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

肺炎链球菌是世界范围内儿童肺炎、脑膜炎和中耳炎的最常见细菌原因。在成年人中，肺炎球菌性肺炎是一种常见且日益增加的住院原因，老年人的死亡率很高。此外，肺炎球菌感染会导致慢性肺部疾病的恶化，特别是COPD和哮喘。然而，肺炎球菌感染中的一个重要矛盾是，在绝大多数人中，这些细菌偶尔被发现无害地栖息在鼻咽部。这种无害的状态，称为肺炎球菌携带，增强了对肺炎球菌疾病的免疫力，因此有一定的好处，但也可能是感染传播的途径。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先决条件，疫苗接种是预防肺炎球菌疾病的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率来看，这一武器库中的武器仍然远远不够理想。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和疾病是可能的，未接种疫苗的成年人因减少循环肺炎球菌携带而间接受益。目前尚不清楚目前的疫苗应如何直接用于成年人或慢性病患者。目前还不清楚疫苗通过何种机制改变携带情况，以及哪种疫苗在这方面最有效。现时有很多新疫苗正处于发展初期，研究这些疫苗如何影响带菌情况，对选择其他疫苗可能十分重要。这项“人类肺炎球菌带菌试验计划”拨款，将利用对健康志愿者和较易感染肺炎球菌疾病的病人进行的研究，以确定健康人士的免疫反应，从而预防肺炎球菌带菌。我们已经开发出一种世界上独一无二的方法，可以安全地将人类从实验中转移出来，现在已经在300多名受试者中进行了测试，没有任何不良影响。这种自然携带模型可用于（a）发现健康受试者如何对携带产生免疫反应，（B）发现具有风险因素（年龄、慢性肺病）的受试者如何对携带产生反应，以及这与健康人有何不同，（c）测试新疫苗在实验性携带中的效果，以及（d）发现宿主如何在携带细菌时改变细菌的生物学。使用EHPC测试新疫苗可以更快地完成，并且成本仅为临床研究的一小部分（100名受试者而不是数千名受试者），因此可以在本计划期间测试几种疫苗，同时进行发现科学。该计划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探讨这些资金选择。总之，该EHPC计划将运行和协调最大限度地使用独特的人类肺炎球菌挑战模型，以研究宿主/病原体相互作用，这对通过疫苗接种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，包括健康的和有肺炎球菌疾病风险因素的志愿者，以确定易感性和疾病保护的潜在因素。我们将使用人类挑战模型与科学发现计划并行管理商业疫苗开发研究组合。

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.