An open-label phase 1/2a trial of a genetically modified rodent malaria parasite for immunization against malaria.

For some diseases, successful vaccines have been developed using a nonpathogenic counterpart of the causative microorganism of choice. The nonpathogenicity of the rodent () parasite in humans prompted us to evaluate its potential as a platform for vaccination against human infection by (), a causative agent of malaria. We hypothesized that the genetic insertion of a leading protein target for clinical development of a malaria vaccine, circumsporozoite protein (CSP), in its natural pre-erythrocytic environment, would enhance 's capacity to induce protective immunity against infection. Hence, we recently generated a transgenic sporozoite immunization platform expressing CSP (Vac), and we now report the clinical evaluation of its biological activity against controlled human malaria infection (CHMI). This first-in-human trial shows that Vac is safe and well tolerated, when administered by a total of ~300 Vac-infected mosquitoes per volunteer. Although protective efficacy evaluated by CHMI showed no sterile protection at the tested dose, significant delays in patency (2.2 days, = 0.03) and decreased parasite density were observed after immunization, corresponding to an estimated 95% reduction in liver parasite burden (confidence interval, 56 to 99%; = 0.010). Vac elicits dose-dependent cross-species cellular immune responses and functional CSP-dependent antibody responses that efficiently block sporozoite invasion of liver cells in vitro. This study demonstrates that Vac immunization elicits a marked biological effect, inhibiting a subsequent infection by the human parasite, and establishes the clinical validation of a new paradigm in malaria vaccination.