P4P: We're interviewing Dr. Peggy Johnston from the National Institute of Allergy and Infections Diseases (NIAID). Dr. Johnston is the Director of AIDS Vaccine Research and Prevention at NIAID. Doctor Johnston, thank you so much for taking the time to come and speak to us.

Dr. Johnston: You're welcome.

P4P: Can you tell our readers a little bit about the difference between preventive and therapeutic vaccines?

Dr. Johnston: All of the vaccines that are licensed today are used in prevention. That means they are given to people before exposure and it stops them from getting the disease if they then later become exposed. All of the vaccines we have currently work that way. However, because of the urgent need to find better treatments for infected individuals, vaccines that are being tested for prevention are also being tested to see if they can help boost the immune response of infected individuals and perhaps lessen their requirement for antiretroviral therapies.

P4P: Could you give us a brief update on where we are at in vaccine development at NIAID?

Dr. Johnston: Well it's been a big year for vaccines, because the first two large definitive efficacy trials, both of which were testing gp120, were completed this year and the results announced. Unfortunately, those vaccines proved not to show any efficacy in preventing HIV acquisition in uninfected individuals. So, now that we have that answer -- gp120 by itself doesn't work -- it's time to move on and look at other vaccines.

P4P: In addition to learning that the gp120 construct doesn't work, what else have we picked up from the other vaccine trials that have already taken place?

Dr. Johnston: There's a range of products in the pipeline, both pre-clinically and clinically, and there's now a combination vaccine that just started the third Phase 3 efficacy trial, which is being conducted in Thailand. That trial, which will enroll 16,000 individuals in a community based setting, primarily heterosexual transmission, just started last fall and has enrolled 1,000 individuals. That's testing a combination vaccine that's pairing the gp120 with a viral vector known as canary pox, to see if the combination of cellular immune responses and antibody responses can do any better than antibody by itself. The problem is that vaccine efficacy trials take a long time, so we're probably not going to get that answer for another 4 years.

Now, there are other products that are in early stages of clinical testing and some of them appear more potent in inducing strong cellular responses, but one of the nuts that we haven't cracked yet in vaccine development is how to get the human body to induce broadly neutralizing antibodies; that are antibodies that can recognize a range of variance, which is important, because, as everyone knows, the virus evolves in infected individuals and escapes from antibodies in infection. We feel that if we can get a broad enough spectrum of immune responses present before the virus comes in, whether it's cellular responses -- which we're doing a pretty good job at getting to -- or antibodies, which we have a whole lot more work to do on that end, then maybe we can prevent establishment of HIV infection in the first place, and more importantly, if the virus does get in, that the immune response is sufficient, both in terms of height and in breadth, to stop the virus if it evolves, so it can't escape. That's the goal. So we have some products in Phase 1 trial that are looking good in terms of the cellular component, but really the challenge now is in the basic research area to try to design new immunogens that can induce this breadth of antibody reactivity. And I think if we can do this for preventive vaccine, then we will also have much better candidates to possibly test and see if they can help infected individuals as well.

P4P: We know that HIV over-activates the immune system. Would these immunological responses that you mention look to counter that inflammatory response of the immune system? Is that what you look for the immunological responses to do, to calm that inflammation?

Dr. Johnston: That's a good question, because some of the emerging data suggest that as the immune response gets activated to fight the virus it's also making itself more susceptible to infection by those viruses. But basically, what we're looking for in immune response to be preventive are the induction of HIV-specific killer cells that can go in and kill a cell that is already infected, and that means clear it from the body, get rid of it; as well as antibodies that, if there are free virus particles that escape while the cell is making virus, that the antibodies can bind and neutralize those virus particles so they can't enter new cells and infect them. So if we can do both of those things, if we can get rid of the infected cells and we can neutralize the free virus particles, than there shouldn't be any HIV there, and we can try to stop infection from becoming established in the first place. That's what we're after.

P4P: Kind of the Holy Grail.

Dr. Johnston: The ideal. Yeah. Of course there's a lot of suppositions here that we know what we're looking for. So one of the challenges in doing clinical research is to determine as we measure a vaccine's efficacy, to see if any of these immunological assays that we think mean something correlate with efficacy. If we can determine that, then getting better and better vaccines will become much easier. The parallel example in treatment was the first trial with AZT. Even though AZT by itself proved not to be the ultimate in therapy, what was done in that trial was to verify the effect of AZT on CD4 counts, verify that CD4 counts were a surrogate and then later studies showed the viral load. So what happened was those markers were validated as being important to what happens clinically, and then drug development could just look at the surrogate, not wait for the clinical outcome. We don't have that in preventive HIV vaccines, so one of the challenges we have is developing appropriate immunological assays to see which, if any of them, can be our correlate or surrogate, and then advance the field very rapidly.

P4P: Last year we spoke to Dr. Judy Lieberman who did some research on RNA interference (RNAi). Are you finding that RNAi is helpful you to as a research tool in your work?

Dr. Johnston: I think that those techniques will be very important in looking at inhibition of HIV replication in the laboratory, but I think what will be more important for us in terms of vaccine development is taking cells and plasma from people who are vaccinated and then exposed and protected to determine what in those cells taken from the vaccinated individual looks like it correlates with the clinical outcome of the trial. We'll be measuring levels of antibodies in individuals, specificity of antibodies, much as Judy does in her other work looking at what's called cytotoxic T-lymphocytes and their specificities.

P4P: Could you give us a brief synopsis of the efficacy trials that are ongoing?

Dr. Johnston: There is one preventive efficacy trial that's underway now, and that's in Thailand. It's evaluating the combination of the recombinant canary pox vector that expresses multiple HIV proteins, combined with gp120. The vaccine that's being tested was specifically designed for the subtypes of HIV that circulate [in Thailand]. Individuals come in and either receive a placebo or several injections of the canary pox, and then later injections to boost the immune response with gp120. They will be followed over a period of time, and then we can look to see if there is a difference in the number of people who become infected that received the vaccine versus those that received the placebo. In addition, for people who become infected even though they have been immunized, we'll also look at viral load, because it might be that some of these vaccines won't protect from infection but will enable a person if they do become infected to control their viral load much better and much longer. Following those who become infected for a long period of time, to see if the vaccine's provided them any benefit, is also a key part of these trials.

P4P: For people who might become infected in these trials, and should it be proved that there is little or no therapeutic value to the vaccine, will these individuals be rolled-over into any sort of treatment? Is that part of the trial?

Dr. Johnston: I think that, first of all, we have to recognize that these vaccines are experimental and we don't know if they will provide protection or not. So everyone enrolled in a vaccine trial will be counseled repeatedly on diminishing their risk-taking behaviors. And that's important for people to understand, that enrolling in a vaccine trial does not mean that you can throw away your condoms or not worry about infection. That's an important aspect. I think that those who become infected during the trial, we are working very hard to make sure that those individuals will have access to antiretroviral therapy when they do progress and want and need to go on therapy. That will be absolutely essential. The challenge, of course, is that much of the vaccine prevention work is being done in developing countries, and so ensuring that our research efforts are linked to the programs that are providing antiretroviral therapies is a major focus of our efforts right now. There won't be a rollover study per se, in which we will offer therapy to those individuals, but we are working very hard to make sure they will have access to therapy if they do become infected.

P4P: That's very encouraging. Now, in terms of where we go from here ... What's the future looking like? Should this particular vaccine demonstrate that it's less efficacious than desirable, what's next?

Dr. Johnston: ... When we learn something from an efficacy trial, that information has to feed back and be used to help better evaluate products in earlier stages of trial, in animal models, and in basic research. And unfortunately, we're not anywhere near having a vaccine that we think will be highly effective against most of the subtypes that circulate in the world. This is going to be a long process. We have to envision this as a big pipeline where there needs to be a tremendous continued fundamental research effort to try to learn as much as possible about the structure of the HIV envelope, which is the target for antibodies; how can we design immunogens that will attack all the different subtypes and primary isolates of HIV? There needs to continue to be animal model studies to look at the immunogenicity of new designs and what they induce, how they induce it; and there also needs to be continued human testing, because as one of my favorite vaccine developers once told me, he said, "My sly, monkeys sometimes lie, but humans never lie."

P4P: [Laughter]

Dr. Johnston: The ultimate goal is, what is the immune response in the human volunteer and what is the efficacy in the human volunteer. We have to keep in mind that each part of that process generates important information and is important research. There isn't one area of focus right now. We need to keep the whole pipeline, the whole span of activity very vibrant.

P4P: Is there anything else in terms of vaccine development that we haven't covered so far that you believe would be important for our readers to know?

Dr. Johnston: Well, I can't emphasize enough the need to ensure that these vaccine trials are integrated into other areas of research and prevention and care. It's going to be a long time before we have a highly effective vaccine; so continued measures to educate individuals about prevention are paramount. There are other prevention technologies that we're also exploring -- microbicides that could be used by both men and women, to be applied and protect themselves upon subsequent sexual exposure to HIV. That's another important area of research. We have to keep fighting on all fronts and make sure particularly in populations in this country, that are disenfranchised, developing-country populations, that there is a holistic integrated approach to research as well as care and prevention. Attacking and being successful in this disease is going to require both finding optimal ways to treat infected individuals and prevent those not infected from becoming infected. It can't be one or the other. We can't pit them against each other. We have to demand that both continue.

P4P: Doctor Johnston, thank you so much for sharing your time and expertise with us.

Dr. Johnston: Oh you're quite welcome. It's been a pleasure. Thank you.

Back to the Spring 2004 issue of Positives for Positives.