NIH Postpones Test Of Experimental AIDS Vaccine The National Institutes of Health has decided to cancel a large-scale test of an experimental AIDS vaccine, saying that more focused research is needed on the way such vaccines interact with the immune system. The trial, known as PAVE 100, was designed to include more than 8,500 people.
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NIH Postpones Test Of Experimental AIDS Vaccine

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NIH Postpones Test Of Experimental AIDS Vaccine

NIH Postpones Test Of Experimental AIDS Vaccine

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This is Talk of the Nation: Science Friday. I'm Ira Flatow. We're going to be switching gear now, talking about AIDS vaccines, because earlier this month, the National Institutes of Health announced that it would not go forward with a planned major trial of a potential AIDS vaccine, that more basic focus research was needed first on how such vaccines interact with the immune system before such a trial could proceed. The news follows the failure last year of another experimental AIDS vaccine produced by Merck.

So, what are we going to do now about the immune system and these vaccines and what more do we need to know? Do we need new thinking? A new direction for AIDS research? Do we need new blood coming in to do the research? More funding? Joining me now is a frequent Science Friday guest, Dr. Anthony Fauci. He is director of the National Institute of Allergy and Infectious Diseases at NIH, and he's the winner of the 2007 Lasker Award for Public Service. Welcome back to the program, Dr. Fauci.

Dr. ANTHONY FAUCI (Director, National Institute of Allergy and Infectious Disease, NIH): It's good to be here, Ira.

FLATOW: Tell us a little bit of the history. Why the cancellation?

Dr. FAUCI: Well, the cancellation because the trial that was proposed was of a size and magnitude that, given what we know, or more frankly, what we don't know, about what we call the correlate of immunity, namely the kind of immune response that we're trying to induce in people who are vaccinated with an AIDS vaccine. I felt that we needed to do a much leaner, meaner trial that precisely asked and answered one question: does this particular vaccine work in lowering the viral set point to the viral load were someone to get infected anyway?

And we don't need a trial as large as was proposed given the failures that we've seen up to now. So, I would entertain a smaller trial, but I thought given the situation we're in and the fact that we know so little about these correlates of immunity that it would be more prudent to try and do a much more precise trial. That's the reason why I did not accept the proposal for the larger trial. So, I'm waiting to see and hopefully they'll come in with a proposal for a much smaller approach to this particular question.

FLATOW: Was there fear on your part that we might have another failure, failure like that Merck trial?

Dr. FAUCI: Well, it was less a question of failure than a question of the balance of resources that you put into what we call an empiric approach, namely taking a product and doing a large trial, not only to see if it works good, but also to see if you can get some hint of some correlation with a particular response, and perhaps the favorable response clinically in some of the vaccinees. What you alluded to when you were introducing the program was we're thinking much more now, towards turning the knob a bit more towards asking and answering some of the fundamental, basic, unanswered questions in HIV vaccine.

It's a very unique situation, much different than what we face with any other virus for which we're trying to make a vaccine, because mostly when you get natural infection with anything, polio, small pox, measles, you call it, the body makes an immune response that, for the most part, in most people, even though it causes death and disease in some, that people's immune system can respond, clear the virus, eradicate it completely from the body, and then allow you to be protected, literally, protected completely from subsequent challenge with the same virus.

Unfortunately, with HIV that's not what we have, because the history of HIV tells us that, for reasons that we still don't understand, the body does not respond adequately to the HIV virus. There are virtually no instances of people who once they get established infection can actually eradicate the virus from the body or even well control it, except some few people who have genetic programming to do that. So, we're really swimming in the dark. We've got to answer some fundamental basic questions of why the body does not make a good immune response against HIV.

FLATOW: 1-800-989-8255 is our number, talking with Dr. Anthony Fauci. You could not learn that from the drugs, not the vaccines, but the drugs that are used to treat people with HIV.

Dr. FAUCI: No, Ira, it's an entirely different ball game, because, as you know, the drugs block the virus by having a direct effect on the virus. It doesn't impact the body's immune response to the virus. When you're dealing with a vaccine, you're trying to marshal the body's defenses and prepping it, so that when it sees the virus for the first time, it will have a head start in making a good immune response, and hopefully, as we see with most successful vaccines, block the initial infection or if not block the initial infection, at least protect the person from severe disease. So, it's really apples and oranges when you're talking about a drug verses a vaccine.

FLATOW: You write in the paper in Science about the need to explore new avenues and to attract new and young investigators into this area and maintain their involvement. I have two questions about that. Is there a shortage of new ideas that you're looking to come through now?

Dr. FAUCI: Well, I would say less a shortage of new ideas than a shortage of good ideas, because what we've tried so far in a empiric way, hoping that by trial and error we would come up with the answer to an HIV vaccine. It's becoming very clear that we need to do some basic fundamental probing and answer the questions. The questions are clear. How we get to the answers is the issue.

Why does not the body make a very good robust response against the virus that's able to control it? We do that with virtually every other virus. Why not with HIV? We have some leads, but we really need to do those fundamental concept-type experiment, as opposed to just empirically testing a group of potential candidates for a vaccine.

And what we say we want new ideas and new blood, and young people who really don't have a predetermined notion about what the direction should be, because that's the way science works. When you get these new fresh ideas, they give leads and then others can take up on them and that's how you get the answers. So, that's really what we're calling for, getting back to answering some of the fundamental question.

FLATOW: Yeah. You write it very well. You write, you know, "the design of a vaccine will require some enormous intellectual leaps beyond present day knowledge."

Dr. FAUCI: Right.

FLATOW: That's - some - so you really want to just brainstorm this even more?

Dr. FAUCI: Well, we want to brainstorm and then we when get the - a good idea to try and test it first, you know, perhaps in an animal model, and you note from the paper that we just put out in Science that we stress the need to enhance what we call the nonhuman primate model, so that we can get some idea. There's no animal model that's a perfect model for HIV, but some of them are pretty close. So, that's the thing that we really need to expand upon and perfect.

FLATOW: And that's one of the mysteries - I think if I read the paper correctly, you get better results in the nonhuman primates and you can't transfer those results.

Dr. FAUCI: Right. Exactly, and some of the models, you cannot transfer the results. Because in one of the models in particular, using, for example, the Merck candidate that actually was the disappointing results from several months ago, one of the animal models looked like they may have been protected from the high level of virus that you get after you get infected and they made a certain immune response. The humans made a similar immune response, but they were not at all protected, and when you looked at the vaccinated verses the unvaccinated, there really was no benefit at all.

FLATOW: Then it sounds like there's something unknown going on here.

Dr. FAUCI: That's exactly the point, Ira, you put your finger right on it, there's something unknown. It's not like the body is the experiment of nature with a natural virus like we've done with polio and with measles and with other virus vaccines that we've been so successful in developing. The body's natural response serves as, you know, your first solid experiment. The body already tells you that it can make a good immune response. Unfortunately with HIV, that doesn't happen and we have to figure out why. So, we don't have the experiment of nature to help us along, because the experiment of nature has actually failed. The body does not do a good job in protecting against HIV.

FLATOW: You know how physicists have their dark energy problem? You've got your dark HIV problem.

Dr. FAUCI: That's in fact the case, unfortunately.

FLATOW: You know, what is their - could there be something about the immune system that is there that we have not discovered how it works yet?

Dr. FAUCI: No, what we suspect it is, Ira, is that the way the virus presents itself to the body that the components of the virus that would induce, and it does sometimes rarely, what we call a good neutralizing antibody response, so something that you would predict would be protected, is presented into the body in a very cryptic way. So, the body surveillance mechanism doesn't see clearly that component of the virus that it needs to make an immune response against it, and if it doesn't see it clearly, it's very difficult to make a good immune response, and you superimpose upon that the fact that this virus is very divergent. It mutates very rapidly and gives it a big head start on eluding the body's immune response. So, there are number of reasons why this is such a difficult scientific problem.

FLATOW: 1-800-989-8255. Carol in Santa Cruz. Hi, Carol.

CAROL (Caller): Hi. What he just said is exactly what I was going to ask the question about. What I heard a long time ago was that the virus mutates within the body very quickly, and for that reason, developing a vaccine would be futile because the virus would just again mutate and then the vaccine wouldn't work against that next variety of the virus.

FLATOW: Is it that hard, Dr. Fauci? Don't other, you know, disease, viruses mutate also?

Dr. FAUCI: Well, first thing, what the caller said is quite correct, and I'll explain a little bit of a difference there. Yes, other viruses mutate, but HIV is the mother of all mutating viruses. I mean, it just mutates extraordinarily rapidly, and becomes very divergent. When you make a vaccine against a virus that mutates, what you try to do is to make a vaccine that gets a response against the constant region of the virus that can't really mutate because if it mutates, it would make the virus functionless.

One of the points on the virus that we want to make the immune response against is the part of the virus that binds to the receptor on the target cell in the body. And that's how the HIV gets its foothold in the body. It binds to particularly vulnerable target cells and it infects them. That binding site is what we call very cryptic. It's very, very difficult to reveal that to the body's immune-surveillance mechanism.

If we can get that binding site that binds to a particular molecule on the cell and put that in a form that when you vaccinate people, they'll make a very robust response against it. That's one big leap towards a successful vaccine. But thus far, we've been unable to get that particular component of the virus into a form that would elicit a good immune response by the body. So, that's one of the directions...

FLATOW: Interesting.

Dr. FAUCI: That we're trying to pursue with this new idea.

FLATOW: Let me see if I can - we can tease that out a little bit. So, there's a site on the cell that the virus binds to.

Dr. FAUCI: Right. It's called the receptor.

FLATOW: The receptor and it fits like a key, like a jigsaw puzzle, any way you'd like to describe it.

Dr. FAUCI: Exactly.

FLATOW: And the idea is that you could make a medication that floods the body and binds to that site so that the virus can't bind to it itself.

Dr. FAUCI: No, it's a little bit different. Almost there, Ira. What it means is that you inject into the body the particular component of a virus in a very safe way that would elicit a response on the body's part so that the body makes an antibody or a cell-mediated response that actually blocks that interaction that you're talking about.

FLATOW: I see.

Dr. FAUCI: That lock-and-key interaction. But you have to induce the body to make a good immune response to do that. That's what we've been unsuccessful in doing. So, you're really trying to ask the body or coax the body to make a response against the critical part that the virus needs to bind to its receptor before the person gets exposed to HIV, so that if and when the person does get exposed to HIV, that substance, which would be an antibody or a particular specific cell, will already be in the body revved up, ready to protect you against HIV.

FLATOW: And we're talking about AIDS research this hour in Talk of the Nation: Science Friday from NPR News. I'm Ira Flatow, talking with Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases. I almost got the opinion from reading your article in Science that you're having trouble finding enough young scientists themselves who want to go into this field. Like, you know, maybe they don't see this having any future, it's not a career path for them. Am I misreading that?

Dr. FAUCI: Well, we always are looking for new blood in the fields of science, particularly in those particularly problematic fields like the development of an HIV vaccine. Right now, as you know, in the biomedical research community, the funding for NIH and other scientific institutions has been relatively flat over the last several years. So, there's not a big inducement to get people into the field back in the days when the slope of increase in funding for HIV, I know you remember that well.


Dr. FAUCI: We discussed that years ago on this show. It was so great. It was a major attraction to young investigators. Things had really been a little sobering over the last several years. That's just one of the reasons. The other reason is that sometimes, young people feel that they would not necessarily be able to contribute because there are a lot of people in the field who've been at it for a long time and have a lot of experience. What we're trying to say is that all bets are off with experience, because experience hasn't got us the answer to these problems. So, we would welcome the fresh new ideas that generally come from young new investigators.

FLATOW: And we also have other fields that we didn't have many years ago, the genetics, and you mentioned, structural biology, all those kinds of things...

Dr. FAUCI: Exactly.

FLATOW: That might help out. Could we, you know, could we find out - give me an example what kind of things genetics might tell us, for example.

Dr. FAUCI: Well, for example, we know that there are some individuals who are genetically programmed to actually be long-term non-progressors in the sense that they seemed to handle the virus very, very well. We are currently probing the immune responses they make to see if, in fact, we can get some insight into inducing that. The problem is, maybe they make that immune response because they have the right genetic background and that people who don't have the right genetic background are not going to readily make those kinds of immune responses.

So, what you have to do is, when you make a vaccine, you put it in a form that elicits a response that you wouldn't necessarily, readily make on the basis of your natural genetically-programmed response to a virus. So, you almost have to trick the body into making the kind of response that would be protective.

The other field of discipline that we are very much joining with, is the whole issue that you mentioned a moment ago, is structural biology and the crystallographic and atomic structures of these binding sites that we speak of and how to get that in a form that would be what we call an immunogen or something that you can inject into someone to make a good immune response against that particular binding site.

FLATOW: So, you're talking about tinker-toy stuff here. Right shapes of things and get them to bind to the right sites and a lot of it may be an engineering problem, too.

Dr. FAUCI: Indeed, and when you talk about structural biology and fitting an antibody into a particular cryptic site on a molecule, that's exactly what it is. That's engineering. That's biological engineering.

FLATOW: So, you're waiting now then to - for a new kind of study or something. A lot more focus.

Dr. FAUCI: Yeah. I would entertain a study using the same product, but it's got to be designed to get the answer as quickly as possible as to whether or not this particular candidate does have the positive effect of lowering the viral load. If it does, then we can expand a study in trying to all the kinds of correlates to see if we can get some clues as to what the right immune response is that's leading to this positive effect.

FLATOW: Well, there are a lot of people out there listening. Maybe you've stimulated somebody.

Dr. FAUCI: I hope so, Ira.

FLATOW: Send you a proposal. Thank you, Dr. Fauci, as always.

Dr. FAUCI: You're quite welcome. It's good to be here.

FLATOW: Thank you for taking your time to be with us. Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases. That's at NIH in Bethesda. We're going to take a break. When we come back, we're going to talk about working with a different kind of vaccine, this one for cancer and growing these vaccines in tobacco plants. Can you imagine tobacco treating cancer? We'll talk about it after this break. Stay with us.

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