Experimentally induced blood-stage malaria in Kenyan adults: understanding disease mechanisms and protection in the context of background immunity

据估计，恶性疟原虫疟疾每年造成5亿例病例，并造成数十万人死亡。非洲的发病率和死亡率很高。需要一种有效的疫苗，疫苗的研制对于提供有效、可持续和具有成本效益的疾病控制至关重要。合理的疫苗开发将基于明确描述的机制，导致寄生虫和免疫相关物的清除。目前的主要疫苗，基于有史以来第一个克隆的恶性疟原虫基因，在4年内提供约30%的保护。理解和识别导致自然获得性免疫的潜在机制有可能为合理的疫苗设计提供信息。我们需要确定保护性免疫反应的抗原靶点;以及所需的阈值和功能特性。迄今为止，对自然获得性免疫力的研究是在对自然接触的儿童进行监测的基础上，利用观察性实地研究进行的。然而，生活在疟疾流行地区的成年人由于反复接触引起疟疾的寄生虫而获得对感染和/或疾病的抵抗力。为了了解这种免疫力是如何影响感染的，我们最近进行了一项有针对性的感染研究，使用了蚊子的寄生虫阶段，子孢子。在总共142名志愿者中，观察到33名没有疟疾寄生虫，并且在研究中的整个感染监测过程中保持未感染。这些在100%发生感染的非地方病志愿者中进行的研究，最近被用于利用引起疾病的寄生虫的阶段来研究疾病的病理生理机制，血液阶段，即故意感染寄生虫感染的红细胞。我们现在建议故意感染我们发现以前没有疟疾的志愿者寄生虫-受感染的红细胞，直接导致与疾病相关的体征和症状。我们打算评估疾病的病理生理机制，并确定免疫的贡献和机制，导致疾病阶段的感染。我们将采用生物标志物和系统免疫学方法来确定与疾病结局相关的机制，包括免疫激活生物标志物的详细表征，包括内皮激活和微血管功能;抗体特异性和功能的分型，细胞免疫分析;以及代谢组学分析。这项研究将在预先存在的免疫背景下定义与疾病相关的机制，并帮助为下一代血液阶段疫苗提供信息。

Plasmodium falciparum malaria causes an estimated 500 million cases per year and hundreds of thousands of deaths annually. Substantial morbidity and mortality occurs in Africa. An effective vaccine is needed, and vaccine development is essential to provide an effective sustainable and cost-effective control of disease. Rational vaccine development would be based on clearly described mechanisms that lead to clearance of parasites and the correlates of immunity. The current lead vaccine, based on the first falciparum gene ever cloned, delivers ~30% protection over 4 years. An understanding and identification of the underlying mechanisms that lead to naturally acquired immunity has the potential to inform rational vaccine design. We need to identify the antigenic targets for protective immune responses; and the threshold required and functional properties. The study of naturally acquired immunity has been conducted using observational field studies to date, based on surveillance of naturally exposed children. However, adults living in endemic areas acquire resistance to infection and/or disease with repeated exposure to malaria causing parasites. To understand how this immunity impacts infection, we recently conducted a deliberate infection study using parasite stages that are infective from the mosquito, sporozoites. Out of a total of 142 volunteers, 33 were observed to be malaria parasite free and remained uninfected throughout monitoring for infection in the study. These studies in non-endemic volunteers, with 100% developing infection, have recently been used to investigate pathophysiological mechanisms of disease utilising the stage of the parasite responsible for disease, blood stages i.e. deliberate infection with parasite infected red blood cells.We now propose to deliberately infect volunteers who we found to be previously malaria-free with parasite-infected red blood cells that directly results in the signs and symptoms associated with disease. We intend to evaluate pathophysiological mechanisms of disease and determine the contribution and mechanisms of immunity resulting from the disease stage of infection. We will adopt a biomarker and systems immunology approach to identify mechanisms associated with disease outcome including detailed characterisation of biomarkers of immune activation including endothelial activation and microvascular function; typing of antibody specificities and function, analysis of cellular immunity; and analysis of the metabolome. This study will define mechanisms associated with disease in the context of pre-existing immunity and help inform targets for the next generation blood-stage vaccines.