Experimental Human Pneumococcal Carriage to determine optimal protection from carriage and mechanisms of mucosal immunisation against disease

肺炎链球菌是引起全球儿童肺炎、脑膜炎和中耳炎的最常见细菌。在成人中，肺炎球菌肺炎是住院的常见和不断增加的原因，在老年人中有相当大的死亡率。此外，肺炎球菌感染会加重慢性肺部疾病，特别是慢性阻塞性肺病和哮喘。然而，肺炎球菌感染的一个重要悖论是，在绝大多数人中，偶尔会发现这些细菌栖息在鼻咽部，对人体无害。这种无害的状态被称为肺炎球菌携带，提高了对肺炎球菌疾病的免疫力，因此有一定的好处，但也可能是感染的传播途径。肺炎球菌携带被认为是控制疾病的关键，因为它是传播途径和疾病的前提。疫苗接种是预防肺炎球菌疾病最重要和最有效的干预措施，但从费用和肺炎球菌类型的覆盖范围来看，这一武器库的武器仍远未达到最佳水平。然而，目前的疫苗已经证明，在幼儿中有效预防肺炎球菌携带者和疾病是可能的，减少循环肺炎球菌携带者对未接种疫苗的成年人间接受益。目前还不太清楚目前的疫苗应该如何直接用于成年人或慢性病患者。目前也不清楚疫苗是通过什么机制改变运输方式的，也不清楚在这方面哪些疫苗最有效。有许多新的疫苗处于开发的早期阶段，对它们如何影响携带的研究在选择可能的替代方案时可能是重要的。这项实验性人类肺炎球菌携带(EHPC)计划赠款将利用对健康志愿者和肺炎球菌疾病风险增加的患者的研究来确定健康中对肺炎球菌携带具有保护作用的免疫反应。我们已经开发出一种在世界上独一无二的方法，用于安全地接种人类疫苗，以便在实验中建立体型，现在已经在300多名受试者中进行了测试，没有不良反应。这种自然运输模型可用于(A)发现健康受试者如何对运输做出免疫反应，(B)发现有风险因素(年龄、慢性肺病)的受试者如何对运输做出反应，以及这与健康人有何不同，(C)在试验运输中测试新疫苗的效果，以及(D)发现宿主在携带细菌时如何改变细菌的生物学。使用EHPC测试新疫苗可以更快地完成，而且成本只有临床研究(100名受试者而不是数千人)的一小部分，因此在该计划期间，可以在发现科学的同时测试几种疫苗。该方案还提供了与赞助特定新疫苗的商业实体或慈善机构建立伙伴关系的机会，并将与MRC一起探索这些供资方案。总而言之，该EHPC方案将运行和协调最大限度地利用独特的人类肺炎球菌挑战模型，以研究宿主/病原体之间的相互作用，这对通过接种疫苗预防肺炎球菌疾病至关重要。我们将使用各种肺炎球菌菌株来挑战人类志愿者，包括健康的和具有肺炎球菌疾病风险因素的志愿者，以确定潜在的易感性和疾病保护因素。我们将在科学发现计划的同时，使用人类挑战模型管理一系列商业疫苗开发研究。

Streptococcus pneumoniae is the most common bacterial cause of pneumonia, meningitis and otitis media in children world-wide. In adults, pneumococcal pneumonia is a common and increasing cause of hospital admission with substantial mortality in the elderly. In addition, pneumococcal infections cause exacerbations of chronic lung disease, particularly COPD and asthma. An important paradox in pneumococcal infection, however, is that in the vast majority of people these bacteria are occasionally found harmlessly inhabiting the naso-pharynx. This harmless state, termed pneumococcal carriage, boosts immunity to pneumococcal disease and is therefore of some benefit but can also be the means by which infection is transmitted. Pneumococcal carriage is considered to be the key to controlling disease as it is the means of transmission and the prerequisite of disease.Vaccination is the most important and effective intervention in the prevention of pneumococcal disease but the weapons in this armoury are still far from optimal in terms of expense and coverage of pneumococcal types. Current vaccines have, however, demonstrated that effective prevention of both pneumococcal carriage and disease is possible in young children, with indirect benefit to unvaccinated adults resulting from reduction of circulating pneumococcal carriage. It is less clear how current vaccines should be used directly in adults, or those with chronic disease. It is also unclear by what mechanism vaccines alter carriage and which vaccines are most effective in this regard. There are many new vaccines at early stages of development and studies of how they influence carriage could be important in choosing between possible alternatives.This Experimental Human Pneumococcal Carriage (EHPC) Programme Grant will make use of studies in healthy volunteers and patients with increased risk of pneumococcal disease to determine the immune responses in health that are protective against pneumococcal carriage. We have developed a method, unique in the world, for inoculating humans safely in order to establish carriage experimentally and have now tested it in over 300 subjects without adverse effects. This model of natural carriage can be used to (a) discover how healthy subjects make immune responses to carriage, (b) discover how subjects with risk factors (age, chronic lung disease) make responses to carriage and how this is different from healthy people, (c) test new vaccines for their effect in experimental carriage and (d) discover how the host alters the biology of the bacteria while it is being carried. Testing new vaccines using EHPC can be done more quickly and at a fraction of the cost of clinical studies (100 subjects rather than many thousands) and so several vaccines can be tested during this Programme, in parallel with the discovery science. This Programme also offers an opportunity for partnership with commercial entities or charities sponsoring particular new vaccines and these funding options will be explored with MRC.In summary, This EHPC Programme will run and coordinate the maximum use of a unique human pneumococcal challenge model to study host/pathogen interactions critical to the prevention of pneumococcal disease by vaccination. We will use a variety of pneumococcal strains to challenge human volunteers, both healthy and with risk factors for pneumococcal disease, in order to determine factors underlying susceptibility and protection from disease. We will manage a portfolio of commercial vaccine development studies using the human challenge model in parallel with the science discovery programme.