AIDS TREATMENT NEWS Issue # 185, October 15, 1993
Dave Gilden

The disagreements did not prevent polio vaccine discoverer Jonas Salk, M.D., from delivering an impassioned plea for rapid steps forward. Addressing representatives of the various vaccine developers gathered for a panel discussion, Salk said, "We risk investigating to exhaustion People in need are waiting impatiently The time has come to move forward. We need to decide now to do something cooperatively."

Salk appeared with a group from the Immune Response Corporation of San Diego, which is investigating his therapeutic vaccine concept, which involves inoculating with virus particles that have been both killed and stripped of their outer coat. The idea is to stimulate an immune response to HIV's inner protein appearing on the surface of HIV- infected cells. This therapeutic vaccine has been in human trials since 1987.

The notion of a therapeutic vaccine has always been saddled with doubts. Unfortunately, Salk's presentation of his data early in the conference was not clear-cut enough to dispel those doubts and demonstrate that we have "enough clues and indications to go forward," as he put it.

In the hallways, Salk privately commented to us that his talk at the conference was, in part, an attempt to reverse the poor impression his associates made earlier this year at Berlin's Ninth International Conference on AIDS.

Once again, though, obscure slides slipped by one after another, purporting to show that the "responders" to the vaccine did better than the "nonresponders." Responders are defined as those who develop skin reactions when HIV proteins are applied in a manner similar to a TB skin test. The percent responding seems to increase with higher doses of inoculant. Responders fared better than nonresponders, in that they had slightly higher CD4 levels, fewer clinical symptoms, slight weight increases, and, for some people, reduced HIV levels in the blood.

When asked by this writer if his slides were available in some form that allowed more thorough review, Dr. Salk demurred, saying the data were very preliminary. The doctor then grew philosophical: "But this is just information. What is important is the knowledge. Tell your readers that the knowledge is there. We know how to make an effective vaccine."

Is that knowledge really there? Another conference speaker, Robert Schooley, M.D., of the University of Colorado, reviewed the state of research on therapeutic vaccines and made it clear there are still plenty of gaps. "Why should this approach work?" Schooley asked, noting that the amount of HIV envelope protein constantly present in the blood is frequently 100 to 1,000 times greater than the amount in any vaccine now being injected at periodic intervals during treatment trials. Vaccine-induced reductions in HIV remain to be definitely established. Also, it is not known whether HIV can mutate to escape the protective antibodies engendered by the vaccine. HIV certainly escapes the defenses the body naturally sets up against the virus, after all.

Although Salk's colleagues have been testing their vaccine for six years, they have been unable to resolve such doubts. Dr. Schooley noted a fundamental problem when comparing therapeutic vaccine responders to nonresponders, as the Salk group and other vaccine developers are doing. If responders, that is those who broaden their anti-HIV immune activity after vaccination, tend to stay healthier longer than nonresponders, maybe it is because their immune systems were superior in the first place. That is what enabled them to be responders.

The data, therefore, may merely reflect the natural variation in response to HIV -- some people progress faster than others to AIDS -- rather than show that the vaccinations produce any benefit. The controversy over results from Army researchers' trials of the therapeutic vaccine developed by MicroGeneSys Corp. of Meriden, CT [see AIDS TREATMENT NEWS #164 and #183] reflects this uncertainty.

Quick, definitive documentation of a vaccine's benefit requires an accepted way to evaluate changes in immunity triggered by vaccines. The lack of consensus continues, though, for preventive as well as for therapeutic vaccines. Dr. Salk acknowledged at the conference that "the correlates of immunity question is holding the effort up. The moment we have something to measure, the game's over." Trials could proceed rapidly and decisively by tracking accepted signs of immune improvement.

Dr. Salk thinks that cell-mediated immunity -- as signified by his skin test for response to HIV antigens -- is the appropriate standard (in addition to T-helper cell count, weight gain, and clinical symptoms). The killer lymphocytes associated with cell-mediated immunity specialize in destroying cells infected by virus. Salk thinks that absolute, complete prevention of HIV transmission from person to person will not be possible with a vaccine. Rather, cell- mediated immunity must be primed to immediately isolate the virus contained within cells and snuff out an incipient infection. In a sense, preventive and therapeutic vaccines have a similar role -- controlling HIV after it has already entered the body -- although the timing of these two vaccines is different.

But in a presentation at the conference, Susan Zolla-Pazner, M.D., of New York University indicated that antibodies are important, too. "Antibodies play a major role in preventing viral infection," she said. "They play a minor role in controlling infection."

Dr. Zolla-Pazner's research concerns monoclonal antibodies, which are laboratory products containing a single specific antibody. She has found an antibody that seems to neutralize all the HIV strains common in North America and Europe (including wild strains, not just laboratory isolates). The antibody reacts to a section of the V3 loop on HIV's envelope molecule (gp120). The V3 loop is a part of the virus that is "out there waving in the breeze," as Dr. Zolla-Pazner describes it. It is easily accessible to antibody recognition and attack. Researchers now plan to try out monoclonal antibodies as a means of preventing HIV transmission during a few special circumstances -- in babies, to prevent transmission from HIV-infected mothers at birth, and then in health care workers exposed to HIV through accidents on the job. A cocktail of these antibodies may also be useful as a treatment, Dr. Zolla-Pazner noted.

Another conference participant, Ron Desrosiers, Ph.D., described a novel approach to a vaccine for preventing SIV, the monkey version of HIV. He told AIDS TREATMENT NEWS, "We tried protecting monkeys from SIV with altered vaccinia virus plus subunit booster [genetically engineered smallpox-vaccine virus containing SIV coat proteins plus later inoculations of pure SIV protein fragments]. It resulted in great antibody production, but the protection was minimal. So we started out on a new strategy."

Dr. Desrosiers' new strategy was actually a standard one for vaccines in other diseases -- a live but weakened, or attenuated, SIV strain. The SIV was weakened by deleting its "nef" gene, whose function is poorly understood. The attenuated virus produced an extremely low-level, benign, persistent infection instead of a rapidly fatal one. When the vaccine's effectiveness was tested in four monkeys more than two years after vaccination, protection was complete against two closely related SIV strains. Dr. Desrosiers is now experimenting with SIV strains weakened by removing three to five minor genes including nef. Last month, his team started an experiment in chimpanzees using a multiply deleted version of HIV.

"All the [existing] HIV vaccines have been tested only under idealized conditions," Dr. Desrosiers said in our interview. "It's likely they will fail in the field. We need to gather some basic safety data on our type of vaccine in humans now."

Linda Gritz, Ph.D., of the Therion Biologics Corporation in Cambridge, MA reports that her company has licensed Desrosiers' method and is considering doing just that. "But we hope we don't have to, that one of the other vaccines we're trying works," she told ATN. "There are tremendous fears about using a live, attenuated HIV vaccine on uninfected people. It could take us twenty years to tell whether we're using a strain of HIV that produces no disease progression or only slow progression."

Gritz mentioned that Therion is also considering testing a gene-deleted HIV vaccine for treatment purposes.

Because of all the doubts, Patricia Fast, M.D., Ph.D., who helps direct AIDS vaccine development at the National Institutes of Health, told the conference, "It is unlikely we have the perfect vaccine but we will continue to push on with every strategy." Her colleague, Dale S. Lawrence, M.D., M.P.H., outlined the reasons for moving quickly to efficacy trials: Vaccines represent an "exquisite weapon" compared to the "sandbag protection" we now have against HIV.

Lawrence envisions trials requiring thousands of volunteers. He would be happy to get a 60 percent reduction in HIV transmission with the present crop of vaccines. For the vaccine failures (the volunteers who later become infected with HIV, despite having received the vaccine -- and there are already rumors of one such failure in a small preliminary trial of one vaccine), Lawrence foresees a prolonged period of followup to see whether the vaccine slowed down or enhanced disease progression.

The community of course desperately needs new forms of HIV treatment and prevention. Community support will be essential for the large trials, including the mass testing of therapeutic vaccines now under consideration by the Army (see below, and see AIDS TREATMENT NEWS #184). It is also important not to squander the community's trust by rushing into mass testing too early, with crudely conceived vaccines that still resemble "sandbags" more than they do "exquisite weapons." Loss of public confidence due to the inevitable failures will make it all the more difficult to test more promising vaccines in the future.

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