An Interview with Stanley Plotkin
The State of the Field
Stanley Plotkin, MD, is widely regarded as a leading authority on vaccines. He invented the rubella vaccine now used exclusively throughout the world and worked extensively on vaccines for polio, rabies, cytomegalovirus, and rotavirus. As the medical and scientific director for Pasteur-Mérieux-Connaught Vaccines in Paris from 1991-97 and now an executive advisor to the CEO of Sanofi-Pasteur, he has also been at the forefront of AIDS vaccine development. In recent months he has been one of the leading voices in the field as researchers struggle to find new directions in AIDS vaccine research after the halting of immunizations in Merck’s STEP trial last year. Plotkin, a soft-spoken man who cites “Henry V” as easily as he does scientific abstracts, credits two widely-acclaimed books—“Arrowsmith” by Sinclair Lewis and “The Microbe Hunters” by Paul de Kruif—with inspiring him to pursue a career in medicine and research. The New York native earned his medical degree from State University of New York College of Medicine in Brooklyn and trained at hospitals both in the US and abroad. Prior to joining Pasteur-Merieux-Connaught, he was a professor of pediatrics and microbiology at the University of Pennsylvania and a professor of virology at the Wistar Institute, a major player in vaccine discovery.
More than 600 scientific publications are to his credit, and Plotkin is also editor of “Vaccines,” now the standard textbook in the field. He has received numerous awards, including the Sabin Foundation Gold Medal and the French Legion of Honor, and has served on several boards related to infectious diseases and vaccinology. He has been chairman of the Infectious Diseases Committee, the AIDS Task Force of the American Academy of Pediatrics, and the Microbiology and Infectious Diseases Research Committee of the US National Institutes of Health, and has been a liaison member of the Advisory Committee on Immunization Practices.
During the early years of the AIDS epidemic, Plotkin advocated strongly for the development of live-attenuated HIV vaccines but US funding agencies thought the strategy was too risky and refused to back his research proposal. He also believes partially effective vaccines that slow disease progression could offer public health benefits in mass vaccination campaigns.
Plotkin recently spoke with IAVI Report Science Writer Regina McEnery about the state of AIDS vaccine research and development.
You have a long history of working in vaccinology but how did you become involved in AIDS vaccine research specifically?
I got involved in AIDS vaccines after I had moved to Paris in 1991 to join what was then called Pasteur-Mérieux-Connaught, now Sanofi Pasteur, and that was because HIV obviously was a significant issue. At that time, Sanofi had just begun to develop an avian pox virus as a vector and so applying that vector to HIV was an obvious thing to do. Parenthetically, that vaccine is now being tested in an ongoing Phase III trial in Thailand, the results of which will be reported in 2009.
So at that point I began to be involved in the problems of developing an HIV vaccine. There was optimism then that a solution was possible. Of course, by that time it was also known that it was not going to be easy and that it wouldn’t be a classical vaccine, but there was not a sense that all avenues had been exhausted.
You were one of the few people in the early years of AIDS vaccine development who advocated for developing live-attenuated vaccines. What made you so fervent about this particular strategy?
Well, it’s sort of obvious. Live vaccines have the virtue of stimulating all arms of the immune system so they could stimulate production of neutralizing antibodies as the result of the vaccine, and they typically provide the best protection. And actually, one can see that in the SIV system the only thing that is really effective is the live-attenuated virus. I guess you could also say that my experience was largely in the development of live vaccines and certainly, as a class, they are usually effective, but I would also acknowledge that they often bring safety issues with them.
Now the criticism of the approach, which I acknowledge, is that attenuation would not prevent incorporation of the viral genome into the cellular genome. It’s a legitimate objection. Even today, few people are willing to try to continue to develop such a vaccine. Ron Desrosiers [director of the New England Primate Research Center] developed an attenuated virus and has been an advocate of attenuated vaccines, but he also acknowledges the time may not be right for that kind of approach.
What type of attenuation were you proposing when you suggested exploring live-attenuated HIV vaccines?
Well, the basic idea, which was naive, was to deprive the candidate virus of its functional reverse transcriptase to try to prevent or reduce incorporation. I think that early assumption was basically wrong, but we hoped to develop a virus that would have limited replication but no latency.
Did you think then it was feasible to pursue a high-risk idea like live-attenuated HIV vaccines, and is it more or less feasible now?
It certainly was and is a high-risk idea. You could still say that a live-attenuated vaccine candidate is foolish, but one could also say, in light of what’s happened since, that it’s an idea still worth pursuing if we’re ever going to have an effective vaccine.
In the absence of a successful vaccine all ideas should be explored, and I think that the exploration of attenuated SIV vaccines may shed some light on what could be a valuable approach to an attenuated HIV vaccine. Based on that knowledge one might be able to attenuate HIV with more understanding.
However, I think one has to admit that having zero risk associated with any live vaccine is probably a dream, and not something that we should anticipate. But everything in life has a risk/benefit analysis and if we had a vaccine that was highly effective and which rarely caused a problem, one could argue that the advantages and the benefits of a vaccine would outweigh the risks.
The history of live vaccines in general goes along with that. Perhaps the best analogy would be to the oral polio vaccine. It’s very clear that there is a risk of paralysis from the vaccine, which is variously estimated but probably is around 1 in 700,000 first doses. That level of risk has been accepted because the oral polio vaccine has been able to eliminate wild-type virus completely in many countries. But in the US, safety frequently takes precedence over everything else.
Which of the other AIDS vaccine strategies that are currently under investigation do you think hold the most promise?
I think at this stage the first thing we need to do is confirm or disconfirm the results of the STEP trial. Leaving aside for the moment the safety issues that arose during the trial, we need to know whether a non-replicating vector will give any efficacy or not and unfortunately we didn’t learn that from the STEP trial. When I say efficacy, I mean control of viral replication using adenovirus serotype 5 (Ad5) in people without pre-existing immunity. If some control of viral replication was to be shown, then we need to deal with the potential safety issues involved with using Ad5 vectors by choosing some other non-replicating vector.
I’m not saying anything that’s new here. If the result in a future trial is negative, meaning no effect of cellular immunity on viral replication is observed, then we have to acknowledge that inserts in non-replicating vectors will not give sufficient stimulation of the immune system and we have to move toward replicating vectors. In addition, no vaccine is going to prevent infection if it doesn’t involve stimulation of antibody responses. So the issue of finding a way to produce antibodies that neutralize primary HIV isolates is still the major issue on the table today.
What do you think is the best hope for vaccines that would not be able to prevent infection?
A vector-based vaccine may allow us to prolong people’s lives in a reasonable state of health, especially if used in combination with antiretrovirals, and also might inhibit transmission by lowering the viral load, but I don’t see it providing substantial protection against infection unless there’s an antibody component.
HIV could be similar to other diseases, like pneumococcal disease, in that reducing the levels of the virus in semen or in the vagina will result in lower transmission rates. With HIV the rate of transmission is already very low, so if you were able to reduce viral load significantly you’re certainly going to diminish the risk of transmission and therefore obtain herd immunity. Mathematical modeling shows us that even a partially-effective vaccine, in the sense of reducing viral load, would reduce HIV transmission to the point where the so-called reproductive number would be less than one and, therefore, the prevalence of infection would gradually decrease.
What do you think might explain the observation in the STEP trial that uncircumcised vaccinees with pre-existing Ad5 immunity were at higher risk of acquiring HIV?
It caught the best minds by surprise, and many are puzzled about it. There’s work from Rafi Ahmed [an immunologist at Emory University] suggesting that adenoviruses may be peculiar in their long-term stimulation of T cells, which may increase susceptibility to infection. But I think at this stage one can only guess.
I remain deeply puzzled by the fact that the so-called enhancement is the result of a lower infection rate in the placebo recipients who had high titers against adenovirus. John Moore [professor of immunology and microbiology at Weill Cornell Medical College] has tried to explain this but today we really only have hypotheses. I still think it’s possible that the result was due to confounding demographic factors and circumcision distribution. That being said, it’s going to be extremely difficult, if not impossible, to go back to Ad5 vectors in a population that has pre-existing Ad5 immunity.
Do you think that a heterologous prime-boost regimen is more likely to provide some degree of effect on viral load?
I think the idea that a vector that is strong in terms of presentation of HIV antigens, such as Merck’s Ad5, was worth trying. It’s easy to criticize in retrospect, but I think it was a logical thing to do. What could be criticized, I suppose, is the choice of Ad5 alone versus a prime-boost schedule. The criticism could be lodged, and has been lodged, that Merck’s results with this regimen in the SIV model were not good enough, but again one has to appreciate the lead time that precedes going into a clinical trial. It’s not that you wake up in the morning and say, ‘Let’s try this vaccine in an efficacy trial.’ It requires years of work and so changing the trial because you have a new idea is not something that is likely to happen. The apparent effect of adenovirus immunity on the result was not something that anyone had predicted.
What do you think of the decision not to go forward with the proposed PAVE 100A trial of the DNA/Ad5 prime-boost regimen developed by researchers at the Vaccine Research Center?
The PAVE trial would have had the virtue of telling us whether or not there was any efficacy from non-replicating vectors, or whether non-replicating vectors are simply not strong enough in antigen presentation and therefore are not going to work. I can accept the eventual compromise of reducing the trial size, on the condition that the new trial is sufficiently powered to tell us whether the vectors employed can reduce viral load. The beauty of science is that you can confirm or disconfirm an idea. It’s not like philosophy where all ideas are equal.
What impact has the STEP trial had on industry’s involvement in research and development of AIDS vaccines?
It’s fair to say that Sanofi Pasteur, like other manufacturers, has been dismayed by the result of the STEP trial. Although let me say that I am a consultant and do not speak for the company, I see no inclination to leave the HIV vaccine field. Sanofi is still developing and testing pox virus vectors, but it remains to be seen whether any non-replicating vector is going to work. If not, for Sanofi and for other companies, it’s back to the drawing board.
The fact is that there are many vaccines for other diseases on the table. Vaccine development is expensive and unless there are new basic discoveries I think the companies will probably not exert themselves strongly in the HIV field. I have suggested to Alan Bernstein [executive director of the Global HIV Vaccine Enterprise] that he really should visit the chief executive officers of the major companies to try to influence them to stay in HIV vaccine development. Companies by and large are not there to do basic research. They are there to develop something that has been discovered in an academic laboratory or at a biotechnology company and to take it to a licensed vaccine, which is a major and expensive effort. Now you cannot reasonably expect a company to spend millions of dollars unless there are promising approaches, realistic approaches, to a vaccine. I think every company is looking for a brilliant idea.
What do you think has been the biggest obstacle to AIDS vaccine development?
Unquestionably, it is technical feasibility. The problem with vaccine development has not been a lack of effort. A lot of money and a lot of scientific effort have been put into it, but it has just been an intractable problem. However, by no means would I give up because vaccine development has never been easy.
You know, people say the easy vaccines have been developed, but it’s always easy in retrospect. The basic work on the Merck rotavirus vaccine was done in my lab in the mid-1980s but the vaccine was not licensed until 2006. So to say that vaccine development takes a long time is a cliché, but it’s true.