Multi-envelope HIV vaccine safety and immunogenicity in small animals and chimpanzees

A significant obstacle to HIV Vaccine development lies in the remarkable di versity of envelope proteins, the major targets of neutralizing antibody. T hat envelope diversity must be targeted is demonstrated by results from non human primate studies in which single-envelope vaccines have protected agai nst homologous, but rarely against heterologous virus challenges. Similarly , in clinical trials, single-envelope vaccines have failed to prevent break -through infections when challenge viruses were inevitably mismatched with the vaccine. To protect humans from infection by any isolate of HIV, we hav e prepared vaccine cocktails combining multiple envelopes from distinct vir al isolates. We have tested several vehicles for vaccine delivery in small animals and have shown that successive immunizations with envelope, present ed first as a DNA recombinant, then as a vaccinia virus (VV) recombinant, a nd finally as purified protein elicited strong neutralizing antibody respon ses. We have also tested the VV recombinant vaccine in chimpanzees. Pairs o f animals received either single- or multi-envelope VV recombinant vaccines ;administered by the subcutaneous route. Results showed that the multienvel ope vaccine was safe, immunogenic, and superior to the single-envelope vacc ine in eliciting HIV-specific antibody measurable in a standard clinical, i mmune assay. The promise of this system has led to the initiation of clinic al trials, with which the hypothesis that cocktail vaccines will prevent hu man HIV infections may ultimately be tested.