Background

New approaches for the prevention and elimination of malaria, a leading cause of illness and death among infants and young children globally, are needed.

Methods

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We conducted a phase 1 clinical trial to assess the safety and pharmacokinetics of L9LS, a next-generation antimalarial monoclonal antibody, and its protective efficacy against controlled human malaria infection in healthy adults who had never had malaria or received a vaccine for malaria. The participants received L9LS either intravenously or subcutaneously at a dose of 1 mg, 5 mg, or 20 mg per kilogram of body weight. Within 2 to 6 weeks after the administration of L9LS, both the participants who received L9LS and the control participants underwent controlled human malaria infection in which they were exposed to mosquitoes carrying Plasmodium falciparum (3D7 strain).

Results

No safety concerns were identified. L9LS had an estimated half-life of 56 days, and it had dose linearity, with the highest mean (±SD) maximum serum concentration (C_max) of 914.2±146.5 μg per milliliter observed in participants who had received 20 mg per kilogram intravenously and the lowest mean C_max of 41.5±4.7 μg per milliliter observed in those who had received 1 mg per kilogram intravenously; the mean C_max was 164.8±31.1 in the participants who had received 5 mg per kilogram intravenously and 68.9±22.3 in those who had received 5 mg per kilogram subcutaneously. A total of 17 L9LS recipients and 6 control participants underwent controlled human malaria infection. Of the 17 participants who received a single dose of L9LS, 15 (88%) were protected after controlled human malaria infection. Parasitemia did not develop in any of the participants who received 5 or 20 mg per kilogram of intravenous L9LS. Parasitemia developed in 1 of 5 participants who received 1 mg per kilogram intravenously, 1 of 5 participants who received 5 mg per kilogram subcutaneously, and all 6 control participants through 21 days after the controlled human malaria infection. Protection conferred by L9LS was seen at serum concentrations as low as 9.2 μg per milliliter.

Conclusions

In this small trial, L9LS administered intravenously or subcutaneously protected recipients against malaria after controlled infection, without evident safety concerns. (Funded by the National Institute of Allergy and Infectious Diseases; VRC 614 ClinicalTrials.gov number, NCT05019729.)

中文翻译：

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低剂量皮下或静脉内单克隆抗体预防疟疾

背景

需要新的方法来预防和消除疟疾，这是全球婴幼儿患病和死亡的主要原因。

方法

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我们进行了一项 1 期临床试验，以评估下一代抗疟疾单克隆抗体 L9LS 的安全性和药代动力学，以及它对从未患过疟疾或未接种过疟疾疫苗的健康成年人的受控人类疟疾感染的保护功效。参与者以每公斤体重 1 毫克、5 毫克或 20 毫克的剂量静脉内或皮下注射 L9LS。在施用 L9LS 后 2 至 6 周内，接受 L9LS 的参与者和对照组参与者都经历了受控的人类疟疾感染，在感染过程中，他们接触了携带恶性疟原虫（3D7 株）的蚊子。

结果

没有发现安全问题。L9LS 的估计半衰期为 56 天，并且具有剂量线性，在接受 20 mg/kg 静脉注射的参与者中观察到的最高平均 (±SD) 最大血清浓度 (C _max ) 为 914.2±146.5 μg/mL在接受 1 mg/kg 静脉注射的患者中观察到的最低平均_{Cmax为 41.5±4.7 μg/mL；}平均 C_最大值静脉注射 5 mg/kg 的参与者为 164.8±31.1，皮下注射 5 mg/kg 的参与者为 68.9±22.3。共有 17 名 L9LS 接受者和 6 名对照参与者接受了受控的人类疟疾感染。在接受单剂​​ L9LS 的 17 名参与者中，15 名 (88%) 在控制人类疟疾感染后得到保护。任何接受 5 或 20 mg/kg 静脉注射 L9LS 的参与者均未出现寄生虫血症。在受控的人类疟疾感染后 21 天内，5 名静脉注射 1 mg/kg 的参与者中有 1 名、5 名皮下注射 5 mg/kg 的参与者中有 1 名以及所有 6 名对照参与者出现寄生虫血症。在低至 9.2 μg/mL 的血清浓度下，可以看到 L9LS 赋予的保护作用。

结论

在这项小型试验中，L9LS 通过静脉内或皮下注射保护接受者在受控感染后免受疟疾侵害，没有明显的安全问题。（由国家过敏和传染病研究所资助；VRC 614 ClinicalTrials.gov 编号，NCT05019729。）