MALARIA VACCINE EVALUATION

疟疾疫苗评估

• 批准号: 9161854
• 负责人: CHRISTOPHER CASE
• 金额: $ 395.18万
• 依托单位: LEIDOS BIOMEDICAL RESEARCH, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-26 至 2017-09-25
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9161854
• 关键词: Address; Advanced Development; Africa; Africa South of the Sahara; Antibodies; Attenuated; Biological Markers; Cause of Death; Child; Clinical; Clinical Research; Clinical Trials; Dose; Flow Cytometry; Human; Immune; Immune response; Immunity; Immunization; In Vitro; Individual; Infection; Malaria; Malaria Vaccines; Parasites; Patients; Phase I Clinical Trials; Regimen; Route; Safety; Sampling; Sequence Analysis; Testing; Time; United States; Vaccination; Vaccine Research; Vaccines; analytical method; immunogenicity; microbiome; pressure; research clinical testing; research study; response; screening; transcriptome sequencing; vaccine candidate; vaccine efficacy

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.

这项任务的总体目标包括开展活动，促进人类候选疟疾疫苗的开发和科学认识。疟疾感染了全世界2亿至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）在I期临床试验（VRC312）中使用静脉注射的减毒全寄生虫疫苗证明了高水平的短期保护。此外，发现保护作用依赖于疫苗剂量。启动了另一项试验VRC314，以扩展这些结果，并进一步确定剂量数、给药间隔和给药途径对更长时间内保护作用的影响。这项试验正在进行中，预计将于2016年年中公布结果。为了进一步扩大此类临床研究，迫切需要了解长期保护的免疫相关性。诸如RNAseq和先进的多参数流式细胞术分析的分析方法先前已被用于鉴定先天特征并定义生物标志物以帮助预测保护性免疫应答。有助于理解保护性免疫应答的其他分析包括使用体外实验筛选抗体的保护活性，并分析临床患者的微生物组以了解微生物群对疫苗接种后免疫应答的影响。此外，在自然感染免疫个体的寄生虫的序列分析可能揭示疟疾寄生虫施加的免疫压力，并推进对潜在的免疫逃逸机制的理解。除了需要复杂的机制来研究和解释临床研究期间的免疫应答外，还需要对疫苗剂量和方案进行显著优化，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，预计还将进行其他临床试验，以确定在美国临床试验中应对同源或异源攻击以及在非洲临床试验中应对自然感染时获得高水平保护所需的最佳剂量和方案。