Impacts of Environment, Host Genetics and Antigen Diversity on Malaria Vaccine Efficacy

摘要 在没有有效疫苗的情况下，全球消灭疟疾的成功机会很小。领导 候选疫苗（RTS，S）在一项已完成的III期试验中仅显示出中等疗效，但最近 得到欧洲药品管理局的科学支持，使其能够为世界卫生组织进行评估， 鉴于疟疾负担的严重性，本组织的首选药物清单具有潜在的巨大影响。 疫苗在不同人群中的效果并不相同;这种变异性可能是由于寄生虫， 环境或宿主因素。此外，任何疟疾疫苗都不会孤立使用，而是作为一部分， 一个综合的计划，利用其他控制措施。因此，了解 调节疟疾疫苗有效性的因素对于指导适当的疫苗使用至关重要， 制定下一代疫苗。本建议旨在提高我们对RTS，S 通过评估可能影响有效性的关键生态、宿主和寄生虫因素来发挥作用。的 所提出的方法将增强我们对RTS，S有效性的理解，也可以被利用 来提高未来疟疾疫苗的效力。数据表明，RTS，S的疗效因 传输强度本提案的第一个目标是将这些调查结果扩大到更大的范围。我们将 调查可能影响三个RTS，S试验中心疫苗效力的生态和行为因素 在马拉维、加纳和加蓬。这些数据与III期试验数据、地理信息 地理信息系统（GIS）和卫星数据，以及同时进行的疟疾传播强度研究，将使我们能够辨别 个体和邻里因素对疫苗有效性的影响， 审判第二个目标是利用拟议的研究小组的经验， 疟疾的多样性，以了解菌株特异性保护对疫苗抗原的重要性 环子孢子蛋白（CS）。最近的证据表明，疫苗的菌株选择， 针对疫苗型CS毒株的疫苗效力水平更高。然而，菌株特异性的寿命 免疫力未知。如果对疫苗型毒株的免疫力比对非疫苗型毒株的免疫力持久， 对疫苗设计具有重要意义，并表明需要多价疫苗。第三个目标 利用第二代测序和人类遗传学方面的专业知识， 与免疫应答和疟疾抗性相关的多态性对疫苗效力的影响。最后一球 对项目前三个目标中确定的关键因素进行综合分析， 在多变量分析中它们对疫苗效力的影响。这项研究将是最全面的评估 迄今为止，影响RTS，S有效性的因素包括宿主、寄生虫和环境。这些信息 将是至关重要的通知目前大规模推出的RTS，S和未来的疟疾疫苗试验，为CS 和非CS疫苗。

ABSTRACT Global malaria elimination has little chance of success in the absence of an effective vaccine. The leading candidate vaccine (RTS,S) has shown only moderate efficacy in a completed Phase III trial but was recently given scientific support by the European Medicines Agency, allowing it to be assessed for the World Health Organization preferred medicines list as it has a potential large impact given the magnitude of malaria burden. The vaccine does not work equally well in different populations; this variability may be due to parasite, environmental, or host factors. Furthermore, any malaria vaccine will not be used in isolation, but rather as part of an integrated program leveraging other control measures. Therefore, understanding the combinations of factors which modulate the effectiveness of a malaria vaccine is essential to guide appropriate vaccine use and formulating next-generation vaccines. This proposal is designed to improve our understanding of how RTS,S works by evaluating key ecological, host, and parasite factors which likely impact effectiveness. The approaches proposed will enhance our understanding of the effectiveness of RTS,S and can also be leveraged to improve the efficacy of future malaria vaccines. Data suggest that RTS,S efficacy varies based on transmission intensity. The first goal of this proposal is to expand these findings to a larger context. We will investigate ecological and behavioral factors that may influence vaccine efficacy across three RTS,S trial sites in Malawi, Ghana, and Gabon. These data, in conjunction with Phase III trial data, geographic information system (GIS) and satellite data, and a concurrent malaria transmission intensity study, will allow us to discern the impacts of individual and neighborhood factors on vaccine effectiveness in an “ecological” analysis of the trial. The second goal leverages the experience in the proposed team of investigators for studying antigenic diversity in malaria to understand the importance of strain-specific protection to the vaccine antigen circumsporozoite protein (CS) during the trial. Recent evidence has shown strain selection by the vaccine, with a higher level of vaccine efficacy against vaccine type CS strains. However, the longevity of strain specific immunity is not known. If immunity to vaccine type strain is longer-lasting than to non-vaccine type strains, this has important implications for vaccine design and suggests the need for a polyvalent vaccine. The third goal leverages expertise in second generation sequencing and human genetics to study the impacts of host polymorphisms associated with immune response and resistance to malaria on vaccine efficacy. The last goal is to provide an integrative analysis of the key factors identified in the first three aims of the project to assess their impact on vaccine efficacy in multivariate analysis. This study will be the most comprehensive evaluation to date of factors, including host, parasite and environmental, that affect RTS,S effectiveness. This information will be critical for informing current large-scale rollouts of RTS,S and future malaria vaccine trials for both CS and non-CS based vaccines.