AIDSWEEKLY Plus, 19 August 1996
Daniel J. DeNoon, Senior Editor

Extensive animal studies show that the vaccine can be used both to treat and to prevent HIV infection.

The first human trial of the vaccine enrolled 15 asymptomatic HIV infected subjects with CD4 counts of more than 500 cells/(micro)L.

"Injection of our plasmid DNA vaccine containing [HIV-1] envelope and rev genes was tolerated without significant clinical or laboratory complications in 15 subjects in doses up to 300 (micro)g," reported Rob Roy MacGregor of the University of Pennsylvania, Philadelphia.

MacGregor presented the findings at the XI International Conference on AIDS, held July 7-12, 1996 in Vancouver, British Columbia, Canada.

The vaccine is being developed by a research team led by David B. Weiner of the University of Pennsylvania in collaboration with Apollon Inc., Malvern, Pennsylvania. Weiner's group recently received a four-year, $4.2 million grant from the U.S. National Institute of Allergy and Infectious Diseases (NIAID) to develop naked DNA for use as an AIDS therapy.

The so-called naked DNA vaccine consists of a gene construct that expresses the envelope glycoprotein and Rev protein of the MN strain of HIV-1 under the control of the human cytomegalovirus (CMV) promoter gene. The DNA construct is administered directly via intramuscular injection.

Weiner's team found that prior intramuscular injections of bupivacaine hydrochloride improved muscle expression of the DNA 20- to 100-fold in animal studies. This "facilitated" method of DNA vaccination was used in the human trial.

Study subjects included 13 men and two women (neither of whom were pregnant and both of whom agreed to use effective birth control throughout the study).

Subjects' mean time since diagnosis of HIV infection was six years and ranged from six months to 10 years. At baseline their mean CD4 count was 705 cells/(micro)L, mean CD8 count was 1186 cells/(micro)L, and mean HIV viral load was 8,694 RNA copies/ml (range 210-22,620 copies/ml). Viral load was less than 6,000 copies/ml in eight subjects and was undetectable in one.

The 15 patients were randomized to three dosage groups (30, 100, and 300 (micro)g) that received three intramuscular vaccinations at 10-week intervals. Only when all members of the lower dosage group completed all vaccinations did vaccination at the next higher dose begin.

At the time of MacGregor's report, the 30 and 100 (micro)g dosage groups had received all three doses and all members of the 300 (micro)g group had received at least two doses.

"Very few adverse experiences occurred and none required change in the study schedule," MacGregor said. "Only local pain and tenderness were thought to be vaccine related."

No hematological or renal abnormalities were detected.

There was considerable interpatient and intrapatient variability in both CD4 and CD8 counts; no trend could be detected in this Phase I study.

Similarly, no trends could be detected in terms of viral load. Seven subjects had a 30 percent decrease in plasma HIV RNA but another seven subjects had a 30 percent increase in plasma HIV RNA.

"Clear antibody responses were seen in patients receiving 100 (micro)g doses," MacGregor said. "Several increases were seen in the 300 (micro)g group, but the data is still incomplete."

Assays of cytotoxic lymphocyte (CTL) number and function are being conducted, but the results were not available at the time of MacGregor's report.

"In summary, injection of our plasmid DNA vaccine containing envelope and rev genes was tolerated without significant clinical or laboratory complications in 15 subjects in doses up to 300 (micro)g," MacGregor said.

"No consistent trend was seen in numbers of CD4 or CD8 cells or in plasma HIV RNA titer. Boosting of antibody responses to envelope were observed. Assays of cell-mediated immune response are in progress. These data indicate the ability of facilitated DNA plasmid vaccine to produce immune responses in humans."

A more complex vaccine including the HIV-1 gag and pol genes will be the next of the Apollon vaccines to be studied in human trials. MacGregor said that his group is considering using this vaccine to boost immune responses in subjects from the initial trial.

In another report to the AIDS conference, Jean Boyer of the University of Pennsylvania, Philadelphia, reported that the facilitated DNA vaccine both protected chimpanzees against HIV infection and improved anti-HIV immune responses in chimps with longstanding HIV infection.

"DNA immunization has therapeutic as well as prophylactic effects," Boyer said.

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