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.

项目摘要 尽管目前的控制努力，但疟疾仍负责非洲的童年死亡率。 开发有效消除疟疾的有效疫苗受到自然知识差距的限制 - 获得和疫苗诱导的免疫力。现有的候选疫苗会引起针对靶抗原的抗体 但是抗体功能活性与水平和保护持续时间之间的关联尚不清楚。 另外，可以在未来的疫苗中使用的新型血阶段抗原，以防止有症状 疟疾已经出现（有些是多态性的），需要进一步研究。首选的抗原应该 引起抗体功能活性，即：i）随着自然感染的增强； ii）持久； iii）与 保护; iv）不是高度应变特异性的，即对各种分离株有效。我们的研究旨在澄清 这些未知数专注于12种细小的血阶段抗原（以及这些多态性的等位基因 抗原）为可能是候选疫苗的抗原选择。 对自然获得抗体免疫的先前研究在很大程度上量化了抗体幅度 特定的蛋白质，通常仅限于量化免疫反应或单一量子 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功能 在研究开始时不能同步，这些在很大程度上横断面的测量掩盖了 感兴趣的结果。此外，先前的研究主要仅测量了IgG响应的幅度。 很少有人评估抗体功能活动的范围和呼吸，抗原的影响 功能抗体活性的多态性。 我们的学习团队的专业知识，加上在纵向研究中收集的样品的访问 采用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获得疟疾的免疫中的重要性。我们的研究将是 基于一群儿童和成人，他们每月在两年中看到受试者 反复的临床和/或亚临床疟疾感染。研究此队列将使我们能够获得新的见解 在对血液阶段抗原的功能抗体活性的耐用性和增强作用上 自然暴露于疟疾。我们还将评估功能的交叉反应性或应变特异性 针对多态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） 功能性抗体活性与症状性疟疾的保护相关 密度寄生虫病，我们将寻求可以准确区分的功能反应的签名 受保护和未受保护的受试者。这些保护的关联将为评估未来提供终点 疫苗。这可能对提高疫苗功效和实施的策略有影响。