Transcript of BioCentury This Week TV Episode 131
Dr. Anthony Fauci, Director, NIH's National Institute of Allergy and Infectious Diseases (NIAID)
PRODUCTS, COMPANIES, INSTITUTIONS AND PEOPLE MENTIONED
Centers for Disease Control and Prevention (CDC), Atlanta, Ga.
National Institutes of Health, Bethesda, Md.
U.S. Food and Drug Administration, Silver Spring, Md.
Steve Usdin, Senior Editor
STEVE USDIN: Flu season in North America is ending, but the search for a better vaccine doesn't stop. NIH's Tony Fauci says unnatural immunity could be the way to fight flu, and even AIDS. I'm Steve Usdin, welcome to BioCentury This Week.
NARRATOR: Your trusted source for biotechnology information and analysis, BioCentury This Week.
STEVE USDIN: They're better than nothing, but today's influenza vaccines aren't very good. Unlike most other vaccines, they have to be given every year. That's because they have to be adjusted as the flu virus mutates. Scientists have to predict which strains will be most prevalent every year, and sometimes they get it wrong. Seasonal flu vaccines are least effective for the people who are at greatest risk, the elderly.
And sometimes there are shortages. Scientists at the NIH's National Institute of Allergy and Infectious Diseases are using some unconventional thinking to come up with a better flu solution, a universal vaccine that would protect against multiple strains of the virus so it wouldn't be necessary to vaccinate every year.
The idea is to create what's called unnatural immunity, to teach the body to mount an immune response against a portion of the virus it doesn't usually recognize. The hope is that it would be more effective than today's vaccines, especially for the elderly. Dr. Anthony Fauci, the head of the National Institute of Allergy and Infectious Diseases thinks the same principle -- unnatural immunity -- could lead to the creation of a vaccine against HIV, the virus that causes AIDS.
To discuss how new approaches could lead to innovative vaccines for influenza and even AIDS, we're joined by Tony Fauci, director of the National Institute of Allergy and infectious Diseases. Dr. Fauci, I want to talk about this idea of what you call unnatural immunity, but I want to start with the idea of natural immunity, the principal that's behind most vaccines. Why doesn't that work to create a lasting vaccine for influenza?
ANTHONY FAUCI: Well, first of all, when you talk about natural immunity to a, let's say smallpox or polio, or measles, what has guided vaccinologists, people who make vaccines over the years has been the fact that the vast majority of people, even though you get some deaths and some morbidity from these types of infections, the vast majority recover.
And when they recover, they have an immune response that you can measure and say, you know that this is associated not only with recovery, but these people are almost invariably protected against subsequent challenge with the same virus. So you guide your vaccine approach to try and elicit that type of response.
The difficulty with influenza is that influenza, although on a given virus with a vaccine that matches it well, it's a good vaccine for the most part, that there are parts of that virus that change from year to year, from strain to strain. And there are parts of the virus that don't change, that stay constant. The body makes an immune response against the part that changes, which will help you recover from this year. The problem--
STEVE USDIN: So it's like that you're seeing a new vaccine every single year.
ANTHON FAUCI: Right. A new virus.
STEVE USDIN: A new virus.
ANTHONY FAUCI: So what happens is that although now you're protected against this virus, so that if it comes back next year, you're not going to get infected. The only trouble is when it comes back next year, it comes back with a slightly, and sometimes moderately mutated part, so that your immune system is there, that was either induced by a vaccine or by actual infection, doesn't protect you against what's around this year.
So when we say unnatural immunity, means we want you to make a response against the part of the virus that you wouldn't normally make a response to. And when you're talking about influenza, that's a very specific part of an important protein on the influenza virus. And that protein is called hemagglutinin, which we refer to as HA. And the part that changes is what we call the head, or the bulb.
And then the molecule has a little stem with a molecule right here that is not seen very well by the body's immune system, or even when you vaccinate somebody. But if you could make an antibody, or a protective protein against that part, then you have the opportunity of protecting not only against this year's virus, but the one that changes on the top, but this doesn't change each year. And even when you might get a pandemic flu.
So when we say unnatural immunity, we say we want you to do better than the response against natural infection. We want you to have natural immunity, but added on that, something that you wouldn't normally have. And that's the challenge for vaccinologists.
STEVE USDIN: So how far have you gotten? That's the basic idea, and it's an intriguing idea, but there's a long way to go from an idea to a vaccine. How far have you gotten?
ANTHONY FAUCI: Well, first it's important to say that we didn't know about this until just a few years ago when investigators, by all of the very sensitive techniques we have to identify and do the molecular sequencing of a lot of antibodies, we didn't realize that this particular stem was the thing that was the protective component. So what has been done?
What has been done is that a number of vaccines have been made where they have been able to show the body's immune system. Specifically this part that it doesn't readily see when you just show with the virus.
And studies have been done in mice, have been done in ferrets, and have been done in animals that show that when you take this approach of presenting to the body that area that they don't usually see, it's been safe, good, but it's also induced a response that you would predict would be protective if that immune response was induced in humans. So then we went to the next step.
And when I say we, I mean scientists at the NIH and people who we are funding outside have then taken it to very early, Phase I, we call it, tests in humans. To show A, is it safe in a few people? And B, does it invoke that response that we saw in animals, and that you would predict would be protective? And so far, the answer has been yes.
But that's not the end of the ball game, because now you've got to show it in a larger number of people. You've got to determine, is it a powerful response? Is it a durable response? And then very importantly, ultimately in the big picture, you do a larger clinical trial to see if it's effective.
So we've made some steps from concept proving in a test tube to preclinical studies in an animal, to early studies in human, which show that we're at least going in the direction that we would like to go about eliciting that response that you could predict would be protective. How and when we're going to get to the end game, which is to have a vaccine that you've proven is effective against multiple strains is going to take years.
STEVE USDIN: And we're going to talk about that a little bit more. Now we're discussing of new approaches to combating deadly viruses. While many think of the flu as an inconvenience, here's a look at the sobering facts about flu mortality.
STEVE USDIN: We're talking about fighting the flu with unnatural immunity. Our guest is Tony Fauci, director of the National Institute of Allergy and Infectious Diseases.
Dr. Fauci, you were talking about the steps that NIH has taken so far. Can you talk a little bit more about what you've done, and what has to happen between now and actually getting a vaccine to people?
ANTHONY FAUCI: OK, what's been done is that there has been an approving of a concept. Namely, that part of the influenza main protein, the hemagglutinin -- that is the one that doesn't change from flu strain to flu strain -- that's been shown by investigators doing fundamental basic science.
Then, that concept was taken into what we call a preclinical arena, where a product was made, was injected into mice, ferrets, and monkeys, and shown to be able to elicit the response that you'd like -- namely, the response that's good against multiple strains of influenza.
Then, they went into the next phase, which is the human phase, early clinical trials Phase I, to show A, is it safe, and B, does it elicit that response? So there's multiple steps that go from basic research to an actual product in your hand that's approved by the FDA.
STEVE USDIN: And usually, for many kinds of products, what you've described -- taking it up to Phase I or Phase Ib, that would be enough. An industry would jump in there, they would license a product, and they would do all the trials and all the regulatory work and they would get it approved. For this vaccine, or this potential vaccine, that's not likely to happen, right?
ANTHONY FAUCI: Well, it's not likely to happen, because we're going to have to do, and we're doing it now -- even more of this than we've done in the past -- is doing public/private partnerships, where you actually engage in a collaborative effort with industry where you take some of that early risk away and push that envelope further and further towards the product.
You do a Phase I, Ib. You do a larger number of individuals. You do different types of viruses to show that it actually works with this strain versus that strain in individuals. And there's a planned trial now that'll have over 100 individuals who will be doing that.
Then, we'll go to the next stage. And then, when you get to the stage where you can actually start to perhaps see some observational efficacy, then you do a prospective trial where you actually hand it over to the company, they make the product in a manner that's acceptable to the FDA, a consistent product reaching all of the standards of the FDA.
Then, you take that product, and you put it into a larger clinical trial. That takes years to do. Because now you've gone, proven the concept, done the preclinical, done the clinical, and now you have to talk about efficacy. And when you talk about efficacy, you're talking about thousands and thousands of people in a trial, which is a large trial that will have to show that it is actually doing what you hope that it would do.
When it does that, that's when the FDA will come in, examine the data, and approve it or not to be used, so that you can go into a pharmacy or go into a doctor's office and get it. Those processes take a long period of time.
But the question you asked is a good one, because right now, because of the risk of this to a company of an investment they have to make, the government -- in the form of the NIH, CDC, and others -- are pushing the envelope further to partner with them to take away some of that risk.
STEVE USDIN: So we've just got a little bit of time left now, but quickly -- one of the things you mentioned was efficacy. The traditional seasonal flu vaccine isn't very effective. It's the best thing that we have. People should take it, but it isn't very effective.
And particularly it isn't very effective in the patients who need it the most -- the elderly. Is there any reason to think that the approach that you're describing now would be more effective, especially in the elderly?
ANTHONY FAUCI: Theoretically so, because if you have a universal flu vaccine that you don't have to play catch-up every season to make a new one, but you have it there -- it's on the shelf, you can give it in a measured way without rushing -- you could give several boosts.
And you could give it to people year after year. You build up a series of what we call memory cells that can remember to make an appropriate response when you actually get exposed.
Now, if you're building up memory cells that actually have a greater breadth and depth of response, then when you get to be 65 years old, you have those memory cells that are still there. A 65-year-old person doesn't respond very well to a classic flu vaccine for a number of reasons.
One, aging individuals don't respond as well to vaccines than younger individuals, all other things being equal. Also, the elderly often have other ailments that make it less likely that they're going to respond.
So if you can get somebody vaccinated when they're 40, 50, 60 -- by the time they're 65, and you give them a vaccine that covers all of that, they may have a store of those memory cells that would make their response much more potent than it would be if you just de novo vaccinate a 65-year-old and never gave him a vaccine before.
STEVE USDIN: Right now, the only protection from catching the flu comes from traditional seasonal vaccines. The U.S. accounts for more than 50% of the growing market for flu vaccines. Here are the numbers.
STEVE USDIN: Is there a better way to combat viruses like flu and HIV? We're talking with Tony Fauci, Director of the National Institute for Allergy and Infectious Diseases. Dr. Fauci, we were talking about the elderly there and the fact that they have memory cells and that they actually might do better with a universal flu vaccine.
ANTHONY FAUCI: Right.
STEVE USDIN: That kind of leads me to another strategy I think that you're working on, the idea of a prime boost and then boosters after. Can you explain that?
ANTHONY FAUCI: Yeah. Well the original experiments that led to these favorable and encouraging results with the universe flu vaccine is to prime first the animals and then we went into humans with what's called a DNA vaccine where you express a protein of just that hemagglutinin that shows that part that doesn't change very much. And you prime them and then you wait a little while. Then you boost them with a regular typical seasonal flu vaccine. That seems to be able to elicit a very good response that's very broad.
The other aspect of boosting has to do with the fact that if you give somebody what is truly -- let's fast forward and say we truly have a good universal flu vaccine, and you give it to someone this year and then you might three or four or five years later give them a boost with that which is the same vaccine and it's still making that broad response but now it's elevating it and making it more powerful.
And then, a few years later, or five or six or 10, depending on how good the universe of flu vaccine, you may give them another boost that would amplify it even more. So that by the time a person gets to be 65 years old, they have really powerful memory cells that are not just specific for one particular type of an isolate but are memory cells for a part of the virus that stays the same from year to year.
So you would give that person an advantage because older people have very few, what we call, naive cells, things that respond newly, but they have good memory cells. If you want to boost them, that's the way to do it.
STEVE USDIN: I want to shift now over to HIV because it's actually kind of a remarkable idea that the underlying idea that you're talking about here, about influenza, might actually also help to develop an HIV vaccine. How could that work?
ANTHONY FAUCI: Well the concept of unnatural immunity does hold true. With HIV, it's quite a lot more complicated, but the fundamental principle is the same. And that is the body, unlike with other viruses like smallpox, measles, mumps, et cetera, the body doesn't make an adequate immune response against HIV. Astoundingly, there have been no documented cases of people who are actually infected, had established infection, and their immune system just dramatically and spontaneously cleared the virus.
STEVE USDIN: Yeah, that doesn't happen.
ANTHONY FAUCI: So it just doesn't happen. So the body's immune system is inadequate in its response. So what you have to do is you have to elicit a response with a vaccine that induces a response that's much better than the response to natural infection and that's why we refer to it in that same category as unnatural immunity. And there are some clues about how we can do that.
STEVE USDIN: And part of it, also, in an analogy, it's similar to what you're talking about with influenza because you're talking about maybe dealing with a portion of the virus that isn't normally seen by the human body, right?
ANTHONY FAUCI: Exactly. The parts of the virus that tend not to change because they're critical to the virus and they're constant, are usually crowded out or covered by a bunch of molecules that make it very difficult for the immune system to see it, see it well, see it quickly, and respond to it. So when you have a vaccine, as long as you know what that part of the virus is, you want to present it in a way that the immune system sees it very clearly. So in some respects, it's analogous to the discussion about a universal flu vaccine.
STEVE USDIN: So to be clear, when we're talking about a potential HIV vaccine based on unnatural immunity, it's not nearly as far along as the influenza vaccine?
ANTHONY FAUCI: No, it's not. It's not. When you talk about a vaccine that is going to be broadly protective, we have a trial that was very modestly effective, 31%, not ready for prime time. In that respect, it's further ahead, but in conceptually, about getting a universal flu vaccine versus an HIV vaccine, I would say that we're really much closer to the light at the end of the tunnel with an influenza than we are with an HIV vaccine.
STEVE USDIN: What are the kind of, stumbling blocks? Or what are the scientific hurdles, the next things, that have to be overcome to be able to get closer on the HIV vaccine?
ANTHONY FAUCI: Well what we need to do -- and this is the big question -- is that you have to show that once you get that part of the virus that's on the envelope or the covering to identify that as that's the thing you want to make an immune response against, you've got to get that into a form that, when you insert it or inject it into a human body, it will induce an immune response. We call that an immunogen. We know what the protein is now. We've done a lot of work in identifying it and getting the right structure. What we don't know is that when you immunize somebody with that, with the immunogen, does it really elicit an immune response that's protected? And that's a big question mark right now.
STEVE USDIN: In those kind of tests, how far away are we from being able to do that kind of challenge? To be able to determine that?
ANTHONY FAUCI: I think realistically speaking, before we even do an early test, I think it's going to be a matter of a couple of years because you have to make that immunogen in a form that you know is a safe thing to even try on a human, much less determine if it's going to be effective. So I think right now we're doing a lot of work on identifying those things that we call epitopes. Getting them to be an immunogen is going to take at least a year or two.
STEVE USDIN: And then once you've done that and you've measured the response, are you even completely confident that that response that you're measuring is actually a correlate of protection?
ANTHONY FAUCI: We don't know because we have no human data to say that when someone has this antibody in them that they're protected against getting infected. Because the great unfortunate, disturbing aspect of HIV/AIDS is that we don't have the model of anyone who's actually recovered, got rid of the virus and was protected against re-challenge.
STEVE USDIN: The single case of a toddler who was treated with antiretroviral drugs when she was very, very young and apparently has been so-called cured --
ANTHONY FAUCI: Right.
STEVE USDIN: -- has too much been made out of that single case?
ANTHONY FAUCI: Yeah.
STEVE USDIN: And can we learn anything from it?
ANTHONY FAUCI: I think a, too much has been made of it, number one. Number two, it doesn't have a lot of relevance to the millions of adults who are infected, who have been infected for a while. It is important to pursue in the realm of treating infants very, very early that you might be able to get to the point where you treat them before the virus establishes a firm reservoir and then that might be a cure. But the thing we have to make sure people understand, this is one case and when you're dealing with biology, be careful about making too much out of one case.
STEVE USDIN: In just a moment, we'll get some final thoughts from Tony Fauci, one of the nation's top thinkers on infectious diseases.
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STEVE USDIN: Now let's get some final thoughts from Tony Fauci about inducing an unnatural immunity in the fight against the flu. Dr. Fauci, I wanted to start with this. To sum up, how did the original insight come up that lead you down this path that might end up in creating a universal flu vaccine?
ANTHONY FAUCI: Yes, the skeptics about an influenza vaccine that's universal saying -- well, you get exposed to influenza practically every year, you get vaccinated. If you're not going to have universal protection against next year's the way we do, how do you imagine that you're going to do that experimentally?
And the insight came when investigators were able to identify a part of that virus that isn't readily seen by the immune system, that when you make an antibody against that, you actually can, in the test tube, protect against a wide range of influenza.
So the thought occurred -- well, you don't make that when you have a natural infection. You don't make a lot of it when you get a vaccination. So how can we get the body to make a lot of that?
And the thought is, if we take this particular part of the virus, which is the stem part of this important hemagglutinin protein, and put it in a way where, if you show it to the body unencumbered by all the other things on the virus that tend to block that response -- if you just show the important component of the protein and then come in with a boost of the total protein -- can you actually specifically tell the body to make that important thing?
And as it turned out -- you start off with animals. It worked in the animals. Then, you go to early clinical trials, not for efficacy, but just to see if you can induce a response. And it turns out it does. So it went from this idea of, why aren't we making a response that protects against everything, to some very smart investigators identifying that part that is the component that you need to make an immune response. And then, everything else after that flows from that.
STEVE USDIN: Mhmm, so then shifting toward the end game on this, is there a clear path toward getting regulatory approval for something like this? Because I imagine that the safety hurdle for a vaccine that you're going to be injecting into millions and millions of healthy people is extraordinarily high.
ANTHONY FAUCI: It is, and that's the reason why we partner with the FDA -- we at the NIH and the people that we fund on the outside of the universities. You get the FDA involved right from the beginning about, this is what we want to do, this is a Phase I trial, how does it look? Is it OK? OK, go to the next phase, Phase IIb.
The next phase, they check on the safety, they check on the consistency of the material that you're making, and then they check ultimately on the efficacy when you do the large clinical trial. They're involved right from the beginning.
STEVE USDIN: So let's also go back again. The thing that everybody wants to know probably in listening to this is, what's the timeline? I know you can't predict, because things are unpredictable. But can you ballpark ideas of what you think the timelines are?
ANTHONY FAUCI: Well, I can give you what it's not going to be and what I think it could possibly be. It's not going to be next year. And I think we're going to have it before 30 years. I think it's going to be somewhere reasonably -- that we'll have it in about 10 years.
And that's always dangerous to put a year on it. But if you look at the way things are progressing, and the length of time it takes for a vaccine trial to prove efficacy, I would think 10 years is not an unreasonable estimation.
STEVE USDIN: Mhmm, and how many people do you think will have to be exposed to it in trials before something --
ANTHONY FAUCI: Well, you're talking about several hundreds to thousands of people before you actually determine in the field if it works. So you're going to have to have thousands of people that are going to have to be in the clinical trial before you can even say anything about it. So it's measured in thousands.
STEVE USDIN: Well, thanks very much. That's this week's show. I'd like to thank Tony Fauci for a very insightful conversation. And thank you for watching.
Remember to share your thoughts about today's show on Twitter. Join the conversation by using the hashtag #BioCenturyTV. I'm Steve Usdin, and I'll see you next week.