AIDSWEEKLY Plus, 26 August 1996
Daniel J. DeNoon, Senior Editor

Three separate multicenter Phase II trials of the product, known as VaxSyn, took place in the U.S., Canada, and Sweden.

"There is no evidence of clinical efficacy by clinical trial endpoints," said Deborah Birx of the Walter Reed Army Institute for Research, Rockville, Maryland.

"We can immunomodulate the immune systems of individuals in relatively early asymptomatic phases of disease with high CD4 counts, but this did not translate into any clinical benefit or virological differences," said Chris M. Tsoukas of The Canadian

HIV Trials Network, Montreal, Quebec, Canada.

The researchers reported data from the clinical trials at the XI International Conference on AIDS, held July 7-12, 1996 in Vancouver, British Columbia, Canada.

VaxSyn was the first HIV vaccine to be tested in the U.S. The vaccine, which contains the HIV gp160 envelope precursor protein produced in genetically engineered insect cells, has been under development since 1987.

A controversial $20 million U.S. military clinical trial of the vaccine, funded in a 1993 special appropriation by Congress, was canceled in early 1994. Army researchers were persuaded that a large-scale clinical trial of a single vaccine product was premature; the money was used for other AIDS research programs.

Following this decision, American Home Products Corporation, Madison, New Jersey, withdrew from a joint agreement to develop the vaccine with MicroGeneSys through its subsidiary, Wyeth-Ayerst Laboratories.

The first of the three trials reported at the AIDS conference was conducted in Sweden. It is now the only ongoing trial of VaxSyn as a therapeutic HIV vaccine.

Ann-Charlotte Leandersson of the Swedish Institute for Infectious Disease Control, Stockholm, noted that the trial began in 1991 and enrolled 40 asymptomatic HIV(+) patients with a mean baseline CD4 count of about 400 cells/(micro)L.

All patients received VaxSyn at doses of 160 (micro)g via intramuscular inoculation at days 0 and 7 and at months 1, 2, 4, and 6. During this six-month period, half of the patients were randomized to receive zidovudine (AZT) or placebo. After six months, no further AZT was administered.

At month 15, patients were re-randomized to receive booster immunizations every two or six months. At month 39, all patients received semi-monthly boosts.

Patients fell into three response groups: those that had only early gp160-specific T-cell proliferative responses, those that had only late responses, and those that had early and durable responses.

"It seems that an early and durable response is correlated to better CD4 development," Leandersson said. "Almost all of the long-term non-progressors have this response pattern, whereas only an early response is correlated to rapid progression."

However, the best CD4 responses were seen in the group that initially received AZT. These were the only patients whose rate of CD4 decline remained improved over baseline at the end of the study.

"In comparison to age-matched controls, the vaccinees have a better CD4 development at 12 months, and the patients who received both AZT and gp160 had a better CD4 development than patients who received gp160 and placebo," she noted.

"Therapeutic vaccination with gp160 gives improved specific T-cell responses, a small increase in viral load, and improved CD4 development for over 15 months. Therapeutic vaccination in combination with AZT gives better CD4 development."

But larger Canadian and U.S. trials were less optimistic.

Tsoukas reported that the multicenter, placebo-controlled trial undertaken by the Canadian HIV Trials Network enrolled 280 asymptomatic HIV(+) participants with CD4 counts of more than 500 cells/(micro)L.

The trial involved six medical centers stretching from Halifax, Nova Scotia, to Vancouver, British Columbia. It began in February 1992.

Eighty-three percent of the subjects completed all three years of the study.

Participants received 320 (micro)g of VaxSyn or placebo via intramuscular injection at days 0, 30, 60, 90, 180, and every 120 days thereafter. After two years, placebo patients received the same dose and injection schedule as patients in the treatment arm.

At enrollment, the mean CD4 count was 662 cells/(micro)L.

"The mean declines in CD4 counts at two years of follow-up were 155 and 111 cells/(micro)L in the VaxSyn and placebo groups respectively (P=0.08)," Tsoukas and colleagues reported in their presentation abstract. "The annual rates of decline in CD4 counts in the VaxSyn and placebo groups were 69 cells/(micro)L and 72 cells/(micro)L, respectively (P=0.30)."

There were five AIDS-defining events and one death in the VaxSyn group and seven AIDS-defining events and one death in the placebo group.

Despite the fact that vaccine recipients developed good vaccine antigen-specific immune responses, there were no significant differences in CD4 counts, rates of CD4 decline, or clinical endpoints between treatment and placebo groups.

Birx said the data derived from the U.S. studies was very much the same as that seen in the Canadian study.

The U.S. study began in 1990 and enrolled 608 patients with asymptomatic HIV infection and CD4 counts of more than 400 cells/(micro)L.

Participants were randomized to receive either placebo or intramuscular injections of 160 (micro)g of VaxSyn on days 0 and 7 and on months 1, 2, 4, 6, and every two months thereafter for the duration of the study; 483 subjects completed the study.

Aside from local reactions, there were no severe adverse effects of vaccination.

Extensive immunologic evaluation of the first 140 patients to finish five years of the study showed that the vaccine was indeed immunogenic.

Assays of viral burden in study participants showed that their HIV levels did not change throughout the study. There were no differences between vaccine and placebo recipients in viral load at any of the six-month intervals at which plasma samples were obtained.

Similarly, there were no differences between groups in HIV p24 antigen levels or (beta)[2]-microglobulin levels.

"We demonstrated that the product was immunogenic, we demonstrated that it was safe - and I don't think that we should minimize that this expression system was safe," Birx said.

She suggested that the MicroGeneSys baculovirus system could be used in the future to generate other vaccine antigens.

But she concluded that the trial had adequate power to assess clinical efficacy, and that there was no evidence that VaxSyn improved the course of HIV disease in infected individuals.

"Is this finally the end of gp160," Tsoukas was asked by a member of the audience.

"I am not the person to ask, but certainly the data are compelling," the Canadian researcher replied.

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