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Speaker 1: Pushkin from Pushkin Industries. This is Deep Background, the show

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Speaker 1: where we explore the stories behind the stories in the news. Today,

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Speaker 1: we're going to talk about how to prevent the coronavirus. Specifically,

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Speaker 1: we're going to talk about vaccines and other approaches that

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Speaker 1: might enable your body to fight off coronavirus before you

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Speaker 1: get sick with it in order to understand this complex

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Speaker 1: set of issues. We're joined by doctor Akiko Iwasaki. She

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Speaker 1: is a professor of immunobiology at the Yale University School

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Speaker 1: of Medicine. She and her lab are heard at work

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Speaker 1: trying to understand COVID nineteen, and she's also been an

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Speaker 1: extremely effective public explainer of the science behind vaccines in

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Speaker 1: this current moment. Akiko, thank you so much for joining me.

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Speaker 1: I want to start deep in the weaths of vaccines.

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Speaker 1: This is your field. You've been crucial in explaining it

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Speaker 1: also to the general public. What are the approaches that

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Speaker 1: are being tried right now? Of the many approaches so

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Speaker 1: currently for COVID nineteen, there are over ninety different vaccines

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Speaker 1: that are in testing, so unfortunately very difficult to predict

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Speaker 1: what type of vaccines are going to work for particular disease,

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Speaker 1: and so at this point we just need to try

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Speaker 1: everything we can, and so there are many many platforms

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Speaker 1: that are vaccine uses. Some of the things that you

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Speaker 1: hear a lot in the media are these nucleic acid

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Speaker 1: based vaccines such as RNA or DNA vaccines, and these

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Speaker 1: are very fast to make because once you know the

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Speaker 1: sequence of the anergen of interest, you can clone these

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Speaker 1: sequences or synthesize these sequences to make RNA or DNA,

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Speaker 1: and you can just inject that material into humans and

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Speaker 1: once they're incorporated into the cell, the cell can then

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Speaker 1: themselves make the energens, and so that is a quick

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Speaker 1: way of generating a vaccine, whereas other approaches take chimeric

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Speaker 1: vectored vaccines, which means that the sequence of interest is

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Speaker 1: inserted into another viral genome to make a trojan horse

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Speaker 1: like vaccine where that virus can then be amplified and

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Speaker 1: given to people. And that's what the Oxford team is

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Speaker 1: doing with the anovirus vaccine. And then there are traditional

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Speaker 1: forms of vaccines like inactivated virus. So there are many

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Speaker 1: many ways to approach vaccine. That was a really good

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Speaker 1: three part analysis of the different approaches. Maybe let's take

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Speaker 1: them in the order that you gave them to me,

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Speaker 1: which is sort of the order of how much attention

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Speaker 1: they're getting at the moment. So, with respect to the

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Speaker 1: RNA DNA vaccines, has anyone ever made a successful RNA

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Speaker 1: vaccine for a disease that's been tested and verified and

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Speaker 1: actually worked. So there has never been a RNA based

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Speaker 1: vaccines that's approved for use in humans yet, So this

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Speaker 1: would be the first of such kind if it becomes

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Speaker 1: a successful vaccine. So if I understand, the upside of

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Speaker 1: the RNA approach is that it's one of the vaccines

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Speaker 1: that if we were able to make it, we could

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Speaker 1: then make it at very large quantities, very very quickly,

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Speaker 1: which will be a challenge for other forms. The downside

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Speaker 1: is it might not work. And this technology has been

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Speaker 1: known for a while, I take it, so the fact

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Speaker 1: that it hasn't worked yet is not because nobody's been trying. Right.

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Speaker 1: The vaccine research is expanding and evolving at such a

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Speaker 1: rapid pace, So just because it hasn't been approved for

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Speaker 1: use before this disease doesn't mean it's not going to work.

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Speaker 1: And the mRNA platform, yes, you're right that it has

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Speaker 1: existed for a while, But for example, the delivery vehicle

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Speaker 1: for the RNA has been developed and made better. It

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Speaker 1: is much more stable and much more likely to be

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Speaker 1: taken up by cells to be expressed within the cell

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Speaker 1: than let's say, five years ago. So things are happening

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Speaker 1: very quickly. It sounds like you are actually a little

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Speaker 1: bit optimistic about the mRNA approach. Is that am I

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Speaker 1: reading you correctly that way? Vaccine is such an empirical

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Speaker 1: area of science that without testing in humans, we can

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Speaker 1: never really tell whether something is going to be promising

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Speaker 1: or not. But at this point, because of the severity

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Speaker 1: of the pandemic, you know, we just have to kind

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Speaker 1: of test many different platforms in the hope that one

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Speaker 1: of them will work. Let's turn then to the trojan

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Speaker 1: horse approach, which the Oxford team is using. They have

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Speaker 1: gotten attention in part because they've been saying that if

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Speaker 1: they get good results soon, they might be able to

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Speaker 1: actually have enough vaccine to use on medical professionals, even

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Speaker 1: by September, which is the kind of thought that makes

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Speaker 1: markets and people feel very optimistic. Say more about the

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Speaker 1: trojan horse approach and what its benefits are, and again

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Speaker 1: tell us whether that has worked so far because I

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Speaker 1: know that team started by working on malaria and that

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Speaker 1: hasn't totally worked out for them, and so they've then

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Speaker 1: shifted to working on COVID. Right. So the trogen horse

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Speaker 1: based vaccine is another area of vaccinology that has taken

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Speaker 1: off in the last decade or so because of our

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Speaker 1: ability to manipulate virus at every nucleic acid base resolution.

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Speaker 1: So these are approaches that are really being tried in

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Speaker 1: new war vaccines like HIV vaccines. A lot of the

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Speaker 1: trials that are done with HIV vaccines use this kind

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Speaker 1: of trogan horse approach of cloning in the energen of

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Speaker 1: interest into a viral vector that we know can infect

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Speaker 1: human cells but don't cause any disease. It's on their own.

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Speaker 1: And so this is another promising approach to vaccinology because

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Speaker 1: you know, we just know very well how the virus

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Speaker 1: enter our cell and can inject the material that we

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Speaker 1: want the cells to generate. And so, you know, while

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Speaker 1: the malaria and HIV vaccines have other problems and barriers

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Speaker 1: to overcome, the whope is that for the coronavirus, because

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Speaker 1: it doesn't mutate us as much and it doesn't have

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Speaker 1: many different life cycle stages as in malaria, that it

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Speaker 1: would be easier to implement such a vaccine. Have there

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Speaker 1: been successful viral vector vaccines trogan horse vaccines produced for

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Speaker 1: other drugs? I think they have, haven't there? Yes, hum

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Speaker 1: been for Ebola virus for example, there have been several

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Speaker 1: of these kind of trojan horse type of vaccines that

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Speaker 1: are pretty efficacious and safe. So I do have some

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Speaker 1: hope in this type of approach as well. Does anyone

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Speaker 1: try this approach for other Stars viruses? Yes? So the

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Speaker 1: Stars Covie one, the original Stars that you know, emerged

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Speaker 1: in two thousand and two. People have generated all kinds

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Speaker 1: of vaccine platforms. Unfortunately, when the epidemic subsided because of

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Speaker 1: public health control of that virus, there was no funding

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Speaker 1: or interest by sort of the public to pursue those

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Speaker 1: types of vaccines. So, unfortunately, we could have made a

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Speaker 1: lot more rapid progress this time around had we pursued

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Speaker 1: those original vaccine ideas for the Stars Covie one. And

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Speaker 1: this is a lesson to you know, the society that

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Speaker 1: we really need to invest in long term solutions to

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Speaker 1: come up with vaccines so that the next time there's

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Speaker 1: a pandemic of a new virus that we're much more

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Speaker 1: ready to deal with these emerging infections. That's sort of astonishing.

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Speaker 1: People were trying to produce vaccines for stars CoV one

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Speaker 1: and then they just stopped because there was no funding.

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Speaker 1: I mean, nobody thought, no foundation, no government, No one thought, well,

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Speaker 1: g this might be back or something similar might be back.

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Speaker 1: I mean that same sort of mind blowing in a

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Speaker 1: bad way. It is mind blowing to most of us

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Speaker 1: scientists working in these areas as well, and so, you know,

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Speaker 1: I really think that we need to take this unfortunately

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Speaker 1: an opportunity to really ensure more funding for basic research

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Speaker 1: and vaccine research, especially because of the change in the

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Speaker 1: world environment and ecology and so on that promotes the

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Speaker 1: emergence of new viruses that we're hearing about all the time,

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Speaker 1: like zeka virus and nibola and many other virus says

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Speaker 1: that we will be facing in the future, and we

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Speaker 1: can't just drop a vaccine trial or vaccine approach just

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Speaker 1: because something is contained for the time being. That brings

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Speaker 1: us to the traditional vaccines, the ones that we were

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Speaker 1: all taught about as kids in school, cowpox in order

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Speaker 1: to fight smallpox, or the polio vaccine in its classic form,

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Speaker 1: where you use a reduced or a weekend form of

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Speaker 1: the virus. What are the paths forward for COVID nineteen

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Speaker 1: with such a vaccine? Are there? Of the ninety that

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Speaker 1: are out there are a bunch of them trying to

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Speaker 1: use the traditional approach. Some of them are certainly trying

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Speaker 1: to use the traditional approach. You know. I teach immunology

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Speaker 1: to medical students every year, and one of the things

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Speaker 1: I talk about during vaccine lectures is that the live

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Speaker 1: attenuative vaccines are the most potent an effective vaccine because

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Speaker 1: it is the closest to the original infectious version of

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Speaker 1: that virus. And so even though it's a very traditional

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Speaker 1: vaccine approach that's been used for hundreds of years, I

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Speaker 1: think we need to, you know, not forget that those

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Speaker 1: are also approaches that we should pursue. Even though they're

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Speaker 1: not the cool latest technology approaches, they might work the best.

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Speaker 1: There's been a fair amount of attention to the theory

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Speaker 1: that one of the classic tuberculosis vaccines seems to provide,

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Speaker 1: at least in some studies, more general protections against things

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Speaker 1: that aren't TB and I understand that that is a

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Speaker 1: somewhat disputed view among immunobiologists. I wonder if you would

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Speaker 1: tell us what we ought to think about this theory

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Speaker 1: and whether it pulls water, and if so, whether this

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Speaker 1: is something worth pursuing, and if not, whether it's as

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Speaker 1: leading and dangerous. So that is the thinking that BCG vaccine,

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Speaker 1: which as you mentioned, Noah, that is traditionally, I mean

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Speaker 1: it is currently used actually in some countries still against

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Speaker 1: TB and there is actually an interesting statistical sort of

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Speaker 1: correlation between countries that still are using the BCG vaccine

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Speaker 1: to the rate of COVID nineteen and mortality. And so,

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Speaker 1: for instance, countries like Japan who are still using the

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Speaker 1: original BCG vaccine in children, they have very low rate

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Speaker 1: of infection as well as death compared to some other

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Speaker 1: countries like the US, which has stopped using the VCG

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Speaker 1: vaccine a while ago. And other experiments have led to

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Speaker 1: this idea that BCG vaccine gives a person a kind

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Speaker 1: of trained immunity, which means that our innate resistance against

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Speaker 1: these viruses are elevated as a result of receiving these

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Speaker 1: types of vaccines. And currently there are countries like Netherland

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Speaker 1: who have begun to immunize healthcare workers with BCG in

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Speaker 1: order to determine whether trained immunity is indeed elicited in

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Speaker 1: those volunteers and whether that would prevent against non TB

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Speaker 1: related diseases like viral infections. And there was even a

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Speaker 1: study done to demonstrate that BCG vaccination induced certain types

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Speaker 1: of innate immune resistance genes to be elevated in human volunteers.

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Speaker 1: So you know, right now it's unknown how long such

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Speaker 1: trained immunity lasts and how exactly that is working. It's

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Speaker 1: still under investigation. We'll be back in just a moment,

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Speaker 1: Like you go, I want to turn now to the

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Speaker 1: question of probabilities and time. These are huge challenges under

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Speaker 1: the intense economic and health pressures that were currently facing.

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Speaker 1: So let's start with the time question. Assuming that one

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Speaker 1: of these ninety vaccines or several start to be proven

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Speaker 1: to work, what sort of time frame will it take

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Speaker 1: to generate them, and what are the barriers to making

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Speaker 1: billions Because we're talking about billions of doses quickly, right,

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Speaker 1: so there are multiple barriers at each checkpoint. First, the

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Speaker 1: vaccine has to be not only effective but safe in people,

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Speaker 1: since the vaccine will be given to millions, if not billions,

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Speaker 1: of people, we need to be absolutely sure about the

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Speaker 1: safety of the vaccine itself. The second barrier is the

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Speaker 1: safety with regards to infection from Sarscovie two, and that

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Speaker 1: refers to this idea that there are some vaccines that

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Speaker 1: unfortunately enhance the disease as opposed to protect the person

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Speaker 1: against the disease. That has been seen with vaccines like

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Speaker 1: dengi virus vaccines, and so we really need to ensure

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Speaker 1: that not only is the vaccine itself, but is it

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Speaker 1: safe for people who are going to encounter the virus,

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Speaker 1: you know, following the vaccination. And so that safety and

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Speaker 1: efficacy issue is absolutely key in going forward with any

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Speaker 1: vaccine candidates. Let's say we find such a safe and

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Speaker 1: effective vaccine, then the challenge will be manufacturing and scale.

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Speaker 1: So we go from a couple hundred doses of vaccines

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Speaker 1: in phase one and two going into a large phase

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Speaker 1: three trial with tens of thousands of people, and then

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Speaker 1: after that, the efficacious and safe vaccine needs to be

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Speaker 1: generated in the you know, millions or millions if we

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Speaker 1: want to cover the entire world. And so that is

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Speaker 1: a huge challenge for manufacturing because imagine having to generate

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Speaker 1: the stoppers for the each vile needles that have to

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Speaker 1: be distributed. I mean, you can imagine the challenge in

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Speaker 1: just generating that kind of doses of not only the

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Speaker 1: the healthcare workers that are needed to deliver those vaccines

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Speaker 1: to billions of people. So it's not as trivial just

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Speaker 1: having a vaccine that's safe and efficacious. It needs to

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Speaker 1: also be scalable to that level of distribution, because if

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Speaker 1: we don't have enough ultimately to cover a large portion

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Speaker 1: of the human population, then there'll be inequity in terms

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Speaker 1: something we need to be very careful about distribution and

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Speaker 1: equity in vaccination. No one's ever done anything like this

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Speaker 1: at this scale before, so it sounds from what you're

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Speaker 1: saying like there is a possible scenario where you could

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Speaker 1: win in the sense that you've got a vaccine but

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Speaker 1: lose in the sense that you didn't get the vaccine

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Speaker 1: two people fast enough to actually substantially affect the course

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Speaker 1: of the pandemic. Is that a plausible scenario that is

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Speaker 1: definitely a plausible scenario, and that's why we you know,

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Speaker 1: just because we have a vaccine, we cannot immediately relax

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Speaker 1: all the physical distancing measures that we're taking, because you know,

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Speaker 1: first of all, we need to wait till you have

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Speaker 1: enough vaccines to administer to the population, and we need

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Speaker 1: testing to see who's being exposed before and who has

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Speaker 1: a virus still replicating in their respiratory system in order

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Speaker 1: to know who can safely go back to society and

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Speaker 1: who needs to be quarantined. So testing and tracing and

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Speaker 1: containment is still going to be important even when the

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Speaker 1: vaccine is made. That brings me to a question that

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Speaker 1: I've really been troubled by in recent days. I feel

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Speaker 1: as though we've all heard public health officials and immunobiologists

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Speaker 1: and others vaccinologists saying to us, as soon as we

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Speaker 1: that point, I think we've been making, at least I've

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Speaker 1: been making the cognitive error of thinking that that means

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Speaker 1: that we will have a vaccine in eighteen months. Those

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Speaker 1: are not at all the same thing. The ideas best

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Speaker 1: case scenario is very different from what's actually going to happen. Right.

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Speaker 1: I invest in a company and someone tells me, best

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Speaker 1: case scenario, will become a billionaire, but the most likely

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Speaker 1: scenario is that I will not. I am worried about

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Speaker 1: our collective almost belief at this point that we're going

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Speaker 1: to get a vaccine. So I want to ask you

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Speaker 1: about probabilities. Do you have the sense that I have

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Speaker 1: these ninety approaches that the probability is relatively good that

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Speaker 1: one of them will work, or do you think that

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Speaker 1: we still can't say with great confidence that we're going

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Speaker 1: to have a success. Yeah, it's like predicting the stock market.

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Speaker 1: I just I won't be able to say, yes, there

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Speaker 1: will be a vaccine that's going to be successful. But

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Speaker 1: my prediction would be that there will be a handful

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Speaker 1: of vaccines out of the night indeed that's being tested

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Speaker 1: that will provide the level of protection we need to

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Speaker 1: reopen society. Let's not forget there are non vaccine related

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Speaker 1: interventions that we can take at the same time, such

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Speaker 1: as development of effective antivirals and monoclonal antibodies that can

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Speaker 1: be generated against the energens of the COVID nineteen virus.

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Speaker 1: And so it is a huge challenge to distribute vaccine

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Speaker 1: to everyone. But there are other measures that we can

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Speaker 1: take in the meantime, so we don't have to rely

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Speaker 1: only on vaccines to reopen society. Would you say more

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Speaker 1: about the monoclonal antibodies and how they work. Yeah, So

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Speaker 1: monoclonal antibodies, unlike vaccine, kind of sidesteps all the process

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Speaker 1: that the immune system has to generate in order to

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Speaker 1: make a antibody. So monocloe antibodies are great for blocking

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Speaker 1: viruses and other pathogens because you know, once you clone

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Speaker 1: these monoclone antibodies from let's say a person who has

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Speaker 1: already recovered from the disease, they are a sort of

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Speaker 1: precision tool that the immunologists can use to give someone

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Speaker 1: a passive immunity. So you don't necessarily have to generate

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Speaker 1: that anybody. You're just getting the antibody directly into your

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Speaker 1: bloodstream in order to protect yourself from further encounter with

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Speaker 1: the virus. And so you hear on TV lots of

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Speaker 1: commercials that use the monoclone antibody for let's say, psoriasis

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Speaker 1: or arthritis, and so many many companies now have a

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Speaker 1: great capacity and expertise to generate a very effective monoclone

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Speaker 1: antibody against variety of things, including viruses and bacteria. So

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Speaker 1: I think that leveraging the existing capacity as well as

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Speaker 1: expertise of the pharma and biotechnology, that we can quickly

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Speaker 1: generate and hopefully distribute safe and effective monoclonal antibodies. How

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Speaker 1: long do those last in the body? I mean, do

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Speaker 1: you need to take them relatively frequently? They're not a

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Speaker 1: vaccine in the sense that you haven't taught your body

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Speaker 1: to generate them yourself. If I understand correctly, this is

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Speaker 1: just you're giving the body the thing it needs to

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Speaker 1: do the fighting off, so they must wear out at

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Speaker 1: some point, that's right. So monoclonal antibodies don't last as

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Speaker 1: long as if you had generated the antibody yourself, but

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Speaker 1: you know it can last up to you know months,

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Speaker 1: you know, maybe up to six months or even longer

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Speaker 1: with these like highly engineered monoclonal antibodies. And not only that,

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Speaker 1: some monoclonal antibody have vaccine effect, meaning that once the

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Speaker 1: monoclona antibody binds to the surface of the virus, that

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Speaker 1: can sort of educate the immune response to generate more

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Speaker 1: These antibodies against the virus by sort of vaccinating a

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Speaker 1: person that way, so you know, the monoclona not only

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Speaker 1: confers transient protection, but potentially can vaccinate you against the

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Speaker 1: virus when the virus enters the body of that person.

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Speaker 1: Why do you think that we're getting a lot of

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Speaker 1: public attention to antiviral therapies and a lot of attention

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Speaker 1: to vaccines and comparatively much less public attention to the

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Speaker 1: monoclonal antibody approach. Is that just because it doesn't present

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Speaker 1: itself as permanent or I mean, tell me why, because

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Speaker 1: it seems, in a sense it has an advantage that

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Speaker 1: neither of the other things has, namely, you don't need

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Speaker 1: a new discovery to do it. Yes, that's correct. I'm

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Speaker 1: also puzzled as to why there isn't more attention paid

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Speaker 1: to the monoclonal antibody therapy. To me, it's one of

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Speaker 1: the most promising area to pursue. Maybe it's, as you say,

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Speaker 1: people assume that it's a transient protection or that it's

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Speaker 1: just the challenge of generating large doses is insurmountable. But

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Speaker 1: both of these things may not be true. If we

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Speaker 1: have a concerted effort to do this. It's your view

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Speaker 1: generally that the ramping up process that we're engaged in

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Speaker 1: now is sufficient. I mean, ninety different approaches sounds good

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Speaker 1: to the general listener. We know that this is costing

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Speaker 1: us so much money that there's really no limit to

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Speaker 1: how much money we could throw at the problem of

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Speaker 1: COVID nineteen and have it still be cost effective, assuming

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Speaker 1: any of these things that works, and even if it

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Speaker 1: doesn't work, it's still cost effective to be trying it.

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Speaker 1: Do you think we should be doing much more than

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Speaker 1: we're doing. Do you think our efforts are roughly appropriate?

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Speaker 1: What's your gut sense of whether we're throwing enough resources

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Speaker 1: at the disease right now? We are not throwing anywhere

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Speaker 1: near enough resources at the problem right now. For instance,

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Speaker 1: we still don't have enough testing throughout the country, and

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Speaker 1: that is key in trying to reopen society. We also

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Speaker 1: don't have enough resource as being allocated for research and vaccines.

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Speaker 1: For instance. You know my lab is working on immune

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Speaker 1: response to COVID nineteen, but you know there is no

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Speaker 1: centralized funding mechanism to rapidly support such effort, and the

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Speaker 1: NIH has announced several emergency funding mechanisms and I'm hoping

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Speaker 1: that some of these will come through, but I feel like,

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Speaker 1: as you say, the economic impact of this pandemic is

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Speaker 1: so large that no amount of you know, this sort

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Speaker 1: of ramping up of the resources, it's going to be

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Speaker 1: a waste, because if even one in a hundred of

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Speaker 1: these things work, then it's it's totally worth the investment.

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Speaker 1: So I am a little frustrated as to how little

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Speaker 1: resource has been poured to research as well as development

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Speaker 1: of drugs. Thank you so much for taking time out

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Speaker 1: of your super busy schedule of saving the world to

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Speaker 1: talk to me, and thank you for the great, great

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Speaker 1: cloud of your analysis as well. Thank you very much.

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Speaker 1: Though speaking to doctor Akiko Iwasaki was really eye opening

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Speaker 1: for me on several dimensions. She's extremely forthright about the

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Speaker 1: challenges and bottlenecks that face the process of producing vaccines

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Speaker 1: on any of the three approaches that she described, yet

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Speaker 1: at the same time she has an underlying optimism that

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Speaker 1: we will eventually make our way to a functioning vaccine.

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Speaker 1: What was also very striking to me is her emphasis

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Speaker 1: on monoclonal antibodies. The antibodies would help the body fight

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Speaker 1: off COVID nineteen and Although they don't confer a permanent immunity,

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Speaker 1: they would in the short run, potentially enable millions of

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Speaker 1: people to avoid getting the disease. The most significant difference

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Speaker 1: between the monoclonal antibodies and either the anti viral treatments

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Speaker 1: or alternatively, the vaccines is that they do not require

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Speaker 1: any new science. We will continue to follow the monoclonal

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Speaker 1: antibodies story and the vaccine story going forward, and we'll

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Speaker 1: try to figure out how it comes to be that

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Speaker 1: we haven't yet had the degree of emphasis on the

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Speaker 1: monoclonal antibodies the doctor Awasaki thinks we ought to have done.

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Speaker 1: Until the next time I speak to you, be careful,

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Speaker 1: be safe, and be well. Deep background is brought to

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Speaker 1: you by Pushkin Industries. Our producer is Lydia Jane Cott,

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Speaker 1: with research help from Zooie Wynn. Mastering is by Jason

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Speaker 1: Gambrel and Martine Gonzalez. Our showrunner is Sophie mckimmon. Our

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Speaker 1: theme music is composed by Luis GERA special thanks to

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Speaker 1: the Pushkin Brass Malcolm Gladwell, Jacob Weissberg, and Mia Lobel.

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Speaker 1: I'm Noah Feldman. I also write a regular column for

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Speaker 1: Bloomberg Opinion, which you can find at bloomberg dot com

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Speaker 1: slash Feldman. To discover Bloomberg's original slate of podcasts, go

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Speaker 1: to Bloomberg dot com slash Podcasts. You can follow me

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Speaker 1: on Twitter at Noah R. Feldman. This is deep background