Blood Stage Malaria Vaccine Eliciting High Antigen-Specific Antibody Concentrations Confers No Protection to Young Children in Western Kenya

ObjectiveThe antigen, falciparum malaria protein 1 (FMP1), represents the 42-kDa C-terminal fragment of merozoite surface protein-1 (MSP-1) of the 3D7 clone of P. falciparum. Formulated with AS02 (a proprietary Adjuvant System), it constitutes the FMP1/AS02 candidate malaria vaccine. We evaluated this vaccine's safety, immunogenicity, and efficacy in African children.
MethodsA randomised, double-blind, Phase IIb, comparator-controlled trial.The trial was conducted in 13 field stations of one mile radii within Kombewa Division, Nyanza Province, Western Kenya, an area of holoendemic transmission of P. falciparum. We enrolled 400 children aged 12–47 months in general good health.Children were randomised in a 1∶1 fashion to receive either FMP1/AS02 (50 µg) or Rabipur® rabies vaccine. Vaccinations were administered on a 0, 1, and 2 month schedule. The primary study endpoint was time to first clinical episode of P. falciparum malaria (temperature ≥37.5°C with asexual parasitaemia of ≥50,000 parasites/µL of blood) occurring between 14 days and six months after a third dose. Case detection was both active and passive. Safety and immunogenicity were evaluated for eight months after first immunisations; vaccine efficacy (VE) was measured over a six-month period following third vaccinations.
Results374 of 400 children received all three doses and completed six months of follow-up. FMP1/AS02 had a good safety profile and was well-tolerated but more reactogenic than the comparator. Geometric mean anti-MSP-142 antibody concentrations increased from1.3 µg/mL to 27.3 µg/mL in the FMP1/AS02 recipients, but were unchanged in controls. 97 children in the FMP1/AS02 group and 98 controls had a primary endpoint episode. Overall VE was 5.1% (95% CI: −26% to +28%; p-value = 0.7).
ConclusionsFMP1/AS02 is not a promising candidate for further development as a monovalent malaria vaccine. Future MSP-142 vaccine development should focus on other formulations and antigen constructs.
Trial RegistrationClinicaltrials.gov NCT00223990

研究目标
恶性疟原虫蛋白1（falciparum malaria protein 1, FMP1）是恶性疟原虫3D7株裂殖子表面蛋白1（merozoite surface protein-1, MSP-1）的42kDa羧基端片段。该抗原与AS02（一种专利佐剂系统）配伍后，即为FMP1/AS02候选疟疾疫苗。本研究在非洲儿童中评估该疫苗的安全性、免疫原性与效力。

研究方法
本研究为一项随机、双盲、IIb期对照临床试验。试验在肯尼亚西部尼安萨省孔贝瓦分区内半径1英里范围内的13个现场站点开展，该区域为恶性疟原虫高度地方性流行传播区。研究共招募400名健康状况总体良好的12~47月龄儿童，以1:1比例随机分配至FMP1/AS02组（50μg）或Rabipur®狂犬病疫苗组。接种程序为第0、1、2个月各接种1剂。主要研究终点为第三剂接种后14天至6个月内，首次出现临床恶性疟发作的发生时间，临床恶性疟定义为体温≥37.5℃且伴无性体寄生虫血症≥50000寄生虫/μL血液。病例检测采用主动与被动结合的方式。首剂免疫后8个月内评估疫苗的安全性与免疫原性；第三剂接种后6个月内评估疫苗效力（vaccine efficacy, VE）。

研究结果
400名儿童中共有374名完成全部3剂接种并完成6个月随访。FMP1/AS02具有良好的安全性谱且耐受性佳，但相较于对照疫苗，其反应原性更强。FMP1/AS02接种者的抗MSP-142抗体几何平均浓度从1.3μg/mL升至27.3μg/mL，而对照组抗体水平无明显变化。FMP1/AS02组共有97名儿童出现主要终点事件，对照组为98名。总体疫苗效力为5.1%（95%置信区间：-26%~+28%；p=0.7）。

研究结论
FMP1/AS02作为单价疟疾疫苗，不具备进一步开发的前景。未来MSP-142疫苗的开发应聚焦于其他配方与抗原构建体。

试验注册
Clinicaltrials.gov NCT00223990