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，全球消除疟疾的成功机会微乎其微。领先者 候选疫苗(RTS，S)在已完成的第三阶段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，允许为世界卫生组织进行评估 考虑到疟疾负担的严重性，该组织列出了首选药物清单，因为它具有潜在的巨大影响。 疫苗在不同人群中的效果并不一样；这种差异可能是由于寄生虫， 环境因素或宿主因素。此外，任何疟疾疫苗都不会单独使用，而是作为 利用其他控制措施的综合计划。因此，了解以下各项组合 调节疟疾疫苗效力的因素对于指导适当的疫苗使用和 研制下一代疫苗。这项建议旨在提高我们对RTS的理解，S 通过评估可能影响效果的关键生态、宿主和寄生虫因素来发挥作用。这个 提出的方法将增强我们对RTS有效性的理解，S，也可以利用 以提高未来疟疾疫苗的效力。数据显示，根据RTS、S的疗效不同 传输强度。这项提议的第一个目标是将这些发现扩展到更大的背景下。我们会 S，在三个RT试验点调查可能影响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，结合第三阶段试验数据，地理信息 系统(地理信息系统)和卫星数据，以及同时进行的疟疾传播强度研究，将使我们能够识别 个体和邻里因素对疫苗效力影响的“生态”分析 审判。第二个目标是利用拟议的研究团队中的经验来研究抗原 疟疾的多样性，以了解对疫苗抗原的毒株特异性保护的重要性 试验期间的环子孢子蛋白(CS)。最近的证据表明，通过疫苗进行菌株选择， 对疫苗型CS毒株有较高水平的疫苗效力。然而，特定菌株的寿命 豁免权还不得而知。如果对疫苗类型毒株的免疫力比对非疫苗类型毒株的免疫力更持久，这 对疫苗设计有重要影响，并建议需要多价疫苗。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来研究宿主的影响 与免疫反应和疟疾耐药性相关的基因多态性对疫苗效力的影响。最后一个进球 是对项目头三个目标中确定的关键因素进行综合分析，以评估 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 到目前为止，影响RTS有效性的因素包括宿主、寄生虫和环境，S提出。此信息 将是目前大规模推出RTS、S和未来CS疟疾疫苗试验的关键 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.