Once Bitten: Acquisition of Malaria Adaptive Immunity (OBAMA - Immunity)

一旦被咬：获得疟疾适应性免疫（奥巴马 - 免疫）

• 批准号: 10753364
• 负责人: Wendy PrudhommeOMeara
• 金额: $ 87.06万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-17 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10753364
• 关键词: Africa; Antibodies; Antigenic Diversity; Antigens; Apical; Back; Bite; Blood; Cessation of life; Classification; Cohort Studies; Coupled; Coupling; Culicidae; Data; Development; Disease; Enrollment; Epidemiology; Event; Exhibits; Exposure to; Falciparum Malaria; Flow Cytometry; Genetic; Genetic Techniques; Genotype; Goals; Helper-Inducer T-Lymphocyte; Household; Human; Immune; Immune response; Immunity; Individual; Infection; Infection Control; Integration Host Factors; Kenya; Licensing; Longitudinal Studies; Longitudinal cohort; Malaria; Malaria Vaccines; Measurement; Measures; Memory B-Lymphocyte; Modeling; Observational epidemiology; Outcome; Parasites; Peptides; Persons; Phenotype; Plasmodium falciparum; Population; Positioning Attribute; Productivity; Proteins; Recording of previous events; Resolution; Risk; Sampling; Shapes; Sporozoites; Subunit Vaccines; Symptoms; System; Testing; Transcend; Vaccine Design; Vaccines; Variant; Work; adaptive immunity; circumsporozoite protein; cohort; community transmission; cytokine; epidemiology study; immunogenic; insight; malaria infection; malaria transmission; member; next generation; novel; novel vaccines; phase III trial; population based; response; transmission process; vaccine candidate; vaccine development; vaccine effectiveness

Plasmodium falciparum control has stalled, and further progress reducing infections and deaths will require a highly-effective malaria vaccine. Individuals exposed to malaria develop protective immune responses gradually over several infections. Studies of immune responses to P. falciparum have consistently demonstrated that targets which exhibit very high diversity are critical for these protective responses. However, immunity to these antigens is dominated by strain-specific responses, which confer partial but imperfect protection to heterologous strains. This is a challenge for current vaccine candidates, including the first licensed malaria vaccine RTS,S, which are based on a single antigenic variant for a protein target and suffer from reduced efficacy to non-vaccine strains. There is evidence for strain-transcendent immunity in naturally exposed populations where individuals mount broadly protective responses after a few infections, despite the presence of dozens if not hundreds of different strains. Understanding how to elicit strain-transcendent immunity towards key, diverse antigenic targets has the potential to transform the next generation of vaccine products. Prior longitudinal studies of infection and disease are unable to furnish this insight mainly because they suffer from the inability to distinguish protection from lack of exposure in naturally exposed populations. As a consequence, there is no clear phenotype of protection, producing an incomplete understanding of the acquisition of protective immunity. Using our unique, longstanding cohort encompassing ~600 people in 75 households (initiated in 2017) in a high-transmission community in Western Kenya, we are able to pinpoint parasite transmission events to the individual-level, characterize the variant composition of multi-strain P. falciparum exposures, and document the outcome (no infection or protected vs. infected with or without symptoms) at the variant level. By leveraging known exposures to clearly define protection phenotypes within a natural system that encompasses a high degree of parasite diversity, we are uniquely-positioned to answer longstanding questions about protective immune responses. The goal of the proposed work is to use our unique system to advance multi-variant vaccine design. In our first Aim, we will quantify the strain-specific risk of malaria infection following a confirmed infectious bite (exposure). In the second Aim, we will leverage peri- exposure and post-exposure samples to correlate strain-specific protection following an infectious bite with strain-specific immune responses in order to identify strain-transcendent responses, and then identify variants that most effectively promote strain-transcendent responses. Our hypothesis is that a minimum set of strain- specific immune responses will be associated with strain-transcendent protection from infection after exposure. By exploring heterologous versus homologous strain-specific responses to elucidate a minimum set of antigenic variants required to confer strain-transcendent protection, we can facilitate the development and delivery of the next generation of P. falciparum vaccines.

恶性疟原虫控制已陷入停滞，减少感染和死亡的进一步进展将需要 高效疟疾疫苗。接触疟疾的个体会产生保护性免疫反应 在几次感染中逐渐消失。对恶性疟原虫免疫应答的研究一直 证明了表现出非常高的多样性的靶标对于这些保护性反应至关重要。但是，在这方面， 对这些抗原的免疫主要是菌株特异性应答， 保护异源菌株。这对目前的候选疫苗是一个挑战，包括第一个 许可的疟疾疫苗RTS，S，其基于针对蛋白质靶标的单一抗原变体， 从效力降低到非疫苗菌株。有证据表明，在自然条件下， 暴露人群，其中个人在几次感染后产生广泛的保护性反应，尽管 存在几十种甚至几百种不同的菌株。了解如何引出应变超越 对关键的、不同的抗原靶点的免疫有可能改变下一代疫苗 产品.以前的感染和疾病的纵向研究无法提供这种见解，主要是因为 他们无法区分自然暴露人群中的保护和缺乏暴露。 因此，没有明确的保护表型，从而导致对保护的不完整理解。 获得保护性免疫。使用我们独特的长期队列，包括75个国家的约600人， 在肯尼亚西部一个高传播社区的家庭（始于2017年）中，我们能够确定 寄生虫传播事件到个体水平，表征多株P. 恶性疟原虫暴露，并记录结果（无感染或受保护vs.感染或不感染 症状）在变异水平。通过利用已知的风险来明确定义 自然系统，包括高度的寄生虫多样性，我们是正确的定位，以回答 关于保护性免疫反应的长期问题。拟议工作的目标是利用我们的 独特的系统，以推进多变异疫苗的设计。在我们的第一个目标中，我们将量化菌株特异性风险 疟疾感染后确认感染叮咬（暴露）。在第二个目标中，我们将利用 暴露和暴露后样本，以将感染性叮咬后的菌株特异性保护与 菌株特异性免疫应答，以识别菌株超越性应答，然后识别变体 最有效地促进应变超越反应。我们的假设是最小限度的应变- 特异性免疫应答将与接触后对感染的菌株超越性保护相关。 通过探索异源与同源菌株特异性反应，以阐明一组最小的 抗原变异需要赋予应变超越保护，我们可以促进发展， 提供下一代恶性疟原虫疫苗。