The Bay Area Reporter - January 26, 1998
Bill Snow, ACT UP/Golden Gate Writers Pool

Some history

The company, VaxGen, 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 make only the protein envelope of HIV, in order to stimulate a protective immune response safely. This approach had worked for Hepatitis B, the first genetically engineered vaccine, shortly before.

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 interest in the program by the company, and led to the hiring of Dr. Don Francis to direct it. Dr. Francis is the well-known central character of Randy Shilts's ...And the Band Played On who tried valiantly to get the Centers of Disease Control to pay attention to AIDS in its early days.

Genentech's vaccine candidate, gp120, had been tested in Phase I trials and had been shown to be safe and to consistently generate antibodies to HIV. In other vaccines, the ability to generate antibodies that can neutralize 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, binding antibodies that stick to virus, and 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 co-receptors for 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 90s, the Genentech gp120 was tested in hundreds of HIV-positive people to see if it could improve their course of infection. It was a bust. It was also tested in the first Phase II trial in HIV-negative people by the National Institutes of Health, as was gp120, developed by Chiron, a competing company. To make a very long and controversial story short, in the summer of 1994 the National Institutes of Health decided not to invest in a government sponsored Phase III trial of the gp120 products, much to the disappointment of Genentech and Chiron.

The reasons are arguable, but one was the inability to neutralize wild virus, which had just been discovered, and another was that scientific opinion was beginning to move toward wanting to generate a cellular immune response in addition to antibody.

After that decision, Chiron maintained its gp120 program as a boost for another vaccine that did stimulate cellular immunity, and that combination has just begun to be tested in a Phase II trial. 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 test it privately.

The VaxGen approach

This brings us to the most interesting part of what VaxGen is doing. About a dozen people from the Phase II trials became infected after receiving gp120 vaccines. It is conventional in vaccine circles to call infections after vaccination "breakthrough infections," which implies that the vaccine worked for the rest of the vaccinees and that these exposures "broke through" the vaccine's defenses. 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, since it aims to block off holes in the vaccine that "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 the uninfected participants in the Phase II trial may have been protected by the original gp120, when there is no statistical evidence for this in a Phase II-sized trial. Presumably, many participants never exposed themselves to HIV or would not have become infected anyway. Only a Phase III trial, with several thousand participants and an equally large placebo group, is statistically powerful enough to demonstrate any efficacy from a candidate vaccine, and no product has gone into efficacy trials yet. In fact, the prospect of a first efficacy trial is what derailed the recent ill-fated VaxGen story.

The original story

This month's VaxGen story began with a front-page article in the San Jose Mercury News. The headline read, "First major trial of an AIDS vaccine," and the lead sentence said, "Scientists at a tiny biotechnology start-up have engineered the first AIDS vaccine that looks promising enough to merit a large-scale human trial." Later, the story went even farther and inaccurately stated that the vaccine is "the first to win Food and Drug Administration support to move to Phase III testing designed to determine the effectiveness of the treatment."

The article went on to misinterpret FDA policy, saying the FDA has "backed down from its stand on pursuing only those vaccines that are highly effective," which is nonsense, since the agency would have no way of knowing prior to testing.

How it took off

No doubt based on the misleading headline, Reuters did a news clip that was circulated widely. Then the Associated Press picked up the story. With the item on two wire services, it managed to attract the attention of others (in the same amount of time it took AP to run one story, sort out that there wasn't really a national story there, and drop it).

By the evening, Channel 4 had pieced together an item without access to VaxGen who, they said, were unavailable for comment. To rub things in, they showed the company's closed door. Fortunately, Brenda Lein from Project Inform was available to answer some questions and provide balanced input. Otherwise, the whole clip was a rework of the Mercury News piece.

The next day, I got an e-mail from someone in the Virgin Islands saying, "Hello, we were just told in the Virgin Islands that a vaccine had been approved. I have had endless phone calls ... please inform ..."

A few days later, the following correction appeared under the title "Setting the record straight" in the Mercury News: "Although FDA officials have said they would support a large-scale human trial of a vaccine known as AIDSVAX, the agency has not yet given formal approval."

Finally, three days after the initial item, PR Newswire got the story right, from VaxGen: "Don Francis today said VaxGen had received approval for confirmatory Phase I and Phase II clinical trials of AIDSVAX. Some press reports indicated that VaxGen has received FDA approval for Phase III clinical studies, but those reports were premature. The company will report results from the Phase I and II confirmatory studies when they become available to FDA before receiving approval to move into Phase III clinical trials. Dr. Francis does say, 'The overall strategy for final phase evaluation of VaxGen's vaccine has been presented to the FDA and its Vaccine Advisory Committee, and has been accepted by those agencies.'"

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, and things are moving so slowly that you probably shouldn't put serious money on meeting President Clinton's challenge to have an HIV vaccine in the next decade, before 2007.
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