Pushkin from Pushkin Industries. This is Deep Background, the show where we explore the stories behind the stories in the news. Today, we're going to talk about how to prevent the coronavirus. Specifically, we're going to talk about vaccines and other approaches that might enable your body to fight off coronavirus before you get sick with it in order to understand this complex set of issues. We're joined by doctor Akiko Iwasaki. She is a professor of immunobiology at the Yale University School
of Medicine. She and her lab are heard at work trying to understand COVID nineteen, and she's also been an extremely effective public explainer of the science behind vaccines in this current moment. Akiko, thank you so much for joining me. I want to start deep in the weaths of vaccines. This is your field. You've been crucial in explaining it also to the general public. What are the approaches that
are being tried right now? Of the many approaches so currently for COVID nineteen, there are over ninety different vaccines that are in testing, so unfortunately very difficult to predict what type of vaccines are going to work for particular disease, and so at this point we just need to try everything we can, and so there are many many platforms
that are vaccine uses. Some of the things that you hear a lot in the media are these nucleic acid based vaccines such as RNA or DNA vaccines, and these are very fast to make because once you know the sequence of the anergen of interest, you can clone these sequences or synthesize these sequences to make RNA or DNA, and you can just inject that material into humans and once they're incorporated into the cell, the cell can then themselves make the energens, and so that is a quick
way of generating a vaccine, whereas other approaches take chimeric vectored vaccines, which means that the sequence of interest is inserted into another viral genome to make a trojan horse like vaccine where that virus can then be amplified and given to people. And that's what the Oxford team is doing with the anovirus vaccine. And then there are traditional forms of vaccines like inactivated virus. So there are many many ways to approach vaccine. That was a really good
three part analysis of the different approaches. Maybe let's take them in the order that you gave them to me, which is sort of the order of how much attention they're getting at the moment. So, with respect to the RNA DNA vaccines, has anyone ever made a successful RNA vaccine for a disease that's been tested and verified and actually worked. So there has never been a RNA based vaccines that's approved for use in humans yet, So this would be the first of such kind if it becomes
a successful vaccine. So if I understand, the upside of the RNA approach is that it's one of the vaccines that if we were able to make it, we could then make it at very large quantities, very very quickly, which will be a challenge for other forms. The downside is it might not work. And this technology has been known for a while, I take it, so the fact that it hasn't worked yet is not because nobody's been trying. Right.
The vaccine research is expanding and evolving at such a rapid pace, So just because it hasn't been approved for use before this disease doesn't mean it's not going to work. And the mRNA platform, yes, you're right that it has existed for a while, But for example, the delivery vehicle for the RNA has been developed and made better. It is much more stable and much more likely to be taken up by cells to be expressed within the cell than let's say, five years ago. So things are happening
very quickly. It sounds like you are actually a little bit optimistic about the mRNA approach. Is that am I reading you correctly that way? Vaccine is such an empirical area of science that without testing in humans, we can never really tell whether something is going to be promising or not. But at this point, because of the severity of the pandemic, you know, we just have to kind of test many different platforms in the hope that one of them will work. Let's turn then to the trojan
horse approach, which the Oxford team is using. They have gotten attention in part because they've been saying that if they get good results soon, they might be able to actually have enough vaccine to use on medical professionals, even by September, which is the kind of thought that makes
markets and people feel very optimistic. Say more about the trojan horse approach and what its benefits are, and again tell us whether that has worked so far because I know that team started by working on malaria and that hasn't totally worked out for them, and so they've then
shifted to working on COVID. Right. So the trogen horse based vaccine is another area of vaccinology that has taken off in the last decade or so because of our ability to manipulate virus at every nucleic acid base resolution. So these are approaches that are really being tried in new war vaccines like HIV vaccines. A lot of the trials that are done with HIV vaccines use this kind of trogan horse approach of cloning in the energen of interest into a viral vector that we know can infect
human cells but don't cause any disease. It's on their own. And so this is another promising approach to vaccinology because you know, we just know very well how the virus enter our cell and can inject the material that we
want the cells to generate. And so, you know, while the malaria and HIV vaccines have other problems and barriers to overcome, the whope is that for the coronavirus, because it doesn't mutate us as much and it doesn't have many different life cycle stages as in malaria, that it would be easier to implement such a vaccine. Have there been successful viral vector vaccines trogan horse vaccines produced for
other drugs? I think they have, haven't there? Yes, hum been for Ebola virus for example, there have been several of these kind of trojan horse type of vaccines that are pretty efficacious and safe. So I do have some hope in this type of approach as well. Does anyone try this approach for other Stars viruses? Yes? So the Stars Covie one, the original Stars that you know, emerged in two thousand and two. People have generated all kinds
of vaccine platforms. Unfortunately, when the epidemic subsided because of public health control of that virus, there was no funding or interest by sort of the public to pursue those types of vaccines. So, unfortunately, we could have made a lot more rapid progress this time around had we pursued
those original vaccine ideas for the Stars Covie one. And this is a lesson to you know, the society that we really need to invest in long term solutions to come up with vaccines so that the next time there's a pandemic of a new virus that we're much more ready to deal with these emerging infections. That's sort of astonishing. People were trying to produce vaccines for stars CoV one and then they just stopped because there was no funding.
I mean, nobody thought, no foundation, no government, No one thought, well, g this might be back or something similar might be back. I mean that same sort of mind blowing in a
bad way. It is mind blowing to most of us scientists working in these areas as well, and so, you know, I really think that we need to take this unfortunately an opportunity to really ensure more funding for basic research and vaccine research, especially because of the change in the world environment and ecology and so on that promotes the emergence of new viruses that we're hearing about all the time, like zeka virus and nibola and many other virus says
that we will be facing in the future, and we can't just drop a vaccine trial or vaccine approach just because something is contained for the time being. That brings us to the traditional vaccines, the ones that we were all taught about as kids in school, cowpox in order to fight smallpox, or the polio vaccine in its classic form, where you use a reduced or a weekend form of the virus. What are the paths forward for COVID nineteen
with such a vaccine? Are there? Of the ninety that are out there are a bunch of them trying to use the traditional approach. Some of them are certainly trying to use the traditional approach. You know. I teach immunology to medical students every year, and one of the things I talk about during vaccine lectures is that the live attenuative vaccines are the most potent an effective vaccine because it is the closest to the original infectious version of
that virus. And so even though it's a very traditional vaccine approach that's been used for hundreds of years, I think we need to, you know, not forget that those are also approaches that we should pursue. Even though they're not the cool latest technology approaches, they might work the best.
There's been a fair amount of attention to the theory that one of the classic tuberculosis vaccines seems to provide, at least in some studies, more general protections against things that aren't TB and I understand that that is a somewhat disputed view among immunobiologists. I wonder if you would tell us what we ought to think about this theory and whether it pulls water, and if so, whether this is something worth pursuing, and if not, whether it's as
leading and dangerous. So that is the thinking that BCG vaccine, which as you mentioned, Noah, that is traditionally, I mean it is currently used actually in some countries still against TB and there is actually an interesting statistical sort of correlation between countries that still are using the BCG vaccine
to the rate of COVID nineteen and mortality. And so, for instance, countries like Japan who are still using the original BCG vaccine in children, they have very low rate of infection as well as death compared to some other countries like the US, which has stopped using the VCG
vaccine a while ago. And other experiments have led to this idea that BCG vaccine gives a person a kind of trained immunity, which means that our innate resistance against these viruses are elevated as a result of receiving these types of vaccines. And currently there are countries like Netherland who have begun to immunize healthcare workers with BCG in order to determine whether trained immunity is indeed elicited in those volunteers and whether that would prevent against non TB
related diseases like viral infections. And there was even a study done to demonstrate that BCG vaccination induced certain types of innate immune resistance genes to be elevated in human volunteers. So you know, right now it's unknown how long such trained immunity lasts and how exactly that is working. It's still under investigation. We'll be back in just a moment, Like you go, I want to turn now to the
question of probabilities and time. These are huge challenges under the intense economic and health pressures that were currently facing. So let's start with the time question. Assuming that one of these ninety vaccines or several start to be proven to work, what sort of time frame will it take to generate them, and what are the barriers to making billions Because we're talking about billions of doses quickly, right,
so there are multiple barriers at each checkpoint. First, the vaccine has to be not only effective but safe in people, since the vaccine will be given to millions, if not billions, of people, we need to be absolutely sure about the safety of the vaccine itself. The second barrier is the safety with regards to infection from Sarscovie two, and that refers to this idea that there are some vaccines that unfortunately enhance the disease as opposed to protect the person
against the disease. That has been seen with vaccines like dengi virus vaccines, and so we really need to ensure that not only is the vaccine itself, but is it safe for people who are going to encounter the virus, you know, following the vaccination. And so that safety and efficacy issue is absolutely key in going forward with any vaccine candidates. Let's say we find such a safe and effective vaccine, then the challenge will be manufacturing and scale.
So we go from a couple hundred doses of vaccines in phase one and two going into a large phase three trial with tens of thousands of people, and then after that, the efficacious and safe vaccine needs to be generated in the you know, millions or millions if we want to cover the entire world. And so that is a huge challenge for manufacturing because imagine having to generate you know, billion vials to contain the vaccines or even the stoppers for the each vile needles that have to
be distributed. I mean, you can imagine the challenge in just generating that kind of doses of not only the vaccine but its containment as well as a needle, and the healthcare workers that are needed to deliver those vaccines to billions of people. So it's not as trivial just
having a vaccine that's safe and efficacious. It needs to also be scalable to that level of distribution, because if we don't have enough ultimately to cover a large portion of the human population, then there'll be inequity in terms of who's going to be protected going forward, and that's something we need to be very careful about distribution and
equity in vaccination. No one's ever done anything like this at this scale before, so it sounds from what you're saying like there is a possible scenario where you could win in the sense that you've got a vaccine but lose in the sense that you didn't get the vaccine two people fast enough to actually substantially affect the course
of the pandemic. Is that a plausible scenario that is definitely a plausible scenario, and that's why we you know, just because we have a vaccine, we cannot immediately relax all the physical distancing measures that we're taking, because you know, first of all, we need to wait till you have enough vaccines to administer to the population, and we need testing to see who's being exposed before and who has a virus still replicating in their respiratory system in order
to know who can safely go back to society and who needs to be quarantined. So testing and tracing and containment is still going to be important even when the vaccine is made. That brings me to a question that
I've really been troubled by in recent days. I feel as though we've all heard public health officials and immunobiologists and others vaccinologists saying to us, as soon as we could have a vaccine is eighteen months, and then from that point, I think we've been making, at least I've been making the cognitive error of thinking that that means that we will have a vaccine in eighteen months. Those are not at all the same thing. The ideas best
case scenario is very different from what's actually going to happen. Right. I invest in a company and someone tells me, best case scenario, will become a billionaire, but the most likely scenario is that I will not. I am worried about our collective almost belief at this point that we're going to get a vaccine. So I want to ask you
about probabilities. Do you have the sense that I have these ninety approaches that the probability is relatively good that one of them will work, or do you think that we still can't say with great confidence that we're going to have a success. Yeah, it's like predicting the stock market. I just I won't be able to say, yes, there
will be a vaccine that's going to be successful. But my prediction would be that there will be a handful of vaccines out of the night indeed that's being tested that will provide the level of protection we need to reopen society. Let's not forget there are non vaccine related interventions that we can take at the same time, such as development of effective antivirals and monoclonal antibodies that can be generated against the energens of the COVID nineteen virus.
And so it is a huge challenge to distribute vaccine to everyone. But there are other measures that we can take in the meantime, so we don't have to rely only on vaccines to reopen society. Would you say more about the monoclonal antibodies and how they work. Yeah, So monoclonal antibodies, unlike vaccine, kind of sidesteps all the process that the immune system has to generate in order to
make a antibody. So monocloe antibodies are great for blocking viruses and other pathogens because you know, once you clone these monoclone antibodies from let's say a person who has already recovered from the disease, they are a sort of precision tool that the immunologists can use to give someone a passive immunity. So you don't necessarily have to generate that anybody. You're just getting the antibody directly into your bloodstream in order to protect yourself from further encounter with
the virus. And so you hear on TV lots of commercials that use the monoclone antibody for let's say, psoriasis or arthritis, and so many many companies now have a great capacity and expertise to generate a very effective monoclone antibody against variety of things, including viruses and bacteria. So I think that leveraging the existing capacity as well as expertise of the pharma and biotechnology, that we can quickly generate and hopefully distribute safe and effective monoclonal antibodies. How
long do those last in the body? I mean, do you need to take them relatively frequently? They're not a vaccine in the sense that you haven't taught your body to generate them yourself. If I understand correctly, this is just you're giving the body the thing it needs to do the fighting off, so they must wear out at
some point, that's right. So monoclonal antibodies don't last as long as if you had generated the antibody yourself, but you know it can last up to you know months, you know, maybe up to six months or even longer
with these like highly engineered monoclonal antibodies. And not only that, some monoclonal antibody have vaccine effect, meaning that once the monoclona antibody binds to the surface of the virus, that can sort of educate the immune response to generate more These antibodies against the virus by sort of vaccinating a person that way, so you know, the monoclona not only confers transient protection, but potentially can vaccinate you against the
virus when the virus enters the body of that person. Why do you think that we're getting a lot of public attention to antiviral therapies and a lot of attention to vaccines and comparatively much less public attention to the monoclonal antibody approach. Is that just because it doesn't present itself as permanent or I mean, tell me why, because it seems, in a sense it has an advantage that neither of the other things has, namely, you don't need
a new discovery to do it. Yes, that's correct. I'm also puzzled as to why there isn't more attention paid to the monoclonal antibody therapy. To me, it's one of the most promising area to pursue. Maybe it's, as you say, people assume that it's a transient protection or that it's just the challenge of generating large doses is insurmountable. But both of these things may not be true. If we
have a concerted effort to do this. It's your view generally that the ramping up process that we're engaged in now is sufficient. I mean, ninety different approaches sounds good to the general listener. We know that this is costing us so much money that there's really no limit to how much money we could throw at the problem of COVID nineteen and have it still be cost effective, assuming any of these things that works, and even if it doesn't work, it's still cost effective to be trying it.
Do you think we should be doing much more than we're doing. Do you think our efforts are roughly appropriate? What's your gut sense of whether we're throwing enough resources at the disease right now? We are not throwing anywhere near enough resources at the problem right now. For instance, we still don't have enough testing throughout the country, and that is key in trying to reopen society. We also don't have enough resource as being allocated for research and vaccines.
For instance. You know my lab is working on immune response to COVID nineteen, but you know there is no centralized funding mechanism to rapidly support such effort, and the NIH has announced several emergency funding mechanisms and I'm hoping that some of these will come through, but I feel like, as you say, the economic impact of this pandemic is so large that no amount of you know, this sort of ramping up of the resources, it's going to be a waste, because if even one in a hundred of
these things work, then it's it's totally worth the investment. So I am a little frustrated as to how little resource has been poured to research as well as development of drugs. Thank you so much for taking time out of your super busy schedule of saving the world to talk to me, and thank you for the great, great cloud of your analysis as well. Thank you very much. Though speaking to doctor Akiko Iwasaki was really eye opening
for me on several dimensions. She's extremely forthright about the challenges and bottlenecks that face the process of producing vaccines on any of the three approaches that she described, yet at the same time she has an underlying optimism that we will eventually make our way to a functioning vaccine. What was also very striking to me is her emphasis
on monoclonal antibodies. The antibodies would help the body fight off COVID nineteen and Although they don't confer a permanent immunity, they would in the short run, potentially enable millions of people to avoid getting the disease. The most significant difference between the monoclonal antibodies and either the anti viral treatments or alternatively, the vaccines is that they do not require
any new science. We will continue to follow the monoclonal antibodies story and the vaccine story going forward, and we'll try to figure out how it comes to be that we haven't yet had the degree of emphasis on the monoclonal antibodies the doctor Awasaki thinks we ought to have done. Until the next time I speak to you, be careful, be safe, and be well. Deep background is brought to you by Pushkin Industries. Our producer is Lydia Jane Cott,
with research help from Zooie Wynn. Mastering is by Jason Gambrel and Martine Gonzalez. Our showrunner is Sophie mckimmon. Our theme music is composed by Luis GERA special thanks to the Pushkin Brass Malcolm Gladwell, Jacob Weissberg, and Mia Lobel. I'm Noah Feldman. I also write a regular column for Bloomberg Opinion, which you can find at bloomberg dot com slash Feldman. To discover Bloomberg's original slate of podcasts, go to Bloomberg dot com slash Podcasts. You can follow me
on Twitter at Noah R. Feldman. This is deep background