S2, E03: Beyond the Headlines: Understanding Accelerated Vaccines

Gina Mullane (00:09):
Today is especially exciting as we welcome Dr. Lauren Black, a distinguished scientist on our scientific advisory services team. As a former regulator who helps companies get their drugs to market, she's here to shed some light on the vaccine development, and approval process and explain what it will take to get a COVID vaccine to the public. If you're like me, you're impressed by the speed at which potential COVID therapeutics have advanced. As you'll hear today, there's a lot more going on behind the scenes than what we see in the news, and Lauren offers some eyeopening insights that you may not have thought about before.

Chris Garcia (00:46):
Today, we're talking with Dr. Lauren Black, a distinguished scientist who has spent more than 30 years in drug development. Dr. Black, thank you for taking time out of your very busy schedule.

Dr. Lauren Black (00:56):
Well, thanks for tracking me down. I can run, but I can't hide. Chris (01:01): So earlier in your career, you worked in pharmacology and in vitro biology, and then you ended up at the FDA around the time of the AIDS crisis. Is that right? Dr. Lauren Black (01:10): Yeah. Starting in '91 at the agency. And then I worked there until 2002, but as it came to be, I wasn't working mainly on AIDS drugs. I was assigned the transplant drugs, during the renaissance of all the drugs that are currently used for high-risk transplantation and treatment of rejection. So I was reviewing lots of animal models of disease, I was reviewing immunology. So I actually had to learn a boatload of immunology to handle the transplant drugs. So here I was out of the postdoc back into education, educating myself again, but it's not a bunny trail. Most of my career has been working on novel immunomodulators.

Chris Garcia (01:53):
It sounds like you have a long history of working with the immune system and high-risk drugs, but what about vaccines?

Dr. Lauren Black (02:00):
So working on vaccines today is still near and dear to my heart. We've got a public health emergency. We've got a relatively high death rate with this virus and it has my full attention. So in my job here at Charles River, is a distinguished scientist, but I'm essentially a consultant industry on how to strategize any kind of treatment or prevention for human diseases. And I still specialize in these very high-risk fields, particularly immunology. So I work intensively with our immunology groups across Charles River to help design and strategize accelerated programs.

Chris Garcia (02:39):
So Lauren, you mentioned the fact that there is another public health crisis right now. On the news, we hear a lot about Operation Warp Speed, which is an accelerated development of a vaccine for COVID. Can you walk us through that normal vaccine development process? And then we can kind of touch more into this expedited process that we're seeing for COVID.

Dr. Lauren Black (03:00):
Sure. I mean, it can be very complicated depending on what the population is, but I think, in general, let's say you're going about an updated vaccine for let's say whooping cough or something like that. If you were going to improve the type of antigen that's being used to make it more weird and wooly and make our immune system more profoundly aware of it. Usually the more complex the antigen, the more grips our immune system can get on it to say, oh, this is foreign. I'm going to react to all of these different parts. And we're going to have, what's called a polyclonal, poly meaning many, clonal meaning many clones or copies of different antibodies. And T-cells will be involved in recognizing and grabbing on to different holds on that antigen. Let's say you're going to improve that antigen and make it so that you only have to give one dose to children instead of two. No boosters needed, more convenient, able to reach more of the world with a single dose improved vaccine.

Dr. Lauren Black (04:14):
So those are our typical track kind of every day vaccine development opportunities. And so when you try to improve on an existing technology, you're going to do a lot of chemistry, you're going to do a lot of protein biochemistry, you're going to do immunization of animals, you're going to track two different parts of the immune system. Humoral means your antibodies, and cellular means all of your T cells and B cells that are involved in recognition, amplification and memory. So it's all the same players. If they're not acting together in a well coordinated manner, well, things go badly. So that's the point of doing trials in animals and humans to try to make sure that we have not only a vaccine that's stable for storage, for public health uses, for shipping. That's very important. We've got to get it to Africa, and Asia and all over the world. It's not just for local people.

Dr. Lauren Black (05:20):
We've got to make sure it's stable, that it lasts that it's cost-effective to manufacture in large billions of doses. And those are very big protein chemistry, and chemistry and storage issues that involve a lot of people who are protein biochemists. So a lot of vaccine everyday work has to do with making sure that those vaccines are stable and do what they say they're going to do. And then you go through a fairly protracted series of studies, because let's say it's an improvement on an existing technology. You already have a vaccine out there so you're trying to take a step up in improving it. That means there's not like a public health emergency. So I would say that when you're in those kinds of situations, you're going to go proceed through development, very expediently. You want to make sure that your "improvement" isn't somehow causing an aberrant immune response because let's say you put more antigens in there. You want to make sure that it's enduring as an immune response, that it develops memory, that it's actually an improvement on our existent technology.

Dr. Lauren Black (06:32):
So everything's sort of building and building and building. And that's when you look at the literature, you say often vaccine development takes a decade. The fastest typical vaccine we've developed lately has taken four years. So that gives you the timeframe. When we say that we're starting up with a novel technology, such as [inaudible 00:06:54]. Moderna has been in the press. There are no existing vaccines using that technology that have already been approved. This is really plowing a new patch of earth to say that we're going to take that from 0 to 100 miles an hour and get a vaccine by Christmas. No, I think we're going to get data by Christmas, but then we've got all these production issues and then we've got, who's going to be released first? Who's going to get the access to the first runs? It's going to be a very long time. And you have to read through all of these articles to say acceleration will mean what? Acceleration of the very first vaccines for the most at-risk healthcare workers? That can probably occur in this next year.

Dr. Lauren Black (07:43):
But for your average you and me, it's going to take quite a while before we get access. So I think the acceleration is really mainly occurring in the fact that we're basically jumping through, bypassing a lot of the intermediate dose ranging studies that would ordinarily be done. We're jumping over some of the toxicology that would ordinarily done to start off with assuming this is not really wacko, really novel, star Trek technology. They're allowing some, I would say expedient short steps in the toxicology in order to get started in humans. And then they're going ahead and enrolling tens of thousands of people. As we see 30,000 people are enrolled in a Pfizer study, and the one other, I can't remember off the top of my head, but 2 of them have enrolled right away, up to 30,000 patients. And that's where we're going to see the actual safety manifest itself.

Chris Garcia (08:41):
And in these phase three studies, are they also shortening the length of that phase to get the safety data?

Dr. Lauren Black (08:46):
Fortunately, this is not something that you have to track for years and years in order to see if it's working. You can see if lower people get infected, if there's a high rate of infections going on. So I think that's the important design of clinical trials that makes things faster is can you get a quick end point, and can you get access to patients who are at high risk? And then you can get good statistics and you can digest them sooner. So those are some of the things that make this a faster end game than say, developing a drug for, let's say, cardiac disease, where you have to enroll 10,000 patients to see if you've got a better statin. You've got to look at heart attack rates over five years in order to see a signal.

Chris Garcia (09:30):
Can you point to any data that we're missing, data that's more challenging to gather?

Dr. Lauren Black (09:35):
So if you read down through a lot of these articles, don't read the headline. Go all the way down, three quarters of the way through the article and say, did they look at something other than antibodies? And sometimes you see this little two liner, seven eighths way through the article that says, yes, they didn't measure the T-cell responses. And I'm like, ah, slap my head. Why not? Well, the truth is that measuring T-cell responses is harder. It's harder to set up a lab to do that, like a central lab to send in all of the fresh cells. It's a juicier more complicated assay to validate. And as you see, all the focus has been on immunoglobulins. The T-cells and the B-cells are the ones that are underlying the foundation of that immune response. The activities between those cells bubbles up, and that's what produces humoral immune response antibodies. But if we don't understand the foundation of what's going on in the bricks, in the foundation of our immune response, then we only have a partial story.

Dr. Lauren Black (10:37):
So to me, we're just starting to peel the onion on what to measure in that immune response and trying to get these clinical trials to look at something that is something other than 27 patients in 1 hospital that say, oh yes, we have a great insight that we are getting some activation of T-cells. I'm going to be like, whoa, which ones? How long do they endure? Sorry, am I shouting here? But you've got to really put the vaccine through its paces. What we're looking for is a vaccine that's durable. And the truth of the matter is what we're seeing is even in people who've been infected, their immune responses, there's lots of [inaudible 00:11:20] out there that say we're not getting durable, natural immune responses.

Dr. Lauren Black (11:23):
Tell me how we're going to beat that with an investigational vaccine if our own responses are not working very well, very long? We really have to study this harder. So acceleration is all well and good, but I believe quality is more important and an enduring response is what we're going for. Otherwise, the virus just makes the rounds. It's sort of like the kids that come up to Halloween and you give them some candy and then the rest of the evening goes by. And then you get another knock on your door and it's the same kids asking for more candy.

Chris Garcia (12:01):
And you mentioned the enduring response. And for the folks listening, what you're talking about is the fact that it seems people are getting possibly reinfected and sick again, three months later.

Dr. Lauren Black (12:12):
Well that, and just the fact that they've measured antibodies. This is the more simple experiment. They've measured anybody's in people, there was an article this past week, and they basically said that they measured a whole series of people who had been infected, whether they're asymptomatic or severe. And then they were characterizing how long they had antibodies. And the truth of the matter is that I think half the people were clear of their antibodies at two months, meaning they were gone and half the people had half the antibodies that they had had.

Chris Garcia (12:43):
Wow.

Dr. Lauren Black (12:43):
Did that makes sense?

Chris Garcia (12:44):
Yeah. Scary sense.

Dr. Lauren Black (12:47):
Yeah. That's what I feel like. So what I'm worried about is that just like colds, Coronavirus is in the cold virus family. It's well understood that there are certain cold viruses that just make the round around the elementary school. I remember getting some of these wondering, why am I sick all winter? It's because the kids are just circulating around themselves. And my kids are getting reinfected with the same old thing that went around the sixth classroom and came back to the first. Because then I'd be sick again. And I'd be like, what's with this? Am I ever going to get an immune response to this thing? So it's the same question we ask about the common cold. Is it the same cold? You don't know.

Dr. Lauren Black (13:32):
So every time we ask these questions, when you see about, when you look in the literature about reinfections, they basically have to do next gen sequencing on the virus to the actual genome of the virus to see if it's exactly the same virus that you got the second time, or if it went latent in your body, like the AIDS virus goes and hides in different reservoirs in your immune system, deep, deep, deep in crevices in a few cells. When you get depleted, it can come back out. Same thing when you get herpes viruses, you get cold sores. When do you get your cold sore back? When you're under stress. That's what's called recrudescence formally. So the question is, are these people getting a recrudescence of a virus that went latent and they're hiding out in their spleen or their kidney, and then when they got a little bit rundown or a little bit stressed, two months later, their immune system had waned, are they getting it back? This is something they're calling long COVID. Or are they actually getting a reinfection with a brand new virus that came from a different community?

Chris Garcia (14:33):
So talking about the vaccine, and you mentioned the common cold, we can even go to discuss the annual flu and how you get that flu shot. They tweak that vaccine every year, but people are still getting the flu. We have therapies such as Tamiflu where you'll get the flu, but you'll take this therapy that will make it a little less severe, which sounds similar to Remdesivir, recently approved for COVID patients. But I believe Remdesivir was previously investigated for other indications and now repurposed for COVID.

Dr. Lauren Black (15:02):
I think it's important to bracket drugs into things that have already been in clinical trials and things that have not. Remdesivir is a very special case because Gilliad had developed it back as early as 2009, possibly earlier for looking at it for a series of antiviral activities on multiple viruses, like RSV. Later on, they studied it in MERS for potential activity when that public health emergency arose. But it really got its clinical trials under its belt in testing back in 2013 or 14 when the Ebola epidemic occurred and they found it had activity against Ebola. So it got clinical trials against Ebola and they were able to get some safety data out of that as well as I'm sure, pharmacokinetic data and dose response information. So when the COVID emergency came along, it wasn't too much of a leap to say, okay, that was a very high risk disease. It has activity in vitro. We're able to leapfrog off of the existing clinical data with Ebola.

Dr. Lauren Black (16:14):
And then there's similar risk brackets in there in the sense that a hospitalized COVID patient is at risk of dying like an Ebola patient is. So they're able to use that risk bracket to say, oh, well the same accelerations would be valid for this particular population. And so I think that's, what's led to its very, very rapid approval for specifically patients that are hospitalized for COVID. In other words, very high-risk. We know a lot of COVID patients are asymptomatic. Some COVID patients are managed perfectly well at home. But the ones that are hospitalized are definitely at risk as an inpatient. So that is a special case. If you're starting off from scratch with a totally new chemical that's being developed from scratch for the COVID, let's say protease or specifically to interfere with the particular cellular machinery that COVID is overtaking to produce itself. Now that's going to be very COVID specific.

Dr. Lauren Black (17:19):
It's going to be designed for purpose for that particular protease, it's very similar to the drug development that we underwent during the AIDS crisis for the very first protease inhibitor, the protease inhibitor, the protease crystal structure was published. And within a very short period of time, like four years, we had a drug that was a highly selective inactive and safe inhibitor of the specifically HIV protease. And that, I call it, it's almost manna from heaven that we were given a protease inhibitor that acted so well, that we had that crystallized structure able to do that drug development, four years was considered very fast for new conception to full approval. I might be wrong exactly on those figures, but it was around four years.

Dr. Lauren Black (18:16):
So I think that we're looking at that kind of timeline here as well if we have to start from scratch with a brand new chemical. So I hate to paint this, some grays and blacks, but our best accelerations in the drug realm are coming from again, repurposed drugs and just continuing to screen a lot of things that we've ever studied as antivirals, maybe things that we didn't think were antivirals. And I know a lot of our large pharmaceutical expert companies are doing exactly that right now to see if we can even find some better drugs like that. If they've been in clinical trials before, if they've had preclinical data under their belt, they can be accelerated too.

Chris Garcia (19:02):
Lauren, to what degree are you involved with these accelerations of these drugs and these vaccines?

Dr. Lauren Black (19:09):
Well, up to my ears in it really. We have an advisory group, we have many different laboratories with different depths and types of expertise, all of which are necessary for regulatory approvals, ranging from chemistry all the way through to evaluation of clinical samples. So when we have a chance to help, we do our best to try to say, oh, well this risk bracket, this chemical type, this past history in clinical trials. We try to get all of that information collaboratively working along with the drug companies and then try to suggest all of the different places where they might negotiate with the agency and try to get a better deal on trying to get started in human trials faster, trying to reduce the number of years involved in discovering the drug, trying to reduce the amount of headwinds associated with a lack of data. I mean like you don't want to go running into clinical trials with a previously uncharacterized chemical class and then find out that your metabolites of that drug are not even represented in animals. There's a lot of pre-work that needs to be done on new chemical classes.

Dr. Lauren Black (20:32):
So we try to say, hey, is this a well-characterized drug? Has it been in very similar drugs, been in human trials before? We start with that kind of interview to try to say, here's places where we can leapfrog forward. And I can't tell you what the most rewarding part of this job is finding those accelerations and helping people identify them.

Dr. Lauren Black (20:55):
I've been here 18 years and that's what makes me get up in the morning. I'm very generally very optimistic about the amount of research effort that's being put into the focus of many drug companies that are all coming together. Some are sharing data in ways that have never been done before, consortium's are being formed. I really believe in our pharmaceutical system and our public health commitment of a lot of our pharmaceutical companies. And they're putting a tremendous amount of basic research and energy into this field. I'm quite sure something good is going to come out, but I'm just saying, it's not going to be at the end of this year. Let's do it right. Let's get quality drugs that are not going to hurt people. Otherwise we can set back this field of research more than accelerated.

Chris Garcia (21:50):
Lauren, thank you so much for your time today and talking with Vital Science, it was so insightful and I for one have learned a lot from you today.

Dr. Lauren Black (21:57):
Thank you, Chris. I think we all have to be good consumers of information right now and just hold onto our hats and hope that science solves our problems for us. I feel confident that with all of the energy that's being put into drug development right now, maybe some of my fears and worries will evaporate when the next miracle comes along. I've seen lots of miracles happen in drug development and I think we just have to keep hanging in there and see another one emerge.

Gina Mullane (22:31):
What an eye opening perspective. It was interesting to hear what has to be in place before a vaccine can reach the general public as there is no way to really know when a vaccine will become available, it's reassuring to know that drug developers are working on vaccine alternatives in parallel. This will be the topic of our final episode in our series on vaccines and I hope you'll join us for that. Tune in next month to hear how molecular biologists and drug discovery chemists are zeroing in on novel compounds that target infectious disease. Have questions or comments about anything you heard today? Reach out to us at [email protected]