Research ArticleMalaria

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

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Science Translational Medicine  20 May 2020:
Vol. 12, Issue 544, eaay2578
DOI: 10.1126/scitranslmed.aay2578

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GMOs for good

Despite decades of progress and a multitude of approaches, a durable malaria vaccine remains elusive. Two new clinical studies in this issue report initial testing of genetically engineered malaria vaccines in malaria-naïve adults. Roestenberg et al. studied PfSPZ-GA1, a Plasmodium falciparum sporozoite vaccine attenuated by deletion of b9 and slarp. Reuling et al. examined PbVac, sporozoites of the rodent-specific parasite P. berghei modified to express the circumsporozoite protein from P. falciparum. Both vaccines were well tolerated and immunogenic. Controlled malaria challenge also indicated some evidence of protection. These genetically engineered vaccines are part of the new wave of malaria vaccines and warrant further clinical testing.

Abstract

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

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