Abstracto

Clinical testing of a novel and promising cmv-Vectored HIV vaccine

Marcel E. Curlina, Louis Picke

Despite nearly four decades of research and 35 million deaths worldwide, an effective HIV vaccine remains lacking. In phase-3 testing, candidate vaccines thus far have elicited immune responses that are too narrowly targeted to offer meaningful protection from infection following exposure to circulating strains. Extreme viral diversity and the rapid establishment of latency represent serious challenges to the development of an effective vaccine. Recent pre-clinical studies in non-human primates using an attenuated cytomegalovirus containing an inserts encoding SIV gag rev/nef/tat, pol and env yield CD8+ effector T cell responses that are robust, highly durable, restricted by unconventional antigen presentation mechanisms, and target common insert epitopes in all experimental animals despite a heterogeneous MHC background (i.e., supertopes). These immune responses are mediated by circulating and pre-positioned, tissueresident, effector-differentiated CD8+ T cells capable of response immediately following challenge, without the delay associated with clonal expansion from the central memory population. This immunological profile is ideally suited to cope with the unique challenge of lentiviral infection, and the vaccine construct has now been shown to consistently abrogate early SIV infection following repeated low-dose in approximately 55% of vaccinated rhesus macaques. Plans for phase-1 testing are underway to establish safety and dose-response in humans, and to determine whether the unique immune responses associated with protection will be observed in humans. Study implementation must take into account important considerations regarding appropriate selection of participants, pre-existing immunity to CMV, use of a live-attenuated viral vaccine, and must employ an optimally informative study design. Keywords: HIV, vaccine, CMV, cellular immunity, phase-1 testing, safety, immunogenicity.