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(Editor’s note: Author Jon Cohen’s new book, Shots in the Dark, is an account of the long struggle to develop a successful AIDS vaccine. AIDS Alert asked Cohen to speak about the vaccine efforts and discuss the potential of various vaccine initiatives now under way. Cohen, a correspondent with Science and a writer for The Atlantic, Discover, and The New Yorker magazines, has followed the AIDS vaccine efforts since the early years of the epidemic. Here are Cohen’s answers to some of AIDS Alert’s questions about the vaccine:)
AIDS Alert: First, could you tell us a little about how close the various vaccine efforts are to developing a product that could be used in at-risk populations, either here or in developing nations?
Cohen: About three dozen vaccines have entered human trials. Human testing requires three phases that moves from small groups to larger and larger groups of people. Only one vaccine has made it to Phase III testing. That vaccine has not impressed most AIDS researchers, and the National Institutes of Health [NIH] decided in 1994 to not even fund the Phase III trials, but that trial is now nearing its end. As early as this coming fall, we could have results from that trial. It was privately funded. A company was started just to run efficacy trials, which I think was unprecedented. I can’t think of another example of that. The company making the vaccine spun off a new company just to stage these efficacy trials. That company is called VaxGEN in the San Francisco Bay area. I think it’s great that this test is happening, and I also think the NIH made a mistake for not funding the test. It’s not because I think the vaccine looks promising, because I don’t. But I think the field could learn a lot from its failure if indeed it does fail, and if it succeeds, obviously that would be a great thing.
AIDS Alert: Would that be a vaccine for HIV-1 or HIV-2 or others?
Cohen: For HIV-1. There is no active development of an HIV-2 vaccine that I know of. That should be a simple matter if any HIV-1 vaccine works, because it should also work.
AIDS Alert: Where are they conducting the VaxGEN tests?
Cohen: There are two big trials going on. One is in the United States, Canada, and the Netherlands. That involves about 5,000 people, mostly gay men. The other trial is in Thailand, and it involves 2,500 people who are injecting drug users. The first trial is a little further along, but they are both Phase III efficacy trials.
AIDS Alert: Please tell me why scientists are skeptical that this particular vaccine will prove to be the one.
Cohen: In the earlier stages — the Phase II studies, which involved hundreds of people — researchers took antibodies from those people’s bodies and mixed HIV in test tubes with the antibodies, and the antibodies could not stop the virus. So researchers basically concluded that the vaccine wasn’t strong enough; it wasn’t leading the immune system to produce the right kind of antibodies.
There also has been a huge shift in thinking about what a vaccine must do to stop HIV. In the early days of the AIDS vaccine search, most everyone focused on antibodies. But there is another arm of the immune system, called cell-mediated immunity, or cellular immunity, and now most of the leading vaccines focus on that, with some attention paid toward antibodies. Antibodies are now taking a back seat.
The difference between these two arms of the immune system is simple to explain: Antibodies stop things from getting inside of cells; cellular immunity does a mop-up job, cleaning up already-infected cells and eliminating them. So you can see how the two can go hand-in-hand, or it could be you only need one. Who knows? That’s still a giant mystery that makes development of an effective AIDS vaccine so difficult, because we don’t know — no one knows — what are called the correlates of protection. No one knows exactly which immune response a vaccine must elicit to work.
AIDS Alert: You’ve detailed in your book a great deal about the problems with primate AIDS vaccine research. Was all that pretty much pointless in the end, or did primate research tell us anything?
Cohen: I don’t think it was pointless. You can do tests in primates that you could never do with humans. Specifically, primates are given an AIDS vaccine and then are injected with live versions of the AIDS virus, which in the case of primates, is HIV’s cousin, SIV. You can never ethically do such a test like that in humans. It’s ethically complicated in monkeys, for that matter, but you couldn’t do this in humans. But you can get strong information from these monkey studies about whether your vaccine has promise.
What most people have done with monkey studies is use them to perfect their own vaccine ideas. What no one has yet done is a major comparative study that allows you to put different vaccines side by side and determine which ones looked like they worked the best in monkeys. So that’s what is so maddening to me, is you can’t compare the results from one lab to another lab. They use different species of monkeys; they use different strains of SIV; they use different reagents; they use different testing protocols; and at the end of the day I’m dizzy, and so is everyone else.
I’m not calling for anything radical. The things I’m pointing out are suggestions and recommendations made by AIDS researchers in official documents. They’ve called for this comparative trial, but it just hasn’t happened. So people only partially gamble on the monkey model. You can always say that monkeys are not human and it’s a model, but that’s always going to be true. Of course SIV is not HIV. But people are kind of playing footsy with the model.
There’s a tremendous amount of AIDS vaccine primate research still under way, and the research that is going on does lead to insights about which immune responses protect monkeys and how to rejigger your vaccine to make it stronger. But again, the real question I think the world has to ask is more ambitious still: Given all the good ideas out there, which ones look best? Certainly, you can answer that question in human trials, but there’s a clock ticking. We have an imperative to move as quickly as we can, and that’s why I’m arguing that a comparative monkey study of every good idea might shave years off the time that it takes to find a working vaccine. I’m not arguing, mind you, to stop anyone from what they’re doing. If what they’re doing is ethical and scientifically sound, then I think that’s fine. I’m saying that in addition to everything that’s going on, there is an entirely different way to approach this whole problem that is not being applied right now.
AIDS Alert: You discuss at length in your book Jonas Salk’s early polio research. If a similar scientist had as few bureaucratic and liability constraints today, do you think we would already have an HIV vaccine?
Cohen: No. I don’t think there is any guarantee we will ever have an AIDS vaccine. And I also think that if HIV were as simple a virus to defeat as polio, we’d have a vaccine today. The biggest obstacle is the virus. But once you accept that, then the question becomes, "Are there ways to improve the way the enterprise moves, to streamline and organize?" And that’s where the March of Dimes model is relevant, because the answer is resoundingly "yes," there are many things we could do that are not being done that could streamline the search.
There are no guarantees, but there never are in wars, and it’s a war of us against the virus. I think that if we better organized our troops, we’d stand more of a chance of winning. But I’m not certain — and nobody can guarantee — there will be an AIDS vaccine. There are lots of hopeful reasons to think there will be. There are a lot of signs that we can defeat HIV with a vaccine, and we know from history that vaccines are one of the most powerful medical tools ever devised. Smallpox virus now only exists in laboratory freezers because of a vaccine. It’s not in the population anymore. That is a tremendous accomplishment. Polio doesn’t exist in the United States any longer, or in Europe or most of the world for that matter, because of vaccines. We have freed generations from fear because of vaccines.
AIDS Alert: You mention in the book some efforts by pharmaceutical companies to get Congress to pass a law offering them special liability protection. Has there been anything passed?
Cohen: No, there has been nothing passed. And I think the California State Supreme Court made an enlightened ruling in 1988 that the federal government should consider. Basically, if you make a vaccine according to FDA standards right now and you do everything right, but it harms someone, you can still be sued under what is called "strict liability." In California, the State Supreme Court said that drugs — and presumably vaccines — are different because they’re for a social good. If you make it according to specifications and you inform the consumer about the risks, then you cannot be held liable if that person gets hurt because they are "unavoidably dangerous" products. I think that’s a very sane way to approach liability. If you have unavoidably dangerous products that are good for the public and you inform people about the risks, then I don’t see why you should be held liable.
AIDS Alert: If you were speaking to a group of high-risk individuals in the United States, would you tell them they shouldn’t hold out hope for a vaccine any time soon?
Cohen: I think people need hope. I think it’s human nature to want hope, but I do speak with groups of high-risk people, and I do tell them that right now there is no working vaccine and that even if there were a working vaccine, they would still be at risk if their behavior was something the virus liked. The virus likes certain behaviors: it likes people to have lots of partners; it likes to get directly into blood; it likes sores; it likes needles.
AIDS Alert: Is there any other point you’d like to get across?
Cohen: The lessons from what has happened so far in the AIDS vaccine research similarly apply to many other infectious diseases: Malaria, TB, hepatitis C all have faced problems because of a lack of interest in vaccines from industry, and it questions the scientific culture to its core. And it’s a critical question because, in each case, time matters. There are now at least 36 million HIV-infected people in the world. One in five adults are infected in South Africa. If we had one in five adults infected in the United States, I suggest that every solution I float in my book would have happened long ago. That doesn’t mean we would have a vaccine today, but that does mean we’d be closer, and the same holds true for these other diseases. So at what point do we learn from our mistakes? And we’ve made plenty of mistakes.