Anti-sporozoite monoclonal antibody for malaria prevention: secondary efficacy outcome of a phase 2 randomized trial

CIS43LS is a long-acting monoclonal antibody specific for the Plasmodium falciparum circumsporozoite protein expressed on sporozoites. We previously reported that CIS43LS is protective against P. falciparum infection as detected by thick blood smear (TBS; primary endpoint) in a phase 2 double-blind randomized trial involving 330 healthy Malian adults receiving placebo or a single intravenous infusion of 10 mg kg<sup>-1</sup> or 40 mg kg<sup>-1</sup> of CIS43LS (1:1:1). At enrollment, all participants received artemether-lumefantrine to clear possible P. falciparum infection. Although TBS examination is the standard assay to assess efficacy in malaria vaccines trials in endemic areas, it has poor analytical sensitivity; therefore, it remained unknown whether CIS43LS had achieved sterile protection against infection. Here we report the prespecified secondary efficacy endpoint that used a Plasmodium 18S rRNA quantitative reverse transcription-PCR (qRT-PCR) assay that is ~2,000-fold more sensitive than TBS. We analyzed 5,015 dried blood spots collected before CIS43LS or placebo administration and biweekly thereafter over a 6-month malaria season. At 6 months, efficacy of CIS43LS against qRT-PCR-detected infection assessed in a time-to-event analysis was 87.4% for 40 mg kg<sup>-1</sup> (adjusted 95% confidence interval (CI), 79.5-92.3; P < 0.001) and 77.0% for 10 mg kg<sup>-1</sup> (adjusted 95% CI, 65.0-84.0; P < 0.001) versus placebo. A post hoc analysis with a gametocyte mRNA-specific qRT-PCR assay showed 6-month efficacy against gametocytemia of 87.7% for 40 mg kg<sup>-1</sup> (adjusted 95% CI, 75.6-93.8; P < 0.001) and 73.0% for 10 mg kg<sup>-1</sup> (adjusted 95% CI, 54.0-84.0; P < 0.001), versus placebo. These data indicate that a single dose of anti-sporozoite monoclonal antibodies can achieve durable, sterile protection against P. falciparum infection, underscoring their potential to reduce malaria disease burden and transmission. ClinicalTrials.gov identifier: NCT04329104 .

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Journal
Nature Medicine
Published
2025-06-03
DOI
https://doi.org/10.1038/s41591-025-03739-y
Citations
6
Primary Topic
Malaria Research and Control
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article
Field-Weighted Citation Impact
11.27

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article

Anti-sporozoite monoclonal antibody for malaria prevention: secondary efficacy outcome of a phase 2 randomized trial

Boubacar Traoré, Siriman Traoré, Amatigué Zéguimé, Mary Peterson et al.
6 citations
Nature Medicine
Malaria Research and Control
11.27
article

Anti-sporozoite monoclonal antibody for malaria prevention: secondary efficacy outcome of a phase 2 randomized trial

Boubacar Traoré, Siriman Traoré, Amatigué Zéguimé, Mary Peterson, Shanping Li, Chris Chavtur, Didier Doumtabé, M’Bouye Doucoure, Hamadi Traore, Kassoum Kayentao, Mohamed Kéïta, Adama Ouattara, Katrina Kelley, Zonghui Hu, Aïssata Ongoïba, Weston Staubus, Dramane Diakite, Ming Chang, Hamidou Cisse, Peter D. Crompton, Adama Djiguiba, Safiatou Doumbo, Sean C. Murphy, Robert A. Seder, Daniel E. Neafsey, Amadou Niangaly, Philipp Schwabl, Annette M. Seilie, Anne C Preston, Mamadou Keita, Jeff Skinner, Sara A. Healy, Mamadou Konaté, Mamadou Alpha Sylla, Diakaridia Diarra, Amagana Dolo, Abdrahamane Traoré
article en
6 citations

Abstract

CIS43LS is a long-acting monoclonal antibody specific for the Plasmodium falciparum circumsporozoite protein expressed on sporozoites. We previously reported that CIS43LS is protective against P. falciparum infection as detected by thick blood smear (TBS; primary endpoint) in a phase 2 double-blind randomized trial involving 330 healthy Malian adults receiving placebo or a single intravenous infusion of 10 mg kg<sup>-1</sup> or 40 mg kg<sup>-1</sup> of CIS43LS (1:1:1). At enrollment, all participants received artemether-lumefantrine to clear possible P. falciparum infection. Although TBS examination is the standard assay to assess efficacy in malaria vaccines trials in endemic areas, it has poor analytical sensitivity; therefore, it remained unknown whether CIS43LS had achieved sterile protection against infection. Here we report the prespecified secondary efficacy endpoint that used a Plasmodium 18S rRNA quantitative reverse transcription-PCR (qRT-PCR) assay that is ~2,000-fold more sensitive than TBS. We analyzed 5,015 dried blood spots collected before CIS43LS or placebo administration and biweekly thereafter over a 6-month malaria season. At 6 months, efficacy of CIS43LS against qRT-PCR-detected infection assessed in a time-to-event analysis was 87.4% for 40 mg kg<sup>-1</sup> (adjusted 95% confidence interval (CI), 79.5-92.3; P < 0.001) and 77.0% for 10 mg kg<sup>-1</sup> (adjusted 95% CI, 65.0-84.0; P < 0.001) versus placebo. A post hoc analysis with a gametocyte mRNA-specific qRT-PCR assay showed 6-month efficacy against gametocytemia of 87.7% for 40 mg kg<sup>-1</sup> (adjusted 95% CI, 75.6-93.8; P < 0.001) and 73.0% for 10 mg kg<sup>-1</sup> (adjusted 95% CI, 54.0-84.0; P < 0.001), versus placebo. These data indicate that a single dose of anti-sporozoite monoclonal antibodies can achieve durable, sterile protection against P. falciparum infection, underscoring their potential to reduce malaria disease burden and transmission. ClinicalTrials.gov identifier: NCT04329104 .

Nature MedicineVol. 31(8)
Seattle Children's Hospital (US), National Institutes of Health (US), Harvard University (US), University of Washington (US), University of Bamako (ML), Université des Sciences, des Techniques et des Technologies de Bamako (ML), Office of Extramural Research (US), Institute of Infection and Immunity (CA)
Bill and Melinda Gates Foundation, Division of Intramural Research, National Institute of Allergy and Infectious Diseases, National Institutes of Health, National Institute of Allergy and Infectious Diseases, NHLBI Division of Intramural Research
Openalex Percentile: Top 1%
Malaria Research and Control
11.27
DOIOpen Access PDFOpenAlex
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