Mechanisms of naturally-acquired immunity to malaria

疟疾自然获得性免疫力的机制

• 批准号: 10927865
• 负责人: Peter Crompton
• 金额: $ 337.9万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10927865
• 关键词: Address; Adult; Africa; Anti-malarial drug resistance; Antibodies; Antibody Response; Antigens; Antimalarials; Area; Artemisinins; Beds; Biology; Child; Clinical Data; Clinical Trials; Cohort Studies; Collaborations; Combined Modality Therapy; Communicable Diseases; Computational Biology; Country; Culicidae; Data; Development; Double-blind trial; Drug Controls; Entomology; Epidemiology; Exposure to; Falciparum Malaria; Future; Generations; Genomics; Geographic Locations; Healthcare; Human; Immune; Immune response; Immune system; Immunity; Immunologics; Immunology; Individual; Infection; Inflammation; Infrastructure; Innate Immune Response; Insecticide Resistance; Insecticides; Intervention; Kinetics; Knowledge; Life Cycle Stages; Longitudinal cohort study; Maintenance; Malaria; Malaria Vaccines; Mali; Molecular; Molecular Profiling; Monoclonal Antibodies; National Institute of Allergy and Infectious Disease; Observational Study; Parasites; Phase; Plasmodium falciparum; Play; Population; Pregnancy; Pregnant Women; Preparation; Public Health; Randomized; Risk; Science; Scientist; Seasons; Site; Specificity; Systems Biology; Techniques; Technology; Translating; Universities; Vaccines; Woman; Work; acquired immunity; adaptive immune response; aged; child bearing; experience; human monoclonal antibodies; insight; malaria transmission; optimism; phase III trial; prevent; safety testing; technology/technique; tool; vector control

Malaria caused by Plasmodium falciparum remains a major public health threat. Over 200 million cases of malaria occur annually among the world's poorest populations, claiming the lives of approximately 500,000 children each year in Africa alone. The widespread implementation of malaria control interventions such as artemisinin-based combination therapy and insecticide-treated bed nets is hampered by the limited health-care infrastructure of many malaria-endemic countries. Moreover, P. falciparum has proven adept at acquiring and rapidly spreading resistance to antimalarial drugs, and vector control is constantly threatened by the inevitability of the emergence of insecticide-resistant mosquitoes. Ultimately, a key tool for the control, elimination, or even eradication of malaria is an effective vaccine. The development of a highly effective malaria vaccine has been hindered in part by a poor understanding of the interaction between P. falciparum and the human immune system. Importantly, protective immunity to malaria can be acquired after repeated P. falciparum infections but wanes rapidly in the absence of ongoing exposure. The quality of the innate and adaptive immune responses that ultimately confers this protection and the mechanisms that underlie their inefficient acquisition and rapid loss are poorly understood. Our objective is to inform the discovery and development of new tools to prevent and treat malaria by addressing these critical knowledge gaps. To this end, we apply recent advances in immunology and genomics-based technology to rigorously conducted longitudinal cohort studies in malaria-endemic areas to deepen our understanding of the interaction between P. falciparum and the human immune system, to define molecular and cellular signatures of malaria immunity and to identify potential malaria vaccine targets. In FY 2023 we continued to pursue five main objectives: 1) obtain high quality clinical data and biospecimens from ongoing longitudinal cohort studies in Mali in which exposure to P. falciparum infection and protection against malaria are reliably assessed, 2) determine the antigen specificity, function, kinetics and cellular basis of the antibody response to P. falciparum, including the isolation of monoclonal antibodies against various stages of the P. falciparum life cycle, 3) define the mechanisms by which P. falciparum-induced inflammation is regulated, 4) identify a molecular signature of immunity to malaria through systems biology approaches, and 5) determine the relationship between persistent asymptomatic P. falciparum infection and malaria risk, and elucidate the host and parasite factors that underlie this phenomenon. The large cohort studies we conduct in Mali are made possible through a close collaboration with an experienced team of clinicians and scientists at the University of Sciences, Techniques & Technologies of Bamako (USTTB). To expand the scope of our work and to maximize the knowledge gained from our cohort studies in Mali, we collaborate with experts in parasite biology, entomology, basic immunology, genomics and computational biology. These ongoing projects are contributing to a more comprehensive understanding of the acquisition and maintenance of immunity to malaria, and also providing insights into the mechanisms at play in human immune responses to infectious diseases more generally. The malaria epidemiology at the study site in Mali has been well characterized through several years of careful observational studies, which now allows for clinical trials of candidate malaria interventions to be efficiently conducted. During FY 2023 we continued the analysis of a randomized, double-blind trial of adults in Mali to test the safety and efficacy of CIS43LS, a human monoclonal antibody against Plasmodium falciparum. We also extended a randomized, double-blind trial of children aged 6-10 years in Mali to test the safety and efficacy of L9LS, a second-generation human monoclonal antibody against Plasmodium falciparum. Finally we initiated a new randomized, double-blind trial to test the safety and efficacy of L9LS in adults in Mali with an emphasis on women of child-bearing potential in preparation for a phase trial of L9LS in pregnant women. These clinical trials are being conducted in collaboration with Dr. Kassoum Kayentao (University of Sciences, Techniques, & Technologies of Bamako), and Dr. Robert Seder (VRC/NIAID).

由恶性疟原虫引起的疟疾仍然是一个重大的公共卫生威胁。世界上最贫穷的人口中每年发生2亿多起疟疾病例，仅在非洲每年就夺去约50万儿童的生命。由于许多疟疾流行国家的保健基础设施有限，青蒿素类复方疗法和驱虫蚊帐等疟疾控制干预措施的广泛实施受到阻碍。此外，事实证明，恶性疟原虫善于获得并迅速传播抗疟药物的抗药性，而且病媒控制不断受到不可避免的抗药性蚊子出现的威胁。最终，控制、消除甚至根除疟疾的关键工具是有效的疫苗。由于对恶性疟原虫和人类免疫系统之间的相互作用缺乏了解，阻碍了高效疟疾疫苗的开发。重要的是，在恶性疟原虫反复感染后可以获得对疟疾的保护性免疫，但在没有持续暴露的情况下迅速减弱。先天性和适应性免疫反应的质量，最终赋予这种保护和机制的基础上，他们的效率低下的收购和快速损失知之甚少。我们的目标是通过解决这些关键的知识差距，为发现和开发预防和治疗疟疾的新工具提供信息。为此，我们应用免疫学和基因组学技术的最新进展，在疟疾流行地区进行严格的纵向队列研究，以加深我们对恶性疟原虫和人类免疫系统之间相互作用的理解，定义疟疾免疫的分子和细胞特征，并确定潜在的疟疾疫苗靶点。 于2023财年，我们继续追求五个主要目标：1）从马里正在进行的纵向队列研究中获得高质量的临床数据和生物标本，其中对恶性疟原虫感染的暴露和对疟疾的保护进行了可靠的评估，2）确定对恶性疟原虫的抗体应答的抗原特异性、功能、动力学和细胞基础，包括分离抗恶性疟原虫生命周期各个阶段的单克隆抗体，3）确定恶性疟原虫诱导的炎症的调节机制，4）通过系统生物学方法鉴定对疟疾免疫的分子标记，5）确定恶性疟原虫持续无症状感染与疟疾风险之间的关系，并阐明这种现象背后的宿主和寄生虫因素。我们在马里进行的大型队列研究是通过与巴马科科技大学（USTB）经验丰富的临床医生和科学家团队密切合作而实现的。为了扩大我们的工作范围，并最大限度地利用我们在马里的队列研究中获得的知识，我们与寄生虫生物学、昆虫学、基础免疫学、基因组学和计算生物学方面的专家合作。这些正在进行的项目有助于更全面地了解疟疾免疫力的获得和维持，并更普遍地深入了解人类对传染病的免疫反应机制。通过几年的仔细观察研究，马里研究地点的疟疾流行病学特征已得到很好的描述，现在可以有效地进行候选疟疾干预措施的临床试验。于2023财政年度，我们继续分析马里成人的随机双盲试验，以测试抗恶性疟原虫人单克隆抗体CIS 43 LS的安全性及有效性。我们还扩展了一项针对马里6-10岁儿童的随机双盲试验，以测试L9 LS的安全性和有效性，L9 LS是第二代抗恶性疟原虫的人单克隆抗体。最后，我们启动了一项新的随机双盲试验，以测试L9 LS在马里成年人中的安全性和有效性，重点是有生育能力的女性，为L9 LS在孕妇中的阶段试验做准备。这些临床试验是与Kassoum Kayentao博士（巴马科科学技术大学）和Robert Seder博士（VRC/NIAID）合作进行的。

项目成果

Assessment of Plasmodium falciparum Antigen-Specific B Cells.

恶性疟原虫抗原特异性 B 细胞的评估。

• DOI: 10.1007/978-1-0716-2189-9_52
• 发表时间: 2022
• 期刊: Methods in molecular biology (Clifton, N.J.)
• 作者: Hopp,ChristineSarah;Taylor,JustinJames;Crompton,PeterDobbs
• 通讯作者: Crompton,PeterDobbs

Dendritic cell responses to Plasmodium falciparum in a malaria-endemic setting.

• DOI: 10.1186/s12936-020-03533-w
• 发表时间: 2021-01-06
• 期刊: Malaria journal
• 影响因子: 3
• 作者: Turner TC;Arama C;Ongoiba A;Doumbo S;Doumtabé D;Kayentao K;Skinner J;Li S;Traore B;Crompton PD;Götz A
• 通讯作者: Götz A

Safety and Efficacy of a Monoclonal Antibody against Malaria in Mali.

• DOI: 10.1056/nejmoa2206966
• 发表时间: 2022-11-17
• 期刊: The New England journal of medicine

[Dynamics of Egg Excretion of Schistosoma haematobium in a Longitudinal Cohort Under Treatment with Praziquantel over a Five-Year Period in Kalifabougou, Mali].

[马里 Kalifabougou 五年期间接受吡喹酮治疗的纵向队列中埃及血吸虫虫卵排泄动态]。

• DOI: 10.3166/bspe-2018-0018
• 发表时间: 2018
• 期刊: Bulletin de la Societe de pathologie exotique (1990)
• 作者: Niaré,DSafiatou;Doumtabe,D;Ongoiba,A;Sidibé,K;Traoré,A;Sangala,J;Kayentao,K;Tran,TM;Crompton,PD;Traoré,B;Doumbo,OK
• 通讯作者: Doumbo,OK

Malaria Vaccines: Moving Forward After Encouraging First Steps.

• DOI: 10.1007/s40475-015-0041-3
• 发表时间: 2015-03
• 期刊: Current tropical medicine reports
• 影响因子: 5.4