Editors' ChoiceInfectious Disease

Targeting a conserved epitope: A new chink in malaria’s armor

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Science Translational Medicine  04 Apr 2018:
Vol. 10, Issue 435, eaat3890
DOI: 10.1126/scitranslmed.aat3890

Abstract

Human monoclonal antibodies targeting a specific epitope of the antigen from Plasmodium falciparum show protection in mice and may offer long-lasting therapies against malaria.

Malaria is a mosquito-borne disease that can strike fast, making it harder to track and treat. Infection with Plasmodium falciparum (Pf) is responsible for the majority of deaths due to malaria, and development of effective, long-lasting vaccines against this parasite has been proven difficult due to its highly complex biology. Kisalu et al. reasoned that invading the parasite’s armor with monoclonal antibodies (mAbs) targeting a specific epitope (part of an antigen molecule) could be highly effective for passive prevention of malaria.

The research team used multiple experimental approaches to isolate human mAbs through memory B cells or plasmablasts from the blood of subjects immunized with an attenuated whole-sporozoite vaccine and protected against controlled human malaria infection. Of various mAbs, a candidate antibody, CIS43, was selected using a combination of in vitro and in vivo experiments. In a function inhibition assay in an in vitro model of Pf liver-stage development in primary human hepatocytes the CIS43 inhibited the sporozoite, and in two mouse models of malaria infection (including a human liver-chimeric mouse) the mAb conferred sterile protection. The authors show superior performance of mAbs against Pf circumsporozite protein (PfCSP) than mAbs against an alternative sequence in Pf. Analysis of CIS43 revealed that the antibody bound a junctional epitope of the PfCSP. Since the epitope is present only once in PfCSP and is highly conserved (>99.8%) amongst Pf strains recovered globally, it provides a conserved site for antibody neutralization through passive transfer and vaccine design to induce production of such antibodies. Although the authors speculate that a CIS43-mediated protection against Pf infection in mice is notable because this concentration may be achievable for up to 6 months in humans, more studies are needed to establish protective efficacy in controlled human malaria infection challenge trials. If successful, the mAbs may be combined with other antibodies or antimalarial drugs toward large-scale efforts to prevent or treat malaria.

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