Excerpt from:
avac.org
Snow, Bill, ed. HIV Vaccine Handbook: Community Perspectives on
Participating in Research, Advocacy, and Progress. Washington, D.C. AIDS
Vaccine Advocacy Coalition. 1999.
Vaxgen: Pushing the Envelope (pp. 195-198)
Bill Snow
Adapted from Bay Area Reporter, January 1998
and radio KALW interview, June 1998
The VaxGen company has an unusual history. Throughout the late 1980s and early 1990s, the pioneer biotechnology company Genentech had an on-again-off-again program to develop a genetically engineered HIV vaccine. The idea was to use only the protein envelope of HIV to stimulate a protective immune response safely. This approach had worked shortly before, in the 1980s, for hepatitis B, the first genetically engineered vaccine.
Genentech had tried to drop this program, but a few scientists persisted on the side and ultimately were able to show protection in a chimpanzee. This success, which was among the first evidence that a vaccine against HIV might work, revived corporate interest in the program and led to the hiring of Dr. Don Francis to direct it. Francis is the well-known central character of Randy Shilts's And the Band Played On, who tried valiantly to get the Centers for Disease Control to pay attention to AIDS in its early days.
Genentech's vaccine candidate, gp120, had been tested in phase 1 trials and had appeared safe and consistently able to generate antibodies to HIV. In other vaccines, the ability to generate antibodies that can neutralize the virus is an important means of protection. Unfortunately, high levels of HIV antibodies don't protect naturally infected individuals, and it is believed that there are many worthless antibodies and relatively few effective ones. One problem with designing and evaluating an HIV vaccine is that we're not sure if antibodies would be protective, which types of antibodies to measure, or what level of these antibodies to achieve. There are measures of overall antibody level, of binding antibodies that stick to virus, and of neutralizing antibodies that disarm it. Antibodies may also work against some viruses and not others, particularly against laboratory-grown virus and not wild virus in the human population, which have different ways of attaching to CD4 cells. Genentech's gp120 was copied from a laboratory strain of HIV before this difference was understood and, like all genetically engineered envelope vaccines at the time, has been totally unable to neutralize wild virus.
During the early 1990s, the Genentech gp120 was tested in hundreds of HIV-positive individuals to see if it could improve their course of infection, and it was a bust. It was also tested in the first phase 2 trial in HIV-negative individuals by the National Institutes of Health along with a gp120 made by its competitor, Chiron. To make a very long and controversial story short, in the summer of 1994, NIH greatly disappointed Genentech and Chiron by deciding not to invest in a government-sponsored phase 3 trial of their vaccines. The reasons are arguable, but one was the inability, which had just been discovered, to neutralize wild virus and the uncertainty that a useful trial could be conducted at that time. Scientific opinion was shifting toward the idea that a cellular immune response would be desirable in addition to antibody.
After that decision, Chiron maintained its gp120 program as a boost for another vaccine that could stimulate a cellular immune response in addition to antibody, and that combination has just begun to be tested in a phase 2 trial (Chiron's commitment to this product has since faded). Genentech spun off VaxGen, giving it an initial investment and making Don Francis its president. Since then, Francis has been raising money outside Genentech to improve the gp120 vaccine and to test it privately.
This brings us to what VaxGen is currently doing. About a dozen people from the phase 2 trials became infected after receiving gp120 vaccines. It is conventional in vaccine circles to call these events "breakthrough infections," which implies that the vaccine worked for the rest of those immunized but "broke through" the vaccine's defenses in some. Scientists at VaxGen made the assumption that the infected individuals had something in common, besides simply being exposed to wild HIV, and designed a second envelope protein to mimic those viruses. This approach is known as a "sieve" analysis because it aims to block off holes in the vaccine that let HIV "sift through" its defenses. VaxGen's new double-strain, or bivalent vaccine, goes by the sexy new name of AIDSVAX©.
The potential problem with this sieve approach, as used by VaxGen, is that it assumes that some of the uninfected participants in the phase 2 trial may have been protected by the original gp120, when there is no statistical evidence for this in a phase 2 trial. Presumably many participants never exposed themselves to HIV or would not have become infected anyway. Only a phase 3 trial, with several thousand participants and a large placebo group is statistically powerful enough to demonstrate even partial efficacy of a candidate vaccine.
In June 1998, VaxGen Began Its Own Phase 3 Trial
The U.S. Food and Drug Administration (FDA) has given the first go-ahead for what's called an efficacy trial for AIDSVAX©. The trial needs to be large in order to have a certain number of infections in its placebo, or control, group to compare with the number in the vaccinees. And in this country, even in the highest- risk populations, we know that the transmission rates are no more than 1.5 % per year. So there are a couple of things the company has to do. It has to look for people at risk, and they it has an ethical obligation to educate those people to minimize their risks. In this case, VaxGen's projection is that it is going to be able to get an answer with 5,000 participants. Two-thirds of those people will get the candidate vaccine, and one-third will get a placebo.
The vaccine looks very safe. There are reasonably long-term results with the original single-virus vaccine, and the only real side effects are on the order of a sore arm, as far as we know. These products haven't been in people a really long time, but there's no reason to think they would cause any harm as safety was the reason for using this approach in the first place. The vaccine is made with recombinant technology with no live virus involved at any point in the manufacturing.
There is, however, an ongoing controversy in the scientific community about the validity of this particular approach and product. Scientists fall into two camps, and their differences tend to be rather extreme. First, there's the group who thinks that the only way to know whether a product is going to work is to run an efficacy trial. A small trial cannot tell you whether the product protects people because you can't go around trying to infect people. So you need several thousand immunized people to determine with any statistical validity whether this approach is even partly protective. This group, mostly clinical scientists and epidemiologists, espouse the empirical or trial-and-error approach - anything with any chance of working ought to be tested in a big trial. They believe that the only reliable way to get an answer is to do the experiment in humans. Also, they hope the first big trials will teach us to design better vaccines and move us ahead faster, because the epidemic is out of control.
Those in the second group are focused on basic science; studying the plausibility of various approaches in the lab or in animals. Many of them have trouble with VaxGen's approach because it only generates antibody, which is one immune response, activating only one arm of the immune system. People who are infected with HIV generate a lot of their own antibody, which doesn't help them much, if at all. There's a lot of "junk" antibody that doesn't really neutralize virus. And it's very hard to find neutralizing antibodies even in infected people. In fact, there are only three antibodies that have ever been found in infected individuals that neutralize HIV envelope, which is what these vaccines are supposed to do. Also, there's the issue of which viruses you can neutralize, at what level, and what will be protective. Also the newly discovered crystal structure of HIV shows how difficult it must be for antibody to neutralize the virus, so there's been a great deal of skepticism about VaxGen's approach.
No matter which camp you're in, the initiation of VaxGen's phase 3 trial is a newsworthy event because starting this first trial is a political breakthrough. It will be much better to conduct this trial and answer the gp120 question than to argue whether we should have done so for another four or five years. This trial also paves the way for other candidate vaccines. If there's any protection at all - which we can't guarantee, but there could be - we may learn something about the mechanism and use that to design better products, which is what we believe VaxGen would like to do.
VaxGen and Francis are to be commended for persisting with their approach, believing in it so strongly, and raising the funds to finance their own trials, whether one believes in their product or not. If only more private companies, investors, and scientists were willing to champion different approaches, we'd have a more robust HIV vaccine research environment. Mostly, companies are taking a wait-and-see attitude. Things are moving so slowly that you probably shouldn't put serious money on meeting President Clinton's challenge to have an HIV vaccine by 2007.
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