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

实验性人体肺炎球菌携带，以确定最佳的携带保护和粘膜免疫对抗疾病的机制

• 批准号: MR/M011569/1
• 负责人: Stephen Gordon
• 金额: $ 292.47万
• 依托单位: Liverpool School of Tropical Medicine
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2015
• 资助国家: 英国
• 起止时间: 2015 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FM011569%2F1
• 关键词: Experimental; Human; Pneumococcal; Carriage; determine

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.

肺炎链球菌是全世界儿童肺炎、脑膜炎和中耳炎最常见的细菌病因。在成人中，肺炎球菌肺炎是一种常见且日益增加的住院原因，在老年人中死亡率很高。此外，肺炎球菌感染会导致慢性肺病，特别是慢性阻塞性肺病和哮喘的恶化。然而，肺炎球菌感染的一个重要矛盾之处在于，在绝大多数人身上，这些细菌偶尔会在鼻咽中被发现。这种无害的状态被称为肺炎球菌携带，增强了对肺炎球菌疾病的免疫力，因此有一些好处，但也可能是感染传播的手段。肺炎球菌携带被认为是控制疾病的关键，因为它是传播手段和疾病的先决条件。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，但就肺炎球菌类型的费用和覆盖范围而言，这一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，由于减少了循环肺炎球菌携带，未接种疫苗的成年人也间接受益。目前尚不清楚目前的疫苗应如何直接用于成人或慢性病患者。目前还不清楚疫苗改变载体的机制，以及哪种疫苗在这方面最有效。有许多新疫苗处于开发的早期阶段，研究它们如何影响携带对于在可能的替代方案之间进行选择可能很重要。“实验性人类肺炎球菌携带计划”拨款将利用对健康志愿者和肺炎球菌疾病风险增加的患者进行的研究，以确定健康人群中对肺炎球菌携带具有保护作用的免疫反应。我们已经开发了一种世界上独一无二的方法，可以安全地给人类接种，以便在实验中建立载体，现在已经在300多名受试者身上进行了测试，没有出现不良反应。这种自然载体模型可用于(a)发现健康受试者如何对载体产生免疫反应，(b)发现具有危险因素（年龄、慢性肺病）的受试者如何对载体产生免疫反应，以及这与健康人有何不同，(c)在实验载体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特性。使用EHPC测试新疫苗可以更快地完成，而且成本只是临床研究的一小部分（100名受试者而不是数千名受试者），因此在本规划期间可以在发现科学的同时测试几种疫苗。该规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探讨这些供资办法。总之，该EHPC计划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来研究宿主/病原体相互作用，这对通过接种疫苗预防肺炎球菌疾病至关重要。我们将使用多种肺炎球菌菌株对健康和具有肺炎球菌疾病风险因素的人类志愿者进行挑战，以确定潜在的易感性因素和对疾病的保护。我们将在科学发现规划的同时，利用人体挑战模型管理一系列商业疫苗开发研究。

项目成果

Activation and Induction of Antigen-Specific T Follicular Helper Cells Play a Critical Role in Live-Attenuated Influenza Vaccine-Induced Human Mucosal Anti-influenza Antibody Response.

• DOI: 10.1128/jvi.00114-18
• 发表时间: 2018-06-01
• 期刊: Journal of virology
• 影响因子: 5.4
• 作者: Aljurayyan A;Puksuriwong S;Ahmed M;Sharma R;Krishnan M;Sood S;Davies K;Rajashekar D;Leong S;McNamara PS;Gordon S;Zhang Q
• 通讯作者: Zhang Q

Serum levels of anti-PspA and anti-PspC IgG decrease with age and do not correlate with susceptibility to experimental human pneumococcal colonization.

• DOI: 10.1371/journal.pone.0247056
• 发表时间: 2021
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Araujo AP;Colichio GBC;Oliveira MLS;German E;Nikolaou E;Chen T;Adler H;Ferreira DM;Miyaji EN
• 通讯作者: Miyaji EN

Pneumococcal Colonization Rates in Patients Admitted to a United Kingdom Hospital with Lower Respiratory Tract Infection: a Prospective Case-Control Study.

• DOI: 10.1128/jcm.02008-15
• 发表时间: 2016-04
• 期刊: Journal of clinical microbiology
• 影响因子: 9.4
• 作者: Collins AM;Johnstone CM;Gritzfeld JF;Banyard A;Hancock CA;Wright AD;Macfarlane L;Ferreira DM;Gordon SB
• 通讯作者: Gordon SB