A Clinical Study of Protective and Pathogenic Immunity to Dengue during Infancy

婴儿期登革热保护性和致病性免疫的临床研究

• 批准号: 8308333
• 负责人: Daniel H. Libraty
• 金额: $ 55.63万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8308333
• 关键词: Acute; Address; Adult; Age; Agonist; Antibodies; Antibody-Dependent Enhancement; Avidity; Biological Assay; Blood specimen; Body fat; Child; Clinical; Clinical Data; Clinical Research; Communicable Diseases; Country; Data; Dengue; Dengue Hemorrhagic Fever; Dengue Virus; Disease; E protein; Epidemiology; Goals; Human; Immune Cell Activation; Immune response; Immunity; Immunoglobulin G; Immunology; Incidence; Infant; Infection; Intervention; Knowledge; Lead; Life; Measurement; Measures; Mediating; Methods; Modeling; Natural Immunity; Nutritional status; Pathogenesis; Pattern; Pattern recognition receptor; Peripheral Blood Mononuclear Cell; Philippines; Play; Prospective Studies; Risk; Risk Factors; Role; Serotyping; Severity of illness; Shapes; Signal Pathway; Site; Solid; Tertiary Protein Structure; Therapeutic; Therapeutic Intervention; Time; Toll-like receptors; Triage; Vaccines; Viremia; Virus Diseases; World Health Organization; design; implementation trial; improved; in vivo; indexing; infancy; innovation; neutralizing antibody; prospective; research study; response

DESCRIPTION (provided by applicant): The World Health Organization has categorized dengue as a high priority emerging viral disease. A fine line exists between protective immunity and pathogenic immune responses that lead to severe dengue hemorrhagic fever (DHF). A better understanding of protective immunity will have a direct impact on dengue vaccine trials and implementation strategies in endemic countries. A better understanding of DHF immunopathogenesis will lead to improved triage, therapeutic, and intervention strategies. The goal of this proposal is to delineate protective and pathogenic human immune responses against dengue virus (DENV) infections in the unique immunological setting of infancy. Studies of primary DENV infections during infancy provide important human immunological data that cannot be obtained from studies of older children or adults. The first aim of this project is to conduct a prospective clinical study of DENV infections during infancy. The study site is in San Pablo, Laguna, Philippines. The prospective study will collect clinical and epidemiological data, anthropometric measurements, and blood samples from infants. Surveillance activities will capture infant DENV infections across the entire spectrum of disease severity, including clinically inapparent infections. The first aim will characterize the wide clinical spectrum of infant dengue, define overall and age-specific incidence rates, and delineate associations between infant age, body fat mass/anthropometric indices, and dengue disease severity. It will also provide crucial pre-infection, post-infection, and longitudinal infant blood samples for the other specific aims. In the second aim, neutralizing antibody titers and anti-DENV E protein domain III IgG levels and avidity will be measured using the pre-infection infant blood samples. Antibody-dependent enhancement (ADE) of DENV infection and anti-DENV prM/anti-E IgG ratios will also be measured. The assays will be conducted so as to reflect circulating antibody levels in infants at the time of their DENV infection. Serotype-specific antibody levels that correlate with in vivo protection against symptomatic dengue will be defined. The proposed ADE assays will provide solid clinical data to either support, refute, or significantly modify the existing ADE dengue pathogenesis paradigm. The third aim will characterize changes in distinct infant innate immune responses with age and body fat mass/nutritional status, and delineate their potential role in shaping dengue disease severity. Innate immune cell activation profiles to specific Toll-like receptor/pattern-recognition receptor agonists and DENV infection will be measured by several methods using peripheral blood mononuclear cells collected longitudinally from infants over ages 2-16 months old. Additional experiments in this aim will focus on identifying specific cellular signaling pathways that contribute to impaired innate immune responses in infants with low body fat stores (i.e. undernourished/malnourished), and subsequently at low risk for developing DHF. This project and innovative clinical study are uniquely poised to address critical gaps in knowledge regarding protective and pathogenic human immune responses in dengue.

描述（由申请人提供）：世界卫生组织已将登革热归类为高度优先的新兴病毒性疾病。在保护性免疫和导致严重登革出血热（DHF）的致病性免疫反应之间存在一条细线。更好地了解保护性免疫将对登革热流行国家的疫苗试验和实施战略产生直接影响。更好地了解DHF的免疫发病机制将导致改善分诊，治疗和干预策略。本提案的目标是描述在婴儿期独特的免疫环境中针对登革病毒（DENV）感染的保护性和致病性人类免疫应答。婴儿期原发性登革病毒感染的研究提供了重要的人类免疫学数据，这些数据无法从年龄较大的儿童或成人的研究中获得。该项目的第一个目的是进行婴儿期DENV感染的前瞻性临床研究。研究地点位于菲律宾拉古纳的圣巴勃罗。这项前瞻性研究将收集临床和流行病学数据、人体测量数据和婴儿血液样本。监测活动将在整个疾病严重程度范围内捕获婴儿DENV感染，包括临床上不明显的感染。第一个目标将描述婴儿登革热的广泛临床谱，定义总体和年龄特异性发病率，并描述婴儿年龄，体脂量/人体测量指数和登革热疾病严重程度之间的关联。它还将为其他特定目标提供关键的感染前、感染后和纵向婴儿血液样本。在第二个目标中，将使用感染前婴儿血液样品测量中和抗体滴度和抗DENV E蛋白结构域III IgG水平和亲合力。还将测量DENV感染的抗体依赖性增强（ADE）和抗DENV prM/抗E IgG比率。将进行测定以反映婴儿感染DENV时的循环抗体水平。将定义与针对症状性登革热的体内保护相关的血清型特异性抗体水平。拟定的ADE检测将提供可靠的临床数据，以支持、反驳或显著改变现有ADE登革热发病机制范例。第三个目标将描述不同婴儿先天免疫反应随年龄和体脂量/营养状况的变化，并描述其在形成登革热疾病严重程度中的潜在作用。特异性Toll样受体/模式识别受体激动剂和DENV感染的先天免疫细胞活化特征将通过几种方法使用从2-16个月大的婴儿纵向收集的外周血单核细胞来测量。在这一目标的其他实验将集中在确定特定的细胞信号通路，有助于受损的先天免疫反应的婴儿低体脂肪储存（即营养不良/营养不良），并随后在低风险发展DHF。这个项目和创新的临床研究是独一无二的，以解决有关登革热的保护性和致病性人类免疫反应的知识的关键差距。