MALARIA VACCINE EVALUATION

这项任务的总体目标包括促进人类对候选疟疾疫苗的开发和科学理解的活动。疟疾在全世界感染2-3亿人，是撒哈拉以南非洲幼儿死亡的主要原因。疫苗研究中心(VRC)已经在I期临床试验(VRC312)中展示了高水平的短期保护作用，该试验使用静脉注射的减毒全寄生虫疫苗。此外，研究发现，保护依赖于疫苗剂量。另一项名为VRC314的试验被启动，以扩大这些发现，并进一步确定剂量数量、剂量间隔和给药途径对更长时间段保护的影响。这项试验正在进行中，预计将在2016年年中读出数据。为了进一步扩大此类临床研究，迫切需要了解免疫相关因素以进行长期保护。RNAseq和先进的多参数流式细胞术分析等分析方法以前曾被用来识别先天特征和定义生物标记物，以帮助预测保护性免疫反应。有助于了解保护性免疫反应的其他分析包括利用体外实验筛选保护性活性抗体，以及分析临床患者的微生物组，以了解微生物区系对疫苗接种后免疫反应的影响。此外，对免疫个体自然感染过程中寄生虫的序列分析可以揭示疟疾寄生虫受到的免疫压力，并促进对潜在免疫逃逸机制的理解。除了需要在临床研究期间研究和解释免疫反应的复杂机制外，还需要对疫苗剂量和方案进行重大优化，以最大限度地提高疫苗效力并评估长期保护潜力。因此，除了正在进行的临床试验和相应的免疫相关性分析外，预计其他临床试验还将解决高水平保护所需的最佳剂量和方案，以应对美国临床试验中的同源或异源挑战，以及非洲临床试验中的自然感染。

The overarching objectives of this task include activities to advance the development and scientific understanding of a candidate malaria vaccine in humans. Malaria infects 200-300 million people worldwide and is a leading cause of death in young children in Sub-Saharan Africa. The Vaccine Research Center (VRC) has demonstrated high-level short-term protection in phase I clinical trials (VRC312) using an attenuated whole parasite vaccine administered intravenously. Furthermore, protection was found to be dependent on vaccine dose. An additional trial, VRC314, was initiated to extend these findings and further determine the effect of dose number, dose interval, and administration route on protection over a longer period of time. This trial is in progress with anticipated readouts by mid-2016. In order to further expand on such clinical studies, there is a critical need for understanding the immune correlates for long-term protection. Analytical methods such as RNAseq and advanced multiparameter flow cytometry analysis have been previously utilized to identify innate signatures and define biomarkers to help predict a protective immune response. Additional analyses contributing to the understanding of protective immune responses involve screening of antibodies for protective activity using in vitro experiments, and analyzing the microbiome in clinical patients to understand the impact of microbiota on immune responses following vaccination. Furthermore, sequence analysis of parasites during natural infection of immunized individuals may reveal immunological pressures exerted on Malaria parasites and advance the understanding of potential immune escape mechanisms. In addition to needing sophisticated mechanisms for investigating and interpreting immune responses during clinical studies, significant optimization of vaccine dose and regimen is required to maximize vaccine efficacy and assess long-term protection potential. Thus, in addition to ongoing clinical trials and the corresponding immune correlates analyses, additional clinical trials are anticipated to address the optimal dose and regimen required for high-level protection in response to a homologous or heterologous challenge in a United States clinical trial, and natural infection in an Africa clinical trial.