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.

backgroundMalaria remains a major cause of mortality globally, especially among young children in sub-Saharan Africa. 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. We assessed the safety, tolerability, and efficacy of L9LS in infants and children in a high perennial malaria transmission setting.

methodsThis double-blind, two-part, randomised, placebo-controlled, phase 2 trial was done in Siaya county in western Kenya. 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). 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. Children were followed up for 12 months with monthly clinic visits and blood smear collections. Primary safety outcomes were incidence and severity of local and systemic solicited adverse events within 7 days of dosing and serious adverse events throughout follow-up. The primary efficacy endpoint was Plasmodium falciparum infection detected by blood smear over 12 months. Primary analyses were done in the modified intention-to-treat population, consisting of all randomly assigned participants who received the study intervention. This trial is registered with ClinicalTrials.gov (NCT05400655) and is complete.

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

interpretationL9LS was protective against malaria in young children in western Kenya without evident safety concerns over 6-12 months. 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.

fundingGates Foundation.