Human monoclonal antibody MAM01 for protection against malaria in adults in the USA: a first-in-human, phase 1, dose-escalation, double-blind, placebo-controlled, adaptive trial.

Abstract

Malaria remains a leading cause of mortality among children in Africa, and recent advances in control have stagnated. Although new vaccines are available, protective efficacy is not optimum. Monoclonal antibodies targeting the Plasmodium falciparum circumsporozoite protein have potential to simplify prevention. We assessed the safety, pharmacokinetics, and protective efficacy of MAM01, a monoclonal antibody preferentially directed against the conserved Asn-Ala-Asn-Pro (NANP) central repeat region of circumsporozoite protein. This phase 1, dose-escalation, double-blind, placebo-controlled, adaptive trial was done at the Center for Vaccine Development and Global Health, University of Maryland, Baltimore, MD, USA. Adults aged 18-50 years, with no previous malaria vaccinations or infections, and BMI of 18-30 kg/m², were recruited sequentially, assigned to dose cohorts, and randomly assigned to receive the monoclonal antibody MAM01 (at 1·5, 5, 10, or 40 mg/kg intravenously or 5 mg/kg subcutaneously) or to placebo (identical buffer solution), with dose escalation staggered by 2-week intervals. Randomisation was done using an interactive response technology system. Participants and investigators were masked to treatment assignments. An untreated infectivity control was enrolled to support evaluation of protective efficacy. Participants from the MAM01 and control groups underwent controlled human malaria infection via the bites of five mosquitoes infected with P falciparum NF54 strain 18-26 weeks after monoclonal antibody or placebo administration. After malaria challenge, participants were followed up daily for ultra-sensitive PCR-based malaria detection on days 6-17, with continued follow-up of participants remaining aparasitaemic on days 20, 23, and 27. Participants who tested positive were treated with atovaquone-proguanil or artemether-lumefantrine; those who remained negative were empirically treated at day 27. A second dose of 5 mg/kg subcutaneously was administered to the cohorts that received 5 mg/kg subcutaneously or intravenously 2-4 weeks after completion of the controlled human malaria infection. The primary outcome was safety and tolerability of MAM01 at each dose level, and after second MAM01 dosing. Secondary outcomes included pharmacokinetic properties and protective efficacy (ie, presence of confirmed parasitaemia) after controlled human malaria infection. Safety was assessed in all participants who received trial intervention (MAM01 or placebo), as well as in participants who underwent controlled human malaria infection. This trial is complete and is registered with ClinicalTrials.gov, NCT05891236. Between Aug 14, 2023, and Dec 13, 2024, 63 participants were assessed for eligibility, 38 were enrolled, and 37 were randomly assigned. After review of sentinel group safety data (1·5 mg/kg [n=1] and placebo [n=1]), 29 participants were assigned to receive MAM01 at doses of 1·5 mg/kg (n=5), 5 mg/kg (n=6), 10 mg/kg (n=6), or 40 mg/kg (n=6) intravenously or 5 mg/kg subcutaneously (n=6) and six were assigned to the placebo group. One participant was included as an untreated infectivity control. MAM01 administration was well tolerated. No treatment-related serious adverse events occurred after one or two doses. After controlled human malaria infection, six of six participants in the control group and 18 of 22 participants in the MAM01 group developed parasitaemia. None of three participants in the 40 mg/kg intravenous dose group developed parasitaemia. Pharmacokinetic analysis showed that serum MAM01 concentrations greater than 88 μg/mL protected against malaria challenge. MAM01 was well tolerated, met safety targets, and showed clinical proof-of-principle by eliciting protection in malaria-naive adults using the controlled human malaria infection model. Progress driving down the cost of goods coupled with dose selection within target populations will dictate the feasibility of malaria monoclonal antibody deployment. Gates Foundation.