Development of a human challenge model of Leishmania major infection as a tool for assessing vaccines against leishmaniasis

利什曼病是一种由一种叫做利什曼原虫的小寄生虫感染引起的严重疾病。这种疾病通过咬人的沙蝇在人与人之间传播，也可以在啮齿动物或狗等其他动物身上发现。利什曼病是最重要的被忽视的贫困疾病之一，在全世界98个国家都有发现。在许多情况下，这种疾病表现为皮肤上的慢性溃疡，通常影响面部。虽然这些伤口可以在几个月内愈合，但严重皮肤利什曼病患者留下的疤痕会严重影响生活质量，特别是对妇女和儿童。在其他形式的疾病中，寄生虫进入内部器官，导致器官衰竭，抑制免疫系统，往往导致死亡。每年大约有2万人死于这种被称为内脏利什曼病的疾病。虽然我们有可以对抗利什曼病的药物，但有些药物有严重的副作用，而且它们的效果在不同的国家有所不同。和其他微生物一样，利什曼原虫也开始找到抵抗现有药物作用的方法。因此，当务之急是开发一种疫苗，从一开始就阻止人们受到感染。最近，在研制利什曼病实验性疫苗方面取得了良好进展，这些疫苗已在动物模型中进行了或多或少的效果试验。然而，动物模型不能完全预测疫苗如何在人类身上起作用，如果有的话。因此，我们需要能够在人体中进行疫苗接种试验。这一过程的第一阶段是使用符合最高质量标准（所谓的GMP）的疫苗进行安全性研究。这被称为第一阶段临床试验，通常只涉及少数志愿者。如果安全，下一阶段是将安全性测试扩展到更多的志愿者，并试图了解人们对疫苗的反应。这通常意味着尝试使用我们认为可以预测保护性免疫反应的血液测试。然而，这些保护的预测因素或相关因素并不总是很清楚，因此，这些试验的结果并不一定意味着疫苗会起作用。目前，这只能通过在人口自然暴露于寄生虫的国家进行大规模试验（称为III期试验）来进行测试。这些研究通常需要数千名参与者，可能需要数年时间。由于大多数疫苗（和药物）在这一后期阶段失败，所涉及的成本和时间都很大，限制了对疫苗开发的投资。在第一阶段试验完成后不久，需要一种安全、具有成本效益和快速的方法来评估有效性，以刺激疫苗开发并就采用哪种疫苗进行第三阶段试验做出更明智的循证决定。在这个项目中，我们建议为利什曼病开发一个“人类挑战模型”，以实现这一目的。人体挑战模型包括志愿者实验性地感染一种微生物，然后跟踪疾病的发展，直到一个合适的终点。这些模型被用来测试疟疾、登革热和其他疾病的疫苗。为了建立利什曼病的人体挑战模型，我们将首先与公众进行焦点小组讨论，以确定对这类研究的态度，并告知我们如何设计研究。由于利什曼病是由沙蝇传播的，因此我们将评估以可控的方式让沙蝇叮咬人类的最佳方法。类似的研究也经常在蚊子身上进行。我们还将开发具有良好特征的寄生虫库存，以供现在和将来使用。最后，我们将在志愿者中进行第一次人体挑战研究，从而确定在未来利什曼病候选疫苗的临床试验中实施这种方法的参数。

Leishmaniasis is a serious disease caused by infection with a small parasite called Leishmania. The disease is transmitted from person to person by biting sand flies and can also be found in a variety of other animals such as rodents or dogs. Leishmaniasis is one of the most important of the neglected diseases of poverty, and is found in 98 countries worldwide. In many cases, the disease presents as chronic ulcers on the skin, often affecting the face. Although these may heal over several months, patients with severe cutaneous leishmaniasis are left with a scar that can significantly affect quality of life, particularly for women and children. In other forms of the disease, parasites enter the internal organs and cause organ failure and suppress the immune system, often leading to death. About 20,000 people die each year from this type of disease, called visceral leishmaniasis. Although we have drugs that can work against leishmaniasis, some have serious side effects and their effectiveness varies in different countries. As with other microbes, the Leishmania parasite is also beginning to find ways to resist the action of the drugs we have available. The need to develop a vaccine to stop people becoming infected in the first place is therefore imperative. Recently, there has been good progress in developing experimental vaccines for leishmaniasis that have been tested with greater or lesser effect in animal models. However, animal models cannot fully predict how a vaccine will work, if at all, in humans. Hence, we need to be able to conduct vaccination trials in humans. The first stage in this process is to conduct a safety study with a vaccine made to the highest quality standards (so called GMP). This is called a Phase I clinical trial and usually involves only a few volunteers. If safe, the next stage is to extend the safety tests to more volunteers and also try to gain an idea of how people respond to the vaccine. This often means trying to use blood tests that we think are predictors of a protective immune response. However, these predictors or correlates of protection are not always clear, so again the results of these trials do not necessarily mean the vaccine will work. Currently, this can only be tested by doing large scale trials (called Phase III trials) in countries where there is natural exposure of the population to the parasite. These studies often require thousands of participants and may take several years. The cost and time involved is substantial and limits investment in vaccine development, given that most vaccines (and drugs) fail at this late stage. What is required to stimulate vaccine development and make more informed evidence-based decisions about which vaccine to take to Phase III trial is a safe, cost effective and rapid way to evaluate efficacy soon after a Phase I trial has been completed.In this project, we propose to develop a "human challenge model" for leishmaniasis that will serve this purpose. A human challenge model involves volunteers being experimentally infected with a microbe and then following the development of disease until a suitable end point. These models are being used to test vaccines for malaria, dengue fever and other diseases. To establish a human challenge model of leishmaniasis, we will first conduct focus group discussions with members of the public to ascertain attitudes to this type of research and inform how we design the studies. As leishmaniasis is transmitted by sand flies, we will then evaluate the best way to allow sand flies to bite humans in a controlled manner. Similar studies are often performed with mosquitoes. We will also develop a well-characterised stock of parasites for use now and in the future. Finally, we will conduct the first human challenge study in volunteers, thereby establishing the parameters by which this approach could be implemented in future clinical trials of leishmaniasis candidate vaccines.