Skinner Jeff, Kayentao Kassoum, Ongoiba Aissata, Healy Sara A, Hu Zonghui, Preston Anne C, Niangaly Amadou, Schwabl Philipp, Cisse Hamidou, Doumbo Safiatou, Doumtabe Didier, Traore Abdrahamane, Li Shanping, Peterson Mary E, Seilie Annette M, Chavtur Chris, Staubus Weston, Chang Ming, Kelley Katrina, Traore Hamadi, Djiguiba Adama, Keita Mamadou, Ouattara Adama, Doucoure M'Bouye, Keita Mohamed, Diarra Djelika, Sylla Mamadou, Diakite Dramane, Konate Mamadou, Traore Siriman, Zéguimé Amatigué, Dolo Amagana, Neafsey Daniel E, Murphy Sean C, Traore Boubacar, Seder Robert A, Crompton Peter D
Malaria Infection Biology and Immunity Section, Laboratory of Immunogenetics, Division of Intramural Research, NIAID, NIH, Rockville, MD, USA.
Malaria Research and Training Centre, Mali International Center of Excellence in Research, University of Sciences, Techniques and Technologies of Bamako, Bamako, Mali.
Nat Med. 2025 Jun 3. doi: 10.1038/s41591-025-03739-y.
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 or 40 mg kg 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 (adjusted 95% confidence interval (CI), 79.5-92.3; P < 0.001) and 77.0% for 10 mg kg (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 (adjusted 95% CI, 75.6-93.8; P < 0.001) and 73.0% for 10 mg kg (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 .
CIS43LS是一种长效单克隆抗体，对子孢子上表达的恶性疟原虫环子孢子蛋白具有特异性。我们之前报道，在一项2期双盲随机试验中，通过厚血涂片（TBS；主要终点）检测发现，CIS43LS对恶性疟原虫感染具有保护作用，该试验纳入了330名健康的马里成年人，他们被随机分配接受安慰剂或单次静脉输注10mg/kg或40mg/kg的CIS43LS（1:1:1）。入组时，所有参与者均接受蒿甲醚-本芴醇以清除可能存在的恶性疟原虫感染。尽管TBS检查是评估疟疾疫苗在流行地区试验疗效的标准检测方法，但其分析灵敏度较低；因此，CIS43LS是否实现了对感染的无菌性保护仍不清楚。在此，我们报告了预先设定的次要疗效终点，该终点使用了一种疟原虫18S rRNA定量逆转录聚合酶链反应（qRT-PCR）检测方法，其灵敏度比TBS高约2000倍。我们分析了在给予CIS43LS或安慰剂之前以及之后在6个月的疟疾季节中每两周收集的5015份干血斑样本。在6个月时，在事件发生时间分析中评估的CIS43LS对qRT-PCR检测到的感染的疗效，40mg/kg组为87.4%（调整后的95%置信区间（CI），79.5 - 92.3；P < 0.001），10mg/kg组为77.0%（调整后的95%CI，65.0 - 84.0；P < 0.001），而安慰剂组为0。一项使用配子体mRNA特异性qRT-PCR检测方法的事后分析显示，40mg/kg组对配子血症的6个月疗效为87.7%（调整后的95%CI），75.6 - 93.8；P < 0.001），10mg/kg组为73.0%（调整后的95%CI，54.0 - 84.0；P < 0.001），而安慰剂组为0。这些数据表明，单剂量的抗子孢子单克隆抗体可以实现对恶性疟原虫感染的持久、无菌性保护，突显了它们在减轻疟疾疾病负担和传播方面的潜力。ClinicalTrials.gov标识符：NCT04329104 。
