Document 11049208

<window type="generic" extraspaces="use" wordwrap="true" width="320" duration="01:10:15.11" bgcolor="#000000"> <center> <time begin="00:00:00.34"/><clear/>>> So good evening everyone on this beautiful spring day. <time begin="00:00:03.12"/><clear/>My name is Pat Thomas. <time begin="00:00:05.28"/><clear/>I'm the Knight Chair in Health and Medical Journalism at the Grady College <time begin="00:00:09.02"/><clear/>of Journalism and Mass Communication. <time begin="00:00:10.68"/><clear/>And I want to welcome you to the conclusion of season three of the Voices <time begin="00:00:16.97"/><clear/>from the Vanguard Global Diseases Lecture Series. <time begin="00:00:20.27"/><clear/>You know, I see a lot of familiar faces out there. <time begin="00:00:25.04"/><clear/>And we really appreciate those of you who have been impelled to come by your teachers, <time begin="00:00:31.69"/><clear/>or by your individual interest in these important topics. <time begin="00:00:36.70"/><clear/>I guess now we know that works. <time begin="00:00:40.18"/><clear/>These lectures are a collaborative venture between Dan Colley, the director of the Center <time begin="00:00:46.37"/><clear/>for Tropical and Emerging Global Diseases at UGA, <time begin="00:00:49.29"/><clear/>who's down in the front row, and my programs. <time begin="00:00:53.11"/><clear/>And we've just had a great time doing them, and we really appreciate you joining us for them. <time begin="00:01:00.55"/><clear/>Remember please, that we have a reception to follow the lecture, where you get a chance <time begin="00:01:05.61"/><clear/>to talk with our speaker in person. <time begin="00:01:09.63"/><clear/>Now tonight it's a real pleasure for me <time begin="00:01:11.54"/><clear/>to introduce Doctor Annie DeGroot to you. <time begin="00:01:15.13"/><clear/>The program notes will tell you that Dr. DeGroot was educated at Smith College, <time begin="00:01:21.85"/><clear/>and at the Pritzger School of Medicine at the University of Chicago, and that she trained <time begin="00:01:26.52"/><clear/>as a physician and a researcher at some of the top places in the country, <time begin="00:01:30.77"/><clear/>Tufts New England Medical Center, and the National Institutes of Health. <time begin="00:01:36.12"/><clear/>And you know that she teaches, and does research in Providence, Rhode Island, at Brown, <time begin="00:01:41.35"/><clear/>and now shifting to the University of Rhode Island campus there. <time begin="00:01:46.30"/><clear/>And you know that she founded a biotech company, and an international HIV vaccine foundation. <time begin="00:01:52.53"/><clear/>Just the typical kind of slacker that we like to have for these lectures. <time begin="00:01:58.32"/><clear/>But the inside front cover of a program is not near big enough to tell you all the things <time begin="00:02:03.08"/><clear/>that you might want to know about this fascinating woman, <time begin="00:02:06.64"/><clear/>who has been committed not just to science, but to social justice for many, many years. <time begin="00:02:14.25"/><clear/>And I'm pleased to have known her for about the last ten of those years. <time begin="00:02:18.10"/><clear/>One of the things that you won't really read in any detail here is some of the programs <time begin="00:02:23.98"/><clear/>that she's done domestically and internationally, that have to do with people <time begin="00:02:28.05"/><clear/>who are pretty much disenfranchised in our world. <time begin="00:02:30.82"/><clear/>And I'm thinking here about some of the health programs for incarcerated people <time begin="00:02:35.93"/><clear/>that Dr. DeGroot has been working in for the past ten years. <time begin="00:02:40.27"/><clear/>Along the way she founded a newsletter and a continuing medical education program <time begin="00:02:44.95"/><clear/>to help the healthcare providers who work <time begin="00:02:46.92"/><clear/>in prisons do a better job taking care of people with HIV and AIDS. <time begin="00:02:50.86"/><clear/>And this little newsletter which she started actually has some fourteen thousand subscribers <time begin="00:02:58.26"/><clear/>around the country. <time begin="00:02:59.53"/><clear/>And she told me over lunch today that it's also about to lose its funding, because you know, <time begin="00:03:04.96"/><clear/>people in prison, they have nothing to do with us. <time begin="00:03:08.35"/><clear/>Except the important thing to remember is that most people in prison come out of prison, <time begin="00:03:12.98"/><clear/>and live and walk among us, and prison is not Las Vegas, <time begin="00:03:16.99"/><clear/>and what happens there doesn't stay there, and it does have an impact on the rest of us. <time begin="00:03:21.87"/><clear/>On a different front, an entirely different front, <time begin="00:03:25.07"/><clear/>Dr. DeGroot founded the GAIA Vaccine Foundation, <time begin="00:03:29.44"/><clear/>which she started to help create a globally relevant HIV vaccine. <time begin="00:03:34.85"/><clear/>Not just a vaccine that would be helpful to those of us <time begin="00:03:37.90"/><clear/>in industrialized countries, but a vaccine for the world. <time begin="00:03:41.50"/><clear/>And furthermore, she wants to do this in a non-profit model, <time begin="00:03:45.91"/><clear/>so that the vaccine not only exists, but is accessible to the people who need it. <time begin="00:03:51.01"/><clear/>And this is actually not a crazy idea. <time begin="00:03:54.32"/><clear/>Back in 2006, the first ever lecturer in the first Voices <time begin="00:03:59.00"/><clear/>from the Vanguard lecture series was Victoria Hale, the founder of OneWorld Health, <time begin="00:04:04.53"/><clear/>a non-profit pharmaceutical company. <time begin="00:04:06.84"/><clear/>So we know that this can be done. <time begin="00:04:09.62"/><clear/>So let's get on with the show. <time begin="00:04:12.64"/><clear/>Dr. DeGroot is going to talk to us tonight about why it would be an enormous mistake, <time begin="00:04:18.57"/><clear/>even given all the bad news you've been reading about HIV vaccine development, <time begin="00:04:23.05"/><clear/>to abandon the quest for such a vaccine. <time begin="00:04:26.29"/><clear/>Dr. DeGroot. <time begin="00:04:27.51"/><clear/>[ applause ] <time begin="00:04:35.22"/><clear/>>> Well it's wonderful to be here, <time begin="00:04:36.60"/><clear/>and the weather is gorgeous, I can't believe you're inside. <time begin="00:04:39.62"/><clear/>So thank you for being with me tonight. <time begin="00:04:43.67"/><clear/>I hope that I will inform you and inspire you, mostly I want to inspire you. <time begin="00:04:49.15"/><clear/>I think it's important for all of us to be active, and to demand improvements in healthcare <time begin="00:04:55.77"/><clear/>for everyone, including people who have very limited access, whether they're here <time begin="00:05:01.39"/><clear/>in the United States, or whether they're in Africa, as this picture so graphically shows us. <time begin="00:05:06.97"/><clear/>So I'm going to talk about why we shouldn't abandon the ship, and we should stay on course, <time begin="00:05:14.02"/><clear/>and we should believe that there can be a new HIV vaccine. <time begin="00:05:16.94"/><clear/>And I'm going to talk a little bit about the work that we're doing to develop such a vaccine, <time begin="00:05:22.50"/><clear/>and kind of where we are in the process. <time begin="00:05:25.04"/><clear/>So first a frame, the picture I think you're familiar with the concept <time begin="00:05:30.06"/><clear/>that AIDS is killing a lot of people, in 2007 2.5 million people. <time begin="00:05:36.43"/><clear/>Five million people got infected, so more people are being infected every year than people <time begin="00:05:42.98"/><clear/>who are getting killed, which means that of course the global epidemic is expanding. <time begin="00:05:48.27"/><clear/>And of those, and if we continue this in this course, there'll be a hundred <time begin="00:05:53.79"/><clear/>and twenty million people dying of AIDS in 2010, in one year there will be a hundred <time begin="00:05:59.89"/><clear/>and twenty million people dying of AIDS. <time begin="00:06:02.35"/><clear/>And that's a pretty scary figure. <time begin="00:06:04.42"/><clear/>The other thing that's very concerning is that there are countries <time begin="00:06:08.56"/><clear/>that are disproportionately affected. <time begin="00:06:10.95"/><clear/>I'm sure from Jim Kim you heard that Africa and Asia are the hardest hit, with 70% of the people <time begin="00:06:18.67"/><clear/>in the world living in the sub Saharan area of the world, 70% of the people living with HIV, <time begin="00:06:26.07"/><clear/>living in sub Saharan Africa, and 95% living in developing world countries. <time begin="00:06:33.26"/><clear/>So what else is going on, children are being affected. <time begin="00:06:37.39"/><clear/>And if you go over to Africa, and you meet the kids who are bearing babies at the age <time begin="00:06:43.05"/><clear/>of twelve, you can understand why they might also be at risk for HIV infection. <time begin="00:06:48.18"/><clear/>So seven hundred thousand children, aged twenty-four or younger became infected with HIV <time begin="00:06:54.32"/><clear/>in 2007, sorry age fourteen or younger. <time begin="00:06:58.73"/><clear/>And of those, over 90% were babies. <time begin="00:07:02.57"/><clear/>And this is actually one of the great tragedies of HIV, that is that HIV positive mothers <time begin="00:07:08.73"/><clear/>who know that they're infected are at risk of transmitting HIV to their babies. <time begin="00:07:14.30"/><clear/>And if we know they're infected, there's actually means to prevent that from happening. <time begin="00:07:19.17"/><clear/>We know that that's true, because in the United States the number of children <time begin="00:07:24.17"/><clear/>who are actively infected with HIV as babies is dropping to near zero. <time begin="00:07:29.79"/><clear/>But more than six hundred thousand babies are acquiring HIV infection in Africa, <time begin="00:07:36.34"/><clear/>and that is a huge problem that's completely preventable. <time begin="00:07:40.14"/><clear/>So by the end of 2007, the impact on children has been dramatic. <time begin="00:07:47.24"/><clear/>Twenty million AIDS orphans, which is actually something that we will have to contend with, <time begin="00:07:51.85"/><clear/>because how those children are growing up in the developing world is unknown. <time begin="00:07:56.01"/><clear/>Who is going to be teaching them to become adults, what behaviors are they learning, <time begin="00:08:02.90"/><clear/>how are they going to become citizens of this society. <time begin="00:08:06.70"/><clear/>And that is something that has to be dealt with as a social disaster. <time begin="00:08:11.83"/><clear/>All of this in the context of the fact that we have treatment for HIV infection. <time begin="00:08:17.74"/><clear/>Treatment is cost saving. <time begin="00:08:19.81"/><clear/>You probably know also from Jim Kim that when Brazil made a decision to break the patents <time begin="00:08:26.94"/><clear/>on HIV drugs, and make their own HIV drugs, and spent the money to make those drugs, <time begin="00:08:33.72"/><clear/>and distributed them to people in Brazil who were HIV infected, they actually came back <time begin="00:08:39.59"/><clear/>and found out that after a few years they were saving money by treating people with HIV. <time begin="00:08:45.49"/><clear/>We know that we can save lives, and if you want to look at it in the most kind <time begin="00:08:49.76"/><clear/>of cost effective sense, we can save money by treating people with HIV. <time begin="00:08:55.55"/><clear/>But the problem is that the need for treatment outstrips available funds. <time begin="00:09:01.06"/><clear/>So the need grows every year. <time begin="00:09:03.00"/><clear/>You can see on this graph here that the bar is going up. <time begin="00:09:06.25"/><clear/>How much it will actually cost to treat people living with HIV infection is going up, <time begin="00:09:10.62"/><clear/>whereas funding has remained relatively flat. <time begin="00:09:14.63"/><clear/> <time begin="00:09:15.64"/><clear/>And when you put this actually in the context of other things that we spend money on, <time begin="00:09:20.42"/><clear/>we ask is this idea, this concept that everyone in the world should have access <time begin="00:09:25.37"/><clear/>to treatment for HIV, asking too much. <time begin="00:09:29.04"/><clear/>Are we caring about something that is simply not achievable on a dollars basis. <time begin="00:09:34.47"/><clear/>Well it has been projected by Jeff Sax, a noted economist, how much it would actually cost <time begin="00:09:40.70"/><clear/>to treat everyone in the world, if we were to make that decision. <time begin="00:09:44.45"/><clear/>And the total is 4.4 billion per year. <time begin="00:09:47.60"/><clear/>Is that a lot of money? <time begin="00:09:48.61"/><clear/>Well billion dollars sounds like a lot of money, <time begin="00:09:51.37"/><clear/>but in actuality we've spent already five hundred billion dollars in Iraq alone, <time begin="00:09:58.43"/><clear/>not counting Afghanistan, just talking about Iraq. <time begin="00:10:02.15"/><clear/>So when you put the numbers in context, you see that this is actually achievable. <time begin="00:10:06.13"/><clear/>It would cost twenty dollars per person in the United States, per year, <time begin="00:10:12.96"/><clear/>to treat everyone with HIV infection, and to me that seems like a totally achievable number <time begin="00:10:18.91"/><clear/>for which we have no leadership, and it is really leadership that we need. <time begin="00:10:24.06"/><clear/>The problem is that we don't have those medications, they're not getting <time begin="00:10:28.56"/><clear/>out to the people who need them, and this young child who lives in Sikoro, <time begin="00:10:33.73"/><clear/>which is where we're working in western Africa, has really no clinic to go to, <time begin="00:10:38.92"/><clear/>she has no doctor to go to, she has no medicine that's accessible to her. <time begin="00:10:44.50"/><clear/>She in fact, if she were to become sexually active doesn't have access to condoms, <time begin="00:10:49.34"/><clear/>because in west Africa to purchase a condom costs as much <time begin="00:10:53.75"/><clear/>as a meal, and most people choose to eat. <time begin="00:10:58.05"/><clear/>So her hope of preventing herself from getting HIV infected in the future becomes slim to none. <time begin="00:11:06.34"/><clear/>So a vaccine is really the best hope for HIV infection. <time begin="00:11:10.25"/><clear/>It is something that you could give to people, and prevent, <time begin="00:11:13.32"/><clear/>theoretically, HIV for the rest of their lives. <time begin="00:11:16.29"/><clear/>It could save millions of lives. <time begin="00:11:18.15"/><clear/>Even a vaccine that's not completely effective. <time begin="00:11:22.22"/><clear/>For example, what's shown here is if you had a 30% effective vaccine you could actually save <time begin="00:11:27.72"/><clear/>5.5 million lives. <time begin="00:11:30.20"/><clear/>A 70% effective vaccine would save twenty five million lives, oops, <time begin="00:11:35.32"/><clear/>my glasses, twenty eight million lives. <time begin="00:11:37.84"/><clear/>So you can see, even with a vaccine that's not 100% effective, we might actually be able <time begin="00:11:43.03"/><clear/>to save that little girl's lives in Sikoro, Mali. <time begin="00:11:47.20"/><clear/>Now why does it take so long to make an HIV vaccine. <time begin="00:11:50.99"/><clear/>We've known about HIV for years, since 1983 as a matter of fact. <time begin="00:11:55.92"/><clear/>Why does it take so long. <time begin="00:11:57.49"/><clear/>In truth, as many of you sitting in this audience who are biologists know, <time begin="00:12:01.32"/><clear/>it does take a long time, first to discover the pathogen, then to figure out what are the correlates <time begin="00:12:06.65"/><clear/>of immunity, what are the critical antigens, how to make the vaccine, <time begin="00:12:10.33"/><clear/>how to formulate it, how to test it. <time begin="00:12:12.00"/><clear/>And we'll talk about that a little bit. <time begin="00:12:13.89"/><clear/>Twenty five years is average. <time begin="00:12:16.29"/><clear/>But we are at that point right now. <time begin="00:12:18.83"/><clear/>And what you have heard in the news perhaps is <time begin="00:12:21.30"/><clear/>that the latest big vaccine trial, the Merck vaccine trial failed. <time begin="00:12:26.49"/><clear/>And so people are beginning to despair. <time begin="00:12:29.16"/><clear/>Will we ever have an HIV vaccine. <time begin="00:12:33.78"/><clear/>So let me just go over a few of the aspects of HIV. <time begin="00:12:37.31"/><clear/>I promise you not too much immunology, for those of you who are not aficionados, <time begin="00:12:41.83"/><clear/>and just enough for those of you who are. <time begin="00:12:44.00"/><clear/>But I want to talk about why it's so difficult to come to the point of making an HIV vaccine. <time begin="00:12:50.18"/><clear/>One of the reasons is that HIV is a retro virus. <time begin="00:12:53.61"/><clear/>It is a virus that makes RNA as its message. <time begin="00:12:57.11"/><clear/>And typically of most viruses that use that mechanism of transmitting their message <time begin="00:13:02.96"/><clear/>to their next generation, RNA is prone to making mistakes. <time begin="00:13:08.72"/><clear/>The process of replicating RNA is prone to making mistakes. <time begin="00:13:12.29"/><clear/>Another virus that is an RNA virus is Hepatitis C, <time begin="00:13:15.47"/><clear/>we don't have a vaccine for Hepatitis C either. <time begin="00:13:18.62"/><clear/>So when HIV gets into the cell, it basically uncoats, <time begin="00:13:23.82"/><clear/>it takes its RNA message out, it converts that into DNA. <time begin="00:13:27.23"/><clear/>The DNA actually can integrate into the host genome. <time begin="00:13:30.42"/><clear/>So people living with HIV have the HIV genes integrated into some of their cells, <time begin="00:13:36.89"/><clear/>where it can stay quiescent for a very long time. <time begin="00:13:40.88"/><clear/>And then once that cell becomes activated, then the genes start getting transcribed <time begin="00:13:45.79"/><clear/>and translated, making protein, making the virus, and then bursting out of the cell. <time begin="00:13:50.83"/><clear/>The biggest problem in HIV vaccine development is this. <time begin="00:13:55.25"/><clear/>When it enters the cell, normally you can make an antibody to protect against entry, <time begin="00:14:00.08"/><clear/>that's how we protect against many viral infections. <time begin="00:14:03.30"/><clear/>We make an antibody that blocks the entry. <time begin="00:14:07.30"/><clear/>The HIV virus has a special trap door. <time begin="00:14:10.86"/><clear/>When it approaches a cell, it opens that trap door, <time begin="00:14:13.99"/><clear/>and then a protein comes out, and allows it to enter. <time begin="00:14:16.88"/><clear/>That happens in a microsecond. <time begin="00:14:18.77"/><clear/>The space involved between the HIV virus and the target cell is so small, <time begin="00:14:24.98"/><clear/>that an antibody can't even actually fit into that space. <time begin="00:14:28.90"/><clear/>So no antibodies have ever been identified <time begin="00:14:31.76"/><clear/>that really effectively protect against HIV entry into the cell. <time begin="00:14:37.33"/><clear/>They are looking at single chain antibodies that might fit in there. <time begin="00:14:41.07"/><clear/>But basically, one of the biggest problems is how to protect using antibodies, <time begin="00:14:45.69"/><clear/>and it's not ever been shown to be effective with the exception <time begin="00:14:49.29"/><clear/>of just a few, which we can talk about later. <time begin="00:14:52.65"/><clear/>This is what a CD4T cell looks like, a target of the HIV virus. <time begin="00:14:57.79"/><clear/>The CD4T cell is the factory for HIV infection. <time begin="00:15:02.56"/><clear/>In fact, it makes, all of the T cells <time begin="00:15:05.32"/><clear/>in the body make a hundred billion new viral particles every day. <time begin="00:15:10.90"/><clear/>Now remember the other point about this, <time begin="00:15:13.02"/><clear/>each one of those particles might not actually be the same as the one that came before, <time begin="00:15:18.59"/><clear/>because this is an RNA virus, and it mutates. <time begin="00:15:22.82"/><clear/>The other point about this virus is that it attacks the T cells, <time begin="00:15:26.37"/><clear/>so that factory is destroyed in the process of creating new HIV particles. <time begin="00:15:32.72"/><clear/>The T cells decline, and then the person has immune paralysis. <time begin="00:15:37.05"/><clear/>Without T cells you can't fight off infection, that's why we have AIDS. <time begin="00:15:42.01"/><clear/>Now to go back to the concept of the HIV virus mutating, <time begin="00:15:46.27"/><clear/>this you probably are very familiar with the concept of evolution. <time begin="00:15:50.64"/><clear/>And in every HIV infected person's body, HIV evolution is going on. <time begin="00:15:57.39"/><clear/>What happens in the person's body is the virus is mutating, it's trying out new forms. <time begin="00:16:02.56"/><clear/>If an immune response occurs to the virus, then it will mutate away from that immune response, <time begin="00:16:08.22"/><clear/>and become immune to the body's attempt to fight it down. <time begin="00:16:14.03"/><clear/>So the host cell is infected, the virus is being produced, the virus is mutating, <time begin="00:16:21.46"/><clear/>the immune response is occurring, and yet it is ineffective. <time begin="00:16:27.05"/><clear/>There are two processes between HIV evolution, and one is drift, <time begin="00:16:31.09"/><clear/>and the other one is selection for more fit virus variance. <time begin="00:16:33.98"/><clear/>When we first started talking about this in 1996, <time begin="00:16:37.03"/><clear/>people were unsure that this actually went on. <time begin="00:16:40.11"/><clear/>But in point of fact now, we know that due to the mutation of the HIV virus, <time begin="00:16:45.26"/><clear/>that it is able to create versions of itself that completely escape the immune response. <time begin="00:16:51.63"/><clear/>How does that happen? <time begin="00:16:53.12"/><clear/>This is a picture, for those of you who like graphics, of a virus entering a cell, <time begin="00:16:58.31"/><clear/>the target cell, which is the CD4T cell, and then it's making more copies of itself. <time begin="00:17:03.36"/><clear/>That cell is actually, when it's able to present immune information to the immune system, <time begin="00:17:10.05"/><clear/>is breaking up the virus, and presenting at the surface of the cell a very small piece <time begin="00:17:15.08"/><clear/>of the virus called a peptide, or a peptide epitope. <time begin="00:17:19.07"/><clear/>It is just a nine amino acid sequence that is derived <time begin="00:17:22.72"/><clear/>from the viral proteins presented on the surface of the cell. <time begin="00:17:26.36"/><clear/>That peptide epitope is recognized by a T cell, that's where all the action happens. <time begin="00:17:31.56"/><clear/>Once the T cell, as shown in this picture, recognizes the viral epitope on the surface <time begin="00:17:36.82"/><clear/>of the target cell, then it will try to kill that cell. <time begin="00:17:40.89"/><clear/>So what does the HIV virus do? <time begin="00:17:43.19"/><clear/>But it changes its epitopes. <time begin="00:17:46.00"/><clear/>And that's actually shown in this slide. <time begin="00:17:48.84"/><clear/>What happens in the course of a single person's infection, if you follow this sequence <time begin="00:17:54.63"/><clear/>of the HIV virus from the point that their infected, to just several years later, <time begin="00:18:00.24"/><clear/>you can see that their virus evolves, and it evolves variance <time begin="00:18:05.06"/><clear/>with mutant epitopes that escape the immune response. <time begin="00:18:09.85"/><clear/>This is a picture of the sequence of a child infected in Philadelphia at birth. <time begin="00:18:15.76"/><clear/>And only four years later you can see how many different sequences <time begin="00:18:19.59"/><clear/>of HIV are circulating in this child's body. <time begin="00:18:24.13"/><clear/>This has also happened worldwide. <time begin="00:18:26.57"/><clear/>What happens in a child happens in a population. <time begin="00:18:30.32"/><clear/>So within a population, HIV again is trying <time begin="00:18:33.57"/><clear/>to escape the immune responses of the collective population. <time begin="00:18:37.14"/><clear/>The result is that in different regions of the world, different variants of HIV have emerged. <time begin="00:18:44.30"/><clear/>These are called clades. <time begin="00:18:46.64"/><clear/>In the United States we have clade B, in Europe clade B, in Africa which is the epicenter <time begin="00:18:52.07"/><clear/>of the epidemic we have five, six, ten different clades. <time begin="00:18:56.47"/><clear/>In a single country, Mali where I work, the clades are mixed, and you have both the A <time begin="00:19:01.27"/><clear/>and the G clade circulating in the population. <time begin="00:19:05.92"/><clear/> <time begin="00:19:07.11"/><clear/>This is a dramatic problem in terms of making an HIV vaccine, <time begin="00:19:12.22"/><clear/>cause you can't make a vanilla vaccine and expect it to protect against chocolate. <time begin="00:19:16.61"/><clear/>It simply isn't going to work. <time begin="00:19:18.75"/><clear/>This picture actually shows how great the variation of the HIV virus has been, <time begin="00:19:25.64"/><clear/>compared to one of the viruses that we are most afraid of, which is the flu virus, <time begin="00:19:30.73"/><clear/>shown over in the corner of the picture right here, I don't have a pointer do I? <time begin="00:19:35.27"/><clear/>I don't think so. <time begin="00:19:37.90"/><clear/>But you can see there's a little dot over in the corner of the picture over here, <time begin="00:19:43.00"/><clear/>and that shows you how variable the flu virus is in the course of a year, <time begin="00:19:49.18"/><clear/>compared to the expanding sequences of HIV. <time begin="00:19:52.48"/><clear/>When we really think about this, it's amazing that HIV can hold itself together. <time begin="00:19:56.77"/><clear/>How can it be so variable and still function as the same virus. <time begin="00:20:01.22"/><clear/> <time begin="00:20:02.26"/><clear/>So this is really, summarizes the immunopathogenesis, <time begin="00:20:05.93"/><clear/>the generation of the bad immune response to HIV, from the vaccine perspective. <time begin="00:20:12.43"/><clear/>First of all, the near impossible task of preventing HIV entry makes it difficult <time begin="00:20:18.58"/><clear/>to make the most standard type of vaccine against HIV, <time begin="00:20:21.77"/><clear/>which would be an antibody directed vaccine. <time begin="00:20:25.56"/><clear/>The HIV variability is also a huge problem, <time begin="00:20:29.30"/><clear/>because if the immune system must recognize those epitopes that are presented on the surface <time begin="00:20:34.01"/><clear/>of the target cell, and the virus mutates the epitopes, the T cells can't keep up, <time begin="00:20:39.65"/><clear/>they can't keep on recognizing an HIV that is mutating away from their immune response. <time begin="00:20:46.01"/><clear/>The other problem is latency. <time begin="00:20:47.67"/><clear/>You may be able to clear HIV infection with drugs in the body, <time begin="00:20:51.60"/><clear/>but there's always the coding sequence for HIV hiding inside of a cell, <time begin="00:20:56.56"/><clear/>waiting for the cell to be activated. <time begin="00:20:58.23"/><clear/>So you can't clear HIV, it's very difficult. <time begin="00:21:02.20"/><clear/>The other problem with HIV is that it destroys the very immune system <time begin="00:21:05.82"/><clear/>that we use to fight it off. <time begin="00:21:07.93"/><clear/>So the T cell which is the target of HIV infection is also the cell that is destroyed, <time begin="00:21:13.16"/><clear/>and leads to the disease that is known as AIDS. <time begin="00:21:18.30"/><clear/>So those are all huge problems in terms of HIV vaccine development. <time begin="00:21:23.51"/><clear/>So what do we think we can possibly do. <time begin="00:21:27.80"/><clear/>There are ways that we could perhaps develop a vaccine, <time begin="00:21:31.32"/><clear/>and that's what I'm going to get into right now. <time begin="00:21:33.52"/><clear/>We're thinking that one of the ways <time begin="00:21:35.15"/><clear/>that we could possibly direct our HIV vaccine effort is to prevent infection. <time begin="00:21:40.49"/><clear/>And one of the greatest problems with that is that most of our preventive vaccines, <time begin="00:21:45.07"/><clear/>like the Hepatitis B vaccine, or the cervical cancer vaccine that you've heard <time begin="00:21:49.22"/><clear/>about are based on antibody response. <time begin="00:21:52.29"/><clear/>Most vaccines that prevent infection are based on antibody. <time begin="00:21:56.56"/><clear/>So it's difficult to conceive of an HIV vaccine <time begin="00:22:00.18"/><clear/>that could actually be effectively prevent infection. <time begin="00:22:04.63"/><clear/>So now we're thinking perhaps a vaccine might be able to prevent disease, <time begin="00:22:09.36"/><clear/>meaning yes you still get infected, but then we're able to control the infection, <time begin="00:22:14.31"/><clear/>and we turn you into a person who has HIV infection, but may be like having diabetes <time begin="00:22:19.53"/><clear/>or high blood pressure, you live with the disease rather than being killed by it. <time begin="00:22:24.01"/><clear/>The other thing that is a potential goal for a vaccine is preventing secondary transmission. <time begin="00:22:29.48"/><clear/>So preventing transmission from one person to another by lowering the amount of the virus <time begin="00:22:34.37"/><clear/>so it doesn't get transmitted during sexual intercourse. <time begin="00:22:37.57"/><clear/>So let's talk a little bit about the different types of vaccines, and then I'm going to talk <time begin="00:22:43.99"/><clear/>about why the Merck vaccine has been such a failure. <time begin="00:22:47.39"/><clear/>The ways that we can work on vaccines are shown here, and I'm just going to first talk <time begin="00:22:52.84"/><clear/>about the simplest approach to making an HIV vaccine, which is what scientists seized upon <time begin="00:22:59.32"/><clear/>in the 1980s when the virus was first identified. <time begin="00:23:03.43"/><clear/>And that is if you look at the surface of this virus, you can see a knob on the surface, <time begin="00:23:07.41"/><clear/>that's called the envelope protein. <time begin="00:23:09.53"/><clear/>When people saw that it had an envelope protein they thought ah, this is just like Hepatitis B, <time begin="00:23:14.91"/><clear/>we can simply sequence that protein, create a whole lot of it in a big vat, make just tons <time begin="00:23:20.30"/><clear/>and tons of this particular protein called GP120, and we can inject that into people, <time begin="00:23:26.38"/><clear/>and we will create an effective antibody response. <time begin="00:23:29.93"/><clear/>By now you should be familiar with the two things that absolutely make that impossible. <time begin="00:23:35.23"/><clear/>So one is the variation of the virus. <time begin="00:23:37.32"/><clear/>This particular envelope protein is the most variant protein in the whole virus. <time begin="00:23:43.51"/><clear/>So maybe it's not so simple to select one single protein that will be effective <time begin="00:23:48.44"/><clear/>against all strains of HIV, that would be problem number one. <time begin="00:23:52.48"/><clear/>And problem number two is that nobody's been able to figure <time begin="00:23:56.04"/><clear/>out what antibody can effectively prevent entry into the cell. <time begin="00:24:01.40"/><clear/>So there are the two problems with that approach. <time begin="00:24:04.25"/><clear/>Nonetheless, as Pat Thomas says in her book, Hot Shots, nonetheless, <time begin="00:24:09.88"/><clear/>even though most scientists were well aware that that approach would not work for HIV, <time begin="00:24:15.91"/><clear/>vaccines were developed, trials went forward, people volunteered all over the world <time begin="00:24:22.35"/><clear/>for the VaxGen trial that came off about two years ago. <time begin="00:24:25.73"/><clear/>And were we surprised that the results were that there was absolutely no protective effect? <time begin="00:24:32.37"/><clear/>Most of the scientists in the field were not surprised at all. <time begin="00:24:36.60"/><clear/>VaxGen went on to capture some defense money, <time begin="00:24:40.20"/><clear/>and is now making Smallpox vaccine somewhere on the west coast. <time begin="00:24:44.28"/><clear/>But that particular vaccine effort completely failed. <time begin="00:24:48.59"/><clear/>At that point, what do we do as scientists? <time begin="00:24:51.53"/><clear/>We go well, maybe that didn't work, we'll try something else. <time begin="00:24:55.12"/><clear/>So two of the leaders of the NIH vaccine effort, Peggy Johnson, a good friend of mine, <time begin="00:25:00.37"/><clear/>and Tony Fauci, who is the director of the division of Aids, <time begin="00:25:04.08"/><clear/>decided that perhaps we would have to think about a different way of making an HIV vaccine, <time begin="00:25:09.10"/><clear/>maybe a less than perfect vaccine would be okay. <time begin="00:25:12.79"/><clear/>Maybe something that didn't completely prevent infection, <time begin="00:25:15.62"/><clear/>but actually diminished disease would be something that would be acceptable. <time begin="00:25:20.41"/><clear/>And the reason for this is that we know that some people can actually control HIV infection. <time begin="00:25:25.98"/><clear/>There are people who are living with HIV today, <time begin="00:25:29.14"/><clear/>twenty years after being infected, who have never been ill. <time begin="00:25:33.19"/><clear/>Something about their body allows them to contain the HIV infection, <time begin="00:25:38.17"/><clear/>and so people started looking into that. <time begin="00:25:40.31"/><clear/>They measured the amount of virus in their blood, and they saw that if you had a low load, <time begin="00:25:45.11"/><clear/>or viral load of HIV virus, then you were a controller, <time begin="00:25:49.20"/><clear/>somebody who was an elite controller they're called. <time begin="00:25:52.60"/><clear/>And this is what people started to study. <time begin="00:25:55.52"/><clear/>They found, low and behold, that probably the most important correlate of protection <time begin="00:26:01.61"/><clear/>from disease was T cell mediated immune response. <time begin="00:26:06.36"/><clear/>The T cells, those same T cells recognizing epitopes, <time begin="00:26:10.11"/><clear/>sometimes were able to keep the virus in check. <time begin="00:26:14.09"/><clear/>So people started working on T cell mediated vaccines, instead of antibody mediated vaccines. <time begin="00:26:21.51"/><clear/>And this illustrates a complete shift in terms of the vaccine paradigm. <time begin="00:26:26.19"/><clear/>Most of the time we think about a vaccine that protects completely against infection, <time begin="00:26:31.32"/><clear/>that's what's shown in the second panel here. <time begin="00:26:33.53"/><clear/>You would have a virus entering the body, and absolutely no virus ever occurs, <time begin="00:26:40.09"/><clear/>because you get clearance with the antibody. <time begin="00:26:43.31"/><clear/>A second type of vaccine would either give a very low amount of virus, <time begin="00:26:47.35"/><clear/>or give you a lower level of virus than complete protection. <time begin="00:26:53.23"/><clear/>And that's actually what was proposed in 2002, in Barcelona, <time begin="00:27:00.20"/><clear/>and that is to basically lower the viral load with a vaccine. <time begin="00:27:04.62"/><clear/>This just recalls what happens in HIV infection. <time begin="00:27:07.53"/><clear/>You get an acute infection which drops your T cell count. <time begin="00:27:11.15"/><clear/>They come back up, and then they slide down towards AIDS. <time begin="00:27:14.71"/><clear/>The CDAT cells are preserved, the viral load varies, <time begin="00:27:19.16"/><clear/>generally is low in chronic HIV infection, but eventually at the end when AIDS occurs, <time begin="00:27:24.21"/><clear/>and there's a complete immune suppression comes up. <time begin="00:27:27.36"/><clear/>So the idea would be that we would be trying to lower the viral load <time begin="00:27:30.76"/><clear/>to prolong life, and limit the impact. <time begin="00:27:34.35"/><clear/>There's actually good data showing that people who have lower viral loads live much longer. <time begin="00:27:40.95"/><clear/>So people who have, as shown on this slide, less than a certain number <time begin="00:27:45.90"/><clear/>of copies per CC are more likely to survive, <time begin="00:27:51.49"/><clear/>89% surviving if they have less than five thousand copies. <time begin="00:27:55.04"/><clear/>Whereas people who have thirty six thousand copies in their blood, <time begin="00:27:58.91"/><clear/>62% of those people are dead within the next five years. <time begin="00:28:02.79"/><clear/>So a vaccine that can lower viral load is one of the targets that we're trying to achieve. <time begin="00:28:08.48"/><clear/>This was actually described at the Barcelona conference in 2002, <time begin="00:28:13.34"/><clear/>and the idea was that we would be trying <time begin="00:28:15.44"/><clear/>to make a T cell mediated vaccine that would contain infection. <time begin="00:28:20.03"/><clear/>There is good data that this would actually protect against transmission. <time begin="00:28:24.36"/><clear/>Remember that's one of the goals of the virus, of the vaccine that we'd like to develop. <time begin="00:28:29.22"/><clear/>This is a study that was done in Rakai, <time begin="00:28:31.70"/><clear/>where they looked at discordant couples, one person with HIV, <time begin="00:28:35.37"/><clear/>the other person either a spouse or a partner, without HIV, and they looked at the virus load <time begin="00:28:40.97"/><clear/>in the person who had the HIV infection. <time begin="00:28:43.09"/><clear/>They're more likely to transmit to their partner if their viral load is high, <time begin="00:28:47.85"/><clear/>and less likely to transmit if their viral load is low. <time begin="00:28:52.09"/><clear/>And people have actually modeled, mathematical modelers have projected <time begin="00:28:56.25"/><clear/>that a partially effective vaccine might actually be able to reduce HIV transmission <time begin="00:29:01.20"/><clear/>in a population, and eradicate HIV, get the HIV transmission below that magic number <time begin="00:29:07.61"/><clear/>that allows it to continue to propagate in a population. <time begin="00:29:11.32"/><clear/>So then what became the focus? <time begin="00:29:15.93"/><clear/>Well the focus became T cell mediated vaccines. <time begin="00:29:18.90"/><clear/>Here are some of the approaches that people have looked at, <time begin="00:29:21.99"/><clear/>and I'm really just going to talk briefly about live recombinant vectors. <time begin="00:29:26.40"/><clear/>These are virus packages that contain the genes from HIV infection, <time begin="00:29:30.67"/><clear/>and the particular virus package that was chosen by Merck is the adenovirus. <time begin="00:29:37.29"/><clear/>That's the standard cold virus, most of us have actually been infected with adenovirus. <time begin="00:29:41.83"/><clear/>They used this as the package to deliver the genes from HIV <time begin="00:29:45.70"/><clear/>to create an immune response that was T cell mediated. <time begin="00:29:50.44"/><clear/>They studied this vaccine all over the world. <time begin="00:29:54.34"/><clear/>The studies actually started about three or four years ago. <time begin="00:29:57.53"/><clear/>A large phase three trial 2B, actually a 2B trial, <time begin="00:30:02.44"/><clear/>which is a particular type of clinical trial. <time begin="00:30:05.01"/><clear/>They enrolled about six thousand people in different regions of the world, <time begin="00:30:08.96"/><clear/>and in parallel there was a study in South Africa with the same strain, <time begin="00:30:14.36"/><clear/>the same particular vaccine, but being performed by the HVTN, the HIV vaccine trial network. <time begin="00:30:21.14"/><clear/>Most of these studies are actually paid for by the U.S. government, <time begin="00:30:24.60"/><clear/>even though Merck made the vaccine. <time begin="00:30:27.49"/><clear/>Now a note about this particular vaccine. <time begin="00:30:30.56"/><clear/>This vaccine is a clade B vaccine. <time begin="00:30:34.17"/><clear/>It is not developed for other regions of the world, it does not contain epitopes, <time begin="00:30:41.18"/><clear/>those little messages to the immune system that represent the flavors of HIV <time begin="00:30:46.29"/><clear/>that are being transmitted in Africa. <time begin="00:30:48.92"/><clear/>And yet it's being studied in Africa. <time begin="00:30:51.52"/><clear/>From what I've just told you, you would think that even generating an immune response <time begin="00:30:57.09"/><clear/>against a clade B virus, it would be unlikely to protect against the clade C's that are found <time begin="00:31:04.38"/><clear/>in south Africa, because the epitopes are not the same. <time begin="00:31:08.66"/><clear/>Merck waved its hands, did some fancy T cell assays with lots of overlapping peptides, <time begin="00:31:16.23"/><clear/>and came up with an answer that seemed to suggest there might be enough cross reactivity <time begin="00:31:21.47"/><clear/>with the whole genes that they were expressing, to perhaps protect. <time begin="00:31:26.63"/><clear/>And they argued that this might be a good idea to at least test this vaccine, <time begin="00:31:31.29"/><clear/>and see if we could get protection against different strains of HIV. <time begin="00:31:37.01"/><clear/>Now I also want to note that most of the pre-clinical studies are done in monkeys, <time begin="00:31:42.17"/><clear/>non-human primates, that are infected with not HIV, but a strain of monkey virus, SIV. <time begin="00:31:49.06"/><clear/>And whenever they're testing vaccines in these monkeys, they usually immunize <time begin="00:31:54.36"/><clear/>with the vanilla flavor, and then they challenge with the vanilla flavor, <time begin="00:31:59.94"/><clear/>and when they get protection they go oh, we can protect monkeys from HIV infection, <time begin="00:32:04.82"/><clear/>or SIV infection, therefore we should go ahead and do studies in humans. <time begin="00:32:09.42"/><clear/>There are very few studies in monkeys that have been performed with the type <time begin="00:32:15.10"/><clear/>of variation that exists in the real world. <time begin="00:32:18.32"/><clear/>So again, the scientists have been concerned, and they have said you're vaccinating <time begin="00:32:24.35"/><clear/>with clade B, that makes sense, you're a Merck, you're gonna be making a vaccine <time begin="00:32:28.60"/><clear/>for the United States of America where you can sell it for lots of money. <time begin="00:32:31.67"/><clear/>You're really not that interested about making a vaccine for other areas <time begin="00:32:34.95"/><clear/>of the world, we understand that. <time begin="00:32:37.06"/><clear/>You argue that it will provide protection, but the scientists were very concerned. <time begin="00:32:41.87"/><clear/>They were concerned there wasn't going to be enough breadth of immune response, <time begin="00:32:45.23"/><clear/>and that there wasn't going to be protection in this trial. <time begin="00:32:48.56"/><clear/>So the news was not surprising to many of us in September, and then in November <time begin="00:32:55.03"/><clear/>when the data finally came out that there was absolutely no protection. <time begin="00:32:58.94"/><clear/>The two trials that I talked to you about, the Merck study that was in north and south America, <time begin="00:33:03.63"/><clear/>and then this South African study were both discontinued. <time begin="00:33:07.95"/><clear/>But even worse, even worse, and I'll show you what actually happened. <time begin="00:33:13.51"/><clear/>And that is as shown here, people who got the vaccine were more likely to come down with HIV. <time begin="00:33:23.37"/><clear/>This is about the worst possible outcome for a vaccine trial. <time begin="00:33:27.40"/><clear/>Imagine you're a vaccinologist, you're me, I'm standing up here, and I'v just told you <time begin="00:33:32.93"/><clear/>that people who got a vaccine, and not placebo, were more likely to get HIV. <time begin="00:33:39.71"/><clear/>This is the worst possible outcome. <time begin="00:33:42.04"/><clear/>The numbers were small, so here you can actually see in the vaccine arm, <time begin="00:33:47.26"/><clear/>forty nine people got infected out of about six hundred when they broke the code here. <time begin="00:33:52.02"/><clear/>And in the placebo arm, thirty three got infected. <time begin="00:33:55.65"/><clear/>And it turned out, what was very strange about this particular study was that the people <time begin="00:34:01.68"/><clear/>who had high pre-existing antibody titers to the adenovirus, <time begin="00:34:05.84"/><clear/>the package that they had put the HIV genes in, <time begin="00:34:09.05"/><clear/>were more likely to get HIV when they were exposed to it. <time begin="00:34:13.44"/><clear/>So twenty one people out of the high adenovirus titer group were infected, <time begin="00:34:19.16"/><clear/>whereas only nine of the placebo group. <time begin="00:34:22.05"/><clear/>So there was something about the reaction to the vector that made people more susceptible <time begin="00:34:26.82"/><clear/>to getting HIV if they got the vaccine. <time begin="00:34:30.09"/><clear/>So they stopped the study, they actually do this as a standard in all clinical trials. <time begin="00:34:34.55"/><clear/>They have what's called a data safety monitoring board that looks at the data to determine to see <time begin="00:34:39.99"/><clear/>if there's any problem with the vaccine as the trial is going on. <time begin="00:34:45.49"/><clear/>They stop the studies, and they started trying to think about what was actually going on. <time begin="00:34:50.77"/><clear/>And I'm only going to present to you a summary slide, because I you know, <time begin="00:34:54.61"/><clear/>there's so much data coming out about this, I just want to really hit the time points. <time begin="00:34:58.96"/><clear/>And basically what they looked at was how the study was designed. <time begin="00:35:03.27"/><clear/>They looked at both groups, the placebo group and the vaccine group. <time begin="00:35:07.21"/><clear/>They saw no behavioral differences, that was almost the first question that they wanted <time begin="00:35:12.17"/><clear/>to ask, were the people in the vaccine group taking more risks and more likely <time begin="00:35:17.05"/><clear/>to be HIV infected than the people in the placebo group? <time begin="00:35:20.31"/><clear/>Both the doctors and the patients and the subjects were blinded, <time begin="00:35:23.62"/><clear/>nobody knew which person got placebo and which person got vaccine. <time begin="00:35:27.42"/><clear/>But when they unblinded the study, they found no differences in terms of risk behavior. <time begin="00:35:32.17"/><clear/>So it wasn't a behavioral issue. <time begin="00:35:35.43"/><clear/>They also looked at some of their intermediate study goals, <time begin="00:35:40.08"/><clear/>one was to either prevent infection, clearly that didn't happen, and they also looked to see <time begin="00:35:45.32"/><clear/>if there was a lower viral set point, the amount of virus <time begin="00:35:48.42"/><clear/>in the blood after infection was decreased. <time begin="00:35:51.10"/><clear/>And I'll show you a little note about that in a minute, but in general there was no difference. <time begin="00:35:56.07"/><clear/>The people who got HIV infection in the placebo group got just as much virus <time begin="00:36:00.43"/><clear/>as the people who got the vaccine. <time begin="00:36:01.89"/><clear/>So there was no difference in terms of the initial control of HIV infection. <time begin="00:36:07.67"/><clear/>There was clearly more infections in the vaccines than placebos. <time begin="00:36:12.23"/><clear/>This is a dramatic problem for HIV vaccine trials. <time begin="00:36:15.81"/><clear/>Imagine you're the next HIV vaccine volunteer, you're signing up for the vaccine trial, <time begin="00:36:20.58"/><clear/>and the researcher is trying to convince you to participate, when in fact you know, <time begin="00:36:26.08"/><clear/>it's been in the paper that the last vaccine trial caused people to get infected. <time begin="00:36:30.77"/><clear/>Are you going to sign up for that? <time begin="00:36:32.19"/><clear/>I think people are going to be a little bit hesitant. <time begin="00:36:34.90"/><clear/>So there's a huge amount of work to do in fact, around vaccine trials, <time begin="00:36:39.62"/><clear/>and a lot of basic research that actually needs to be done. <time begin="00:36:43.66"/><clear/>The lack of efficacy did not appear to be explained <time begin="00:36:46.56"/><clear/>by suboptimal immune responses to the vaccine. <time begin="00:36:49.70"/><clear/>So people did get T cell responses, u7 I think that's in this slide. <time begin="00:36:54.10"/><clear/>Now I have to note here as an immunologist, these are not whopping T cell responses. <time begin="00:36:59.96"/><clear/>You can see here that they did pools, they looked at pools of peptides from the HIV virus, <time begin="00:37:05.53"/><clear/>and you can see to the different proteins the average response was really one pool. <time begin="00:37:11.98"/><clear/>Most people only responded to one pool of peptides, overall the average was three. <time begin="00:37:17.37"/><clear/>This is probably not going to be effective. <time begin="00:37:21.01"/><clear/>If you think about how variable the HIV virus is, and how many different pieces <time begin="00:37:25.89"/><clear/>of information it can show to the immune system, what we're saying here is <time begin="00:37:30.92"/><clear/>that this vaccine caused three pieces of HIV to be recognized by the immune system, <time begin="00:37:37.14"/><clear/>in a virus that starts mutating the minute it hits your body. <time begin="00:37:42.00"/><clear/>Recognizing three pieces of HIV is not going to be enough. <time begin="00:37:47.40"/><clear/>So I think that that's probably one of the main problems here, and what we actually think is <time begin="00:37:53.68"/><clear/>that there's going to be a difference between the vaccine epitope, <time begin="00:37:56.95"/><clear/>remember they picked vanilla as the flavor that they wanted to vaccinate against. <time begin="00:38:01.53"/><clear/>And if you're coming in with a different strain of HIV, the epitope, <time begin="00:38:04.99"/><clear/>the piece of information presented to the immune system is going to be different. <time begin="00:38:09.43"/><clear/>So you might as well not get vaccinated, because what the immune system is going <time begin="00:38:13.93"/><clear/>to see is a different kind of HIV than the one it was trained to recognize. <time begin="00:38:19.82"/><clear/>And that's actually what they're thinking in terms of this particular vaccine, <time begin="00:38:24.22"/><clear/>possibly, that the challenge virus was different enough from the vaccine virus <time begin="00:38:31.54"/><clear/>that we will not see protection. <time begin="00:38:35.86"/><clear/>And that's what I'm trying to point out here, is that when the challenge virus gets <time begin="00:38:40.69"/><clear/>into those cells, they start presenting the information to the immune system, <time begin="00:38:45.10"/><clear/>the T cell's looking around for the vaccine that it was trained to recognize, <time begin="00:38:48.93"/><clear/>and it doesn't recognize the HIV infection, so it's not able to protect. <time begin="00:38:54.93"/><clear/>How will we know this? <time begin="00:38:56.08"/><clear/>We'll know this by studying the people who were somewhat protected. <time begin="00:38:59.41"/><clear/>And this actually shows that in the vaccine, in the vaccine group there was actually some, <time begin="00:39:06.38"/><clear/>a number of people who had very low viral loads after infection. <time begin="00:39:10.01"/><clear/>So they were somehow able to contain the infection. <time begin="00:39:13.69"/><clear/>That tells us that perhaps their T cells actually recognize the challenge virus <time begin="00:39:18.62"/><clear/>that they were challenged with. <time begin="00:39:20.05"/><clear/>So they're going to look at their T cell responses, they're going to sequence the virus <time begin="00:39:23.93"/><clear/>that they were infected with, and they're going to compare that to the vaccine strain. <time begin="00:39:27.83"/><clear/>I will bet anyone in this room lunch that the epitopes in the vaccine are the same as the one, <time begin="00:39:34.00"/><clear/>as the HIV they were infected with, <time begin="00:39:35.97"/><clear/>and therefore they were able to control the infection. <time begin="00:39:39.13"/><clear/>But we know this. <time begin="00:39:40.39"/><clear/>We already know that HIV mutates, that three T cell responses is not sufficient. <time begin="00:39:46.55"/><clear/>Why do we go forward with this kind of study? <time begin="00:39:49.64"/><clear/>It's a good question, and I'm going to have Pat Thomas get up here and answer the questions <time begin="00:39:53.64"/><clear/>with me when we go to the questions section. <time begin="00:39:56.07"/><clear/>So what's going to happen now? <time begin="00:39:58.26"/><clear/>Basically, most of the vaccine trials have been put on hold. <time begin="00:40:02.13"/><clear/>We're going to try and figure out, this is what they're doing with these subjects <time begin="00:40:05.66"/><clear/>who were exposed to HIV, they're going to look at their type of T cell responses, <time begin="00:40:09.92"/><clear/>they're going to look at how the T cells responded to the HIV infection, they're going to look <time begin="00:40:14.19"/><clear/>at the different roots of exposure, <time begin="00:40:16.21"/><clear/>was a certain sexual practice more likely to cause exposure. <time begin="00:40:20.48"/><clear/>There is some discussion actually that circumcision might have played a role here. <time begin="00:40:26.25"/><clear/>They think that the people who were more likely to get infected were uncircumcised men, <time begin="00:40:31.03"/><clear/>and that's certainly played out in Africa. <time begin="00:40:32.87"/><clear/>We know that circumcision can protect against HIV infection. <time begin="00:40:36.86"/><clear/>So they're going to start looking at that. <time begin="00:40:38.45"/><clear/>And they're going to stratify future vaccine studies by circumcision status, <time begin="00:40:43.14"/><clear/>which makes it very complicated for HIV vaccine researchers. <time begin="00:40:46.97"/><clear/>They're going to sequence the virus, and they're going to follow the HIV positive patients to see <time begin="00:40:52.09"/><clear/>if the vaccine had any impact on the course of their disease. <time begin="00:40:55.88"/><clear/>If you remember what I said, that is one possible endpoint for a vaccine program. <time begin="00:41:03.32"/><clear/>There's lots more to do. <time begin="00:41:04.77"/><clear/>They need to look at the set points, they need to look at the immune correlates of protection, <time begin="00:41:09.29"/><clear/>they need to figure out if the breadth of T cell response, <time begin="00:41:13.08"/><clear/>which is what we would argue is critical, was important in terms of the patients who were able <time begin="00:41:18.74"/><clear/>to actually control their initial infection. <time begin="00:41:21.98"/><clear/>Meanwhile, what is the vaccine world, research world going to do. <time begin="00:41:26.94"/><clear/>So basically, if you were working on an adenovirus vaccine for HIV, you're dead in the water. <time begin="00:41:32.62"/><clear/>You might as well forget that program, put your RO1 grant on the shelf, <time begin="00:41:36.06"/><clear/>and start working on something else, because that's not going to get funded, <time begin="00:41:40.14"/><clear/>nor is it going to get into trials now. <time begin="00:41:42.48"/><clear/>People are looking at alternative ways of delivering the HIV information either <time begin="00:41:46.33"/><clear/>by a DNA vaccine, which we can talk about, or the Smallpox vaccine, <time begin="00:41:51.28"/><clear/>the pox vaccinia virus could be a potential means <time begin="00:41:54.18"/><clear/>of delivering this information. <time begin="00:41:56.12"/><clear/>So people are now looking at those potential alternatives. <time begin="00:41:59.54"/><clear/>The three vaccine trials here, if you go on the website, which is what I did a couple days ago <time begin="00:42:05.39"/><clear/>to get this information, the three adenovirus vaccine trials that were in process, <time begin="00:42:10.30"/><clear/>including one funded by a consortium of donors, including the Europe <time begin="00:42:15.16"/><clear/>and the CDC called the PAVE trial, all adenovirus virus directed vaccines, are dead in the water. <time begin="00:42:21.98"/><clear/>The vaccine trials have been cancelled, the people who recruited <time begin="00:42:25.26"/><clear/>to participate basically being told that right now we cannot go forward. <time begin="00:42:30.68"/><clear/>Now the list of potential candidates is pretty huge. <time begin="00:42:34.62"/><clear/>What I want to point out about this list, in this huge list of vaccines that are actually <time begin="00:42:39.77"/><clear/>in the pipeline, is that they are all vanilla vaccines. <time begin="00:42:44.69"/><clear/>They are all basically based on whole protein, they are all basically based <time begin="00:42:49.89"/><clear/>on delivering a whole protein to the immune system, and never really focused <time begin="00:42:55.26"/><clear/>on the variability of the HIV virus, and some way of stimulating a broad immune response <time begin="00:43:02.11"/><clear/>against all the different flavors of HIV. <time begin="00:43:05.05"/><clear/>There are three vaccines that are pointed to with arrows on this slide <time begin="00:43:09.57"/><clear/>where they are actually considering that. <time begin="00:43:11.53"/><clear/>But again, they're using one or two or three epitopes, <time begin="00:43:15.81"/><clear/>which really would not be sufficient to protect. <time begin="00:43:18.16"/><clear/>One is the Wyeth vaccine. <time begin="00:43:20.04"/><clear/>They're using four CTL epitopes, and they seem to think <time begin="00:43:23.65"/><clear/>that that might be effective, and I really doubt that. <time begin="00:43:27.45"/><clear/>So here's the issue that I have, and a lot of scientific researchers have <time begin="00:43:31.51"/><clear/>with the vaccine development field so far. <time begin="00:43:34.44"/><clear/>And that is HIV is a global problem. <time begin="00:43:37.68"/><clear/>HIV doesn't just exist in the back yard of the Merck vaccine company, <time begin="00:43:43.42"/><clear/>where only the clade B flavor is circulating. <time begin="00:43:46.74"/><clear/>HIV's incredibly variable, and we really need to think outside the box, <time begin="00:43:51.29"/><clear/>and how best to address this problem. <time begin="00:43:54.11"/><clear/>So that's actually something that we've been working on since about 1996 at Brown, <time begin="00:43:58.44"/><clear/>and that's what I'm calling a new vision. <time begin="00:44:00.66"/><clear/>I'm not the only researcher working in this area. <time begin="00:44:03.65"/><clear/>And this is kind of what we're hoping to develop. <time begin="00:44:06.51"/><clear/>We want to develop an HIV vaccine that's effective everywhere in the world, <time begin="00:44:10.63"/><clear/>where all the different flavors of HIV occur. <time begin="00:44:13.90"/><clear/>We want to make sure that we induce a broad T cell response, <time begin="00:44:17.74"/><clear/>not something that just recognizes three little tiny pieces of HIV, but a broad T cell response <time begin="00:44:24.04"/><clear/>that can recognize any variant of HIV that you would throw at it. <time begin="00:44:27.66"/><clear/>We want to reduce the chance of transmission, <time begin="00:44:30.33"/><clear/>we want to use low risk vectors, I would not use adenovirus. <time begin="00:44:34.63"/><clear/>We want to make it low cost, if not entirely free, because the average income in countries <time begin="00:44:40.70"/><clear/>like Mali is thirty dollars per year. <time begin="00:44:45.28"/><clear/>We want to make sure that this vaccine could actually be made in the developing world. <time begin="00:44:49.09"/><clear/>Why should we make the vaccine here, why can't we transfer that technology to Mali, <time begin="00:44:54.29"/><clear/>or to Kenya, or to Cambodia, where they can actually make the vaccine themselves. <time begin="00:45:00.28"/><clear/>And we need to make it with a technology that's scalable, so we can make small research batches, <time begin="00:45:05.36"/><clear/>and quickly translate to make larger batches in developing world countries. <time begin="00:45:10.66"/><clear/>So that's really what we've started out to do. <time begin="00:45:13.97"/><clear/>And the other very important point is that this has to be done in collaboration <time begin="00:45:18.44"/><clear/>with developing world scientists. <time begin="00:45:19.93"/><clear/>If the target is the developing world, you cannot do this in a vacuum, you cannot do this <time begin="00:45:24.97"/><clear/>without actively getting scientists in the developing world engaged. <time begin="00:45:29.68"/><clear/>So that's what we've been working on, I'll just give you my example <time begin="00:45:33.89"/><clear/>which is the Guya HIV vaccine, which we hope to be globally relevant and globally accessible. <time begin="00:45:40.01"/><clear/>The way that we're approaching this vaccine program is <time begin="00:45:43.23"/><clear/>to basically build it based on epitopes. <time begin="00:45:45.67"/><clear/>And this is actually a picture of an epitope lying in the MHC molecule. <time begin="00:45:49.29"/><clear/>We use computer programs to predict these sequences, <time begin="00:45:52.76"/><clear/>that are highly conserved in all strains of HIV. <time begin="00:45:56.53"/><clear/>So epitopes are the minimum essential unit of information that stimulates an immune response. <time begin="00:46:01.81"/><clear/>We use our immuno informatics tools to identify what we now call these Achilles heels. <time begin="00:46:07.37"/><clear/>If the HIV virus is so variable, it still needs to function. <time begin="00:46:12.33"/><clear/>There are pieces of the HIV virus that stay the same, those are the vulnerable targets for HIV. <time begin="00:46:18.61"/><clear/>If you can find the sequences that stay the same no matter which flavor of HIV you're looking at, <time begin="00:46:24.60"/><clear/>then you probably have something that will work in a vaccine. <time begin="00:46:28.60"/><clear/>So we've focused on these very conserved epitopes. <time begin="00:46:32.86"/><clear/>These epitopes that we've selected are not just conserved in one particular year, <time begin="00:46:37.68"/><clear/>but we show that they're conserved over time. <time begin="00:46:40.19"/><clear/>In the twenty years of the HIV epidemic, as long as we've been sequencing HIV, <time begin="00:46:44.02"/><clear/>we know that our epitopes are conserved in all of those viruses. <time begin="00:46:48.62"/><clear/>And we also tailor this vaccine so that it can be presented in the immune response <time begin="00:46:54.91"/><clear/>of all peoples of the world, no matter what their genetic background is, <time begin="00:46:58.66"/><clear/>no matter what their HLA is. <time begin="00:47:01.39"/><clear/>And the other concept, as Pat so well summarized, <time begin="00:47:04.25"/><clear/>is to make this vaccine a not-for-profit endeavor. <time begin="00:47:08.01"/><clear/>So we take computer programs, we basically digest down all of the sequences. <time begin="00:47:14.65"/><clear/>Fortunately for us, most of the work has actually been done <time begin="00:47:17.61"/><clear/>by the Los Alamos National Laboratory. <time begin="00:47:20.01"/><clear/>They have created a huge database of HIV sequences, they're also available in Gen Bank. <time begin="00:47:25.07"/><clear/>We basically dump those into the top of the computer, and what we're selecting, <time begin="00:47:30.22"/><clear/>if you want to think about this in a different analogy, if we have all the dialects of French <time begin="00:47:36.95"/><clear/>in the world, Haitian Creole, Senegalese French, all the different dialects of French <time begin="00:47:42.70"/><clear/>in the world, we're picking out the words, Bonjour, Comment ca va, Tres Bien, Aujourd'hui. <time begin="00:47:50.19"/><clear/>The words that are conserved in the French, in the HIV virus, <time begin="00:47:55.04"/><clear/>that are conserved in all the different dialects. <time begin="00:47:57.93"/><clear/>We use computer programs, and those are the epitopes, <time begin="00:48:01.42"/><clear/>the sequences that we're putting into our vaccines. <time begin="00:48:05.20"/><clear/>We start with the genome, we predict the T cell epitopes, <time begin="00:48:08.64"/><clear/>we confirm them using blood from HIV infected patients. <time begin="00:48:11.67"/><clear/>We've had donors from all over the world, from Thailand, from Cote D'Ivoire, from west Africa, <time begin="00:48:18.47"/><clear/>and also from Providence donate their blood to have these T cell epitopes tested. <time begin="00:48:23.42"/><clear/>We then clone them into a DNA vector, <time begin="00:48:27.99"/><clear/>and we produce also the peptides, and we've been vaccinating. <time begin="00:48:31.10"/><clear/>So far just in mice, but we have pretty dramatic results. <time begin="00:48:34.81"/><clear/>So this really kind of summarizes the informatics approach. <time begin="00:48:38.17"/><clear/>You take all the sequences, you dump them into the top of the computer, you ask the computer <time begin="00:48:42.64"/><clear/>to find the letters that are actually conserved, nine amino acids, <time begin="00:48:46.83"/><clear/>strings of letters, it's as simple as that. <time begin="00:48:49.30"/><clear/>This program is called Conservatrix, <time begin="00:48:51.07"/><clear/>it's an algorithm that we wrote to do this. <time begin="00:48:54.56"/><clear/>We then find these conserved sequences. <time begin="00:48:56.94"/><clear/>This just basically shows how it might look in the sequence. <time begin="00:48:59.94"/><clear/>You find this nine amino acid string, and that's your conserved epitope. <time begin="00:49:04.22"/><clear/>We've also developed another program called the Epi Assembler, <time begin="00:49:08.99"/><clear/>which assembles those conserved sequences into longer ones, so we can get longer sequences <time begin="00:49:14.27"/><clear/>that contain highly immunogenic, and very highly conserved T cell epitopes <time begin="00:49:19.96"/><clear/>to turn on a T cell response. <time begin="00:49:24.61"/><clear/>When you look at them over time, <time begin="00:49:26.23"/><clear/>this just basically illustrates how well conserved they are. <time begin="00:49:29.77"/><clear/>In orange are the epitopes that are conserved, not just in a single year as shown in one <time begin="00:49:35.07"/><clear/>of the columns, but across time over the ten, fifteen years of the HIV epidemic <time begin="00:49:40.58"/><clear/>that we have selected epitopes that this virus cannot change, because it uses that piece <time begin="00:49:47.30"/><clear/>of its protein to do something critical. <time begin="00:49:50.33"/><clear/>So we've found the Achilles heel of the HIV virus, <time begin="00:49:53.25"/><clear/>and that's what we're putting into our vaccine. <time begin="00:49:56.69"/><clear/>Basically where we are in terms of the epitopes, we mapped four hundred epitopes, <time begin="00:50:00.72"/><clear/>we confirmed two hundred of them, and that's pretty good when you look at computer programs. <time begin="00:50:05.64"/><clear/>We're now aligning them so that when you put two <time begin="00:50:08.11"/><clear/>of these words together you don't create a new word at the junction. <time begin="00:50:11.79"/><clear/>This is a computer program called Vaccine CAD, or Vaccine Computer Assisted Design, <time begin="00:50:17.27"/><clear/>that allows you to put epitopes in a string and not create gobbly gook. <time begin="00:50:21.88"/><clear/>And then we clone the strings of words into a DNA vector, and that's shown in this picture. <time begin="00:50:30.23"/><clear/>We basically take the amino acid sequence, we create the DNA, <time begin="00:50:34.57"/><clear/>we then make a vaccine using that DNA. <time begin="00:50:36.87"/><clear/>That's our delivery vehicle. <time begin="00:50:38.90"/><clear/>We also use proteins to boost the immune response, this is a prime boost vaccine <time begin="00:50:43.14"/><clear/>that we're working on. And we test them in mice that have human <time begin="00:50:47.35"/><clear/>like immune systems. That's how we test our vaccine. <time begin="00:50:50.87"/><clear/>And I can't show you results from challenge in mice, because basically HIV doesn't infect mice. <time begin="00:50:56.98"/><clear/>So the best proxy I have are two proxies. <time begin="00:50:59.98"/><clear/>One is a vaccine that we've made, there's a DNA based vaccine using epitopes alone, <time begin="00:51:04.67"/><clear/>and showing here that we can protect against a very virulent bacterial infection <time begin="00:51:10.72"/><clear/>with a vaccine composed just of fourteen epitopes. <time begin="00:51:13.83"/><clear/>This particular example is Tularemia a biodefense project <time begin="00:51:17.62"/><clear/>that we now have funding on thanks to the Bush administration, to protect against bio terror. <time begin="00:51:23.38"/><clear/>But it's a great model for our HIV vaccine. <time begin="00:51:26.18"/><clear/>And we will be doing studies in mice that have a chimeric virus <time begin="00:51:31.12"/><clear/>that is created to look like HIV, that does infect mice, <time begin="00:51:34.30"/><clear/>and we will show that we can protect against HIV infection using this chimeric virus <time begin="00:51:39.85"/><clear/>in the mouse models. <time begin="00:51:40.76"/><clear/>So that's basically where we are. <time begin="00:51:42.89"/><clear/>It's also important to point out that we're working in collaboration <time begin="00:51:46.18"/><clear/>with Ousmane Koita of the University of Bamako. <time begin="00:51:49.86"/><clear/>And a wonderful collaborator who has his PhD from Tulane here, and is very interested <time begin="00:51:56.34"/><clear/>in vaccine. Is building a vaccine research building in Bamako, <time begin="00:52:00.67"/><clear/>so that when we have our vaccine, we can actually test it there. <time begin="00:52:04.50"/><clear/>In the meantime, we're working in west Africa, so I have roped some Brown students <time begin="00:52:10.48"/><clear/>into doing some basic research with me in the neighborhood where we hope to test our vaccine. <time begin="00:52:16.31"/><clear/>And they've been doing what are called KAP studies, knowledge, attitudes, practices, <time begin="00:52:20.35"/><clear/>looking at HIV risk behaviors, and asking people what they think about getting an HIV vaccine, <time begin="00:52:25.62"/><clear/>would they be willing to participate in a trial. <time begin="00:52:28.58"/><clear/>We've done this in a particular region of Bamako, which is the poorest neighborhood <time begin="00:52:34.21"/><clear/>in the poorest, one of the poorest cities in the world. <time begin="00:52:37.16"/><clear/>The neighborhood is called Sekaro, and over the course of many trips <time begin="00:52:41.58"/><clear/>to Sekaro I finally met the chief. <time begin="00:52:43.77"/><clear/>The chief said look, you know, I know this is a lot to ask, <time begin="00:52:47.09"/><clear/>could you please build me an HIV clinic in my neighborhood. <time begin="00:52:52.02"/><clear/>And I said well you know, if you never ask, you never get. <time begin="00:52:56.47"/><clear/>So let me ask. <time begin="00:52:57.70"/><clear/>And I went home, and I asked my board, and basically that's what we've been doing. <time begin="00:53:01.86"/><clear/>This is a picture of the new HIV clinic that we've built in the neighborhood <time begin="00:53:06.06"/><clear/>of Sekaro over the past three years. <time begin="00:53:08.61"/><clear/>It took us about two years to raise the money, and about six months to build the clinic. <time begin="00:53:12.79"/><clear/>But basically what this clinic will be doing is providing state of the art HIV care, <time begin="00:53:18.05"/><clear/>accessible HIV care right out at the fringes in the village system, <time begin="00:53:23.33"/><clear/>the village infirmary of Bamako, Mali. <time begin="00:53:27.14"/><clear/>And we're setting an example. <time begin="00:53:28.47"/><clear/>There are seven hundred such infirmaries in Mali. <time begin="00:53:31.67"/><clear/>If we can show that we can provide HIV care in this center, <time begin="00:53:34.91"/><clear/>they can replicate the model in all the other sectors. <time begin="00:53:39.52"/><clear/>So I don't want you to go away from this discussion <time begin="00:53:42.53"/><clear/>and think we'll never have an HIV vaccine. <time begin="00:53:45.18"/><clear/>I think we will have an HIV vaccine. <time begin="00:53:47.79"/><clear/>It takes ten years to really get a vaccine through trials. <time begin="00:53:51.34"/><clear/>But what we have to do as a group is decide that we want an HIV vaccine. <time begin="00:53:57.51"/><clear/>And what does that mean? <time begin="00:53:58.90"/><clear/>The vaccine trials that we're currently in process, that took years to get to this point, <time begin="00:54:03.93"/><clear/>ten years to do the basic science, and they were just starting the clinical studies, <time begin="00:54:08.36"/><clear/>they were projecting that we would have the actual data either this year or the year <time begin="00:54:12.88"/><clear/>after from these studies that were now stopped. <time begin="00:54:15.70"/><clear/>You can see that it takes years and years and years. <time begin="00:54:18.15"/><clear/>So if we don't make a decision now that that's what we want to do, these vaccines that are <time begin="00:54:22.72"/><clear/>in the pipeline will never bear fruit. <time begin="00:54:26.16"/><clear/>So we are actively carrying our work forward, even though that there is no NIH funding <time begin="00:54:32.25"/><clear/>for this particular program right now, we continue to try to compete for funding. <time begin="00:54:36.46"/><clear/>But the funding for HIV vaccine research has really gone down to just a trickle. <time begin="00:54:44.28"/><clear/>Meanwhile, this is a world map or picture of AIDS deaths in the world. <time begin="00:54:50.30"/><clear/>Meanwhile the problem gets bigger and bigger. <time begin="00:54:53.81"/><clear/>So AIDS deaths are predominantly concentrated in southeast Asia and sub Saharan Africa, <time begin="00:55:01.03"/><clear/>as you can see by this map, whereas health spending again, disproportionately <time begin="00:55:06.83"/><clear/>in Europe, Japan, and the United States. <time begin="00:55:10.48"/><clear/>There is money being invested, so this is actually a picture of the funding being spent <time begin="00:55:17.34"/><clear/>by different countries of the world, 759 million dollars <time begin="00:55:22.44"/><clear/>in the year 2005, about 4% of the gross domestic product of the United States, <time begin="00:55:29.94"/><clear/>a little bit less for Ireland and Australia, Brazil, and a number of countries way <time begin="00:55:33.90"/><clear/>down at the bottom of the list spending less than 0.5% of their GDP on vaccine development. <time begin="00:55:39.29"/><clear/>But remember this in context. <time begin="00:55:42.72"/><clear/>The war budget, 1.4 trillion U.S. dollars in 2008, that's what's projected. <time begin="00:55:50.76"/><clear/>The U.S. will be spending 711 billion dollars on war. <time begin="00:55:56.89"/><clear/>Meanwhile 759 million dollars is being spent <time begin="00:56:01.44"/><clear/>on AIDS vaccines, which is less than 0.1%. <time begin="00:56:07.23"/><clear/>So I do think that we can change that dynamic, and to do that we have to be politically active. <time begin="00:56:14.09"/><clear/>Not necessarily scientifically active, but politically active. <time begin="00:56:18.85"/><clear/>And there are lots of people who have written about this, some of the journalists <time begin="00:56:21.87"/><clear/>like Pat Thomas, who's been a leader in terms <time begin="00:56:24.62"/><clear/>of questioning how HIV vaccines have been developed, but also John Cohen, <time begin="00:56:29.44"/><clear/>who says basically you know, we need a March of Dimes. <time begin="00:56:32.50"/><clear/>There was a March of Dimes to make a polio vaccine. <time begin="00:56:35.38"/><clear/>There was a public support for the creation of a polio vaccine <time begin="00:56:40.86"/><clear/>to keep kids from getting paralyzed. <time begin="00:56:43.37"/><clear/>And 25 years later we had a polio vaccine. <time begin="00:56:47.28"/><clear/>But we can't say the same about AIDS. <time begin="00:56:51.11"/><clear/>The way funding goes, and the researchers among you know this very well, <time begin="00:56:55.12"/><clear/>is that the AIDS researcher is always trying to publish, look around, <time begin="00:57:00.08"/><clear/>figure out how they can possibly create publishable information <time begin="00:57:04.45"/><clear/>with the research that they're doing. <time begin="00:57:05.71"/><clear/>Because if they don't publish, then they don't make a vaccine. <time begin="00:57:08.77"/><clear/>We really just need to go back to basics here, and say just make a vaccine. <time begin="00:57:13.47"/><clear/>Use your best tools, we will fund you, let's let a thousand flowers bloom, <time begin="00:57:19.47"/><clear/>let's try lots of different approaches, and let's get an AIDS vaccine. <time begin="00:57:24.55"/><clear/>Is this asking for too much? <time begin="00:57:27.57"/><clear/>And this is Pat Thomas's book if you haven't read it. <time begin="00:57:31.15"/><clear/>It only takes really 20 million dollars for one vaccine from start to finish. <time begin="00:57:36.71"/><clear/>And yet we spend 500 billion for Iraq. <time begin="00:57:41.42"/><clear/>So I just want to leave you with the concept that hope is a vaccine. <time begin="00:57:45.99"/><clear/>This is the direction that we're going in, we really want to get there, <time begin="00:57:49.80"/><clear/>and that is all I have to say tonight. <time begin="00:57:53.94"/><clear/>So thank you for your attention. <time begin="00:57:55.07"/><clear/>I'd be happy to take any questions. <time begin="00:57:57.51"/><clear/>[ applause ] <time begin="00:58:04.52"/><clear/>You better get up here and answer questions with me. <time begin="00:58:10.75"/><clear/> <time begin="00:58:13.13"/><clear/>So read Hot Shots. <time begin="00:58:19.81"/><clear/>Burning questions. <time begin="00:58:21.76"/><clear/>Yes. <time begin="00:58:22.51"/><clear/>[inaudible-too far] <time begin="00:58:35.12"/><clear/>>> It's, it would be a therapeutic preventative is what we call it, <time begin="00:58:38.87"/><clear/>because basically we would be trying to induce that immune response that would lower the amount <time begin="00:58:42.90"/><clear/>of virus in your body after you got infected. <time begin="00:58:45.73"/><clear/>So that's really what people are hoping to achieve right now, <time begin="00:58:48.50"/><clear/>is a vaccine that would contain infection, like the elite controllers. <time begin="00:58:53.84"/><clear/>It's a DNA prime and protein boost. <time begin="00:58:58.83"/><clear/>So no live viral vectors either. <time begin="00:59:02.51"/><clear/>[inaudible-too far] <time begin="00:59:15.04"/><clear/>>> Would problems arise, misuse of the Merck vaccine? <time begin="00:59:19.94"/><clear/>GAIA vaccine? <time begin="00:59:23.29"/><clear/> <time begin="00:59:24.42"/><clear/>Well first we have to have the vaccine, and then we'll see if it's misused. <time begin="00:59:27.80"/><clear/>In what way do you mean? <time begin="00:59:29.59"/><clear/>If it's made in developing world countries, or? <time begin="00:59:31.51"/><clear/>[inaudible-too far] <time begin="00:59:44.30"/><clear/>>> One of the points about the vaccine that we're trying to develop is <time begin="00:59:47.18"/><clear/>that it actually doesn't contain any viable genes from the HIV. <time begin="00:59:51.61"/><clear/>In fact, all vaccines are made that way now. <time begin="00:59:54.25"/><clear/>They're either whole virus killed, or they're just pieces, like a single protein, <time begin="00:59:59.79"/><clear/>like that first vaccine I talked about that Vacs Gen made. <time begin="01:00:02.91"/><clear/>And ours is made of even smaller pieces. <time begin="01:00:05.87"/><clear/>You can kind of think of a whole virus vaccine as being the whole book, the encyclopedia, <time begin="01:00:11.40"/><clear/>some people make just the protein which is like a chapter, and we're just putting words. <time begin="01:00:16.33"/><clear/>So you can't actually make anything with those words, the virus, <time begin="01:00:20.40"/><clear/>that machinery's not functional, it can't cause a bad effect. <time begin="01:00:25.63"/><clear/>So that's so, and also when you give a vaccine, the dose is controlled. <time begin="01:00:30.19"/><clear/>You actually do dose ranging studies to look at the most effective <time begin="01:00:33.82"/><clear/>and the safest dose before you decide on how it's going to be marketed. <time begin="01:00:38.32"/><clear/>So even in developing countries, the dose would be identified, and it would be controlled, <time begin="01:00:42.74"/><clear/>it would always be the same dose. <time begin="01:00:44.46"/><clear/>Maybe a little bit less for children, <time begin="01:00:45.86"/><clear/>a little bit more from adults, but it would be the same dose. <time begin="01:00:50.87"/><clear/>Yes. <time begin="01:00:51.51"/><clear/>[inaudible-too far] <time begin="01:01:05.15"/><clear/>>> So the question is whether this vanilla vaccine would work in a country <time begin="01:01:09.87"/><clear/>where vanilla is the form of the virus being transmitted. <time begin="01:01:14.07"/><clear/>When I, I sort of oversimplify when I say vanilla clade B. And when you talk <time begin="01:01:18.77"/><clear/>about the virus in the United States, it is mostly clade B, <time begin="01:01:23.78"/><clear/>but even within clade B there's so much variation. <time begin="01:01:27.45"/><clear/>Remember the kid that I showed you, that pediatric patient? <time begin="01:01:30.23"/><clear/>That was a clade B infection, but over four years he developed what, <time begin="01:01:35.26"/><clear/>a hundred different strains of the same clade B virus, each of it which has different epitopes. <time begin="01:01:41.72"/><clear/>So I don't think that a single protein from a single virus will actually protect. <time begin="01:01:47.38"/><clear/>You do have to use the computer approach to find those Achilles heels, <time begin="01:01:52.35"/><clear/>the piece of the virus that is conserved. <time begin="01:01:54.51"/><clear/>And that hasn't been done, that simply hasn't been done yet, until we started doing it. <time begin="01:01:59.83"/><clear/>And also now the Gates foundation is starting to think about doing it. <time begin="01:02:03.76"/><clear/>Yes. <time begin="01:02:05.51"/><clear/>[inaudible-too far] <time begin="01:02:09.18"/><clear/>>> It all depends on funding. <time begin="01:02:12.42"/><clear/>So if some wonderful person, Larry Ellison, Bill Gates were to come along <time begin="01:02:19.45"/><clear/>and give me the twenty million dollars that I need <time begin="01:02:21.88"/><clear/>to make the vaccine, it would happen very soon. <time begin="01:02:25.79"/><clear/>It's all about money. <time begin="01:02:27.47"/><clear/>And it doesn't have to be my vaccine, it could be the Gates vaccine that they're working on, <time begin="01:02:32.37"/><clear/>there's a multi-epitope, multi-clade vaccine. <time begin="01:02:36.13"/><clear/>It's just about funding. <time begin="01:02:37.60"/><clear/>I do not believe, that's what I hope you go away with. <time begin="01:02:40.86"/><clear/>The Merck vaccine is not the end of this story. <time begin="01:02:44.02"/><clear/>It shows a failed approach, one that we really didn't think was going <time begin="01:02:48.14"/><clear/>to succeed, even from the get go. <time begin="01:02:50.38"/><clear/>Now we need to abandon those failed approaches and start funding the approaches that will work. <time begin="01:02:55.17"/><clear/>And if we do that, we will have a vaccine. <time begin="01:02:58.42"/><clear/>>> And a note about the funding of vaccines. <time begin="01:03:03.39"/><clear/>I mean I think that historically one of the problems that's happened is <time begin="01:03:08.51"/><clear/>that we've been able all along to see the people most at risk for AIDS as other than ourselves. <time begin="01:03:18.02"/><clear/>At first in this country we said well, it's homosexual men, <time begin="01:03:22.82"/><clear/>it's IV drug users, it's not us sitting here. <time begin="01:03:27.19"/><clear/>And then there was a tremendous wave of political activism, <time begin="01:03:30.85"/><clear/>which proved that the government does listen, and the government can be made to allocate money <time begin="01:03:36.06"/><clear/>on the basis of an outcry from the citizenry, <time begin="01:03:38.29"/><clear/>and that's when funding really increased in the 1980s. <time begin="01:03:41.65"/><clear/>I mean that's a remarkable story, and AIDS activists showed the way <time begin="01:03:46.10"/><clear/>to breast cancer activists, and every other patient advocacy movement <time begin="01:03:50.60"/><clear/>that has gotten substantial tax dollars for its research. <time begin="01:03:54.55"/><clear/>But now more recently, we during the last decade or so, we have conceptualized HIV and AIDS <time begin="01:04:02.45"/><clear/>as a problem of people on other continents. <time begin="01:04:05.88"/><clear/>And so the demand side from the citizens and voters is not there, you know? <time begin="01:04:12.44"/><clear/>We're not saying to congressman Paul Brown, you know, <time begin="01:04:16.37"/><clear/>we're not saying to George's republican senators you know what? <time begin="01:04:20.66"/><clear/>We really think that getting an HIV vaccine for the world is important. <time begin="01:04:25.47"/><clear/>We talk about the University of Georgia's commitment to international careers <time begin="01:04:30.19"/><clear/>for our students, and I love that, that's an important thing. <time begin="01:04:34.01"/><clear/>I don't know what marvelous things people <time begin="01:04:36.34"/><clear/>in this room may accomplish working outside our own country. <time begin="01:04:39.95"/><clear/>But you know what? <time begin="01:04:41.05"/><clear/>It is just one world, and a disease of this magnitude, <time begin="01:04:45.20"/><clear/>with these kinds of modeling projections for transmission and spread, <time begin="01:04:49.63"/><clear/>we have to see it as our problem, we have to say this is a political issue. <time begin="01:04:53.78"/><clear/>We think this is a top health funding priority, but we've not done that, so it's been, <time begin="01:05:02.26"/><clear/>and you know, great ideas, great scientific ideas. <time begin="01:05:06.02"/><clear/>They are in a sense a dime a dozen. <time begin="01:05:08.51"/><clear/>Not to denigrate the kind of accomplishment of a lab like [inaudible], <time begin="01:05:13.16"/><clear/>but what's really expensive is moving those ahead into factories to make vaccines, <time begin="01:05:18.34"/><clear/>and then moving them ahead into clinical trials, which are enormously expensive, <time begin="01:05:23.50"/><clear/>but cost less than the wing of a stealth bomber. <time begin="01:05:30.78"/><clear/>Yes. <time begin="01:05:31.51"/><clear/>[inaudible-too far] <time begin="01:05:50.52"/><clear/>>> Well there's, what's interesting about drugs these days is that there was a big effort <time begin="01:05:55.97"/><clear/>to get tiered pricing, part of which was led by Paul Farmer and Jim Kim, who Jim Kim spoke here. <time begin="01:06:02.96"/><clear/>And that has actually happened. <time begin="01:06:05.19"/><clear/>So there is tiered pricing, and countries, developing world countries are able <time begin="01:06:08.87"/><clear/>to purchase drugs at a discounted price. <time begin="01:06:12.19"/><clear/>And that, and Bill Clinton, to his credit, has been a major driver as well, <time begin="01:06:17.47"/><clear/>reducing the cost of drugs in developing world countries <time begin="01:06:20.67"/><clear/>from fifteen thousand dollars per patient per year, which is untenable, <time begin="01:06:24.44"/><clear/>to three hundred dollars per patient per year, which is paid for by the global fund, usually. <time begin="01:06:30.02"/><clear/>But the problem with that, and I will actually talk about this <time begin="01:06:32.95"/><clear/>in the journalism class tomorrow, is that it still doesn't get out to the people who need it. <time begin="01:06:37.94"/><clear/>So in Mali, the country I know the most about, there are probably about a hundred and twenty, <time begin="01:06:42.79"/><clear/>a hundred and eighty, a hundred and fifty thousand people living with HIV in that country, <time begin="01:06:47.27"/><clear/>three times the size of Texas, but only eighty thousand people on medication. <time begin="01:06:52.04"/><clear/>Because there aren't enough doctors, and because there simply isn't enough push <time begin="01:06:56.80"/><clear/>or pull to get the drugs out. <time begin="01:06:59.36"/><clear/>So there, the same level of activism that we have in the United States, act up, <time begin="01:07:04.52"/><clear/>all of the gay men's health crisis, all of those groups don't exist <time begin="01:07:08.60"/><clear/>in developing world countries, and there isn't the same level of advocacy. <time begin="01:07:11.87"/><clear/>There's still a huge amount of stigma, even the doctors are afraid of treating patients <time begin="01:07:17.79"/><clear/>with HIV, because they haven't seen them live with HIV the way we have. <time begin="01:07:21.85"/><clear/>So getting the medications out is one of the biggest problems, and yet that's not going <time begin="01:07:26.81"/><clear/>to be enough, that will only treat the people who get infected, <time begin="01:07:29.80"/><clear/>and it won't prevent people from getting infected. <time begin="01:07:33.65"/><clear/>>> Treatment, the expansion of treatment programs globally is a great thing. <time begin="01:07:39.71"/><clear/>Jim Kim, when he spoke to us two months ago talked though about how the centerpiece <time begin="01:07:43.78"/><clear/>of his time, as leader of the World Health Organization's AIDS programs, <time begin="01:07:48.10"/><clear/>was a so called three by five program. <time begin="01:07:50.43"/><clear/>The goal of treating three million people in the developing world <time begin="01:07:53.97"/><clear/>by the year 2005, it simply didn't happen. <time begin="01:07:57.64"/><clear/>It hasn't happened. <time begin="01:07:58.75"/><clear/>>> Same reason failure of funding, not sufficient funding, <time begin="01:08:02.05"/><clear/>and we talk about the numbers that were you know, twenty dollars per person <time begin="01:08:06.06"/><clear/>in the United States per year would get funding to everybody on the planet. <time begin="01:08:11.38"/><clear/>So it's, there, you know, this is doable, but it's just lack of leadership. <time begin="01:08:16.51"/><clear/>[inaudible-too far] <time begin="01:08:35.74"/><clear/>>> So we actually mapped our epitopes with some of those patients. <time begin="01:08:40.87"/><clear/>So we were able to get a cohort of patients in Providence who are elite controllers, <time begin="01:08:45.97"/><clear/>and when we predicted our epitopes, we then confirmed using their blood <time begin="01:08:49.63"/><clear/>that they donated, whether we were right. <time begin="01:08:52.01"/><clear/>And so that was the great news, that paper was published in 2005. <time begin="01:08:56.90"/><clear/>Very good question. <time begin="01:08:57.77"/><clear/>There was one in the back, yea. <time begin="01:08:59.51"/><clear/>[inaudible-too far] <time begin="01:09:04.10"/><clear/>>> Well they're actually found even in the envelope, <time begin="01:09:06.62"/><clear/>which is the most variable protein in the body. <time begin="01:09:09.17"/><clear/>And what are they involved in? <time begin="01:09:11.13"/><clear/>They are probably involved with holding the structure <time begin="01:09:13.86"/><clear/>of the protein together so that it has its function. <time begin="01:09:17.81"/><clear/>I mean the proteins of the HIV virus perform a function. <time begin="01:09:21.94"/><clear/>One of them is a [inaudible], it cuts pieces of protein. <time begin="01:09:24.91"/><clear/>But if it doesn't have the scissor like shape, then it can't actually cut. <time begin="01:09:29.41"/><clear/>So perhaps some of these epitopes are actually at the functional part of the scissors, <time begin="01:09:35.58"/><clear/>and that's why they're conserved. <time begin="01:09:38.11"/><clear/>But you can't actually ascribe a function <time begin="01:09:41.15"/><clear/>to something that's only nine amino acids long, usually. <time begin="01:09:43.98"/><clear/>You can say it's within this particular region. <time begin="01:09:47.08"/><clear/>>> So I think we can take this discussion next door to [inaudible] Hall, <time begin="01:09:50.98"/><clear/>where refreshments are waiting for us all. <time begin="01:09:54.15"/><clear/>And let's thank Doctor Degrut for coming. <time begin="01:09:55.28"/><clear/>>> Thank you. <time begin="01:09:56.51"/><clear/>[ applause ] <time begin="01:10:09.11"/><clear/> </center> </window>

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