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

The vaccine, developed by Immunotech SA, Marseille, France, works differently than most vaccines. Instead of inducing antibodies to an antigen, it induces antibodies to an antibody. The so-called idiotypic antibodies raised in this fashion are high ly specific.

A German multicenter clinical trial of the Immunotech product enrolled 158 patients with asymptomatic HIV infection.

"The clinical Phase II trial demonstrates that anti-CD4 idiotype vaccination might be an effective treatment in early-stage HIV disease," said Ingolf Schedel of the Medical School of Hanover, Germany.

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

The vaccine consists of a monoclonal antibody (mAb) that recognizes a conserved portion of the human CD4 T-cell receptor (the CDR3-homologous CD4/D1 region) implicated in binding the gp120 HIV envelope glycoprotein.

The anti-CD4 mAb, designated IO4Ta (13B8.2) is not itself supposed to be therapeutic. According to the network theory of immune regulation it acts as an idiotype, i.e., an antigenic determinant characterizing an individual antibody. Antibodies eli cited by vaccination with the IO4Ta idiotype - anti-idiotype antibodies - should theoretically recognize (and neutralize) the HIV gp120 binding site.

In vitro studies showed that anti-idiotype antibodies against IO4Ta bound and neutralized HIV better than other anti-CD4 antibodies (anti-Leu 3a, B66.1, and 7.3F11).

"Specific anti-idiotype antibodies to IOT4a were capable of inhibiting the gp120/CD4 interaction as well as HIV infection of susceptible culture cells and HIV cell-to-cell spread in vitro," Schedel noted.

In a Phase I dose escalation study, 10 HIV infected individuals with CD4 counts of 200-400 cells/(micro)L received 0.6, 1.2, or 2.4 mg doses of alum-precipitated IO4Ta.

In a previous presentation Schedel said that the major adverse event in this trial was local redness and swelling at the site of injection. There were no adverse systemic reactions (see AIDS Weekly, March 20, 1995).

The Phase II trial was conducted at the 30 units of the German AIDS Clinical Trials program (KAAD).

The trial enrolled asymptomatic HIV(+) individuals with CD4 counts of 300-500 cells/(micro)L and no prior antiretroviral therapy to receive either placebo (adjuvant only) or 1.2 mg of alum-precipitated IO4Ta with a 0.6 mg boost after three months.

Of the 158 subjects enrolled in the trial, half were randomized to the placebo group and half to the treatment or verum group.

There were no statistically significant differences between the arms in clinical side effects, although three vaccine recipients developed a systemic rash or Quincke's edema.

Antibody measurements on study days 77, 161, and 242 demonstrated the presence of significant anti-gp120 antibodies in the vaccine recipients. Neutralization was evaluated by the ability of antibodies to prevent HIV cytopathicity in culture.

"At day 77 ... significant elevated titers of HIV neutralizing serum antibodies were observed," Schedel said.

The study design defined two clinical endpoints: the development of an AIDS-defining condition and/or a 20 percent decrease in CD4 count.

Although the difference between the treatment and placebo groups were not statistically different, the trend favored the treatment group. Nine of the vaccinated subjects and 16 of the placebo subjects reached clinical endpoints.

Schedel said that a multivariate analysis of CD4 count, clinical endpoints, and HIV p24 antigen showed a significant difference in favor of vaccine recipients.

Onset of the CDC Classification B diseases (symptoms associated with HIV but not considered AIDS defining in and of themselves) occurred more frequently among placebo recipients.

Of interest was the finding that no clinical endpoints occurred in any of the vaccine recipients who developed a greater than five-fold increase over baseline in anti-IOT4a antibodies.

There were no increases in HIV plasma RNA after treatment.

"Most of the patients observed did not change at all [in HIV viral burden]," Schedel said. "There is no sign, no evidence, for promoting or activating of the HIV-1 infection during the vaccination period of one year."

Schedel said that vaccine recipients were significantly more likely than placebo recipients to have their plasma HIV RNA drop to undetectable levels, and they were significantly less likely to have their plasma RNA levels increase to more than 200,000 copies/ml.

"In conclusion, the idiotype vaccine was found to be tolerable concerning clinical side effects," Schedel said. "IOT4a-specific and HIV gp120 cross-reactive humoral immune reactions showing HIV neutralizing activity were shown to be raised by vaccination. In a prospective, double-blind, placebo-controlled clinical trial the combined evaluation of one set of AIDS-defining diseases, CD4 positive mononuclear cell count, and HIV plasma antigen levels revealed a significant advantage for the verum vaccinated group of patients."

Schedel said that he believed better results would be obtained if patients received antiretroviral therapy in addition to anti-idiotype vaccination.

960826
AW960814

Published by Charles Henderson, Publisher. Editorial & Publishing Office: P.O. Box 5528, Atlanta, GA 30307-0528 / Telephone: (800) 633-4931; Subscription Office: P.O. Box 830409, Birmingham, AL 35283-0409 / FAX: (205) 995-1588 http://www.newsrx.net

Copyright © 1996 - Charles Henderson, Publisher. All rights Reserved. Permission to reproduce granted to AEGIS by Charles W. Henderson. Authorization to reproduce for personal use granted granted by C. W. Henderson, Publisher, provided that the fee of US$4.50 per copy, per page is paid directly to the Copyright Clearance Center, 27 Congress Street, Salem, Massachusetts 01970, USA.