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

Background: Malaria 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 school-age children exposed to seasonal transmission but remains untested in perennial transmission settings and younger children.

Methods: We conducted a double-blind, placebo-controlled randomised phase 2 trial assessing safety, tolerability, and efficacy of L9LS in healthy infants and children in a high perennial malaria transmission setting in western Kenya. In parts 1a/1b, we tested safety and tolerability, using an age de-escalation and dose escalation approach and randomising 96 children (5–10 years and 5–59 months) 3:1 to L9LS at 5, 10, 20, 30, or 40 mg/kg subcutaneously or to placebo (normal saline). In part 2, 324 children aged 5–59 months were randomised 1:1:1 using 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 for 12 months with monthly clinic visits and blood smear collections. The primary endpoint was Plasmodium falciparum infection detected by blood smear over 12 months. This completed trial was registered at clinicaltrials.gov (NCT05400655).

Findings: Across all study parts, grade 3 or worse treatment-related adverse events (AEs) occurred after 4/384 (1·0%) L9LS injections and 1/235 (0·4%) placebo injections; these events all resolved by study end. The proportion of solicited and unsolicited AEs was similar across all L9LS dose groups. There were no serious adverse events (SAEs) related to the trial. In part 2, 70 of 106 (66%) children who received two doses of L9LS were infected over 12 months versus 91 of 110 (83%) who received placebo at both timepoints (protective efficacy [PE] = 42·7% [95% CI: 22·5–57·7], p=0·0003). At 6 months, after a single dose of L9LS or placebo, infections occurred in 103/214 (48%) after L9LS and 69/110 (63%) after placebo (PE = 45·9% (95% CI: 26·5–60·1).

Interpretation: L9LS was protective against malaria in young children in western Kenya without evident safety concerns over 6–12 months. A higher dose of L9LS may be needed to achieve high-level efficacy against malaria in young children exposed to intense perennial P. falciparum transmission.

Funding: Bill and Melinda Gates Foundation