Alkema M, Smit M J, Marin-Mogollon C, Totté K, Teelen K, van Gemert G J, van de Vegte-Bolmer M, Mordmüller B G, Reimer J M, Lövgren-Bengtsson K L, Sauerwein R W, Bousema T, Plieskatt J, Theisen M, Jore M M, McCall M B B
Department of Medical Microbiology, Radboud University Medical Center, Nijmegen, the Netherlands.
Novavax AB, Uppsala, Sweden.
BMC Med. 2024 Apr 23;22(1):170. doi: 10.1186/s12916-024-03379-y.
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.
全球疟疾控制进展停滞不前，凸显了开发新型疟疾消除工具的必要性，包括传播阻断疫苗。传播阻断疫苗旨在诱导人体产生抗体，阻止疟原虫在蚊子体内发育，从而使蚊子无法具有传染性。Pfs48/45蛋白是恶性疟原虫传播阻断疫苗的主要候选蛋白。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的N端区域（R0）组成，此前已在乳酸乳球菌中生产，并在啮齿动物中引发了功能性抗体。在此，我们评估了吸附于氢氧化铝且添加或不添加Matrix-M™佐剂的R0.6C在人体中的安全性和传播减少效果。
在这项首次人体开放标签临床试验中，18至55岁未感染疟疾的成年人在荷兰奈梅亨的拉德堡德大学医学中心招募。参与者在第0、28、56和168天接受四次肌肉注射疫苗，分别注射30μg或100μg的R0.6C，并随机分配接受两种不同佐剂组合之一：单独的氢氧化铝，或氢氧化铝与Matrix-M1™佐剂联合使用。记录从纳入研究至第四次疫苗接种后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，通过标准膜饲法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。
31名参与者完成了四次疫苗接种并纳入分析。所有剂量的疫苗接种均安全且耐受性良好，发生了1例3级相关不良事件（短暂发热），未发生严重不良事件。30μg和100μg R0.6C组的抗R0.6C和抗6C IgG滴度相似，但在Matrix-M1™组中更高。在蚊子饲血实验中，未经处理的参与者血清未诱导出显著的传播减少活性，但从第四次疫苗接种后两周收集的血清中纯化出的浓缩疫苗特异性IgG实现了高达99%的传播减少活性。
添加或不添加Matrix-M1™的R0.6C/氢氧化铝是安全的、具有免疫原性的，并能诱导功能性Pfs48/45特异性传播阻断抗体，尽管血清浓度不足以使未经处理的血清导致传播减少。未来的工作应侧重于确定能够增强功能性抗体反应的替代疫苗配方或接种方案。
该试验已在ClinicalTrials.gov上注册，标识符为NCT04862416。
