Speech before the Los Angeles World Affairs Council on November 9

Speech before the Los Angeles World Affairs Council on November 9, 2000:

Dr. David Baltimore

President, California Institute of Technology

Good evening. Most of us have spent the last couple of days focused on small numbers in the election. This will take your mind off of it. What I want to do tonight is something relatively simple, which could get us mired down a lot of complex biology but I’ll try to avoid that. And that is to try to explain why we do not have a vaccine against HIV and I will do that in the context of describing a little bit about the seriousness of the problem. It’s an odd problem to have in front of the World Affairs, a group interested in world affairs because it’s fundamentally a medical problem. But on the other hand it’s not an odd problem because this disease, which really only appeared in the late 1970s is so devastating that countries, particularly in Africa today but spreading though out the world are being destabilized as a consequence of the vast number of people who are infected, of children who are being left without parents, children themselves who are infected and have to be cared for. And from the enormous loss of people in their most productive years, in the years when they should be contributing to the development of their societies.

So, there is, there are a few problems in the world that are more important than trying to get a handle on HIV. Trying to put it back in the box from which it came. HIV came, as far as we know, and we know pretty well now, from chimpanzees. From large apes where it is an endemic infection causing not particularly sever symptoms, if any among those animals. And I’ll come back to that oddity at the end of my talk. It jumped into human populations in ways that we’ll never really know, we can guess at. Perhaps as early as the 1930s and was not evident to medical, to epidemiologist, to people who were searching for disease probably because its symptoms are not particularly characteristic. And it was only when it became wide spread, particularly when it moved to the United States that doctors saw that there was a new disease because we have such terrific medical surveillance in the United States. And recognized that there was afoot a new disease that was spreading in our country.

For many years, thereafter, that’s as I say, the late 1970s early 1980s. For many years, thereafter, the major focus of activity was to try to develop therapies for the people who were infected and the pharmaceutical industry has been notably affective in that. In fact, we hear a lot today about biotechnology. One of the great triumphs of the techniques of biotechnology has been the development of anti-AIDS drugs. And those drugs can, in many people, stop the infection, reverse the symptoms, at least for some time bring them back to health. I say for some time because we don’t know how long we can maintain people. We don’t really know whether people who are infected, have been infected for a long time, can be maintained with the drugs, but we do know that they have made a huge difference. And you can see that difference and I have a few slides and I’ll point to those slides. I had to look from the back earlier and it’s not so easy to see them. If you can’t see what I am point to or talking about don’t worry, I mean what I’m pointing to. Don’t worry, I’ll try to talk about everything in a way that makes the slides just a prop for me. So this, this very primitive picture appeared in a journal a number of years ago. And it shows the deaths from HIV and it run along form 1994, 95, 96 and suddenly around ‘96 the curve takes a big dip. And what you can see is that’s just the time when the latest kinds of inhibitors were available, the protease inhibitors. So there is a very good argument for saying that what caused the drop in the death rate is these new drugs.

Now, I don’t want to go into anymore about drugs but this was a very significant time, 1996-97 because the AIDS activist community, which is a very powerful group of people who have a remarkable effect in Washington and the state houses around the nation, in local towns, because they’re well educated, very savvy. They turned their attention at that point from drugs, because the drugs were obviously coming along. The pharmaceutical industry was seeing that it was profitable and putting their attention to making new drugs. They turned their attention away from drugs and started talking about vaccines. Now vaccines had been talked about for HIV from the day that HIV was announced. Margaret Heckler, if you might remember, who was then Secretary of what was called HEW, now HHS. Margaret Heckler, brought Bob Gallow (?) the American discoverer of the virus up on to the platform in Washington said here’s our great hero now we know it’s a virus, we should have a vaccine in a short time. And she had every reason to say that because she knew that we had stopped polio with a polio vaccine, that we had stopped mumps and measles with vaccines. That small pox had been stopped with a vaccinary (?) virus vaccine a generous time. And we were already, I think, then eliminating small pox from the face of the earth using the vaccine. And so it was a reasonable extrapolation to say once we know it’s a virus you know how to make a vaccine. That was 1983-4 something. Today we don’t have a vaccine. And if fact, those of us who knew about the biology of this virus, knew at that time that it wasn’t going to be that easy. And it’s pretty simple to figure out why it wasn’t going to be easy and that is because if it were so easy there shouldn’t be so many people dying of the disease. Very few people die of poliovirus infection, maybe a couple percent of the people. 95-98% of people either get well from a relatively mild illness or don’t get ill at all. Even small pox was never lethal the way HIV is. So disease, which seems to be as lethal as that, it’s clear that the normal protections that our body has don’t work. And that protection we call the immune system. So, somehow HIV was able to grow in the face of the immune system where as other viruses can’t and that was the clue that this wasn’t going to be an easy problem. And of course it has not been.

I’m not sure this thing, thank you. Except go forward. So, what’s happened in the world since HIM appeared? It appeared in the early, late ‘70s early ‘80s. Well, if we follow what went on in Africa, that’s the red bars here. There was a rapid rise in infections and although it’s fallen some in recent times it continues at a very high rate. What happened in the United States? There was a rapid rise in infections, the yellow bars came to a plateau level, has fallen quite significantly and now is at a steady, unacceptable rate of about 40,000 people a year in fact. Northern Europe -- basically Europe is basically the same picture. Latin America rose to higher levels stays at higher levels. And the remarkable change in recent times has been the rapid rise of infections in Asia, with India leading the way, other countries Thailand, other countries in Asia. And not on here, because this was actually made a year or two ago, we’ve even though it goes to 2000, is the former Soviet Union, which many people feel is the present exploding time bomb. Although the data from there is very poor because the medical surveillance is very poor.

Next slide. So the awful statistics that Ms. Ahmanson read though for you, my numbers are slightly different, everybody’s numbers are different because the numbers are not that precise. And anyway, it’s a snap shot of a moment in time is that something like 50 million people have been infected by this virus world wide, 16 million dead, 34 million people living with AIDS. I point out that four million of those are already in India and the epidemic is just getting going in India. Something like 15 thousand people a day infected, 5.5 million over a year. Something like 2.6 million people dying per year. That makes HIV among the leading infectious diseases of the world. Diseases we are used to thinking about malaria, tuberculosis killed roughly the same number of people. And the effect in Africa, where the epidemic has been longest and where the largest number of people infected is devastating in many countries with reductions in life expectancy greater than 20 years in many countries and serious disruptions of economic and social life.

Next slide please. So what can you do about an infection like this? You can try to get people to control their behavior. We know how HIV is transmitted. It’s transmitted sexually. It’s transmitted through people sharing needles. And we can encourage people to protect themselves by using clean needles, by protecting themselves during sexual encounters. We can use new forms, we can develop new forms of protection like Micorbisides (?) and we of course have condoms. We can help people get clean needles. All of these things including, of course, behavioral advice, which is critical here, all of these things are being tried, are being done and are affected and should be done more widely. But the right way to do it would be with a vaccine, vaccination of the population. And if we had the right kind of vaccine that would be harmless but would give people a protection for life. However what I want to say today is, that we’re very far from that. And so if you’re concerned about this issue, as for instance the World Health Organization is concerned, the World Bank is concerned, they must put their money, into on the one hand to research for a vaccine and on the other hand into methods of education and the dissemination of protection. Next slide please. Has the United States stood by? No, not at all. We have major research programs; we actually spend now, in the range of 2 billion dollars a year on HIV research. Of that, about ten percent or over 200 million, this is actually the number is about 239 million this year. This was an estimate a year or two ago. We spend more than the aggregate of the rest of the world. There is no vaccine program in the world that comes anywhere near close to what we do in the United States.

Next slide please. Now what do we want? We want a vaccine, which is broadly protective, which is safe, which can prevent either infection or disease, and I’ll come back to that. Which easily transported so that it can be brought and used in in under developed environments and it protects against both nucotial (?) and intravenous exposure. That’s what we need. That’s a big order but not impossible.

Let me just focus on infection or disease because that’s a point I’ll make over and over again. We tend to think of vaccines as preventing infection, they do not. Virtually, no, maybe no vaccine protects against infection. What happens is that you get infected with the virus but then the immune system remembers that it’s seen it previously and reacts faster, better than it would have if it, if you had not been vaccinated. So, vaccination is a way of developing a memory not actually providing a barrier against infection. So, all, really all vaccines present prevent disease not infection. And that’s critical for HIV. So the big question to us all is, can you prevent HJV disease with out preventing infection? And I’ll show you that you can.

Next slide. I’m not going to go into ethical considerations and testing considerations and market forces. Those are all big issues but they’re not the topic of tonight. Next slide please. So, when I was asked 1996 by the then director of the National Institutes of Health whether I would take on to run an advisory committee to the federal government on I-IIV vaccine development. We at that time had very fragmented programs. The programs were not getting the kind of advice they needed. We didn’t have kind of scientific involvement that we needed. And I asked myself the question at the top here. “Why do I have to, why do I think that a vaccine is possible?” Because I don’t think a vaccine is possible, I’m not going to start running committees and things to do the impossible. And there was around that time an experiment that said it was possible. It involved making, what called a live attenuated SLY. SLY is the simuino (?) deficiency virus, very similar to HIV but it infects monkeys rather than humans. So, it’s the model that we use for the development of vaccine. And a live attenuated virus, is a virus which actually is a live virus but has had mutations put into it, changes put into it so that it can’t cause disease but it can cause protection. And the saben (?) polio vaccine is a vaccine like that. So, this is nothing new. And some investigators developed a live attenuated SLY vaccine and showed that it could protect against wild type SLY, against viral SLY. And that was very exciting because here was the model; here was the direction to move. Over the next two or three years it became clear that this will not work in humans. And I’m not going to go into why but basically it’s not safe enough. It’s protective enough but not safe enough. So we had a model that said it would work but didn’t know how we were going to get it to work in humans and for a while I must say I began to wonder whether I really belonged in this business because I wasn’t sure that there was a route to making a vaccine.

Next slide please. I’m going to skip a bunch of these things because otherwise we’ll be here all night. And, but not this one because this shows the time course of HIV infection. So you imagine a person who’s been exposed to HIV, within a few weeks the amount of HIV in their blood starts rising very rapidly. And that’s the first indication that they’ve actually been infected. The same time, a key cell in the body, called the CD4 cell, begins to fall. And that’s because HIV infects those cells. It’s very selective for those cells. They’re key cells for the immune system. And then the virus hits a peak and falls. And this is actually here on a semi log scale; this fall is a hundred fold or a thousand fold. It’s an enormous fall. And the CD4 cells get better for a while and slowly the virus begins to creep back, the CD4 cells fall away and after what is now years because we have switched from weeks to years. The number of CD4 cells falls so far that the immune system can’t work anymore. And when that happens you start getting infections with other viruses, with bacteria, with fungi, cancer starts occurring and that’s the thing that actually kills people. HIV infection probably would not be lethal were it not for all of these other things that come into play. And we call this here the plateau because it’s more a constant level of virus even if it’s slightly going up in this particular rendition. And that plateau varies from person to person. One infected person may have a very high plateau, another person a very low plateau, and the variation can be a thousand fold.

Next slide please. Next slide. And if the plateau is very high as in this curve, then the patient will get AIDS, which is the viral infection that follows from HIV, fairly soon, within the first five years or so. If on the other hand, the plateau is very low, the individual won’t get AIDS for a very long time -- maybe never. And there are people with below the detection threshold and many of those have gone out 20 years without showing signs of AIDS. So, it is not uniformly lethal but it’s usually lethal. That’s only a few percent of people, the rest of them have plateau levels which are high enough which are high enough that they will get disease and generally die of the infection, unless treated with drugs.

Next slide. Now what we’d like to do is take this picture, which I went over for you before and by vaccination turn them into this picture. In which the CD4 cells don’t fall. In which the virus may go up a little bit but goes down to a very low plateau and the plateau is so low in the number of CD4 cells involved is so small that the individual can live for 20 years and maybe for a lifetime. We know many animals which get infected with HIV like viruses and live a lifetime without showing symptoms, so that’s no unreasonable. So, now we’ve asked the question, is there a vaccine that will do this. And as I’ve said before the only thing that looked like it was on the horizon was a live attenuated virus and that won’t work.

Next slide please. The late two months have seen the publication of two papers that provide hope that it is possible to make a live, to make a human vaccine. One is an experiment in monkeys, which uses a vaccine, which is based on pure DNA. DNA is, of course, the heredity material. DNA encodes proteins. It’s actually the proteins that provide the protection but one investigator and now I think others have shown that with a pure DNA vaccine given a little boast, which I won’t talk about. It is possible to protect monkeys against a highly pathogenic challenge and DNA is safe. So, translating this into the human situation, we don’t have to worry about safety. We will have to worry about whether the efficacy is as good as in monkeys. But we won’t have to worry about safety and this now will be tested by many people, pharmaceutical companies as well as public investigators over the next couple of years.

Now, you might say, well fine, monkeys work but how do you know humans can ever be protected? That experiment appeared a month or two ago. And it was done in a very odd way. The investigator, Bruce Walker, at Masters General Hospital in Boston, had been following a cohort of gay men for a very long time. And every once in a while one of them would come into him and say, I’m not feeling well and he would test them and realize that they’d gotten themselves infected. But he saw them very early after infection, earlier than most cases are ever caught because very few people are under this kind of surveillance. And so he had a small population of people who had been infected for a very short time and he treated those people aggressively with drugs right away. And their virus levels fell and have been maintained steadily at a low level over a long period of time. It’s not a prescription that we can carry out to our whole society and certainly not to Africa or to anywhere else -- but interesting experiment. And so he tired out a little test. He took a couple of these people and he stopped their drug treatment. In general they were people who were begging him to stop because the drug treatments are a terrible regimen that really controls your life. These people said, isn’t there any way maybe I’m all right, I feel all right, maybe I’m alright. So he said okay, we’ll stop; we’ll monitor you very, very carefully. And to his amazement, a number of those people did not get the virus back. If you do the same thing with people who are infected, who have been infected for a year or five years, that wouldn’t happen. We know that. People have been trying it for a while. And if you, some of them the virus came back he treated them again, went down to a low level, he stopped again for a little while and in some of those people it didn’t come back. And he now has a population of people who have, who are controlling their own virus; they’re almost certainly doing it through their immune system. And this is the first proof that it is possible to get a vaccine like state in humans. Now this is obviously something that we can do with everybody but again this is a proof of principle in humans. This suggests to us the route to go in humans. This is very exciting. This is a whole new world. How do you translate this into a vaccine? I can imagine it happening in five years I think it will probably take between five and ten years and there is no certainty that it will work because both of these are exciting but either one are real vaccinations and until we are trying to do the real thing, we can’t be sure. But this is exciting

Next slide please. Now how come they were able to make a vaccine using the DNA tricks in monkeys? To explain to you how come that works I got to do a little bit of immunology. So this is immunology 101, although it may sound a lot worse than that. We have three kinds of cells in our blood and in our lymph nodes that protect us and that make up the immune system or make up a large part of it, they’re called B-cells, T killer cells, and T helper cells. And whenever you are infected with a bacterium, or a virus or a fungus, the b cells go and make antibody. An antibody is a protein in your blood, freely soluble. And it protects you at every portal. It gets into the mucus membranes. It gets out throughout your body and it basically protects you against viruses and it’s what we induce with the polio vaccine or with the flu vaccine. The t-helper cells are the CD4 cells that I talked about before which HIV infect and they help the b-cells work and they also help a population of t-cells called “T-killer cells” and these are cells that go looking in your body for any cell that was infected by a virus and they kill it and they try to kill it early before it makes any new virus. So this is a very powerful form of protection. So we have two powerful forms of protection: anti-bodies and t-killer cells. All vaccines that have ever been made have focused on stimulating antibodies but as I will not tell you in any detail, but you’ll see that I have slides where I could tell you, HIV has found ways to make itself basically immune to antibodies. I should use the word “immune” because that’s confusing, basically “resistant” to antibodies. It coats itself with sugar, it puts variable loops in its protein—does all sorts of tricks that lead it to be insensitive to antibodies. So this part of the immune system is no good against HIV. Now, there are still people trying to prove me wrong when I say that and there are many ideas about how you might twig this system so it doesn’t do what it ordinarily does but does something more intelligent and I’m hopeful that one day one of those might work but right now no one in the world knows how to induce these in antibodies that will work against HIV. So, basically the whole history of vaccine research just went down the drain because that’s all we’ve ever done is to induce antibodies, but we have these t-killer cells. Actually they’re only very recently discovered—well, they were discovered maybe twenty years ago, but the properties of this system which are complicated have only been worked out in the last few years. One Nobel Prize was given for that and lot of people have contributed. And so, one of the reasons we’ve never focused a vaccine on t-killer cells is because we didn’t know they existed or we didn’t know how to stimulate them. Now we do and a DNA vaccine turns out to be a terrific way to do it. So this DNA vaccine is designed around stimulating the t-killer cells. A new kind of vaccine. So if in fact we make such a vaccine against HIV, it will be a brand new way of making a vaccine and now you get a sense of why it’s taking so long. We’ve had to learn new biology, we’ve had to learn new technology, we have to learn new forms of delivery and we have to do all of these things in a context of this raging disease around us. So, there is enormous urgency to move ahead.

Next slide, please. That’s a picture of HIV. We needn’t worry about it.

Next slide. Why don’t you just go quickly through a bunch. They’re all about antibodies and I’m not going to try to go through that. That’s the HIV surface protein, all the sugars are around here.

Next slide. That’s the one I wanted because I wanted just to tell you a little bit about how t-killer cells work. It isn’t anything like we ever imagined. It’s new biology of very recent times. So here’s a virus infected cell. Every time a virus gets into our body it finds cells and infects them—flu virus infects our respiratory tract, polio infects our gut, hepatitis virus infects our liver, and on and on. And the virus gets in very rapidly if it gets by the antibodies that are in there and it can make a thousand fold more of itself inside one cell. So its multiplication abilities are enormous. So, this body wants to get rid of it and so what the cell does that’s infected is it puts a flag on its surface. It says “help. I’m infected,” and what it carries on this flag is a little piece of the virus. That’s this red thing. So, here’s the flag carrier and there’s the little flag. It’s really a smart way of doing business although it took a long time to figure out what was going on because the t-killer cells come by and they look for these little flags. If they see the flag and actually they recognize the flag on a flag pole with their little receptor then they tell this cell to kill the virus infected cell and actually the cell can put this flag on its surface very soon after infection because it can take just the earliest consequences of infection, recognize them and put the flag on. So you get a dead cell and a consequence of this because this killer cell secretes material that just kills the cell its bond to and it’s very effective. So that’s what we’re trying to stimulate. We’re trying to basically produce a set of cells that have the memory necessary to recognize HIV specific flags so they can tell whether a cell is infected with HIV or not.

Next slide. So what can we use as vaccines that will do this? Well, if we go back and look at what people have been using for years. They’ve been using proteins. Proteins are a great way of inducing antibodies and so the first thing that people did when they wanted to use antibodies was to make virus proteins and put them into volunteers. Thousands of humans have had these proteins injected into them and they don’t work. They don’t make the right kind of antibodies. But the bulk of the time, since Margaret Heckler got up and said “A vaccine is around the corner,” the bulk of the time has been spent doing that which has been largely fruitless. How do you stimulate t-cells? Well, you stimulate them with ___(522)___ like for instance the pox virus, a vaccinia vaccine strain of virus and many viruses have been tried. You can do it in other ways, but the best way it turns out is with just pure DNA. It’s the safest, it’s the cheapest, very stable, we can use it in Africa, we use it anywhere and so a lot of attention is being put on that today, more attention than on any other modality.

Next slide, please. So this just give you an idea of how many tests have been done in people. Pox viruses have been tested in five different trials. This is actually old data. It’s more than that now. Other things have been tried and the proteins have been tried in thirteen trials, DNA which is nucleic acid, as of this time has only been tried at one trial. This was a year or two ago. But there are more trials now underway.

Next slide. Now I can’t leave this talk without mentioning one thing. All of you have heard about how HIV varies enormously and the reason that’s generally given for why you can’t make a vaccine is because there are so many different kinds of HIV and they keep changing their nature. All of that is true, but that isn’t why you can’t make a vaccine. This just give you an idea of the family tree of HIVs. There are all these different subgroups—subgroup A, B, C, D. There’re in different places. B is in the United States; E is in Africa, actually I think E is in Thailand. As you can see, the virus has been very busy mutating and changing itself, but I don’t think this is the key problem although it’s true that it exists.

Next slide. Finally, let me just finish up with the question that I raised at the beginning. Why is HIV so different than other viruses? Why can you control these other viruses and not HIV? And the answer actually is that there are two kinds of relationships that viruses have to us. One kind I call equilibrium relationship. It’s where the virus infects people, people transmit it to other people, other people transmit it further to other people and the viruses have been doing that for many millions of y ears or thousands of years. And so the virus has mutated itself to be a very comfortable part of our lives and we live with it, we generally don’t die from it, generally we get over it -the common cold is a perfect example. There are maybe a hundred different kinds of common cold viruses and periodically you get one of them and then we get well and we never get that one again. We get other ones later. Those are equilibrium viruses, but there are non-equilibrium viruses.

Next slide. There are viruses that have an equilibrium situation but its some other species not us. So influenza is actually a virus of birds and periodically it comes into the human population, generally through Asia which is why all the flu strains have names from Asia – Beijing and others, because they get it through pigs, but we don’t have to worry about that. So there’s constantly an influx of new flu viruses. Ebola virus, which you’ve been reading about maybe recently, is a virus which has some species that its endemic to, we don’t know what species that is, probably a rodent or a bat in Africa. It periodically gets into humans. It’s devastating. So the story about non-equilibrium viruses that get into humans; things that don’t belong to us is that they can be devastating and HIV is one of those. It came into the human population from monkeys. It hasn’t adapted so it’s still very virulent and dangerous. We can’t wait for the virus to adapt to us and us to adapt to the virus. My guess would be that if we were willing to wait over a thousand years maybe the virus would become less virulent, we’d develop resistance, but meanwhile the devastation would be so extraordinary that it would make the plague look like a simple problem. So we can’t wait. We have to develop a vaccine. I think we’re seeing the first light at the end of the tunnel and I’m glad to be able to say that, but right now if I had to give advice to people who are trying to control this devastation don’t depend on the vaccine coming along because we simply don’t know when that will be. We have to take protective measures and I must say that I am very impressed with how many of the leaders in Africa in just the last year or two have stepped up to the plate, developed prevention programs, and in fact are reducing transmission levels.

So with that, let me thank you all for your attention and I’ll be glad to take a couple of questions.