Jeff Skinner, Kassoum Kayentao, Aissata Ongoiba, Sara A. Healy, Zonghui Hu, Anne C. Preston, Amadou Niangaly, Philipp Schwabl, Hamidou Cisse, Safiatou Doumbo, Didier Doumtabe, Abdrahamane Traore, Shanping Li, Mary E. Peterson, Annette M. Seilie, Chris Chavtur, Weston Staubus, Ming Chang, Katrina Kelley, Hamadi Traore, Adama Djiguiba, Mamadou Keita, Adama Ouattara, M’Bouye Doucoure, Mohamed Keita, Djelika Diarra, Mamadou Sylla, Dramane Diakite, Mamadou Konate, Siriman Traore, Amatigué Zéguimé, Amagana Dolo, Daniel E. Neafsey, Sean C. Murphy, Boubacar Traore, Robert A. Seder, Peter D. Crompton
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引用次数: 0
摘要
CIS43LS是一种针对恶性疟原虫环孢子子蛋白表达的长效单克隆抗体。我们以前报道过CIS43LS对恶性疟原虫感染有保护作用，通过厚血涂片(TBS；主要终点)在一项2期双盲随机试验中进行，该试验涉及330名健康的马里成年人，他们接受安慰剂或单次静脉输注CIS43LS 10 mg kg - 1或40 mg kg - 1（1:1:1）。在入组时，所有的参与者都接受了蒿甲醚-氨苯曲明，以清除可能的恶性疟原虫感染。虽然TBS检查是在疟疾流行地区评估疟疾疫苗试验效力的标准检测方法，但它的分析灵敏度较差；因此，尚不清楚CIS43LS是否达到了无菌保护。在这里，我们报告了预先指定的次要疗效终点，使用疟原虫18S rRNA定量逆转录pcr （qRT-PCR）测定，比TBS灵敏度高约2000倍。我们分析了在使用CIS43LS或安慰剂之前收集的5,015个干血点，之后每两周收集一次，为期6个月的疟疾季节。在6个月时，CIS43LS对qrt - pcr检测到的感染的疗效在事件时间分析中评估为87.4%,40 mg kg - 1(调整95%置信区间（CI）， 79.5-92.3；P < 0.001)， 10 mg kg - 1为77.0%(校正95% CI， 65.0-84.0；P < 0.001)。配子细胞mrna特异性qRT-PCR事后分析显示，40 mg kg - 1的配子细胞6个月疗效为87.7%(校正95% CI， 75.6-93.8；P < 0.001)， 10 mg kg - 1组为73.0%(校正95% CI， 54.0-84.0；P < 0.001)。这些数据表明，单剂量抗孢子虫单克隆抗体可以实现持久的、无菌的保护，防止恶性疟原虫感染，强调了它们在减少疟疾疾病负担和传播方面的潜力。ClinicalTrials.gov识别码：NCT04329104。
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−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.
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