Impact on Malaria Parasite Multiplication Rates in Infected Volunteers of the Protein-in-Adjuvant Vaccine AMA1-C1/Alhydrogel+CPG 7909

BackgroundInhibition of parasite growth is a major objective of blood-stage malaria vaccines. The in vitro assay of parasite growth inhibitory activity (GIA) is widely used as a surrogate marker for malaria vaccine efficacy in the down-selection of candidate blood-stage vaccines. Here we report the first study to examine the relationship between in vivo Plasmodium falciparum growth rates and in vitro GIA in humans experimentally infected with blood-stage malaria. MethodsIn this phase I/IIa open-label clinical trial five healthy malaria-naive volunteers were immunised with AMA1/C1-Alhydrogel+CPG 7909, and together with three unvaccinated controls were challenged by intravenous inoculation of P. falciparum infected erythrocytes. ResultsA significant correlation was observed between parasite multiplication rate in 48 hours (PMR) and both vaccine-induced growth-inhibitory activity (Pearson r = −0.93 [95% CI: −1.0, −0.27] P = 0.02) and AMA1 antibody titres in the vaccine group (Pearson r = −0.93 [95% CI: −0.99, −0.25] P = 0.02). However immunisation failed to reduce overall mean PMR in the vaccine group in comparison to the controls (vaccinee 16 fold [95% CI: 12, 22], control 17 fold [CI: 0, 65] P = 0.70). Therefore no impact on pre-patent period was observed (vaccine group median 8.5 days [range 7.5–9], control group median 9 days [range 7–9]). ConclusionsDespite the first observation in human experimental malaria infection of a significant association between vaccine-induced in vitro growth inhibitory activity and in vivo parasite multiplication rate, this did not translate into any observable clinically relevant vaccine effect in this small group of volunteers. Trial RegistrationClinicalTrials.gov [NCT00984763]背景 抑制寄生虫生长是血液阶段疟疾疫苗的核心研发目标。寄生虫生长抑制试验（Growth Inhibitory Assay, GIA）作为体外检测方法，被广泛用作疟疾候选血液阶段疫苗筛选流程中评估疫苗效力的替代指标。本研究首次探讨了实验感染血液阶段疟疾的人体中，体内恶性疟原虫（Plasmodium falciparum）生长速率与体外GIA结果之间的关联。 方法 本研究为一项I/IIa期开放标签临床试验，共纳入5名未接触过疟疾的健康志愿者，以AMA1/C1-Alhydrogel佐剂+CPG 7909进行免疫接种；同时设置3名未接种疫苗的对照组受试者，所有受试者均经静脉途径接种恶性疟原虫感染的红细胞以完成攻击感染。 结果 研究观察到，48小时寄生虫增殖倍数（Parasite Multiplication Rate, PMR）与疫苗诱导的生长抑制活性（Pearson相关系数r=-0.93，95%置信区间：-1.0~-0.27，P=0.02）以及疫苗组受试者的AMA1抗体滴度（Pearson相关系数r=-0.93，95%置信区间：-0.99~-0.25，P=0.02）均存在显著负相关。然而，与对照组相比，疫苗组的总体平均PMR未出现显著降低（疫苗组16倍，95%置信区间：12~22；对照组17倍，置信区间：0~65；P=0.70）。因此未观察到疫苗对预显性期产生影响：疫苗组中位数为8.5天（范围7.5~9天），对照组中位数为9天（范围7~9天）。 结论 尽管本研究首次在人体实验性疟疾感染中观察到疫苗诱导的体外生长抑制活性与体内寄生虫增殖速率之间存在显著关联，但在这一小规模志愿者队列中，该关联并未转化为具有临床意义的疫苗保护效应。 试验注册信息：ClinicalTrials.gov [NCT00984763]