Population differences in vaccine response: the role, reversibility and mediators of immunomodulation by chronic parasitic infections in the tropics

传染病继续对低收入国家的健康和发展产生重大有害影响。正如最近的埃博拉和寨卡疫情所表明的那样，它们还构成了全球威胁。疫苗是对抗它们的有力武器，也是解决新出现的抗生素耐药性的潜在方案。然而，与城市相比，一些重要的疫苗在热带LIC和农村地区的效力较低，或诱导较弱的免疫反应。一个重要的例子是卡介苗(用于预防结核病)，它在一些温带国家提供80%的保护，但在一些热带地区提供0%的保护。新疫苗(包括结核病、疟疾和埃博拉)似乎也受到了影响。我们的目标是了解为什么会这样。更多地接触寄生虫和疟疾是一种可能的解释，并在这项提案中得到了解决。几千年来，寄生虫一直在进化，以控制宿主的免疫反应，以便它们能够存活和繁殖，如果不治疗，有时会持续数十年。长期以来，人们一直认为，这些机制可能会溢出，损害对疫苗和无关感染的反应，但目前尚不清楚这种情况会在多大程度上发生。我们计划在乌干达的青少年中解决这个问题。寄生虫在这个年龄段非常常见，这也是学校免疫计划的目标。首先，我们将比较三组人群的疫苗反应：(1)参与恩德培母婴研究出生队列的城市居民[我们从出生起就对这些儿童进行跟踪调查，知道他们寄生虫暴露水平较低]；(2)岛屿社区，超过80%的社区患有血吸虫病[一种通过湖中蜗牛传播的蠕虫感染]；(3)疟疾高暴露的农村社区，超过50%的学龄儿童在不知情的情况下感染了疟疾。当然，除了寄生虫感染之外，城市人和农村人之间的差异可能会影响疫苗的反应。因此，为了获得寄生虫有效的更有力的证据，我们将在每个农村组中随机选择一半的参与者接受针对其环境中主要寄生虫的强化治疗。如果这改变了疫苗的反应(我们预测它将改善它们)，我们可以肯定涉及到寄生虫。一些寄生虫的影响可能是间接的。除了寄生虫(来自生物界的“动物界”)，人类还寄生了许多细菌和病毒。在宿主内部，这些主要生命形式之间的相互作用被称为“跨王国”效应。例如，寄生虫的免疫抑制可以激活休眠病毒，进而可能增加免疫效果。此外，蠕虫还会破坏肠道内壁。这会导致细菌产物渗入血液，刺激免疫系统。因此，我们将测试寄生虫感染及其治疗是否会改变血液中病毒复制和细菌产品的水平，并将其与疫苗反应联系起来。接种疫苗是为了针对特定的感染提供持久的保护性免疫反应。因此，寄生虫对疫苗反应的影响必须通过宿主免疫系统发挥作用。我们将使用免疫学工具，包括可以前所未有的详细检查免疫细胞类型的尖端方法“质量细胞术”，来调查寄生虫改变了哪些细胞和介质。为了将我们所有的工作结合在一起，我们将采用一种名为“因果中介分析”的统计方法，以探索城乡环境、寄生虫、“跨界”效应和免疫反应如何相互关联来确定疫苗反应。这些基本信息将有助于为生活在低收入热带环境中的人口开发合适的疫苗，这些地区非常需要这些疫苗；并帮助公共卫生专家了解控制寄生虫是否也将提高疫苗计划的有效性：最终为所有人带来更好的健康(和更大的财富)。

Infectious diseases continue to have major detrimental impacts on health and development in in low-income countries (LICs). They are also pose a global threat, as shown by recent Ebola and Zika epidemics. Vaccines are potent weapons against them, and a potential solution to emerging antibiotic resistance. However, some important vaccines have lower efficacy, or induce weaker immune responses, in tropical LICs and in rural, compared to urban, settings. An important example is BCG (used to protect against tuberculosis [TB]) which provides 80% protection in some temperate countries, but 0% in some tropical settings. New vaccines (including for TB, malaria and Ebola) seem also to be affected. Our goal is to understand why this is so.Greater exposure to parasites, such as worms and malaria, is one possible explanation, and addressed in this proposal. Parasites have evolved over millennia to control host immune responses so that they can survive and reproduce, sometimes for decades, if left untreated. It has long been suggested that these mechanisms might spill-over to impair responses to vaccines and to unrelated infections, but it is not yet clear to what extent this is so. We plan to address this among adolescents in Uganda. Parasites are very common in this age group, which is also the target for school-based immunisation programmes.First, we will compare vaccine responses between three groups: (1) urban-dwellers participating in our Entebbe Mother and Baby Study birth cohort [we have followed up these children from birth and know that they have low parasite exposure]; (2) island communities where over 80% have schistosomiasis [a worm infection transmitted through snails in the lake]; (3) rural communities with high malaria exposure, where over 50% of school-children have malaria infection, without knowing it. Of course, differences between urban and rural people, other than parasite infections, probably influence vaccine response. So, to obtain stronger evidence that parasites have an effect, we will randomly select half the participants in each rural group to receive intensive treatment for the main parasite in their setting. If this alters the vaccine responses (we predict it will improve them), we can be sure that parasites are involved.Some parasite effects may be indirect. As well as parasites (from the biological kingdom "Animalia"), humans host many bacteria and viruses. Interactions between these major life-forms, within the host, have been termed "transkingdom" effects. For example, immune suppression by parasites can activate dormant viruses which, in turn, may add immunological effects. Also, worms damage the intestinal lining. This causes leakage of bacterial products into the blood, stimulating the immune system. So, we will test whether parasite infections and their treatment change levels of viral replication and of bacterial products in the blood, and relate this, also, to vaccine responses. Vaccines are given to deliver lasting protective immune responses against specific infections. Thus, parasite effects on vaccine responses must act via the host immune system. We will use immunological tools, including the cutting-edge method "mass cytometry" which can examine immune cell types in unprecedented detail, to investigate which cells and mediators are altered by parasites. To bring all our work together, we will undertake a statistical approach called "causal mediation analysis" to explore how urban-rural environment, parasites, "transkingdom" effects and immune responses interrelate to determine vaccine responses. This fundamental information will contribute to the development of suitable vaccines for populations living in low-income, tropical settings, where they are greatly needed; and help public health experts to know whether controlling parasites will also improve effectiveness of vaccine programmes: ultimately leading to better health (and greater wealth) for all.