Important note: Information in this article was accurate in April 2001. The state of the art may have changed since the publication date. IAVI Report - April / June 2001
In April, 1999, Gary Nabel became the first director of the new Vaccine Research Center (VRC) at the National Institutes of Health in Bethesda, Maryland. Prior to taking this position, he was director of the Center for Gene Therapy and a Howard Hughes Medical Institute investigator at the University of Michigan in Ann Arbor. Nabel is well-known for his work on HIV, cancer, and Ebola virus, and for his gene therapy clinical studies. Here he talks with the IAVI Report about the research program at the recently opened VRC, which will work primarily on AIDS vaccine development, and about the scientific challenges facing the field.
We began our building and recruitment of staff two years ago, and are now at the point where we're beginning to gel as a center. Hiring is complete and our investigators are moving in and setting up their laboratories. Four labs are running, and we hope that all the investigators will be here in July-about ten tenure-track scientists and some high-level professional staff to run our core facilities.
We're directing most of our efforts at the early stages of AIDS vaccine development—translating concepts from the laboratory into the clinic, and testing approaches and methodologies for identifying promising leads and advancing good candidates. We have brought in people from areas as basic as X-ray crystallography, to work on the structure of HIV envelope, and from virology, immunology, clinical production and clinical trials.
We view our mandate as being, first of all, to address the major scientific problems before us. And second, to use that knowledge to expand the pipeline of candidates into trial.
The key thing is critical mass. In putting this building together literally from the ground up, we've had the luxury of starting with a blank slate and asking what we want to build and how to assemble a group to accomplish it. Although we're not a large center—altogether we will have between 100 and 125 scientists-it is sufficient for getting things done, without being so big as to lose the personal connections that help people work well together.
All the investigators here have a common purpose. And we hope that having them under one roof will catalyze progress in difficult areas.
I think the rate-limiting step for a highly successful AIDS vaccine will be the development of broadly neutralizing antibodies. Scientifically that's the major question we would like to impact here.
Most people in the field believe that cytotoxic T-cells will be important in containing the virus, and that we should be able to develop vaccines which elicit CTL responses and confer some degree of protection. How well they work is likely to depend on how long we can sustain active responses and how quickly we can recall them. I think we can do more to help that process along, but my guess is that we'll hit a wall in terms of how effective this approach will be.
The virus envelope is a very formidable target. It's been possible to generate neutralizing antibodies to specific strains of virus from specific laboratory isolates. But it's been quite uncommon to have broad antibody responses that neutralize many strains within a clade, even less so multiple clades. That's the key issue we need to address.
Another challenge is that, behind every successful vaccine is an example of immunity in humans or a good animal model to guide our efforts. With HIV we have exactly the opposite—the virus has figured out pretty successfully how to evade immune detection. We have to get at the heart of how the virus accomplishes this and try to build the immune correlates that will help us develop an effective vaccine.
We will come at it from several directions, starting with a structure-based approach. Joining us in the Center are two scientists who were major movers in solving the crystal structure of gp120—Peter Kwong and Rich Wyatt. Together with Wayne Hendrickson and Joe Sodroski, they published the first structure of gp120 complexed with CD4 and a monoclonal antibody. We're hoping to identify structure-based modifications of gp120 that might allow us to present otherwise cryptic epitopes or hidden structures which could be useful immunogens for eliciting broadly neutralizing antibodies.
It may or may not be possible to develop antibodies of this sort. But we need an answer to that question, one way or another.
We will also approach the problem genetically by making a series of mutants, again based on what we know about the structure and function of gp120 and on gp41, from the Kim and Wiley laboratories.
The real issue—like for other challenging infectious diseases nowadays—is that the HIV envelope is a moving target. Literally moving, because it's conformationally active and never allows you to have a static view of structures you'd like to neutralize. And genetically moving, because it's constantly evolving new sequences.
My laboratory has been generating vaccine candidates based on DNA and on viral vectors, primarily adenovirus, to test different vaccine concepts. The approach is to hypothesize what components are needed for a vaccine and then develop candidates to test that concept. We're looking at combinations of immunogens that generate cytolytic T-cell responses, particularly to the internal proteins of the virus—mostly Gag and the pol gene products—and to Nef. We also think it's important to generate CTL responses to envelope. In terms of antibody, obviously the exposed proteins would be the ones we target, primarily envelope.
We now have prototypic DNAs encoding all these gene products. We'll also take the same inserts used in the DNA and introduce them into viral vectors.
The product is a gag-pol fusion, engineered to express the pol-encoded proteins at higher levels than in wild-type HIV. It's part of our strategy to try to enhance the breadth of the immune response.
This is a prototypic construct. I don't expect it will be the only immunogen in the end. But it's an important step because it allows us to develop our methodology for starting with a construct in the lab and moving it into the clinic. We should now be able to introduce new candidates more rapidly.
Once we have screened all the patients, which usually takes about two months, we'll start the trial. It's a standard Phase I study, with seven people per dose and a dose escalation—altogether 20 to 25 patients.
The trial will be done here at the NIH clinical center. We'd like to use these early trials to collect safety and immunogenicity data and begin looking at strategies for enhancing immune responses. When we identify the more promising approaches, those candidates will be fed into the HVTN pipeline and then progress to Phase II and III trials—a passing of the baton to the larger networks.
In our preclinical studies, we look for immunogens that give the broadest and most potent responses. For CTLs, we start in mice. For antibody responses we look for the highest titers and best neutralization, primarily in guinea pig and sometimes rabbit.
Our other criterion is the response in non-human primates. We are trying to move directly from small animal models into Phase I human studies, at the same time that we move these prototypes into monkeys. In the primate models, we can again get readouts of immunogenicity. More important, we can look at how those vaccine candidates respond to a viral challenge.
That's correct. If there was less urgency, we might take the more traditional path of progressing from small animals to non-human primates to human. Also, we are still not convinced that the monkey model is exactly predictive of what will happen in people. The Indian rhesus and some other macaques are very good models, but there are differences among the animals and between HIV and the viruses that infect monkeys. At the end of the day, it's the Phase III trial that will tell us whether the vaccine works. We need to get to that endpoint sooner rather than later.
We can't yet say with confidence. But there are trends emerging. Roughly speaking, an immunogen that works really well in mice also works in primates, and a little less well in humans. In other words, many vaccine candidates show roughly similar results in the different systems, but with a decreasing level of performance as you move up the evolutionary tree.
This is really is a critical issue, and many of us are trying to approach it in different ways. When you have a problem as rate-limiting and important as this, you can't rely on any single solution.
Clearly, we need to increase breeding supply. That takes great discipline, because we also have urgent experiments to be done. So we as a field have to look carefully at the experiments we do, and use the available animals in the most intelligent way. Making matters worse is that demands for these animals come not only from the research community, but also from the pharmaceutical industry. And we are not in a position to control them.
We also need to look for alternative sources of animals and for solutions we might not otherwise find ideal—like doing experiments abroad in countries with animal colonies, but where we will need to invest in infrastructure so the experiments can be done with state-of-the-art analysis.
The other important avenue, which I think can move forward relatively quickly, is to look at other monkey species or strains. We've been very high on the Indian rhesus macaque because there are so many specific reagents for looking at their immune responses. But there's really no reason we can't do the same in Chinese macaques or cynomolgus macaques. It may be easier to make new reagents than to wait for until enough Indian macaques have been bred.
Yes. Norm Letvin is our director for primate studies. Together with John Mascola, our deputy director, he has been involved in looking globally at the broader questions, not just for the VRC, but for the whole field.
The VRC alone cannot solve this problem. But we can help develop some reagents and make them broadly available. We're also looking at the Chinese rhesus and cyno models, and at different virus challenge stocks and how they behave.
There may be a silver lining to this cloud. There's some suggestion from preliminary data, not yet published but being discussed at meetings, that viral loads in Chinese rhesus monkeys better approximate viral loads seen in humans, both at the peak of infection and at steady state. We'll know within six months whether this is more widely true. If so, it might be a more realistic model than Indian rhesus macaques.
We shouldn't underestimate how much work it would be to sequence the MHC region of the Chinese macaque and to develop reagents like tetramers. But it can be done.
The adenovirus we use is a very potent immunogen. As a vector it does very well in eliciting both cell-mediated immune responses and very high titer antibody responses, particularly when combined with DNA.
We became very impressed with the power of this approach when we began working on Ebola virus vaccines several years ago. In a rodent model, the DNA vaccines alone worked perfectly fine to protect animals against lethal challenge. But when we applied our correlates of immunity from these models to monkeys, the same DNA vectors couldn't come close to inducing those responses. We then found that adenovirus was very effective in achieving these correlates of immunity, and it proved its efficacy in a monkey challenge model. So we're using it again.
In terms of what HIV antigens you put into those vectors, or the different prime boost strategies—there are many possible directions to go. Merck is moving its own set of genes forward. Many of their products appear to be directed towards generating CTL responses against internal proteins. We agree that this is a good idea. But we also want to make sure that envelope is well-represented. The issue of targeting any vulnerable structures on envelope is very high on our agenda.
I liken our efforts with adenovirus to the situation when different groups were trying to develop anti-retrovirals. Many people developed anti-retrovirals against reverse transcriptase, and many products came forward. There was no way to know ahead of time which ones would work best. Clearly, the only way to find out was by testing them in the clinic. So I suspect at the end of the day, that's how we'll work with vaccines. As the virus has taught us, we're best served by having diverse approaches.
Ebola has many parallels to HIV infection. When we first started working on it, it wasn't at all clear you could generate immunity to the virus, or what those correlates of immunity were. But we've developed approaches that generate immune responses which seem to be protective, and which allow us to establish correlates of immunity in animal models that we now apply to the human situation—much as we're trying to do this for HIV.
And, as we just discussed, with Ebola we also identified some very promising technology platforms, and some important concepts in terms of how to move reagents out of the laboratory into the clinic. We're using those concepts in our HIV work.
We are in the process of making clinical-grade material and beginning the regulatory process. We would love to begin Phase I studies of Ebola on DNA and adenoviral candidates as well.
The bottlenecks are highly dependent on what candidates you're talking about. DNAs are now among the easiest to get into the clinic. But even then, there are a limited number of facilities that can make GMP-grade DNA. It's even more challenging to produce viral vaccines.
Beyond the capacity to manufacture vaccines, the issue of what packaging cell lines are safe and can be used to produce vaccines is a critical one. For many years, we've been tied to primary cell lines for producing vaccines. We, the FDA and the whole field are trying to develop an approach that will make it possible to use permanent cell lines, by addressing the various questions this raises.
At this point, since we're not fully staffed, I don't think so. When our activities grow and we have all the scientists on board, then yes, we may have increased needs. But I'm quite comfortable that the NIH leadership knows what those needs are and will keep ahead of the curve. Already we've had tremendous recognition by NIH, not only in terms of research support, but in thinking about new ways of giving that support. There is not another organization on campus like the VRC, where the entire building is dedicated to a single purpose like our mission of developing an AIDS vaccine.
We've also had recognition from the leadership that we might need new types of infrastructure. For example, another major impediment to making new vaccines is being able to produce clinical lots. We don't have that capacity here, but NIH is supporting the construction of a pilot plant with five or six production rooms, which is now going up in Frederick, Maryland. It should come on line in about three years.
This tells me that not only are the resources there, but so is the vision, commitment and dedication. So I'm not worried about funding.
My view of the timeframe suggested by our former president is that it was a very useful device to mobilize the field. There have been very few, if any, vaccines ever developed in that timeframe. But this is a very special circumstance and we should leave no stone unturned in terms of getting to that end.
I think it's conceivable that there could be a vaccine in that timeframe. But we would have to be extraordinarily lucky, considering that it will take another at least two years to get good candidates to the point of entering Phase III trials, which then take several years to perform.
But I do think we should know within that timeframe whether the AIDS pandemic can be contained through vaccination. I'm very hopeful that vaccination will be the answer and that within the ten year period we will see the end and know that the goal is achievable. Whether that end will then take another two years or five years, I don't know. That's what I think we need to aim towards in the VRC and in every other laboratory that's trying to solve the problem.
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©2001. The IAVI Report.
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