IAVI Report - February / March 2001

Jon Cohen is a science journalist who began following the AIDS vaccine field in 1989 while working as a general reporter. A year later he started contributing to Science magazine, and since then, in his continuing role there as Contributing Correspondent, has written dozens of articles on the progress and difficulties along the road to an AIDS vaccine. In January 2001, Norton published his provocative book, "Shots in the Dark: The Wayward Search for an AIDS Vaccine," a chronicle and critique of the 15-plus year effort. He spoke with IAVI Report editor Patricia Kahn at the recent Retrovirus Conference.

You've followed the AIDS vaccine field longer and closer than just about any other journalist. What drew you into it?
I come from an era when Jonas Salk was a hero. Even though my generation wasn't afraid of polio, I knew the lore.

When I was an undergraduate in San Diego, Salk worked close by. I convinced him to let me write about his work and the controversy with the polio vaccine, which was still going on. We made a deal. I knew he hated journalists, for the most part, so I told him, 'I don't want to publish anything, I just want the exercise of writing about you.' He agreed. I wrote about him, and that was that.

In 1989, I was an editor and reporter at City Paper in Washington, D.C., writing about anything and everything. I read in the Washington Post that Joe Gibbs at NIH was collaborating with Jonas Salk on an AIDS vaccine. So I went to see Gibbs.

I came back and told my editor, I don't know if there's a story here. It's basically Salk being Salk—challenging the world once again with the same sorts of ideas and doing interesting things. My editor goes, whoa, whoa—what do you mean it's not a story?

So I did a search and looked at every article that had been written about AIDS vaccines. There wasn't a single one that had a point of view or critically analyzed the field. They were all about either the latest scientific pronouncement at a conference or in a journal, or they were about the hope meter—it's up, it's down, it's going to happen next year, it's never going to happen. Or they were catalogues: here's what everyone's doing.

I thought this was bizarre. Salk was approaching this wildly differently from everybody else, with his classic sort of empiricism—just push forward as quickly as you can, don't worry yourself to death about mechanism—which reflected what I had written about him and the polio vaccine.

I looked at this and thought, it's history repeating itself. I went back to the editor and said, I've got to do this. So I did a big point-of-view story, in 1989. That article led to a book contract.

Was there that much to say about AIDS vaccines in 1989?
The book was supposed to be a narrative about one year in the search for an AIDS vaccine—1990. But about four chapters into it, Bob Gallo said something which made me realize that this year didn't mean anything to AIDS researchers. The idea was a writer's conceit. After that, I couldn't go on.

So I asked the publisher if I could shift gears and write a book about the first vaccine to come to market. I thought, if I'm lucky, that will take me five years; if I'm unlucky, ten years. The idea was to watch the field over time. 'Process' stories like this are terrific, because you can show all the nuances of trying to accomplish something. There's always conflict. It's always difficult to do anything that matters.

Then I started to write for Science, so I was really able to follow the field closely.

Why did you decide to come out with the book now, even though there isn't an AIDS vaccine coming to market?
When Bill Clinton made his famous declaration in 1997 about the goal for an AIDS vaccine, it crystallized in my mind how the whole effort seemed badly off track. Clinton, who was making a big difference in AIDS—he even once proposed a Manhattan Project for AIDS—had really not provided the leadership he could have.

It harked all the way back to polio, and FDR [former US president Franklin D. Roosevelt]. There the president made a difference. He started the March of Dimes, put his law partner in charge and really directed and targeted research. Clinton just didn't get it.

I see a real problem with an illusion of leadership and progress, in AIDS research and in many other fields. Where an idea is put forward, the critics come out with all the reasons why the idea doesn't mean anything. The proponents defend it, but often the idea just disappears—even though it's never been fully tested, never really ruled in or ruled out.

You can argue that if the idea is right, the proponents will ultimately win the war and all is fine. Well, I don't see things that way. I think a lot of good ideas get stopped dead in their tracks, or end up running in place, with the same two or three people advocating for them. Critical experiments that need to happen, don't happen—because funding doesn't come forward or because people get sick of being advocates.

Anyway, after hearing Clinton's speech, I decided that I have a book in me now. I've catalogued all these problems and I want to put it out there: here are all these promising leads that have gone nowhere; creative ideas that haven't been put to use; research gaps and legal liability problems that aren't being addressed, and market problems that aren't being solved. I wanted to put it all in one place and then offer my own idea of a solution. And I really wanted the book to acknowledge that if this were polio, we would have a vaccine today.

HIV is a tough bug. That's a given. The science is the biggest obstacle. There would be a vaccine if it were easy. Okay, fine. I've been attacked on this level many times. It's tiresome to me—the scientists who say to me, Jon, you underestimate how difficult it is. No, I don't. All I'm saying is, given this difficult problem, are researchers as organized as they could be? Is the field taking advantage of everything that it could? And I think the answer is no.

Where do you see the fundamental failures?
One is that industry hasn't rushed forward here. You have two, three, four pharmaceuticals that are serious, but their interests wax and wane. Aventis Pasteur has been there all along and has tried hard to progress. But according to the NIAID-NIH plan at the ARAC meeting in 1994, canarypox was supposed to be in efficacy trials in 1996. Well, that hasn't happened. Merck is back into the game now. I think everybody is cheered about that. But that is only one big pharma. The biotechs come and go; they're always cash-strapped, and they always are in danger of selling hope rather than a product.

Another failure is that the monkey model isn't being effectively exploited. Again and again, leading researchers have called for organizing a large-scale, comparative trial of all the best vaccine ideas in monkeys, and setting it up in such a way that new vaccines which come along can be plugged into that protocol—or several protocols, even.

But if you go downstairs to one of the vaccine sessions at this conference, you'll get dizzy, because somebody is using SHIV89.6 as the challenge strain, and somebody is using E660, and somebody is challenging after one year, and someone else with two boosts after three months—it's mind-boggling. There is no uniformity, no ability to make sense of how one vaccine stacks up against another. What ultimately happens, in my mind, is that vaccine experiments almost become propaganda tools. If people like the data, they say, look how great my vaccine is—it worked in monkeys. And if they don't like the data, they say, it's not humans, it's only a monkey model.

What about the approach of doing human and monkey studies in parallel?
That's fine; things should proceed that way. But in addition to what's going on, I'd like to see a monkey study that creates a public database around the testing of 50 or 100 of the best ideas using, for example, three different challenge strains, three different protocols. Then choose the five or six vaccines that look better than anything else and move them into humans, assuming their safety profiles are okay.

What I'm saying is, let's move things forward based on the gamble that the monkey model means something. Granted, it's a gamble. But let's not play footsie with the model, let's really move things quickly into clinical trials, with the only rationale being that they work better in monkeys than other vaccines do, and the only real concern being safety. Let's stop using immunogenicity as the gatekeeper. To me, that delays things. We see that with Aventis Pasteur and canarypox. We saw it with Genentech and Chiron and gp120 vaccines.

Study immune response, absolutely. Great to know that stuff. But you don't have to know that to make a working vaccine. As much as there are advocates for CTLs, for sexy new antibodies that will be uncovered when you take the dress off over here, nobody really knows the immune correlates of protection. So let's stop pretending that we do.

It's great that there are people who believe in CTLs, or in neutralizing antibodies. They should run with it; carry their vaccine forward.

But there's a clock ticking. We've known for years that a 60% efficacious vaccine introduced today will prevent more infections and disease ten years down the road than a 90% effective vaccine introduced five years later. So there's a great reward in coming up today with a mediocre vaccine that is crudely understood.

You also said that many scientific ideas are prematurely dropped.
That's another one of the big failures. There is no real gap-filling committee; no group of people who meet regularly and ask, what are all the promising leads? Who's doing what, and how can we speed these things along? This type of committee is something I propose in my book.

Instead, the field is ruled by grants and investigator-initiated science, which is the culture of American science. It's a great culture; it pushes forward knowledge and creativity. But it doesn't embrace risky ideas. And it doesn't follow up on itself very well. It's sort of a free-for-all, without real leadership.

Targeted programs have something to offer. You could have smart people sit around a table—including someone with a checkbook—saying, the group over there has something going, so let's ask them to e-mail us how much money they need to speed things along, and why. The next day, we can decide whether we're going to send them the money. That's it. No formal grant proposal. Or maybe they come and present in front of the board and explain why. Once they get some money, the committee could find two or three other smart groups that want to do a similar thing and light a fire under the first group. Create some competition in the way that many companies do, by starting two or three projects in-house to spur things forward.

What type of organization should this be?
The way I envision it, it can't be government money. Government doesn't have the freedom to move money around like that. Partly to be provocative, I call it a March of Dollars in the book. I think we have a lot to learn from the March of Dimes model.

It's an organization that wouldn't be wildly different from IAVI, but would have some different approaches. IAVI is approaching the problem with a certain approach—a blueprint—that makes sense. But it's not the only one. The new organization would raise money from philanthropists. Bill Gates is not the only person out there who has a lot of money and cares about public health. It would also draw on the public, which IAVI hasn't tapped into. The public all around the world would like to contribute, and there is a way to involve them—just as the March of Dimes did.

I'm not sure it needs a scientist or doctor at the top. The March of Dimes model says to have a lawyer, someone with clout and influence around the world—as Basil O'Connor had. In my book, again to be provocative, I suggest Randall Robinson [the lawyer who heads TransAfrica, an organization that helped pressure the US government to adopt sanctions against South Africa in the apartheid era].

What are some specific examples of research gaps or missed opportunities?
There is an incredible fascination with new technology, to the detriment of old technology. We have not had the definitive experiment which says that whole-killed approaches are worthless. I'd like to see them in a comparative monkey study. We have never seen the whole-killed experiment cleanly done, with monkey-grown SIV to make the vaccine and a monkey-grown SIV challenge.

We do not have definitive information saying that the Th1/Th2 concept [describing the inter-relationships among T-cell subclasses] is worthless. I don't know that low-dose vaccination is a worthless idea; I see lots of hints that it might be a useful idea. I'd like to see that experiment done cleanly.

The same with attenuated vaccines. Why is Ron Desrosiers out there alone? It's a great idea to exploit. Desrosiers has also come up with some new ideas. I think deleting V1 and V2 [regions of the envelope protein] deserves attention.

Another neglected area is cellular proteins. We know from Jim Stott's early work that cellular proteins by themselves are protective. Gene Shearer argues that we can do alloimmunization, at least in countries where they don't have organ transplantation. Why haven't we seen that move forward in a comparative fashion?

Those are several ideas that I think deserve more attention. I could keep going.

What are some of the positive signs you see now?
I'm excited by the notion that the field is now much more diverse. When I started following it, nearly all the approaches were based on envelope alone. The few other approaches were either dying on the vine or were mocked. I like the fact that there is so much creativity happening right now, and that different targets are getting serious attention.

The world has also changed since the book was finalized. I think the field still has major problems—and the problems seem to keep changing. But I see some of the things discussed in my book getting better.

There's a lot of optimism in the field.
Yes. Having Merck and Glaxo in the game is exciting. Overall, things have gone up a notch. The field has matured.

But it's important to recognize that we've moved the goalposts. We went from aiming for sterilizing immunity to delay of disease. And when we look at old, "failed" data using today's criteria, we see that some of those older vaccines didn't actually fail—there's data from ten years ago showing some real protection. Another thing to realize is that a lot of the excitement today is about mechanism—it's about the ability to explain why monkeys are controlling viral load.

How do you now see the prospects for a vaccine?
There's more serious attention being paid to the problem than ever before. I think a vaccine is eminently doable, and I think there will be a bevy of efficacy trials starting in the next five years. I would hope that, within the next ten years, we at least have conclusive data that something doesn't work, and maybe have a vaccine ready to go out to the world. I think that's possible.

There is not going to be the answer. There was a mistake on the cover of my book early on—fortunately, it was corrected. The subtitle said, "The Wayward Search for the AIDS Vaccine." I got very concerned—that was never my subtitle, and it's not my point. There isn't going to be the AIDS vaccine; it's an AIDS vaccine. I think there will be many ways to beat HIV with vaccines.

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