Safety and Efficacy of a Monoclonal Antibody against Malaria in Mali

Abstract

Background: CIS43LS is a monoclonal antibody that was shown to protect against controlled Plasmodium falciparum infection in a phase 1 clinical trial. Whether a monoclonal antibody can prevent P. falciparum infection in a region in which the infection is endemic is unknown.

Methods: We conducted a phase 2 trial to assess the safety and efficacy of a single intravenous infusion of CIS43LS against P. falciparum infection in healthy adults in Mali over a 6-month malaria season. In Part A, safety was assessed at three escalating dose levels. In Part B, participants were randomly assigned (in a 1:1:1 ratio) to receive 10 mg of CIS43LS per kilogram of body weight, 40 mg of CIS43LS per kilogram, or placebo. The primary efficacy end point, assessed in a time-to-event analysis, was the first P. falciparum infection detected on blood-smear examination, which was performed at least every 2 weeks for 24 weeks. At enrollment, all the participants received artemether-lumefantrine to clear possible P. falciparum infection.

Results: In Part B, 330 adults underwent randomization; 110 were assigned to each trial group. The risk of moderate headache was 3.3 times as high with 40 mg of CIS43LS per kilogram as with placebo. P. falciparum infections were detected on blood-smear examination in 39 participants (35.5%) who received 10 mg of CIS43LS per kilogram, 20 (18.2%) who received 40 mg of CIS43LS per kilogram, and 86 (78.2%) who received placebo. At 6 months, the efficacy of 40 mg of CIS43LS per kilogram as compared with placebo was 88.2% (adjusted 95% confidence interval [CI], 79.3 to 93.3; P<0.001), and the efficacy of 10 mg of CIS43LS per kilogram as compared with placebo was 75.0% (adjusted 95% CI, 61.0 to 84.0; P<0.001).

Conclusions: CIS43LS was protective against P. falciparum infection over a 6-month malaria season in Mali without evident safety concerns. (Funded by the National Institute of Allergy and Infectious Diseases; ClinicalTrials.gov number, NCT04329104.).

Figure 1.. Screening, Enrollment, Randomization, and Follow-up.

The trial was conducted in two parts. Part A was an open-label, dose-escalation study conducted before the malaria season to evaluate the safety and side-effect profile of CIS43LS. Part B was a double-blind, randomized, placebo-controlled trial to assess the safety and efficacy of CIS43LS. In Part B, 330 participants underwent randomization and received a single intravenous infusion of CIS43LS or placebo between May 5 and August 6, 2021, before the peak of the malaria season. The final trial visits for Part B occurred after the malaria season on January 24, 2022. As prespecified in the protocol, the efficacy analysis was based on the modified intention-to-treat data set that included all randomly assigned participants who received CIS43LS or placebo, including those who withdrew or were lost to follow-up. One participant who completed the trial (Part B) died 165 days after the administration of 10 mg of CIS43LS per kilogram of body weight, within the window of the last trial visit. In Parts A and B, artemether–lumefantrine was given to all the participants as a standard, directly observed treatment course at enrollment, 7 to 21 days before administration of CIS43LS or placebo, to clear any possible Plasmodium falciparum blood-stage infection. In Part B, one participant was administered artemether–lumefantrine 7 days before enrollment when symptomatic malaria was diagnosed at the screening visit.

Figure 2.. Kaplan–Meier Plot of Efficacy against P. falciparum Infection.

Shown is the cumulative incidence of P. falciparum blood-stage infection during a 6-month malaria season (irrespective of symptoms being present) after a single intravenous infusion of 10 mg of CIS43LS per kilogram, 40 mg of CIS43LS per kilogram, or placebo. P. falciparum infections were detected by microscopic examination of thick blood smears collected during scheduled trial visits and unscheduled illness visits. Blood smears were collected before the administration of CIS43LS 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 smears collected between weeks 1 and 24 were included in the efficacy analysis. Shaded areas indicate the 95% confidence intervals.