In:
Science Translational Medicine, American Association for the Advancement of Science (AAAS), Vol. 12, No. 544 ( 2020-05-20)
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 Pf CSP ( Pb 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 Pb Vac is safe and well tolerated, when administered by a total of ~300 Pb 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, 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). Pb Vac elicits dose-dependent cross-species cellular immune responses and functional Pf CSP-dependent antibody responses that efficiently block Pf sporozoite invasion of liver cells in vitro. This study demonstrates that Pb Vac 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.
Type of Medium:
Online Resource
ISSN:
1946-6234
,
1946-6242
DOI:
10.1126/scitranslmed.aay2578
Language:
English
Publisher:
American Association for the Advancement of Science (AAAS)
Publication Date:
2020
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