Longitudinal Antibody Profiles Correlated with Protection from Malaria in Malawi

项目摘要 尽管目前正在努力控制疟疾，但疟疾仍然是非洲儿童死亡率居高不下的原因。 开发一种有效的消灭疟疾疫苗受到自然- 获得性免疫和疫苗诱导的免疫。现有的候选疫苗会引发针对靶抗原的抗体 但抗体功能活性与保护水平和保护持续时间之间的关系尚不清楚。 此外，新的血液阶段抗原可用于未来的疫苗，旨在预防症状 疟疾已经出现（有些是多态的），需要进一步调查。优选的抗原应 引发抗体功能活性，所述抗体功能活性是：i）用天然感染加强; ii）持久; iii）与 保护; iv）不是高度菌株特异性的，即，有效地对抗各种各样的隔离物。我们的研究旨在澄清 这些未知因素集中在12个未充分研究的血液阶段抗原（以及那些多态性抗原的等位基因）上， 抗原）以告知可能是潜在疫苗候选物的抗原的选择。 先前对天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， 特异性蛋白质，并且通常局限于不频繁地或以单一的剂量定量免疫应答。 时间点因为个体的免疫状况是动态的，是暴露于感染的函数， 不能在研究开始时同步，这些主要的横截面测量模糊了 利益的结果。此外，先前的研究主要仅测量IgG应答的幅度; 很少有人评估抗体功能活性的范围和呼吸，以及抗原的影响。 多态性对功能性抗体活性的影响。 我们研究团队的专业知识，结合纵向研究期间收集的样本 通过密集的随访和全面的研究方法，提供了解决这些问题的机会。 问题和阐明这些抗原在获得性免疫疟疾的重要性。我们的研究将是 基于一组儿童和成人，他们在两年中每月接受一次检查，其中受试者 反复的临床和/或亚临床疟疾感染。研究这一群体将使我们获得新的见解 进入针对血液阶段抗原的功能性抗体活性的持久性和随时间的增强， 自然接触疟疾。我们还将评估功能性抗体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） 针对该抗体的功能性抗体活性与保护免受有症状的疟疾相关， 密度寄生虫血症，我们将寻求功能反应的签名，可以准确地区分 受保护和未受保护的受试者。这些保护的相关性将为评估未来 疫苗。这可能对提高疫苗效力和实施的战略产生影响。

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.