4-1BB antibody significantly enhances SIV-specific CD8+ T-cell immunity and proliferation following naked DNA vaccination in cynomolgus macaques (47.10)

Abstract

Abstract A major challenge in the development of an effective vaccine for HIV is to stimulate potent cell-mediated immunity that includes the induction of long term memory. Ligation of the activation-induced co-stimulatory molecule, 4-1BB, stimulates CD8+ T-cell proliferation and the generation of memory in mice. We evaluated monoclonal antibody (mAb) agonists for 4-1BB to enhance DNA vaccines. Two studies were performed in cynomolgus macaques to evaluate the ability of these mAb to augment intramuscular DNA immunizations with either plasmid SIV-Gag or with codon-optimized consensus SIV-Gag, SIV-Env, and SIV-Pol plasmid DNA. Administration of anti-4-1BB mAb doubled the CD8+ T-cell killing ability as measured by granzyme B ELISpot assays. Furthermore, the proliferative response of SIV-specific CD8+ T-cells was increased by more than 5-fold after one immunization as measured by CFSE proliferation assays. Our data demonstrate the ability of 4-1BB stimulation to enhance cellular immunity following DNA vaccination in NHPs. These findings have clinical importance in that they represent a considerable improvement in the efficacy of naked intramuscular DNA vaccines in large animals and demonstrate the ability of 4-1BB agonists to direct CD8+ T-cell responses and memory. This work is supported in part by NIH and NIAID funds.