The stalling global progress in malaria control highlights the need for novel tools for malaria elimination, including transmission-blocking vaccines. Transmission-blocking vaccines aim to induce human antibodies that block parasite development in the mosquito and mosquitoes becoming infectious. The Pfs48/45 protein is a leading Plasmodium falciparum transmission-blocking vaccine candidate. The R0.6C fusion protein, consisting of Pfs48/45 domain 3 (6C) and the N-terminal region of P. falciparum glutamate-rich protein (R0), has previously been produced in Lactococcus lactis and elicited functional antibodies in rodents. Here, we assess the safety and transmission-reducing efficacy of R0.6C adsorbed to aluminium hydroxide with and without Matrix-M™ adjuvant in humans. In this first-in-human, open-label clinical trial, malaria-naïve adults, aged 18–55 years, were recruited at the Radboudumc in Nijmegen, the Netherlands. Participants received four intramuscular vaccinations on days 0, 28, 56 and 168 with either 30 µg or 100 µg of R0.6C and were randomised for the allocation of one of the two different adjuvant combinations: aluminium hydroxide alone, or aluminium hydroxide combined with Matrix-M1™ adjuvant. Adverse events were recorded from inclusion until 84 days after the fourth vaccination. Anti-R0.6C and anti-6C IgG titres were measured by enzyme-linked immunosorbent assay. Transmission-reducing activity of participants’ serum and purified vaccine-specific immunoglobulin G was assessed by standard membrane feeding assays using laboratory-reared Anopheles stephensi mosquitoes and cultured P. falciparum gametocytes. Thirty-one participants completed four vaccinations and were included in the analysis. Administration of all doses was safe and well-tolerated, with one related grade 3 adverse event (transient fever) and no serious adverse events occurring. Anti-R0.6C and anti-6C IgG titres were similar between the 30 and 100 µg R0.6C arms, but higher in Matrix-M1™ arms. Neat participant sera did not induce significant transmission-reducing activity in mosquito feeding experiments, but concentrated vaccine-specific IgGs purified from sera collected two weeks after the fourth vaccination achieved up to 99% transmission-reducing activity. R0.6C/aluminium hydroxide with or without Matrix-M1™ is safe, immunogenic and induces functional Pfs48/45-specific transmission-blocking antibodies, albeit at insufficient serum concentrations to result in transmission reduction by neat serum. Future work should focus on identifying alternative vaccine formulations or regimens that enhance functional antibody responses. The trial is registered with ClinicalTrials.gov under identifier NCT04862416.

中文翻译：

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基于 Pfs48/45 的疫苗可阻止恶性疟原虫传播：第一阶段、开放标签临床试验

全球疟疾控制进展停滞凸显了消除疟疾的新工具的必要性，包括阻断传播的疫苗。阻断传播的疫苗旨在诱导人类产生抗体，阻止蚊子体内寄生虫的发育以及蚊子的传染性。 Pfs48/45 蛋白是一种领先的恶性疟原虫传播阻断疫苗候选药物。 R0.6C 融合蛋白由 Pfs48/45 结构域 3 (6C) 和恶性疟原虫富含谷氨酸蛋白 (R0) 的 N 端区域组成，此前已在乳酸乳球菌中产生，并在啮齿动物中引发功能性抗体。在这里，我们评估了 R0.6C 吸附在氢氧化铝上（有或没有 Matrix-M™ 佐剂）在人体中的安全性和减少传播的功效。在这项首次人体、开放标签临床试验中，在荷兰奈梅亨的 Radboudumc 招募了 18 至 55 岁的未患过疟疾的成年人。参与者在第 0、28、56 和 168 天接受了四次肌内疫苗接种，剂量为 30 µg 或 100 µg R0.6C，并随机分配两种不同佐剂组合之一：单独使用氢氧化铝，或氢氧化铝与 Matrix 组合-M1™佐剂。记录从纳入到第四次疫苗接种后 84 天的不良事件。通过酶联免疫吸附测定法测量抗R0.6C和抗6C IgG滴度。使用实验室饲养的斯氏按蚊和培养的恶性疟原虫配子体，通过标准膜喂养测定来评估参与者血清和纯化的疫苗特异性免疫球蛋白 G 的传播减少活性。三十一名参与者完成了四次疫苗接种并被纳入分析。所有剂量的给药都是安全且耐受性良好的，发生了一项相关的 3 级不良事件（短暂发热），并且没有发生严重不良事件。 30 和 100 µg R0.6C 组的抗 R0.6C 和抗 6C IgG 滴度相似，但 Matrix-M1™ 组的滴度较高。在蚊子喂养实验中，纯参与者血清并未诱导显着的传播减少活性，但从第四次疫苗接种两周后收集的血清中纯化的浓缩疫苗特异性 IgG 实现了高达 99% 的传播减少活性。含有或不含 Matrix-M1™ 的 R0.6C/氢氧化铝均安全、具有免疫原性，并诱导功能性 Pfs48/45 特异性传播阻断抗体，尽管血清浓度不足以导致纯血清减少传播。未来的工作应侧重于确定增强功能性抗体反应的替代疫苗配方或治疗方案。该试验已在 ClinicalTrials.gov 注册，标识符为 NCT04862416。