Active anti-interferon-alpha immunization: A European-Israeli, randomized,double-blind, placebo-controlled clinical trial in 242 HIV-1-infected patients (the EURIS study)

This randomized, double-blind, placebo-controlled, phase II/III study was d esigned to evaluate safety, immunogenicity, and efficacy of an active antii nterferon-a (anti-IFN-alpha) vaccine in asymptomatic HIV-1-infected patient s. The active immunization was aimed at inducing anti-IFN-alpha antibodies to counteract IFN-alpha overproduction. In all, 242 patients, recruited bet ween December 1995 and July 1996 in eight centers in Europe and Israel, wit h CD4(+) counts from 100 to 634 cells/mm(3) who were receiving or not recei ving antiretroviral therapy (including protease inhibitors) were randomized to receive either anti-IFN-alpha vaccine or placebo. The anti-IFN-alpha im munization regimen consisted of three priming injections delivered intramus cularly at 1-month intervals in a water-in-oil emulsion of inactivated reco mbinant IFN-alpha-2b (i-IFN-alpha) followed by intramuscular booster inject ions of i-IFN-alpha adsorbed onto calcium phosphate every 3 months. Immunog enicity to vaccine was defined as an increase of anti-IFN-alpha antibody le vel of more than twofold the preimmunization value. Clinical progression, c hanges in antiretroviral treatment, and decrease of CD4(+) counts to <200 c ells/mm(3) were considered endpoints for efficacy evaluation. Contrary to o ur previous experience, in which six to seven oil priming injections induce d a >90% response rate, thr three oil-adjuvanted injections in this trial w ere suboptimal because only 40 of 122 vaccinees (33%) had raised anti-IFN-a lpha antibody following immunization. In vaccinees, both antibody responder s (AbRV) and nonresponders (AbNRV), the tolerance to the vaccine was good a nd was without evidence of significant safety concerns. During the course o f the trial, 62% of vaccine responders, 64% of nonresponders, and 63% of pl acebo patients elected to add protease inhibitor-containing regimens as new treatment guidelines were established, resulting in a marked decrease in c linical and laboratory progression such that the expected end-points of the study could not be achieved and further follow-up was halted. Despite the unexpectedly low immunogenicity and fewer than expected endpoints, anti-IFN -alpha vaccine recipients, in comparison with placebo recipients, showed a lower rate of disease progression, nonelective treatment changes, and/or CD 4(+) count decrease to <200 cells/mm(3), but the difference was not statist ically significant. Nevertheless, the subgroup of patients immunized to IFN -alpha who experienced a rise in anti-IFN-alpha antibodies had a significan tly lower rate of occurrence of HIV-l-related events and of any combination of the endpoints compared with those of either placebo patients or vaccine es who failed to develop anti-IFN-alpha antibodies, the latter two groups b ehaving similarly. Further studies of this approach are warranted because t hese data suggest a beneficial effect of this adjuvant approach.