A phase I clinical trial of replication-competent Ad4-HIVenv and Ad4-HIVmosaic gag vaccines has been initiated in the NIH clinical center in collaboration with NIAID and Dr. Mark Connors as Principal Investigator. The study is evaluating the safety and immunogenicity of the vaccines formulated as enteric coated capsules for oral administration and as a liquid for administration to the upper respiratory tract. This study follows a previous Phase I trial of an Ad4-flu vaccine, tested in the clinical center with Dr. Connors as PI. It's value for the HIV vaccine trial was to provide initial safety and dosage informaiton, allowing jump-starting of the HIV vaccine trial. Data from the Ad4-flu study are now being evaluated. New Ad-recombinants are under development both for future clinical use and for pre-clinical studies in the rhesus macaque model. These include recombinants containing novel envelope inserts intended to generate broad, potent neutralizing antibodies. This work includes assessment of the immunogenicity of the newly constructed recombinant vaccines in appropriate animal models. In addition, Ad vectors with deletion of genes not essential for replication of the virus have been developed and expand the carrying capacity of the vaccine vector. They will be evaluated in future preclinical vaccine studies. Previously, the STEP trial, a phase III clinical trial of a non-replicating Ad5-HIV vaccine showed lack of protective efficacy in people together with a suggestion that infection might have been enhanced in individuals with pre-existing immunity to Ad5. To explore the basis for the possible enhancement in Ad seropositive individuals, a recent study examined effects of repeated administration of replication-competent Ad5 to rhesus macaques. The results revealed a complex pattern of responses, including suppression of innate immune responses and transient activation of CD4 T cells.
