On the Trail of a Vaccine
An Interview With David M. Gold, J.D.
With HIV infection continuing to spread, an AIDS vaccine is the world's best hope for controlling the epidemic.
The recent XIV International AIDS Conference in Barcelona, Spain, provided an opportunity for researchers and observers to mark progress in vaccine development.
At the center of this quest is The International AIDS Vaccine Initiative (IAVI), an organization dedicated to speeding development of an AIDS vaccine. Based in New York City with an office in Europe, IAVI representatives at the recent conference included David M. Gold, J.D., IAVI's Vice President for Policy and Public Sector Support.
Besides Mr. Gold's work for IAVI, his portfolio includes advocacy work for the Washington, D.C.-based AIDS Vaccine Advocacy Coalition, and education at Gay Men's Health Crisis. He has also served on research advisory panels for UNAIDS and the U.S. NIAID, among other organizations.
During the conference, Mr. Gold took time to be interviewed for Positive Living by AIDS Project Los Angeles' Associate Director of Education David Pieribone.
Q: In the past, vaccine research seemed to be a priority for the government, such as the polio vaccine. Why is HIV vaccine research so different?
A: I'm not sure it's not a priority. It's becoming more of a priority at the National Institutes of Health (NIH) in the U.S. and for other governments. But it's still not a huge priority. If you look at the $420 million spent on developing an AIDS vaccine in both the public and private sectors, it is still relatively small given the horrific impact of this epidemic. That may sound large to some people but -- and living in Los Angeles, you can appreciate this -- Hollywood spends that much on producing two major movies a year. So, if you just follow the money, you can see where we as a global society, place our priorities.
Q: Scientists and researchers have been working on a HIV vaccine for a long time. What are some of the major scientific roadblocks?
A: Number one -- the most important -- we still don't know exactly what kind of immune response a vaccine should generate that could be protective. There's strong evidence for a cellular response. CD8 and CD4 helper cell responses seem to be very important in both monkey and human studies. And there's clearly some evidence that antibodies can be protective. Now we're seeing evidence supporting these ideas, but we're not sure.
Q: Most vaccines in the past have focused on the antibody response, right?
A: That's correct. Take, for example, the Polio and Hepatitis B vaccines. They generate a certain level of antibodies that are protective. But HIV is different. As you know, the so-called HIV test [the ELISA test] is an antibody test, so we know people with HIV are generating antibodies. But these levels of antibodies are not protecting them from disease and infection. We know some of the vaccines that are currently in clinical trials, including the VaxGen product, generate a low-to-moderate level of antibodies. However, in lab tests, these antibodies don't seem to neutralize human strains of HIV. In monkey studies that have been done more recently, it's been shown that monoclonal antibodies generated high enough levels of antibodies to protect monkeys against SIV (a cousin of HIV). The problem is, none of the vaccines tested so far seem to generate anything near the level of antibodies that the monoclonals do. So, I think it's fair to say that if you can generate the highest levels of antibodies, you can probably be protective.
Q: What are some of the promising vaccine candidates that are being studied now?
A: Well, there's VaxGen's AIDSVAX®, which is a gp120 protein vaccine. gp120 is from the outer surface of HIV, its envelope. This vaccine is in Phase III trials in North America and in Thailand. The population being studied in North America is men who have sex with men (MSM); in Thailand it is injection drug users (IDUs). The North American study will be completed at the end of 2002 and we should have some results at the beginning of 2003. The Thai trial should have some results the following year.
So the VaxGen product is the only vaccine to go into a Phase III trial so far and I think that's a problem. We are now in the 21st year of the epidemic and there is only one vaccine that has ended up in efficacy studies. Beyond that, the product that most people are excited about is the Merck combination vaccine, a DNA vaccine combined with an adenovirus vector that uses pieces of the HIV genes inserted into the vector. In monkeys, it seems to be quite protective against a certain challenge strain -- a combination of HIV and SIV, known as a SHIV virus. The vaccine combination is now in human trials and, they are also testing it as a therapeutic vaccine for individuals already infected with HIV. Another product people are focusing on is IAVI's own product: a combination of a DNA vaccine and a viral vector known as MVA (modified vaccinia Ankara) which is a weakened strain of the smallpox virus. This vaccine is in Phase I and II trials in the UK and Kenya. The interesting thing about this vaccine is that it is based on a strain of HIV that is common in Kenya know as clade A. Most of the other HIV vaccines that have been tested are based on clade B, which is the strain common in North America and Europe. IAVI's goal is to put the combination into Phase III trails by the end of the 2004. That is a very fast track development plan.
Beyond these, there are a bunch of other DNA plus viral vector combinations being tested by different groups. There's a canarypox vector combined with gp120 that is about to start Phase III trials in Thailand. The canarypox vector has been tested for a while; we know what it does and it seems very safe. So those are probably the four products that are most advanced.
All these vaccines, with the exception of the VaxGen gp120, are focused on generating a cellular response. But antibodies will clearly be needed to provide complete protection. At the International Conference on AIDS in Barcelona, IAVI announced the creation of a consortium of researchers that will focus on developing vaccines that generate strong and broadly neutralizing antibodies. The consortium is being led by Dennis Burton of the Scripps Institute, who is one of the top antibody researchers in the world. Other participants include the Dana Farber Cancer Institute, Cornell Institute in New York and the NIH, which is offering advice and assistance. So the goal of this initiative is to bring these researchers together to focus on developing vaccine that produces potent antibodies.
Q: What exactly is the prime boost strategy and does this mean that you will need more than one dose of a vaccine for it to be effective?
A: Well, the prime boost is when you use one type of vaccine to prime the immune system, and another vaccine to boost it. In the HIV arena, it's been tested primarily with a DNA prime to start with and then a viral vector boost. But in the Thai trial, it's a canarypox prime and a gp120 boost.
Your second question about how many doses will be needed is an important one. The VaxGen trial, for instance, includes six or seven doses and that's clearly not an easy thing to do. The Hepatitis B vaccine, which is safe and approved, needs three immunizations and they found that getting people to come back for the third dose was not easy. Records need to be kept, and it points to an even bigger problem of how to develop vaccines that are practical to deliver in resource-poor countries. One of IAVI's prime focuses is the development of a vaccine that is safe and effective and can be delivered in a resource-poor setting.
One oral vaccine that we are developing is based on a salmonella bacterial vector. This should be a more practical way of delivering vaccines in poor countries so you don't have to use needles and it also may be relatively inexpensive to produce. We also hope that the vaccine will generate more potent immunity in the mucosal system.
IAVI has another vaccine in development that is an adeno-associated virus. In monkeys, this vector seems to generate a more persistent immune response with one immunization. But even with a vaccine that needs just one dose, it's important to see if it can be effectively delivered. Even in an industrialized country with great amount of wealth, such as the United States, it is not easy to get a vaccine out to adults.
The Hepatitis B vaccine is a good example. It's been available in the U.S. for some 20 years but we still see that in groups that are at high risk for Hepatitis B infection, such as men who have sex with men, less than 50 percent of the population is immunized. Imagine the complications of getting a vaccine out in a poor country. The challenge is trying to keep track of who's going to get the fourth shot and who's getting their third, which won't be easy.
So clearly we have to look at how we develop products that are practical to be delivered. Interesting enough, this is where I feel there's an overlap between treatment and prevention, because as we build up the infrastructure to deliver treatment, if we do it right, it's going to be the infrastructure we use to deliver the AIDS vaccine. Instead of looking at it like conflicts between treating people in developing countries and developing prevention technologies to prevent them from getting infected, we should look at the tremendous areas of commonality.
Another commonality is in therapeutic vaccines. As I mentioned before, Merck's vaccine is already in trials in people with HIV. Glaxo is going to do the same thing with their AIDS vaccine candidate. And the IAVI DNA/MVA combination that is being developed by Dr. Andrew McMichael at Oxford University is scheduled to move into trials in HIV-positive people shortly. These will not be IAVI-sponsored trials. Our mission is very clear; it is to develop a preventative HIV vaccine for the world. But what Dr. McMichael is doing is taking the vaccine that we have paid to develop and conducting his own trials of the vaccine as a therapy. We are thrilled that it's being done and we think it points to the importance of investing in good product development and immunology research, and when that happens everyone benefits.
Q: OK, we talked about vaccines in the U.S. and Africa. Will a vaccine that is effective in the United States be effective in Africa and other parts of the world?
A: As you know, there are a number of different subtypes or clades of HIV around the world. HIV has a great deal of genetic variability; will a vaccine that is developed for one population be effective in another population? We don't know. And that's why we have to conduct clinical trials.
As I have mentioned, IAVI is developing an AIDS vaccine based on a strain of HIV that is circulating in Africa and Asia. We've flipped around the model, in the past, most of the other products being developed were based on strains prevalent in U.S. and Europe. Now the question is, is that relevant? We don't know. Merck has some data showing that the cellular immune responses their vaccines generate can neutralize virus from other strains, but it's not conclusive and until we do the studies where we take a vaccine developed from one strain and test it both in areas where the circulating virus is the same and different, we will never know. It will take political and scientific leadership to make sure we can test vaccines in human trials as soon as possible.
Q: Most vaccines are not 100 percent effective. What kind of effectiveness do you need to bring an epidemic like HIV to a halt?
A: Again, we don't know for sure. The VaxGen trial, for instance, is designed to detect protection above 30 percent. And the way they define protection is sterilizing immunity, meaning that people either get infected or they don't. Vaccines that stimulate a cellular immune response are more likely, based on the monkey studies, to prepare the immune system for exposure/infection of HIV. So if it doesn't stop infection, these vaccines may still be protecting the monkeys against disease. So the vaccinated monkeys and the unvaccinated monkeys will both get infected. But the unvaccinated monkeys will get sick and die from monkey AIDS while the vaccinated monkeys will have undetectable viral loads and normal CD4 counts.
But again, that's the monkey model, and again, most of these monkeys are challenged with an infectious dose of about 50 times of what we normally would take to infect. The reason for that is efficiency of cost. You cannot do good studies if your control monkeys do not get infected or sick. So, they need a high threshold and a very efficient infection. We don't know how similar that is to human infection. But we do know that, compared to these monkey studies, it is more difficult for people to become infected with HIV. I'm not advocating for people not to protect themselves, but clearly there is a different rate of risk from transmission of HIV in an actual human, sexual transmission and a monkey vaccine study where you want the monkeys to become infected. So whether the cellular immune vaccines provide so-called sterilizing immunity in some people, we won't know until we do the studies.
And, what's your definition of effectiveness? Is it 50 percent of the people don't get infected? Is it all of the people who get vaccinated get infected but none of them get disease for 15 years? In some developing countries, there's massive HIV infection. So if 30 percent of the adult population become protected against HIV, it could be a very important step forward. So, even when you define effectiveness it's difficult because effectiveness could also be preventing disease for 10 to 12 years, but not infection. And if we treat people who become infected, most of them won't progress for a long time anyways. So how do you detect differences in progression in a vaccine trial? Can you go by the difference in "viral set point" if a vaccinated person has a very low viral set point while an unvaccinated person has a typical set point? Is that enough for licensing a vaccine? How long do we have to wait out before we decide whether we want to get that vaccine out to a population? Is there a different risk-benefit analysis in Botswana compared to Belgium?
But if we get a partially effected vaccine out to people, some may very likely increase their risk behaviors, thinking the vaccine is fully protective. So you may have a moderate level of protection and people engaging in more high-risk behavior. So the vaccine may net out without a real public health gain, or in fact create more infections. These questions are just not easy.
Q: Some people I've talked to are worried that an HIV vaccine could infect you with HIV, or cause symptoms of HIV disease. What can you tell us about that?
A: None of the vaccines in development at this point have a risk of infecting the trial participant with HIV. The current vaccines in clinical trials contain genetic pieces of the HIV, which have been tested thoroughly in animals and humans. The only vaccine that has a risk is the live attenuated vaccine that has been studied in monkeys, and that is not currently in active development, and my guess is that would only be considered for human trials in 10 to 15 years, if everything else fails. The whole-killed vaccine also could possibly pose a theoretical risk, but again human trials are not likely. Both of these vaccine approaches have been used widely for vaccines against other diseases, but no one is talking seriously about moving any of those types of products to humans at this time.
Q: If we had a vaccine that was effective, or partially effective, do you think it would be mandatory in the United States?
A: My guess is that it would not. At the first stage, it would be given to adults and adolescents at high risk of HIV. Eventually, after a long and a very clear safety profile, it would be considered for child immunization programs. So I think there's almost no chance it's going immediately to so-called mandatory infant immunization programs.
Q: You talked a little bit about vaccines for people who are already infected with HIV. Do you think we are close to a vaccine that will help people get their immune systems to fight HIV without the need for medications?
A: Again, we don't know. And again the only way we are really going to find out is doing studies -- so it's good to hear that these studies are getting done. The goal with therapeutic immunization would be to immunize people while they're on HAART. Hopefully, the vaccine will generate a more potent cellular immune response. A strong, HIV-specific cellular immune response is often found in so-called long-term non-progressors who are not in treatment. Almost all of these individuals have good cellular immune responses to HIV and seem to control HIV without medication. But paradoxically, when you treat people with HIV, the cellular immune responses go down because the amount of virus that causes the immune responses often goes down to undetectable levels. The goal of a therapeutic vaccine would be to generate a cellular immune response while the virus is undetectable, then take people off therapy, and see whether the vaccine can, in a way, teach the immune system to control the virus without antiretroviral drugs. The attractive thing about this concept is that you can test this relatively rapidly. You can take people off therapy, and you should know within 12 months, whether there is significant difference in controlling the virus, for those who were on the vaccine during HAART and maybe continued getting the vaccine versus those who are unvaccinated and went off therapy.
Q: If someone were interested in joining a vaccine trial, what kind of advice would you give to him or her?
A: The NIH has an information number for those who are interested in vaccine trials. And I also encourage people to look at www.iavi.org. We have a database of vaccine trials. amfAR's Web site: www.amfar.org also has a clinical trials database. For those who are interested in the overall issue of vaccines, I would suggest to look at our Web site, we have an excellent newsletter on AIDS vaccines, The IAVI Report, and a wealth of other information on efforts to develop a vaccine.
This article was provided by AIDS Project Los Angeles. It is a part of the publication Positive Living.
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