that there is going to be a use case, a commercial opportunity for this technology that will allow you to make it sustainable and scalable and appealing to purchasing entities after the pandemic is over. So that would be my one word of advice. The other is to get to know the funding entities, not just the venture community, but there are also philanthropic efforts led by the Wellcome Trust, the Gates Foundation, there's IMI in Europe, many more that I haven't mentioned. Those can be complex processes to navigate, but lots of people have gotten resources to get them off the ground. So I'd recommend that as well.

• 34:44Speaker 01

  I love this concept of wartime and peacetime in this space. You started the conversation talking a bit about things that are happening in parallel that used to happen serially, things that are being done at economic risk like manufacturing that wouldn't normally be done in parallel in a non-emergency situation. When we think about the return to peacetime, do you think that some of the regulatory status quo retains this level of urgency? Or does it sort of revert back to the way it used to be done where things that might now are being done in parallel will be done serially again? I always wonder in our world, how much of status quo is really just stasis?

• 35:25Speaker 02

  It should not take 10 to 15 years to develop the vaccine. And when you talk about stasis, that comment applies in vaccine development more than perhaps any other type of product development. The vaccine development, generally speaking, has not kept up pace with product development in other areas. So I think that will happen. However, it's very important that we don't compromise on assessments of safety, particularly when it comes to vaccines, because we're giving vaccines to healthy people. This is very different from giving a medicine to somebody that is dealing with a condition or an illness that is causing them suffering, where you will accept a different risk benefit profile than for something that you're being given to protect you against a theoretical

• 36:10Speaker 02

  risk. So we can't let go of the bar for safety and efficacy on vaccine development, but I'm hopeful we'll find smarter risk-based approaches to develop vaccines faster and in a less capital-intensive way in the future.

• 36:21Speaker 01

  Assuming you have a crystal ball, if we were to roll the tape forward, where do you think we net out? Do you think we have a vaccine within the next 12, 18 months? You know, play the movie forward for me. How does the story end?

• 36:32Speaker 02

  So first of all, there is one vulnerability that we need to be aware of. Nearly all the vaccine programs that are moving forward at a rapid clip are focused on the same part of the virus, the spike protein and a portion of that called the receptor binding domain. And so in the unlikely event that that proves to not be the key set of antigens necessary to protect a person from a vaccine standpoint, then we're going to be in a lot of trouble. That is, I think, very unlikely, but I just want to mention that. I am very optimistic about vaccine development. The early data that we've seen from the messenger RNA vaccines,

• 37:15Speaker 02

  the vector vaccines and the recombinant vaccines looks very, very promising from the standpoint of the type of immune system that is being elicited by these vaccine approaches. And when I say type of immune system, I'm talking about the antibody responses, which are not just generic antibodies as people know of them, but they're specifically antibodies that we call neutralizing. They actually prevent the virus from entering into cells and causing the disease, and that's really, really important. We're seeing that with all the vaccines that are going into late-stage clinical trials or are likely to in the very near future. We don't know things like level of protection, durability of protection, and so on, that all needs to be defined over time.

• 37:58Speaker 01

  I believe we have some early data that suggests that we're also generating T-cell immune response.

• 38:03Speaker 02

  Yes, thank you for pointing that out. I mentioned the antibodies, but cell-mediated immunity, T-cell immunity is also likely to be very valuable in protecting against this virus, as we know it is important for other viruses. And we've seen a lot of promising data on that side as well. Not just that we're getting a T-cell response, but that it appears to be, in most cases, preferentially directed toward what we call a TH1, T helper cell one response, which is thought to be more likely to correlate with a safer vaccine. And to expand on that a little bit, there is this concept called antibody mediated disease enhancement that has occurred with other viral infections and there is a theoretical

• 38:47Speaker 02

  risk that that could happen with this virus. And what that means is that after you are exposed to the virus or potentially a vaccine, you could generate some antibodies that can bind, but they don't neutralize. And that is thought to potentially contribute to more severe disease, once you're actually exposed to the virus itself.

• 39:07Speaker 01

  And this is what happened in the Dengue example.

• 39:09Speaker 02

  This is the leading hypothesis for what has been seen with the first licensed Dengue vaccine, and it is a theoretical possibility here. I wouldn't necessarily say that it's a high likelihood risk, but it is something that people are watching out for. We believe that a T cell response that is more polarized toward TH1 is less likely to result in that phenomenon. A TH2 response is thought to be potentially associated with that finding.

• 39:36Speaker 01

  While we're talking about theoretical possibilities, given that all of the vaccine candidates are targeting the spike protein, and that we're talking about generating neutralizing antibody response, is it plausible that if it is in fact an effective target, because you're going after the spike protein, which is sort of the vector of attack that the virus uses to get into a cell, does it mean that this is likely to be a vaccine that protects us against evolution of the virus? Because presumably, if you have mutations in the spike protein, most likely the spike protein itself, which has evolved to enter the cell, becomes less fit, and you have lower viral fitness in the virus as it evolves

• 40:18Speaker 01

  away from the target. Does that mean that it's possible, or even maybe likely, that a vaccine gives us broad coverage from coronavirus for future evolutions of the virus?

• 40:31Speaker 02

  It's a great question. It's a huge problem with influenza viruses, this constant antigenic shift and drift. So far, we haven't seen the same level of mutation or frequency of mutation that affects critical proteins with coronavirus that we have seen with, say, flu viruses, but it's certainly a possibility. And it's conceivable that once you have a certain level of population immunity, that that will allow some other mutants to emerge that can escape the vaccine protection. I would say this is a theoretical possibility at this point. We haven't seen solid evidence or concern of this so far. But of course, this is before, you know, we have fairly limited experience with this virus. It's been less than a year. And so

• 41:14Speaker 02

  it certainly is theoretically possible. And you would hope that if you have, say, a number of different proteins that a person has been exposed to, that if there are mutations that affects some antibodies' ability to neutralize a virus, that there would be other antibodies that would still cover you from a protection standpoint. But this is all speculative at this point.

• 41:34Speaker 01

  So you're optimistic that in the next 12, 18 months, we have a vaccine?

• 41:38Speaker 02

  I think this calendar year before the end of the year, we will know about the ability of probably more than one vaccine to actually protect people against the virus. And we'll have a good sense as to how good that protection is. The next question is, when are we going to have meaningful quantities or volumes of vaccine to immunize people in the US? I think that could happen early next year or by the middle of next year. For the rest of the world, it is likely to take longer for a variety of reasons that we can talk about. But I think that we will have, for the world, by the end of next year, meaningful quantities of vaccine. I'm not saying we'll have vaccine for everyone. That almost certainly will not be the case. But we'll have meaningful quantities, I would expect.

• 42:18Speaker 01

  So let's touch on that. There are obviously a lot of policy and even geopolitical implications for all of this. Assuming we start to have vaccines come online, who gets them? Who should get them first? And who decides that? Let's say here in the US.

• 42:33Speaker 02

  So let's start with the US then. For all of the problems we've had with the overall US response to this pandemic, one place where I think things have gone very, very well is in vaccine development. And I think the government coordination through the Warp Speed Initiative, setting aside the name, because I think that was some concerns amongst people that were prioritizing speed over other things, which is not the case, that that effort has coordinated vaccine development and clinical trials for vaccines in a way that we've never seen before. The speed with which we're getting into tens of thousands of person clinical trials is extraordinary because of that level of coordination. And while the US government, at least so far,

• 43:18Speaker 02

  has not contributed a lot of financial resources to making vaccines available for other countries, I would call this a huge in-kind scientific contribution, because the data is going to be generated here in the US that will support use of the vaccines everywhere in the world.

• 43:33Speaker 01

  As vaccines do come online, should we be getting it to the most at-risk populations, like the elderly or healthcare workers or school-aged children? Like, where do we point the resources as we get them?

• 43:45Speaker 02

  Yeah, that prioritization question that you're asking is really important. And I wouldn't say that we have an answer to that just yet, but there are a couple of efforts that I know of underway to look at this question. One is from the ACIP, which is a committee on immunization practices here in the US that recommends the use of vaccines for certain populations. The other is the National Academy of Medicine is convening an expert panel to look at this question as well. I don't know where these recommendations will end up, but I can tell you, most people feel that healthcare workers should be at the top of the list for getting access to safe and effective vaccines, because they are very much in harm's way. Unfortunately, we've learned in this pandemic that healthcare workers can be infected because they're exposed to large quantities of virus.

• 44:31Speaker 02

  And in many cases, they don't have enough personal protective equipment to adequately protect them. And so they would... Likely be near the top of the list. And then after that, it would likely be vulnerable populations. We know that in long-term care facilities and nursing homes where you have a lot of older adults that have co-existent diseases, they're at very high risk. And we also know that there are frequent outbreaks in these facilities. And so protecting those populations will be important. Then, of course, there are a lot of other high-risk populations, usually because individuals have other diseases that place them at risk that potentially would be prioritized as well. I would not expect young children or children to be prioritized based on what we've seen so far.

• 45:13Speaker 02

  And while there's still an open question as to what role children may play in transmission in a community from the standpoint of disease severity, I would not expect them to be prioritized.

• 45:24Speaker 01

  So, given that point, do you think that the question of how and when we reopen schools is decoupled with how and when we have a vaccine?

• 45:32Speaker 02

  So, I do think that we need to look at schools as a special circumstance, and we also need to think about schools as something that should not wait. School reopening should not wait until we have a vaccine. We know that schools are very, very important for the development and well-being of children. We know that beyond the education and social benefits, that for many children, they are at greater risk if they are kept at home. Some children don't have access to nutritional lunches unless they are going to school. And so, we have to think very carefully about reopening schools safely. However, you can't ask somebody, "Should we reopen schools or not?" without knowing certain things about the school and where it is.

• 46:15Speaker 02

  The biggest driver of transmission in schools, if it happens, is likely to be the level of community transmission that is happening. And so, the number-one thing that any community can do to make schools safe for reopening is controlling community transmission of virus. Now, that has happened in many parts of the world, and so they have been able to open schools with presumably relatively low risk of transmission in the schools. That is not the case in many communities in the US right now, where there is fairly high incidence of infections happening in the community. And almost certainly, the virus is going to be coming into schools. We don't know how much transmission will be happening in schools.

• 46:56Speaker 02

  And so until we have better data on what's happening in kids in schools, we have to be very careful. The other element beyond community transmission is how exactly we are opening schools. So when you reopen a school, are you able to reduce the density of children in a classroom? Are children wearing masks? Are they physically distanced as well as using hygiene measures to reduce the likelihood of infection transmission? Are they being cohorted so that you're not having mingling of children across the entire school? Are they on a reduced schedule, which also helps with density? Those and a host of other things can be done within schools to make that environment much safer. So I would say the two considerations to inform decisions on whether and how to reopen schools are,

• 47:40Speaker 02

  number one, the level of transmission of the virus in the community. And number two, what the schools are doing to keep kids, and importantly, teachers and staff, safe.

• 47:50Speaker 01

  So there are obviously many other policy implications when it comes to thinking about the arrival of sufficient amounts of COVID vaccine. I think one of the most intriguing ones and important ones is this question of vaccine nationalism. This idea, as you've pointed out, the US has had a very effective and concerted effort to coordinate and accelerate the development of vaccines so that they're available. When they do become available, there's going to be this drive to make sure that we take care of America first. How do other nations address this question of vaccine nationalism? I know you at Takeda are doing some work to help support Japan in terms of vaccine production there for COVID vaccines in that part of the world. How are different countries thinking about this question?

• 48:35Speaker 02

  So this is a very big challenge. We have this unprecedented global pandemic. Everybody in the world, or at least every country, needs to have access to safe and effective vaccines as quickly as possible. And yet we know that there will not be enough vaccine to go around in the beginning. And so there is the potential for massively inequitable distribution of vaccine toward those countries that have the most resources. And in fact, that is what has happened in the past. The tendency of political leaders to protect their own populations first is not unique to the US. We've seen this happen in countries around the world. In fact, political leaders are put in office in order to protect their populations.

• 49:17Speaker 02

  Their priorities are national security, the economy, and somewhere on the list is health. And so they have a duty to do what they can to, in this case, make vaccine available to their populations. The question is, how can we do this in such a way that does not have the wealthy countries reserving all of the supply from the companies that have the most advanced vaccines in development? So that there's nothing left for developing countries, middle income countries, and so on. In order to tackle this challenge, the WHO and CEPI and GAVI have come together to create an R and D effort for vaccines and a scale up to produce large volumes of vaccines as quickly as possible, but also to ensure global equitable access to those vaccines.

• 50:02Speaker 02

  And they have created this financing facility called COVAX, which is essentially pooling resources from many countries and then taking those resources and entering into contingent contracts with companies. So going to a company that has a vaccine in development and saying, if your vaccine meets certain criteria, we can commit to you that we will buy X number, hundreds of millions of doses of that vaccine. So you have the certainty that you'll be able to sell that vaccine at a given price. If they're able to do that successfully, this facility will be able to not only ensure that developing countries get vaccine, but also the higher income countries that don't know which

• 50:43Speaker 02

  Company to bet on, they can guarantee them that if they put money into this facility, they'll get a vaccine that works. Now, this is still in the formative stages. We don't know how many countries will sign up, although a lot have expressed interest. But I think if we can get this right, if we can show that we can achieve significant equitable distribution of this vaccine, it will set the stage for how we do everything in public health and access to medicines for the next several decades.

• 51:11Speaker 01

  That would be amazing. So, Rajiv, you're a physician. You've practiced medicine. You've been in the White House. You're in industry developing vaccines. As you look back over the span of your career, if you put back your white coat on, what from the perspective of healthcare practitioners has surprised you? And if you put on now your thinking cap as someone who's thought a lot about policy, what from the perspective of policymakers has surprised you throughout the course of this pandemic?

• 51:39Speaker 02

  I have been involved in a number of pandemic influenza planning exercises when I was in the White House and afterward. And a number of things that came up in this pandemic, we didn't expect to actually get in the way of the response when we were doing tabletop exercises. The notion of having a single national response was actually taken as a given, that we would have the same approach across the country. Our team drove the development of the original flattening the curve strategy, which was called community mitigation, and that was released in 2007. And it was a roadmap for the things you would do from the earliest days of virus entry to limit transmission, to lower the peak of the curve, to delay the peak of the curve,

• 52:21Speaker 02

  and reduce the total area under the curve as measured in cases or deaths. But those measures required targeting. They had to be coordinated, and they had to be done early. And we just assumed that we would be able to do that because we would have early situational awareness. And a lot of it comes down to swift action with leadership to ensure that people are doing things early and in a synchronized way in order to stop transmission. There's no question that we have learned some hard lessons about our lack of investment in our public health capacity in this country.

• 52:58Speaker 02

  Another area that has been interesting is the difference in thinking between the medical community and the public health community. And here I will reference the testing strategy. So Michael Mina here at Harvard, based here in Boston, has been talking a lot about the value of having low-cost, rapid diagnostic tests that can be used at home that may not have as good sensitivity as the diagnostic tests that you would say use in a hospital. And when I say sensitivity, that means the ability of a test to detect, in this case, the virus. You want that sensitivity to be very, very high. You'd like it to be over 95% in a medical setting. But in a public health context, it may not be necessary to have that high a degree of

• 53:42Speaker 02

  sensitivity because from a public health standpoint, your goal is to dramatically reduce the number of cases in a community. And when you're awash in virus, as we are in the US, it's like bailing out a boat. You don't need to have the perfect bucket. You use whatever's available to you to try to identify as many cases of virus as you can and take them out of circulation through voluntary quarantine so you can get a handle on the pandemic. If you look at what's been most effective in this pandemic, a lot of those things were the same things that were used in 1918. Things like keeping distance between people, wearing masks, not having large public gatherings. Those things worked in 1918, and those are the same things that we're doing now.

• 54:23Speaker 02

  Having said that, there is a part of the story that isn't obvious to a lot of people, and that is that none of these things alone is perfect. All of them are imperfect. And if you're relying on any one of those things, then you will fail at stopping virus transmission. The way I like to think about it is like each of these interventions is a layer of Swiss cheese that has holes in it. So it's not perfect. But if you put the slices of Swiss cheese, let's say you have a slice for masks, you have another one for physical distancing, you have another one that is quarantining people at home voluntarily if they are sick, and you stack these on top of each other, the cheese covers up the holes and other slices, and you end up with a pretty good barrier to virus transmission.

• 55:08Speaker 02

  That is the underlying concept behind these layered interventions in a community that together can have a massive impact on reducing virus transmission. Another analogy that I would use is around automobile safety. When people get into an accident, they're not just relying on a seatbelt to keep them safe. In fact, they're relying on hundreds of other things, and it's not just what's in the vehicle itself. It's everything that happens upstream. It's driver's education, it's traffic rules, it's deterrence from people getting into cars if they've had something to drink. All of these interventions have to come together, and the same thing applies when we talk about this virus. By doing all of these things together, we can save many,

• 55:52Speaker 02

  many lives and lots of illnesses and weather the storm until we get what we really need, which is a safe and effective vaccine.

• 55:59Speaker 01

  There are a couple of things that are clearly true. Number one, we will increasingly depend on people's behavior to help bend the curve, where we're asking people to wear masks and stay at home if they don't feel well, and social distance, et cetera. It's also clear that we're going to be heavily reliant on technology to help end the curve, and that might be better diagnostics, better vaccines, better antivirals or antibodies. A big takeaway for me is we really are at the brink of a real renaissance for all things vaccines, and I think the implications that that has for how we protect ourselves and the planet going forward is a silver lining for what's obviously been a very dark time for so many. Rajiv, thank you so much for joining us today on the A6 and Z podcast.

• 56:43Speaker 02

  Thanks, Jorge. It's been great being with you today, and I'm hopeful about the future.