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⁻¹ or 40 mg kg⁻¹ 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⁻¹ (adjusted 95% confidence interval (CI), 79.5–92.3; P < 0.001) and 77.0% for 10 mg kg⁻¹ (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⁻¹ (adjusted 95% CI, 75.6–93.8; P < 0.001) and 73.0% for 10 mg kg⁻¹ (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。我们之前报道过，在一项 2 期双盲随机试验中，CIS43LS 对恶性疟原虫感染具有保护作用，通过厚血涂片 （TBS;主要终点） 检测到，该试验涉及 330 名接受安慰剂或单次静脉输注 10 mg ^kg-1 或 40 mg ^kg-1 CIS43LS 的健康马里成年人 （1：1：1）。在入组时，所有参与者都接受了蒿甲醚-苯芴醇以清除可能的恶性疟原虫感染。尽管 TBS 检查是评估流行地区疟疾疫苗试验疗效的标准检测方法，但它的分析敏感性较差;因此，目前尚不清楚 CIS43LS 是否实现了无菌的感染保护。在这里，我们报告了预先指定的次要疗效终点，该终点使用疟原虫 18S rRNA 定量逆转录-PCR （qRT-PCR） 测定，其灵敏度是 TBS 的 ~2,000 倍。我们分析了 CIS43LS 或安慰剂给药前收集的 5,015 个干血点，此后在 6 个月的疟疾季节中每两周收集一次。6 个月时，对于 40 mg ^kg-1，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为 87.4%（调整后的 95%置信区间（CI），79.5-92.3;P < 0.001）和 77.0% 对于 10 mg ^kg-1（调整后的 95% CI，65.0-84.0;P < 0.001） 与安慰剂相比。 使用配子细胞 mRNA 特异性 qRT-PCR 测定的事后分析显示，40 mg ^kg-1 对配子细胞血症的 6 个月疗效为 87.7%（调整后的 95% CI，75.6-93.8;P < 0.001）和 73.0% 对于 10 mg ^kg-1（调整后的 95% CI，54.0-84.0;P < 0.001） 与安慰剂相比。这些数据表明，单剂量的抗子孢子单克隆抗体可以实现针对恶性疟原虫感染的持久、无菌保护，强调了它们减少疟疾疾病负担和传播的潜力。ClinicalTrials.gov 标识符：NCT04329104。