Subcutaneous Administration of a Monoclonal Antibody to Prevent Malaria

Abstract

Background: Subcutaneous administration of the monoclonal antibody L9LS protected adults against controlled Plasmodium falciparum infection in a phase 1 trial. Whether a monoclonal antibody administered subcutaneously can protect children from P. falciparum infection in a region where this organism is endemic is unclear.

Methods: We conducted a phase 2 trial in Mali to assess the safety and efficacy of subcutaneous administration of L9LS in children 6 to 10 years of age over a 6-month malaria season. In part A of the trial, safety was assessed at three dose levels in adults, followed by assessment at two dose levels in children. In part B of the trial, children were randomly assigned, in a 1:1:1 ratio, to receive 150 mg of L9LS, 300 mg of L9LS, or placebo. The primary efficacy end point, assessed in a time-to-event analysis, was the first P. falciparum infection, as detected on blood smear performed at least every 2 weeks for 24 weeks. A secondary efficacy end point was the first episode of clinical malaria, as assessed in a time-to-event analysis.

Results: No safety concerns were identified in the dose-escalation part of the trial (part A). In part B, 225 children underwent randomization, with 75 children assigned to each group. No safety concerns were identified in part B. P. falciparum infection occurred in 36 participants (48%) in the 150-mg group, in 30 (40%) in the 300-mg group, and in 61 (81%) in the placebo group. The efficacy of L9LS against P. falciparum infection, as compared with placebo, was 66% (adjusted confidence interval [95% CI], 45 to 79) with the 150-mg dose and 70% (adjusted 95% CI, 50 to 82) with the 300-mg dose (P<0.001 for both comparisons). Efficacy against clinical malaria was 67% (adjusted 95% CI, 39 to 82) with the 150-mg dose and 77% (adjusted 95% CI, 55 to 89) with the 300-mg dose (P<0.001 for both comparisons).

Conclusions: Subcutaneous administration of L9LS to children was protective against P. falciparum infection and clinical malaria over a period of 6 months. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT05304611.).

Figure 1.. Screening, Enrollment, Randomization, and Follow-up of Pediatric Participants.

For pediatric participants, the trial was conducted in two parts. Part A was a double-blind, randomized, placebo-controlled, dose-escalation trial that was conducted before the malaria season to evaluate the safety and side-effect profile of the monoclonal antibody L9LS. Part B was a double-blind, randomized, placebo-controlled trial to assess the safety and efficacy of L9LS. A total of 268 participants were enrolled. Of the 41 participants who were initially enrolled in part A, 4 served as backups and were not needed but were reenrolled in part B. In part A, 36 participants underwent randomization between May 3 and May 17, 2022, and received a single subcutaneous injection of placebo or L9LS in one of two dose-escalation groups: 18 participants received placebo, 9 received 150 mg of L9LS, and 9 received 300 mg of L9LS. In part B, 225 participants underwent randomization between July 18 and August 15, 2022, and received a single subcutaneous injection of placebo or L9LS, with 75 participants in each group, before the peak of the malaria season. The final trial visits for part B occurred after the malaria season, on January 31, 2023. As prespecified in the protocol, the efficacy analysis was based on the modified intention-to-treat data set, which included all the participants who had undergone randomization and received L9LS or placebo, including those who withdrew or were lost to follow-up. In parts A and B of the trial, artemether–lumefantrine was given to all the participants as a standard, directly observed treatment course at enrollment, 7 to 12 days before the administration of L9LS or placebo, to clear any possible Plasmodium falciparum blood-stage infection.

Figure 2.. Efficacy against P. falciparum Infection.

Shown is the cumulative incidence of the first P. falciparum blood-stage infection during a 6-month malaria season (regardless of the presence of symptoms) after a single subcutaneous injection of 150 mg of L9LS, 300 mg of L9LS, or placebo. P. falciparum infections were detected by means of microscopic examination of thick blood-smear samples obtained during scheduled trial visits and unscheduled visits due to illness. Samples for blood smears were obtained before the administration of L9LS or placebo on day 0 and then on days 3, 7, 14, 21, and 28 and every 2 weeks thereafter, for a total of 24 weeks. Only blood-smear samples that were obtained between week 1 and week 24 were included in the efficacy analysis. Shaded areas indicate 95% confidence intervals.

Figure 3.. Efficacy against Clinical Malaria.

Shown is the cumulative incidence of the first clinical malaria episode due to P. falciparum infection during a 6-month malaria season after a single subcutaneous injection of 150 mg of L9LS, 300 mg of L9LS, or placebo. The prespecified definition of clinical malaria that was used in this analysis was an illness accompanied by a measured axillary temperature of at least 37.5°C or a history of fever (subjective or objective) in the previous 24 hours and P. falciparum asexual parasitemia of more than 5000 parasites per cubic millimeter as detected on microscopic examination of thick blood smears (definition 1). Episodes of clinical malaria were detected during scheduled trial visits and unscheduled visits due to illness. Only clinical malaria episodes that occurred between week 1 and week 24 were included in the efficacy analysis. Shaded areas indicate 95% confidence intervals.