Longitudinal Antibody Profiles Correlated with Protection from Malaria in Malawi

与马拉维疟疾预防相关的纵向抗体谱

• 批准号: 10327328
• 负责人: James Beeson
• 金额: $ 13.96万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-08 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10327328
• 关键词: 5 year old; Address; Adult; Africa; African; Alleles; Antibodies; Antibody Response; Antibody Specificity; Antibody-mediated protection; Antigen Targeting; Antigens; Antimalarials; Beds; Blood; Cessation of life; Child; Childhood; Clinical; Cohort Studies; Complement; Data; Development; Drug resistance; Enrollment; Evaluation; Event; Exposure to; Future; Genetic; Genetic Polymorphism; Geographic Locations; Health care facility; Immune; Immune response; Immune system; Immunity; Immunoglobulin G; Immunoglobulin M; Individual; Infection; Insecticide Resistance; Insecticides; Knowledge; Location; Longitudinal Studies; Longitudinal cohort; Machine Learning; Malaria; Malaria Vaccines; Malawi; Measurement; Measures; Outcome; Parasitemia; Parasites; Phagocytosis; Pharmacotherapy; Play; Proteins; Recording of previous events; Research; Residual state; Risk Factors; Sampling; Specificity; Statistical Models; Surface; Time; Vaccines; Variant; Visit; acquired immunity; base; cohort; combat; cross reactivity; density; design; epidemiology study; experimental study; follow-up; improved; insight; interest; international center; malaria infection; mortality; novel; novel strategies; prevent; receptor binding; response; vaccine candidate; vaccine development; vaccine efficacy; vaccine-induced immunity

PROJECT SUMMARY Malaria continues to be responsible for substantial childhood mortality in Africa despite current control efforts. Developing an effective vaccine for malaria elimination is constrained by knowledge gaps in both naturally- acquired and vaccine-induced immunity. Existing vaccine candidates elicit antibodies against the target antigen but the associations between antibody functional activity and level and duration of protection are unknown. Additionally novel blood-stage antigens that could be used in future vaccines aimed at preventing symptomatic malaria have emerged (some are polymorphic), that need to be further investigated. Preferred antigens should elicit antibody functional activity that is: i) boosted with natural infection; ii) long-lasting; iii) correlated with protection; iv) not highly strain-specific, i.e., effective against a diversity of isolates. Our study aims to clarify these unknowns focusing on 12 understudied blood-stage antigens (and the alleles of those polymorphic antigens) to inform selection of antigens that could be potential vaccine candidates. Prior studies of naturally-acquired antibody immunity have largely quantified antibody magnitude to specific proteins and have typically been limited to quantifying immune responses infrequently or at a single time-point. Because the immune profiles of individuals are dynamic and a function of exposure to infection that cannot be synchronized at the beginning of a study, these largely cross-sectional measurements obscure outcomes of interest. Furthermore, prior studies predominantly measured only magnitude of IgG responses; few have assessed the range and breath of functional activities of antibodies, and the impact of antigen polymorphisms on functional antibody activities. The expertise of our study team, combined with access to samples collected during a longitudinal study with intensive follow-up and a comprehensive study approach, provides an opportunity to address these questions and elucidate the importance of these antigens in acquired immunity to malaria. Our study will be based on a cohort of children and adults who were seen monthly over two years in which subjects had repeated clinical and/or sub clinical malaria infections. Studying this cohort will enable us to gain new insights into the durability and boosting over time of functional antibody activity against blood-stage antigens upon natural exposure to malaria. We will also evaluate the cross-reactivity or strain-specificity of functional antibodies against alternative alleles of polymorphic antigens. Finally, we will evaluate antigens (and alleles) against which functional antibody activity is correlated with protection from symptomatic malaria and high density parasitemia, and we will seek signatures of functional responses that can accurately discriminate protected and unprotected subjects. These correlates of protection will provide endpoints for evaluating future vaccines. This may have implications for strategies to improve vaccine efficacy and implementation.

项目概要 尽管目前采取了控制措施，但疟疾仍然是非洲儿童大量死亡的原因。 开发消除疟疾的有效疫苗受到自然和疟疾知识差距的限制。 获得性免疫和疫苗诱导的免疫。现有候选疫苗可引发针对目标抗原的抗体 但抗体功能活性与保护水平和持续时间之间的关联尚不清楚。 此外，新的血液阶段抗原可用于未来旨在预防症状的疫苗 疟疾已经出现（有些是多态性的），需要进一步研究。优选的抗原应该 引发抗体功能活性，即： i) 通过自然感染增强； ii) 持久； iii) 相关于 保护; iv) 菌株特异性不高，即对多种分离株有效。我们的研究旨在澄清 这些未知物集中于 12 种尚未充分研究的血液阶段抗原（以及这些多态性的等位基因） 抗原）以告知可能成为潜在候选疫苗的抗原的选择。 先前对自然获得性抗体免疫的研究在很大程度上量化了抗体的大小 特定蛋白质，并且通常仅限于不频繁或单次量化免疫反应 时间点。因为个体的免疫特征是动态的，并且是暴露于感染的函数， 在研究开始时无法同步，这些很大程度上是横截面测量模糊 兴趣的结果。此外，之前的研究主要只测量 IgG 反应的强度； 很少有人评估抗体功能活动的范围和呼吸，以及抗原的影响 功能性抗体活性的多态性。 我们研究团队的专业知识，结合纵向研究期间收集的样本 通过密集的后续行动和全面的研究方法，提供了解决这些问题的机会 问题并阐明这些抗原在疟疾获得性免疫中的重要性。我们的研究将是 基于一组儿童和成人，他们在两年内每月接受一次检查，其中受试者 反复的临床和/或亚临床疟疾感染。研究这个群体将使我们获得新的见解 随着时间的推移，针对血液阶段抗原的功能性抗体活性的持久性和增强 自然接触疟疾。我们还将评估功能性的交叉反应性或菌株特异性 针对多态性抗原的替代等位基因的抗体。最后，我们将评估抗原（和等位基因） 功能性抗体活性与预防症状性疟疾和高风险相关 密度寄生虫血症，我们将寻找能够准确区分的功能反应特征 受保护和不受保护的对象。这些保护的相关性将为评估未来提供端点 疫苗。这可能对提高疫苗功效和实施的策略产生影响。