Last month, HIV scientists gathered for the Keystone Symposia on HIV Pathogenesis, where research results highlighted continued momentum in the search for an effective HIV vaccine. The current positive outlook among vaccine researchers is based in part on the modest efficacy data of RV144, the vaccine that completed testing in Thailand last year. This was the first time that an AIDS vaccine showed protection in humans, proving that an effective, preventive AIDS vaccine is possible. What’s more, several new neutralizing antibodies against HIV were also discovered this past year and have given researchers new vaccine avenues to explore.
Some basic scientists, however, think it is premature to do more trials, given the cost and past disappointments, and they argue that money needs to go into the basic science questions first; other clinical researchers feel strongly that without ongoing human trials, the search for an effective vaccine will be unduly delayed. With HIV Vaccine Awareness Day on the horizon, we spoke with Rick King, the vice president of vaccine discovery at the International AIDS Vaccine Initiative, about what’s next in AIDS vaccine research and development.
Q: In the wake of the RV144 AIDS vaccine efficacy study, which reduced the HIV infection rate by about one-third, there seemed to be more questions than answers about the vaccine candidate. Scientists were not sure why that vaccine regimen worked, and the efficacy was relatively low. What specific scientific lines of inquiry are being pursued to learn from those trial results?
A: The RV144 trial was very exciting and important because it was the first trial to demonstrate that an AIDS vaccine candidate could protect humans from HIV infection. We cannot attribute the protective efficacy to any given finding or mechanism in the trial as of yet. But the enthusiasm now is to try to figure out just that. The U.S. Military HIV Research Program, one of the trial sponsors, is working together with the international scientific community to outline a very careful and sophisticated approach to trying to find some clues about the mechanism that was able to give some protective efficacy. Data will emerge probably over the next several years on this point. We hope use the knowledge we obtain to advance the field.
Q: What other promising AIDS vaccine research is currently underway?
A: There have been exciting advances in the area of pre-clinical research that will greatly contribute to our ability to develop an effective vaccine. We are developing vectors that we think can have high potency. What I mean by this is that the vectors will present the vaccine components more effectively, thereby stimulating a more robust and targeted immune response. And we also have a major effort to generate proteins that elicit antibodies that have the kind of activity that is likely to have an effect on HIV. If the antibodies can bind to the virus and neutralize it, that means the virus can’t get into cells, so it could be a powerful component of a vaccine.
Q: What is it about the HIV virus that makes vaccine development so much more challenging than other kinds of infections?
A: There are a number of unique characteristics about HIV that make the development of an AIDS vaccine challenging. One is the extreme variability of the virus as it circulates around the world. With polio, for example, there are just a couple of different variations. With flu, at least every season, there are only one or two major strains that affect everyone. But with HIV, there’s a larger number of different molecular species existing at any one time, so we can’t just go after one specific target. The subtype of virus that affects most people in the U.S. is different than the subtype that affects people in South Africa. The molecular structure of HIV varies within a country and even within an individual, which gives the immune system a very challenging target.
Another challenge is that HIV disables the very system that is designed to reject it—the immune system. This means that any vaccine we design will have to strike at HIV as early as possible, well before it has a chance to begin killing the very soldiers of the immune response that the vaccine must harness.
Third, HIV incorporates itself into the DNA of the host. This means that unless every infected cell is removed and rejected by the system, there’s always a seed that allows the virus to come back. Those are very big problems faced by HIV vaccine researchers.
Q: What other vaccine trials are currently underway in the field, and when can we expect some answers about the efficacy of other vaccine candidates?
A: There are currently 24 other clinical vaccine trials taking place. Most are in an early phase testing safety and looking at preliminary immune responses. There is one efficacy trial underway, HVTN 505, a study that is being run by the HIV Vaccine Trials Network. It will be another couple of years at least before we see data from this study. [Click here to see a database of all clinical AIDS vaccine trials: http://www.iavireport.org/trials-db/Pages/default.aspx]
Q: How effective does an HIV vaccine have to be to make a real impact on the epidemic?
A: Vaccines that have efficacies under 100% can still have a major impact on disease prevention and the severity of the epidemic. For example, modeling research conducted by IAVI and partners shows that a vaccine that is 50% effective and is given to just 30% of the population could reduce the number of new HIV infections in the developing world by 24% over 15 years. It is important to remember that a vaccine doesn’t have to be 100% effective to provide a significant public health benefit. When many people in a community are vaccinated against a disease, even those who are not vaccinated may also get some protection because there is a lower risk of exposure to the virus. This is a concept known as herd immunity. So while of course we want to make efficacy as close to 90% or higher, something a little less than that can make a major impact on the epidemic.
Q: There have also been discussions of a so-called therapeutic HIV vaccine that might delay or halt disease progression in individuals already infected with HIV. Is this kind of vaccine more or less challenging or likely than a preventive vaccine? Are there therapeutic HIV vaccine candidates in development?
A: Both are very challenging. The therapeutic vaccine, which would attempt to boost the immune response in HIV-infected individuals to help them to better control the infection, is an area where there has been a fair amount of work. However, IAVI’s mission is to support in every way possible the development of a prophylactic vaccine because we believe such a vaccine would offer the best hope for ending the epidemic.
Q: Are there efforts under way to ensure that an efficacious vaccine will reach those populations most in need—i.e. developing countries with high HIV burdens?
A: IAVI’s mission is to develop a vaccine that is effective around the world, especially in developing countries where HIV prevalence is the highest. What we’re doing right now to address that from the science side is, we don’t design a vaccine only for one population. Our focus is to develop a vaccine that would have the ability to be used in all populations around the world and particularly in those countries and among populations where infection rates are highest. And we build into all our intellectual property arrangements with scientific partners provisions that require that any future vaccine developed in partnership with us would be made available immediately in the developing world as inexpensively as possible.
Q: When is the soonest we can conceivably expect an efficacious HIV vaccine to emerge?
A: Most of the clinical trials that are going on right now are early phase clinical trials. So if there is, in those clinical trials right now, a vaccine that will prove to be the vaccine we want, then the soonest a vaccine such as that could be approved would be somewhere between at a minimum of seven and 10 years. That’s a rough estimate. If a vaccine we want is only in the discovery phase now, it would be even longer. This is a long distance race. We cannot predict when scientific breakthroughs will occur – this is something that will require commitment and continued scientific inquiry over a large number of years and a significant amount of resources to make it happen.
Q: What makes you hopeful about our chances of success, despite the failures over the years?
A: There are a number of reasons. First, there’s the data from the RV144 efficacy trial in Thailand that showed protection in humans for the first time. The second reason is we are beginning to see activity in animal model systems that suggest vaccines can control infections of SIV [simian immunosuppressive retrovirus, a disease similar to HIV] down to a level where it is essentially a chronic disease of relatively little consequence. If we can do that with a human vaccine, that would be fabulous. And the third thing is, very recently, within the last year, antibodies have been discovered that can neutralize a broad range of virus strains from around the world. These were identified in people who are sick, so we know that, when exposed to these HIV proteins, people can mount an immune response that we would love to be able to make using a vaccine. That gives us a lot of clues as to how to design future generations of HIV vaccines. And that’s what IAVI is all about. We are working as hard as we can to make it happen.