F Ndungu, Pwani University, Determining Cellular Correlates of Immunity to Malaria in an Experimental Human Challenge Model of Exposed Adults

由恶性疟原虫引起的疟疾仍然是撒哈拉以南非洲的一个主要公共卫生问题，影响到50%以上的人口。然而，目前的控制努力受到多种挑战的阻碍，包括分别出现抗药性和抗药性寄生虫和蚊子的持续威胁，以及资金不足和卫生基础设施差造成的后勤挑战。彻底控制疟疾的主要希望是有效的疫苗接种，这将大大降低疟疾传播，使消除疟疾成为现实。然而，尽管经过数十年的努力，研制有效的抗疟疾疫苗一直存在问题。具有讽刺意味的是，在开发抗疟疾疫苗方面的大量投资并没有与在了解疟疾免疫机制或试验疫苗取得有限成功的原因方面的类似投资相匹配。虽然患有地方性疟疾的儿童获得免疫，最初保护他们不受严重疟疾和死亡的影响，然后反复出现轻度疾病，但控制症状严重程度、保护性抗体产生和免疫个体体内寄生虫生长的机制仍然存在重大知识空白。我们今天对疟疾免疫的了解大多来自动物和人类的实地研究，这些研究很难直接转化为控制人体内感染的机制。相比之下，故意让人感染疟疾的实验将提供关于人对感染的免疫反应的更相关和直接的信息。我们的初步数据表明，在肯尼亚成年人的实验感染后，血液阶段寄生虫的生长速度是可变的，这些速度与个体免疫的基线水平呈负相关，表明寄生虫的生长速度可以准确地衡量自然获得性免疫的水平。我们目前正在进行一项前瞻性筛选，以确定具有不同基线免疫水平的肯尼亚成年人实验性人感染后基于抗体的免疫的相关性。由于赋予免疫和参与产生保护性抗体机制的细胞反应尚不清楚，因此我建议利用这一独特的机会，在肯尼亚成年人的实验性疟疾感染后，测试哪些细胞反应与个体控制感染（炎症和寄生虫生长）的能力相关。我的研究将确定免疫反应的模式，这些模式可以作为个体控制炎症、产生高质量抗体保护水平和控制寄生虫生长能力的预测标记。

Malaria, caused by Plasmodium falciparum parasites, remains a major public health problem in sub-Saharan Africa, affecting over 50% of the population. However, the current control efforts are hampered by a multiplicity of challenges including persistent threats of emerging drug and insecticide resistant parasites and mosquitoes, respectively, and logistical challenges owing to insufficient funding and poor health infrastructure. The main hope for the complete control that will bring down malaria transmission dramatically to the point where elimination is a reality is effective vaccination. However, despite decades of work, the development of an effective antimalarial vaccine has been problematic. Ironically, the substantial investment in developing anti-malaria vaccines has not been matched with similar levels of investment in understanding either the mechanisms of immunity to malaria, or the reasons the limited success with test vaccines. Although, children living with endemic malaria acquire immunity that initially protects them from severe malaria and death, and then recurring episodes of mild disease, the mechanisms that control the severity of symptoms, production of protective antibody, and parasite growth in the immune individual remain major knowledge gaps. Much of what we know today about immunity to malaria comes from animal and human field studies, which are hard to translate directly to the mechanisms that control infection inside the human body. In contrast, deliberate experimental infections of humans with malaria would give more relevant and direct information on the human immune response to infection. Our preliminary data demonstrated variable blood stage parasite growth rates following experimental infections of Kenya adults, and these rates were inversely correlated with the baseline levels of the individual's immunity, indicating that parasite growth rates can be accurate measures of the level of naturally acquired immunity. We are now conducting a prospective screen to determine correlates of antibody-based immunity following experimental human infections of Kenyan adults with different levels of baseline immunity. Because the cellular responses that confers immunity and participates in the mechanisms that produce protective antibodies are not known, I am proposing to take advantage of this unique opportunity to test which cellular responses correlate with the ability of an individual to control infection (inflammation and parasite growth) following experimental malaria infections in Kenyan adults. My study will identify patterns of immune responses that can be used as predictive markers of an individual's ability to control inflammation, produce protective levels of high quality antibodies, and to control parasite growth.