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

Abstract

For some diseases, successful vaccines have been developed using a nonpathogenic counterpart of the causative microorganism of choice. The nonpathogenicity of the rodent <i>Plasmodium berghei</i> (<i>Pb</i>) parasite in humans prompted us to evaluate its potential as a platform for vaccination against human infection by <i>Plasmodium falciparum</i> (<i>Pf</i>), a causative agent of malaria. We hypothesized that the genetic insertion of a leading protein target for clinical development of a malaria vaccine, <i>Pf</i> circumsporozoite protein (CSP), in its natural pre-erythrocytic environment, would enhance <i>Pb</i>'s capacity to induce protective immunity against <i>Pf</i> infection. Hence, we recently generated a transgenic <i>Pb</i> sporozoite immunization platform expressing <i>Pf</i>CSP (<i>Pb</i>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 <i>Pb</i>Vac is safe and well tolerated, when administered by a total of ~300 <i>Pb</i>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, <i>P</i> = 0.03) and decreased parasite density were observed after immunization, corresponding to an estimated 95% reduction in <i>Pf</i> liver parasite burden (confidence interval, 56 to 99%; <i>P</i> = 0.010). <i>Pb</i>Vac elicits dose-dependent cross-species cellular immune responses and functional <i>Pf</i>CSP-dependent antibody responses that efficiently block <i>Pf</i> sporozoite invasion of liver cells in vitro. This study demonstrates that <i>Pb</i>Vac immunization elicits a marked biological effect, inhibiting a subsequent infection by the human <i>Pf</i> parasite, and establishes the clinical validation of a new paradigm in malaria vaccination.