Identification of vaccine candidates against severe malaria

鉴定针对严重疟疾的候选疫苗

• 批准号: 8232030
• 负责人: ANDREW V OLEINIKOV
• 金额: $ 48万
• 依托单位: SEATTLE BIOMEDICAL RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8232030
• 关键词: 5 year old; Adhesions; Africa; African; Anemia; Antibodies; Antibody Formation; Antigens; Area; Binding; Biological Assay; Blocking Antibodies; CD36 gene; Cerebral Malaria; Child; Clinical; Cohort Studies; Complex; Data; Disease; Disease susceptibility; Endothelium; Epidemiology; Epitopes; Erythrocyte Membrane; Erythrocytes; Evaluation; Family; Grant; Hospitalization; ICAM1 gene; Immune response; Immunity; Immunoglobulin G; Immunologic Epidemiology; Individual; Life; Malaria; Malaria Vaccines; Measures; Mediating; Membrane Proteins; Methods; Organ; Parasitemia; Parasites; Pattern; Placenta; Plasma; Plasmodium falciparum; Pregnancy; Protein Family; Proteins; Receptor Cell; Recurrence; Resistance; Respiratory distress; Sampling; Serum; Severity of illness; Source; Surface; Syndrome; Testing; Time; Vaccines; Variant; Virulence; Work; acquired immunity; aged; base; collected works; genome wide association study; genome-wide; killings; member; mortality; novel vaccines; prevent; public health relevance; receptor; receptor binding; vaccine candidate; vaccine development; vascular bed

DESCRIPTION (provided by applicant): The long-term aim of this work is to identify vaccine candidates to prevent severe malaria syndromes through understanding natural protective immune response. Plasmodium falciparum parasite-infected erythrocytes (IE) adhere to the host endothelium and to red blood cells. The adhesion is mediated by a large family (~60 members) of parasite multidomain variant proteins called PfEMP1. They express on the surface of IE in a mutually-exclusive manner. IE adhesion may result in severe complications including cerebral malaria, pregnancy malaria, severe anemia and respiratory distress, major contributors to malaria mortality. Severe malaria episodes are rare and almost never occur more than 1 or 2 times in a lifetime. This epidemiology supports our first hypothesis that only a limited number of parasite lines, possibly expressing particular variants of PfEMP1 that determine specific parasite adhesion, may be the source of severe disease. Immunological profiling of sera for reactivity against different antigens is an important method for assessing acquired immunity and identifying potential vaccine candidates. However, relating immune responses to malaria resistance is not straightforward since exposed individuals are typically infected repeatedly throughout life, and develop diversified immune responses against multiple antigens, in many cases without comprehensible relevance to disease severity. Our second hypothesis is that functional antibody responses that inhibit adhesion of IE to host receptors are likely to have a stronger association to protection from severe malaria. Extensive studies in pregnancy malaria strongly support both our hypotheses. During our previous work we collected thousands of serum samples obtained in longitudinal cohort studies of children living in malaria endemic areas of Africa. We also constructed functional genome-wide PfEMP1 domain arrays and used them to identify domains that bind specifically to the two main adhesion host receptors in malaria (ICAM1 and CD36). We further demonstrated that total anti-domain IgG and functional antibodies (that block adhesion of PfEMP1 domain to its receptor) can be quantified in the plasma samples using our multiplexed high throughput sample-sparing platform. To better understand the protective humoral immune responses in severe malaria, we propose the following specific aims: 1) Measure serum total IgG reactivity against a genome-wide array of PFEMP1 domains, and measure functional serum activity that inhibits CD36 and ICAM1 receptor binding to relevant PFEMP1 domains. We will test about 5000 children's sera including ~200-400 severe malaria cases. 2) Associate defined antibody responses (total and functional) against PfEMP1 domains with disease parameters and protection against severe disease. We will perform a broad range of statistical analyses using the longitudinal data obtained in Aim 1. This would be the first genome-wide study of seroreactivity and a comprehensive study of functional immune responses against PfEMP1 proteins. This study may provide candidates for development of vaccines against severe malaria. PUBLIC HEALTH RELEVANCE: The long-term aim of this work is to identify vaccine candidates to prevent severe malaria syndromes caused by Plasmodium falciparum. These syndromes kill over 1 million African children each year. Specific adhesion of parasites in vasculature mediates these severe complications. Various host endothelial receptors and domains of parasite PfEMP1 proteins that express on the surface of infected red blood cells are responsible for this adhesion. In most children naturally developed immunity prevents severe disease. Inhibition of adhesion by natural IgG might be one of the protective factors. In this proposal we will measure host immune responses (IgG reactivity and inhibition of adhesion to the two main host receptors) against a genome-wide array of PfEMP1 proteins using 5000 children's sera collected in endemic areas in East Africa. These measured immune responses will be associated with various disease parameters to understand protection and to identify PfEMP1 domains that can be developed further into vaccines directed against severe malaria.

描述（由申请人提供）：这项工作的长期目标是通过了解自然保护性免疫反应来确定预防严重疟疾综合征的候选疫苗。恶性疟原虫感染的红细胞（IE）粘附在宿主内皮和红细胞上。这种粘附是由一个名为PfEMP1的寄生虫多结构域变异蛋白大家族（约60个成员）介导的。它们在IE的表面上以互斥的方式表达。IE粘连可能导致严重并发症，包括脑型疟疾、妊娠疟疾、严重贫血和呼吸窘迫，这些都是疟疾死亡率的主要原因。严重的疟疾发作很罕见，一生中几乎不会发生超过1或2次。这种流行病学支持了我们的第一个假设，即只有有限数量的寄生虫系，可能表达决定特定寄生虫粘附性的PfEMP1的特定变体，可能是严重疾病的来源。免疫分析血清对不同抗原的反应性是评估获得性免疫和确定潜在候选疫苗的重要方法。然而，将免疫反应与疟疾耐药性联系起来并非易事，因为接触者通常在一生中反复感染，并对多种抗原产生多样化的免疫反应，在许多情况下与疾病严重程度没有可理解的相关性。我们的第二个假设是，抑制IE与宿主受体粘附的功能性抗体反应可能与预防严重疟疾有更强的关联。对妊娠期疟疾的广泛研究有力地支持了我们的两个假设。在我们以前的工作中，我们收集了在非洲疟疾流行地区儿童纵向队列研究中获得的数千份血清样本。我们还构建了功能性全基因组PfEMP1结构域阵列，并利用它们鉴定了特异性结合疟疾两种主要粘附宿主受体（ICAM1和CD36）的结构域。我们进一步证明，总抗结构域IgG和功能抗体（阻断PfEMP1结构域与其受体的粘附）可以使用我们的多路复用高通量样本保留平台在血浆样品中定量。为了更好地了解重症疟疾的保护性体液免疫反应，我们提出以下具体目标：1)测定血清总IgG对全基因组PFEMP1结构域的反应性，以及测定抑制CD36和ICAM1受体结合相关PFEMP1结构域的功能血清活性。我们将检测约5000名儿童的血清，其中包括约200-400名严重疟疾病例。2)将针对PfEMP1结构域的抗体反应（总抗体和功能性抗体）与疾病参数和对严重疾病的保护联系起来。我们将使用Aim 1中获得的纵向数据进行广泛的统计分析。这将是第一个全基因组的血清反应性研究和针对PfEMP1蛋白的功能性免疫反应的综合研究。该研究可能为研制重症疟疾疫苗提供候选材料。