Safety and efficacy of the monoclonal antibody L9LS for malaria prevention in children exposed to perennial malaria transmission in Kenya: a randomised, double-blind, placebo-controlled, phase 2 trial.

The long-acting monoclonal antibody L9LS has shown high efficacy in preventing malaria in children aged 6-10 years exposed to seasonal transmission but remains untested in perennial transmission settings and younger children.

长效单克隆抗体L9LS在预防6-10岁儿童季节性疟疾传播方面显示出高效率，但在全年性传播环境和更年幼的儿童中尚未进行测试。

We assessed the safety, tolerability, and efficacy of L9LS in infants and children in a high perennial malaria transmission setting.

我们在高常年疟疾传播地区评估了L9LS在婴儿和儿童中的安全性、耐受性和疗效。

Methods

This double-blind, two-part, randomised, placebo-controlled, phase 2 trial was done in Siaya county in western Kenya.

这项双盲、两部分、随机、安慰剂对照的2期试验在肯尼亚西部的Siaya县进行。

In parts 1a and 1b, we tested the safety and tolerability of L9LS using an age de-escalation and dose escalation approach and randomly assigned (3:1) cohorts of healthy children (three cohorts aged 5-10 years, three cohorts aged 5-59 months, and two cohorts aged 5-71 months) to L9LS at doses of 5, 10, 20, 30, or 40 mg/kg subcutaneously or to placebo (normal saline).

在第1a和1b部分，我们采用年龄递减和剂量递增的方法测试了L9LS的安全性和耐受性，并随机分配（3:1）了三组年龄在5-10岁、三组年龄在5-59个月以及两组年龄在5-71个月的健康儿童，分别接受5、10、20、30或40 mg/kg的L9LS皮下注射或安慰剂（生理盐水）。

In part 2, healthy children aged 5-59 months were randomly assigned (1:1:1) by use of centralised computer-generated lists to receive two doses of L9LS at 10-20 mg/kg at baseline and month 6, one dose of L9LS at baseline and placebo at month 6, or placebo at both timepoints.

在第2部分，通过使用中心计算机生成的列表，随机分配（1:1:1）年龄在5-59个月的健康儿童，分别接受两剂L9LS（在基线和第6个月时，剂量为10-20 mg/kg）、一剂L9LS（在基线时）和安慰剂（在第6个月时），或在两个时间点均接受安慰剂。

Children were followed up for 12 months with monthly clinic visits and blood smear collections.

儿童随访观察了12个月，每月进行一次诊所访问和血涂片采集。

Primary safety outcomes were incidenceand severity of local and systemic solicited adverse events within 7 days of dosing and serious adverse events throughout follow-up.

主要的安全性结果是给药后7天内局部和全身不良事件的发生率和严重程度，以及随访期间严重不良事件的发生。

The primary efficacy endpoint was Plasmodium falciparum infection detected by blood smear over 12 months.

主要疗效终点是通过血涂片检测到的12个月内的恶性疟原虫感染。

Primary analyses were done in the modified intention-to-treatpopulation, consisting of all randomly assigned participants who received the study intervention.

主要分析是在修改后的意向治疗人群中进行的，该人群包括所有接受研究干预的随机分配参与者。

This trial is registered with ClinicalTrials.gov (NCT05400655) and is complete.

该试验已在ClinicalTrials.gov注册（NCT05400655），并已完成。

Results

In parts 1a and 1b, 96 children were enrolled and randomly assigned between Oct 1, 2022, and Jan 16, 2024; 72 participants were assigned to L9LS and 24 were assigned to placebo.

在1a和1b部分中，共有96名儿童在2022年10月1日至2024年1月16日期间被纳入并随机分配；其中72名参与者被分配至L9LS组，24名被分配至安慰剂组。

In part 2, 324 children aged 5-59 months were enrolled and randomly assigned between Jan 26 and June 2, 2023; 108 children were assigned to one-dose L9LS, 106 to two-dose L9LS, and 110 to placebo.

在第二部分中，从2023年1月26日至6月2日，共有324名5-59个月大的儿童被纳入并随机分配；108名儿童被分配到单剂量L9LS组，106名到双剂量L9LS组，110名到安慰剂组。

Across all study parts, grade 3 or worse treatment-related adverse events occurred after four (1%) of 384 L9LS injections and two (1%) of 338 placebo injections; these events all resolved by study end.

在整个研究中，严重的与治疗相关的不良事件在384次L9LS注射中有4次（1%），在338次安慰剂注射中有2次（1%）；这些事件都在研究结束时得到解决。

The proportion of solicited and unsolicited adverse events was similar across all L9LS dose groups.

所有L9LS剂量组中，主动报告和非主动报告的不良事件比例相似。

There were no serious adverse events related to the trial. In part 2, 70 (66%) of 106 children in the two-dose L9LS group had at least one P falciparum infection during the 12-month follow-up versus 91 (83%) of 110 children in the placebo group (protective efficacy 42·7%, 95% CI 22·5-57·7; p=0·0003).

在第二部分研究中，106名接受两剂L9LS治疗的儿童在12个月随访期间有70名（66%）至少发生了一次P falciparum感染，而110名接受安慰剂的儿童中有91名（83%）发生感染（保护效力为42.7%，95%置信区间22.5-57.7；p=0.0003）。

interpretation

L9LS was protective against malaria in young children in western Kenya without evident safety concerns over 6-12 months.

在肯尼亚西部，L9LS对年幼儿童具有抗疟疾保护作用，在6-12个月的观察期内未见明显安全问题。

A higher dose of L9LS might be needed to achieve high-level efficacy against malaria in young children exposed to intense perennial P falciparum transmission.

对于暴露于高强度全年P falciparum传播的年幼儿童，可能需要更高剂量的L9LS才能实现高水平的抗疟疾效果。

funding

Gates Foundation.

盖茨基金会。