Lyke Kirsten E, Berry Andrea A, Laurens Matthew B, Winkler Jennifer, Joshi Sudhaunshu, Koudjra Abra Rachida, Butler Lauryn, Billingsley Peter F, Pascini Tales, Patil Asha, Sim B Kim Lee, Fitzgerald Grace, Riegel Julie, Andrews Kayla, Levi Micha, Anderson Aparna B, Wells Charles D, Liu Hong, Huleatt James, Miller R Scott
Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, USA.
Center for Vaccine Development and Global Health, University of Maryland School of Medicine, Baltimore, MD, USA.
Lancet Infect Dis. 2025 Sep 23. doi: 10.1016/S1473-3099(25)00481-5.
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/m, 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.
疟疾仍是非洲儿童死亡的主要原因，且近期疟疾防控进展停滞不前。尽管已有新型疫苗，但保护效力并不理想。靶向恶性疟原虫环子孢子蛋白的单克隆抗体具有简化预防措施的潜力。我们评估了MAM01的安全性、药代动力学和保护效力，MAM01是一种优先靶向环子孢子蛋白保守的天冬酰胺 - 丙氨酸 - 天冬酰胺 - 脯氨酸（NANP）中央重复区域的单克隆抗体。
本1期剂量递增、双盲、安慰剂对照、适应性试验在美国马里兰州巴尔的摩市马里兰大学疫苗开发与全球健康中心进行。招募年龄在18 - 50岁之间、既往未接种过疟疾疫苗或未感染过疟疾且体重指数为18 - 30 kg/m²的成年人，依次纳入剂量队列，并随机分配接受单克隆抗体MAM01（静脉注射剂量为1.5、5、10或40 mg/kg或皮下注射5 mg/kg）或安慰剂（相同缓冲溶液），剂量递增间隔为2周。使用交互式应答技术系统进行随机分组。参与者和研究者对治疗分配情况不知情。纳入未治疗的感染性对照以支持保护效力评估。MAM01组和对照组的参与者在接受单克隆抗体或安慰剂给药后18 - 26周，通过被五只感染恶性疟原虫NF54株的蚊子叮咬进行受控人体疟疾感染。疟疾攻击后，在第6 - 17天每天对参与者进行基于超灵敏PCR的疟疾检测随访，对在第20、23和27天仍无寄生虫血症的参与者继续随访。检测呈阳性的参与者用阿托伐醌 - 氯胍或蒿甲醚 - 本芴醇治疗；检测呈阴性的参与者在第27天进行经验性治疗。在受控人体疟疾感染完成后2 - 4周，对接受皮下或静脉注射5 mg/kg的队列再皮下注射一剂5 mg/kg。主要结局是MAM01在每个剂量水平以及第二次MAM01给药后的安全性和耐受性。次要结局包括受控人体疟疾感染后的药代动力学特性和保护效力（即确诊寄生虫血症的存在情况）。在所有接受试验干预（MAM01或安慰剂）的参与者以及接受受控人体疟疾感染的参与者中评估安全性。本试验已完成，并在ClinicalTrials.gov注册，注册号为NCT05891236。
在2023年8月14日至2024年12月13日期间，评估了63名参与者的资格，38名参与者被纳入研究，37名参与者被随机分组。在审查哨点组安全性数据（1.5 mg/kg [n = 1]和安慰剂 [n = 1]）后，29名参与者被分配接受静脉注射剂量为1.5 mg/kg（n = 5）、5 mg/kg（n = 6）、10 mg/kg（n = 6）或40 mg/kg（n = 6）的MAM01或皮下注射5 mg/kg的MAM01（n = 6），6名参与者被分配到安慰剂组。纳入1名参与者作为未治疗的感染性对照。MAM01给药耐受性良好。一剂或两剂后未发生与治疗相关的严重不良事件。在受控人体疟疾感染后，对照组6名参与者中的6名以及MAM01组22名参与者中的18名出现寄生虫血症。40 mg/kg静脉注射剂量组的3名参与者均未出现寄生虫血症。药代动力学分析表明，血清MAM01浓度大于88 μg/mL可预防疟疾攻击。
MAM01耐受性良好，达到了安全性目标，并通过在未感染疟疾的成年人中使用受控人体疟疾感染模型诱导保护作用，展示了临床原理验证。降低产品成本的进展以及在目标人群中选择剂量将决定疟疾单克隆抗体应用的可行性。
盖茨基金会
