So, where do you go without relying on natural infection?
What we have to do is develop immunogens and find out the fundamental, basic questions: Why is it so difficult for the body to develop a neutralizing antibody response? And given that, what can we do to present an immunogen to the body to allow it to develop a neutralizing antibody response readily—not in a very difficult situation, but readily in the vast majority, if not all, of the people that get vaccinated? Those are fundamental questions, the answers to which we don't have.
Do you think we got this far without very basic questions being answered because the HIV vaccine is such a desperately sought after goal—that the world is truly hungry for one to exist?
Obviously the world is very hungry, as you put it, for an HIV vaccine. But following the classical vaccine paradigm, what we were doing was not unusual. It was only when we had the full realization that, "Wait a minute. There's something very very different about this virus, so therefore the classic paradigms might not hold so strictly." So, I don't think the only motivation to move ahead was that we were "hungry for a vaccine." Our motivation was that that approach had been imminently successful with other viruses.
But, these moments of realization, have they come in nuggets over the past 20 years or are they big signs like the failure of Merck's STEP vaccine last year?
There were suggestions and hints of it very early on when we found out that antibodies that were elicited in people generally neutralized lab-adapted strains [of HIV], but did not neutralize the wild type strains from the body. This indicated that antibodies that were elicited weren't particularly effective against the kinds of viruses that were circulating in the community. That was a hint, but most of the people felt, "Well, let's just give it an empiric shot and vaccinate people with the envelope [the antigen, or protein on HIV's surface] and see if we can elicit a really good neutralizing antibody response.
It was only as the science moved along in parallel with those empiric attempts that we realized that the part of the envelope that neutralizing antibodies bind to is very cryptic in its conformation and doesn't reveal itself to the immune system very well or for a significantly long period of time. It's hidden. It has a confirmational component to it that doesn't allow the immune system to see it very well, much less elicit an antibody. We didn't really know that until we'd already launched some trials way back years ago using the empiric approach of what we would do with any other virus: get the outer coating, that is, the envelope, and use it as an immunogen. We didn't appreciate that the part of that immunogen that you would need to show to the immune system didn't readily reveal itself.
So, how does the STEP trial factor in? Its failure seems to be one of the primary triggers for the HIV vaccine reassessment.
The STEP trial was another interesting thing because as the antibody component failed, and we needed to go back to the basics to figure out how to elicit an antibody response, there were studies in an animal model that suggested that perhaps you couldn't block acquisition of infection. But, perhaps you could get the lowering of the viral set point so low that the person who was vaccinated would benefit because their disease would not progress. They would almost be like a long-term nonprogressor, and the other herd immunity-type benefit would be that if their viral load was low, then perhaps they would not readily transmit the virus to someone with whom they come into contact.
So, that's when the STEP trial approach of a T cell immune response was done. But, the correlates of immunity that were measured in the early part of the trial and in the animal were assumed to be correlates that would be therapeutic. As it turned out, when you vaccinated people in the STEP trial, it neither blocked acquisition—which we didn't expect it to do anyway—but it had virtually no effect on the viral set point. So, the question was, "Well maybe we can look at the immunological response and get some information from a subset of people in the trial who seem to have responded well?" That's a fallacious approach. If the vaccine doesn't work, doing immunological correlates, in my mind, and the minds of many many of my colleagues, is not worth doing.
That's really the fundamental reason why I elected to not accept the proposal for a moderately sized—or big-sized—PAVE 100 trial. I said, "I reject that." The reason I reject that is we really need to know that if the product is interesting and different enough from the STEP product. It's a DNA–DNA–DNA followed by an adeno and it also contains envelope, in addition to the other viral genes. I think it's worth pursuing, but not in such a large trial that it will allow you to get all the immunological correlates you want.
I first want to find out if it has a beneficial effect. If it does, then we'd be willing to invest more resources, more people, more specimens. If it doesn't succeed in lowering the viral set point, then I don't think it's worth going and pursuing these elusive immunological correlates. You don't even know what they are correlated with.