AIDSWEEKLY Plus, 29 July 1996
Daniel J. DeNoon, Senior Editor

They suggested that a carefully selected cocktail of gp120 subunits might protect against the majority of viral strains in a given population.

"We think this vaccine may be protective against some virus strains," said Genentech researcher Donald P. Francis.

"The extent, breadth, and duration of such protection awaits initiation and completion of efficacy trials."

Francis and colleague Phillip W. Berman presented data from clinical trials of the Genentech subunit vaccines during separate presentations at the XI International Conference on AIDS, held July 7-12, 1996 in Vancouver, British Columbia, Canada.

Nine of the 499 HIV seronegative U.S. volunteers who received Genentech vaccines became infected with HIV via sexual exposure to the virus. But both Francis and Berman downplayed the significance of these infections.

"Breakthrough infections are a normal part of all vaccine trials," Berman said, noting that in four of the nine cases infection occurred before the subjects had received all of their immunizations. "No data was obtained that would discourage development of MN gp120 as a vaccine antigen."

Berman, who conducted genetic and immunologic characterizations of the breakthrough viruses, said that all of the infections were due either to inadequate immunizations, decay of the immune response elicited by the vaccine, or antigenic divergence of the infecting strain from the vaccine strain.

However, during a later plenary debate in which he argued against going forward with large-scale vaccine trials until better vaccines are available, John P. Moore of Aaron Diamond AIDS Research Center said that the breakthrough viruses were not significantly different from the vaccine strain.

"It is not the fact of breakthroughs that is so disturbing," Moore said. "It is the individual cases where there was a good vaccine response but infection occurred nonetheless."

Moore maintained that new human trials of gp120 subunit vaccines will not provide any new information.

But Francis was adamant in defending the morality not only of previous trials, but of the large-scale trials he advocates.

"We do not feel we are putting people at risk by testing this vaccine," he said. "We would be putting people at risk by not testing it."

Berman suggested that since 60 percent of the HIV-1 strains in the U.S. are closely related to the MN strain of HIV-1, the Genentech MN gp120 vaccine may actually have protected some vaccinees against infection.

By adding gp120 antigens from other strains of the virus, he said, Genentech hopes to develop a cocktail of antigens capable of preventing infection by the vast majority of strains a person would be likely to encounter.

New studies of the antibodies developed by vaccine recipients show that they can indeed elicit neutralizing antibodies not only to laboratory virus strains but also to primary isolates (see accompanying article).

This is good news to Genentech, which, as Francis noted, bases its vaccine program on the hypothesis that a humoral antibody response is sufficient to protect against HIV infection and/or disease.

Francis pointed to chimpanzee and human studies showing that:

• Both of two chimpanzees vaccinated with LAI strain gp120 were protected against challenge with infectious LAI while unvaccinated control animals became infected.
• All three chimpanzees vaccinated with MN strain gp120 were protected against challenge with peripheral blood mononuclear cells (PBMC) infected with the primary HIV-1 isolate SF2. Again, all unvaccinated control animals became infected.
• Nearly all humans given 100 (micro)g, 300 (micro)g, or 600 (micro)g doses of MN gp120 at 0, 1, and 6 months develop antibodies capable of neutralizing HIV-1 strains MN, LAI, and SF2.
• A fourth dose of the vaccine at 12 or 18 months elicits higher titer and more persistent antibodies.
• HIV-specific cytotoxic lymphocyte (CTL) activity is rarely seen in recipients of gp120 vaccine.

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