. Osier, KEMRI-CGMRC, Defining the merozoite targets of protective immunity against Plasmodium falciparum malaria through multi-centre cohort studies

疟疾仍然是撒哈拉以南非洲许多地区的一个主要公共卫生问题。世界卫生组织估计，在这个地区，每小时有近90名5岁以下的儿童死于疟疾。可以使用许多工具来控制疟疾，包括经杀虫剂处理的蚊帐、快速有效的药物以及更好地控制蚊子。虽然这些方法在非洲的使用取得了不同程度的成功，但许多专家现在同意，需要采取新的措施来实现更好的控制，并逐步消除。疫苗历来是防治传染病最有效和最具成本效益的公共卫生工具，目前没有获得许可的疟疾疫苗。迄今为止，最有希望的疫苗仍在临床试验中进行测试，但早期数据显示，它只能提供30%的预防疟疾临床发作的保护。虽然这标志着重大进展，但迫切需要提高这种疫苗的效力。相信有可能开发出有效的疟疾疫苗，部分原因是对疟疾高发地区疾病模式的观察。五岁以下的幼儿易患严重和复杂的疟疾，而年龄较大的儿童和年轻人只患较轻的疟疾，尽管受到感染，但逐渐没有疟疾。这种免疫力是如何获得的？50多年前进行的研究表明，从对疟疾具有免疫力的成年人身上提取的抗体可用于成功治疗疟疾住院患者。我们知道抗体通过与微生物或感染因子上的特定分子结合而起作用，从而阻止它们的进展。随着技术的进步，我们现在已经能够识别构成疟疾寄生虫的数千种蛋白质。我们未能做到的是确定这数千种蛋白质中的哪一种是保护性抗体的目标。以前的研究只集中在少数抗原上，在小型研究中，使用了不同的方法，没有考虑到影响抗体测量的疟疾传播强度的巨大差异。由于这些原因，目前尚不清楚哪些寄生虫蛋白会诱导保护性抗体。我建议通过四种主要方式克服这些缺点。首先，我将测试大量的寄生虫蛋白质，只选择那些由于暴露于体内抗体而可能成为生物靶点的蛋白质。其次，我将研究从撒哈拉以南非洲（sSA）多个地点收集的样本中的抗体反应，这些样本代表了非洲大陆经历的不同疟疾传播水平。第三，我将使用已经从不同地点收集的血液样本进行一项非常大的研究。这有三个重要的优点：i）研究将足够大，使我能够测试对许多寄生虫蛋白质的抗体应答，并确信所识别的任何保护性关联不是偶然的，ii）所有测定和分析将以相同的方式进行，使我们能够直接比较来自各个站点的数据，iii）研究将具有极高的成本效益，避免了在非洲多个地点建立和纵向监测儿童所需的高昂费用。最后，我将研究针对我们认为重要的寄生虫蛋白质的抗体的作用机制，因此，这项研究将是迄今为止最全面的关于测试的特定寄生虫蛋白质的数量，整个sSA的结果的普遍性，并得到最佳候选物的抗体作用机制的证明的支持。这一信息对于开发下一代疟疾疫苗极为宝贵。

Malaria is still a major public health problem for many parts of sub-Saharan Africa. The World Health Organization estimates that nearly ninety children under the age of five years die from malaria each hour, in this region. Many tools can be used to control malaria including, insecticide-treated bed-nets, rapidly acting and effective medications, and better control of mosquitoes. Although these have been used in Africa with varying degrees of success, many experts now agree that novel measures will be needed to achieve better control, and move towards elimination. Vaccines have historically been the most effective and cost-effective public health tools against infectious diseases.There is currently no licensed malaria vaccine. The most promising vaccine so far is still being tested in clinical trials but early data show that it only offers 30% protection against clinical episodes of malaria. Whilst this marks significant progress, there is an urgent need to improve on this vaccine efficacy. The conviction that it will be possible to develop an effective malaria vaccine comes partly from observations of disease patterns in areas that experience a lot of malaria. Young children under the age of five are susceptible to severe and complicated forms of malaria, while older children and young adults experience only milder forms of the illness, and gradually remain symptom-free despite being infected. How is this immunity acquired? Studies conducted over fifty years ago showed that antibodies taken from adults who had become immune to malaria could be used to successfully treat individuals hospitalized with malaria. We know that antibodies act by binding to specific molecules on microbes or infecting agents, thus halting their progress. With advances in technology, we have now been able to identify the thousands of proteins that make up a malaria parasite. What we have failed to do is to identify which of these thousands of proteins are the targets of the protective antibodies. Previous studies have concentrated only on a small number of antigens, in small studies, used varied methodologies, and not taken into account the wide differences in malaria transmission intensity that affect antibody measurements. For these reasons, it is still not clear which parasite proteins induce protective antibodies.I propose to overcome these shortcomings in four main ways. First, I will test a large number of parasite proteins, selecting only those that are plausible biological targets by virtue of being exposed to antibodies in the body. Second, I will study antibody responses in samples collected from multiple sites in sub-Saharan Africa (sSA) that are representative of the varying levels of malaria transmission experienced on the continent. Third, I will conduct a very large study using blood samples that have already been collected from the different sites. This has three important advantages: i) the study will be sufficiently large, allowing me to test antibody responses to many parasite proteins with the confidence that any protective associations identified are not due to chance, ii) all assays and analyses will be performed in an identical manner, allowing us to directly compare data from individual sites, iii) the study will be extremely cost-effective, avoiding the prohibitive costs that would be required to set up and longitudinally monitor children in multiple sites in Africa. Finally, I will examine the mechanisms of action of the antibodies directed against the parasite proteins that we find to be important.This study will therefore be the most comprehensive to date with regards to number of specific parasite proteins tested, generalizability of results across sSA, and supported by the demonstration of antibody mechanisms of action for the best candidates. This information will be extremely valuable for the development of the next generation of malaria vaccines.