Hope for New Vaccines
Dr. Sarah J. Schlesinger has been actively engaged in HIV/AIDS and HIV vaccine research for over ten years. She is currently conducting clinical trials to test a new vaccine called ADMVA, designed to stimulate immune responses and thereby prevent HIV from ever being contracted. A graduate of Wellesley College and Rush Medical College, Schlesinger has been interested in medical science since she was a teenager. As a high school student attending a lecture at Rockefeller University, she boldly asked scientist Ralph Steinman for a job in his laboratory.
Schlesinger worked in Steinman's lab just a few years after he and Zanvil Cohn published their famous discovery of dendritic cells. She then went on to head her own dendritic cell lab at Walter Reed Hospital from 1990 to 2002. With new knowledge about the ability of dendritic cells to orchestrate the body's immune response, Schlesinger and her colleagues are attempting to develop customized immune therapies to target specific infections such as HIV/AIDS, malaria and influenza; certain cancers; and autoimmune diseases.
Sarah Schlesinger: What we know now is how a lot of things don’t work. Right now is a very challenging time in HIV vaccine development because nothing has worked. And not only has nothing worked, but the most promising candidates we’ve recently found out haven’t worked. There was a trial that was being conducted by NIH and Merck with a vaccine that was using an adeno-viral vector. So adeno virus is a virus that causes like a cold. Colleagues of mine, I wasn’t involved in this trial, though when it was beginning to be worked on, I was wishing that I could have been, because it seemed so promising, take this virus that’s an attenuated adeno virus, and they genetically engineer it to express, in this case, three different genes from HIV.
It looked very promising. It was inducing immunity, and it was inducing immunity in some animal models and early phase human trials, and there was a large trial that was conducted the past few years. Unfortunately, last fall we found out not only did it not protect people from HIV, in a subset of people it made them more susceptible. And that’s really a horror, because it’s obviously very frustrating to test things that don’t work, but as a physician our primary responsibility is something called “first do no harm.” It’s a Hippocratic dictum of “primum non nocere.” So you might not help people. You might not cure them. You might not prevent something, but the last thing you want to do is hurt them. And so for a preventive vaccine to even have the specter of causing increased infection, was horrible. Now, it’s very important to make the distinction that the vaccine did not cause HIV.
So there were several polio vaccines, for instance, that were tested in the ‘30s that were made from live polio virus that actually gave children vaccine associated polio. That is not the case with any AIDS vaccines. All the vaccines that have been tested are very safe in that they have nothing from live HIV, nothing from human blood. They, themselves, have not given anybody a disease. It’s not clear how it happened, and it’s being worked on avidly by many colleagues, but it appears that certain people were made more susceptible, and they were people who had high antibody ties to the adeno virus, which is a vector. And what that means is not clear yet, but people are still working on it. So to make an HIV vaccine is very hard for a lot of reasons.
Question: What makes HIV different from other viruses?
Sarah Schlesinger: HIV is a chronic viral infection, so people who get infected are not only not protected from other strains of HIV, they’re not even protected from your own strain of HIV. And why that is a subject of a lot of investigation, and it may be that HIV has evolved to induce immunologic silence or tolerance. And that’s a kind of current thinking, and I think that that’s probably correct. But what that means is we don’t have the model of natural infection conferring protection to make a vaccine. And this is one of the reasons that there are some people who query if it’s even possible to make a vaccine for HIV, and they might be right. My view is, is that it’s easy to say why things won’t work, and this is the worst epidemic that hits mankind. There are 15,000 new infections everyday.
Eight thousand people are dying everyday. And so it’s a moral imperative to try. So even if the kind of classic vaccine, when you think of smallpox or polio, where you get sterilizing protection, if you will, may not be possible. Perhaps we can develop a vaccine that will reduce, not prevent infection, but prevent disease. And, in fact, when you look really carefully at most licensed vaccines, that’s what they do. You get a certain amount of replication of the virus, and then disease is prevented. When you think about it, what is it that we really want to prevent? It’s disease and death. So the natural infection issue is one. As I mentioned earlier, there’s no animal model. Only humans get HIV, so we don’t have a good animal model.
Nobody’s ever been protected by a vaccine, so we don’t even know what to measure in the blood. We have our favorite ideas. We know from our other vaccines, from smallpox, from tetanus, the sorts of things that one needs. We know you need neutralizing antibody. We know you need cytotoxic T-cells. We know you need helper T-cells, but which of those is the most critical? Whether you need them all, at what level you need them, nobody knows.
And so we end up having a terrible time knowing what even to move forward. So if we have 10 candidate vaccines, and candidate vaccine is a vaccine that’s not licensed. And even if we can test them in a small group of humans, how do we know which one is better? That’s yet another challenge. So those three challenges make it very hard to develop an HIV vaccine. And that isn’t even getting into the sort of the political and social challenges, which are complicated and myriad and probably you’ll have somebody else to address those.
Recorded on: June 10, 2008
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