Enhancing neonatal immunity to Streptococcus pneumoniae

增强新生儿对肺炎链球菌的免疫力

• 批准号: 8639459
• 负责人: RICHARD MALLEY
• 金额: $ 49.64万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8639459
• 关键词: Accounting; Adjuvant; Adult; Animal Model; Antibodies; Antibody Formation; Antibody-mediated protection; Antigen-Presenting Cells; Antigens; Attenuated; CD4 Positive T Lymphocytes; Cells; Child; Childhood; Clinical Trials; Conjugate Vaccines; Data; Development; Disease; Effectiveness; Epidemiologic Studies; Future; Immune; Immune response; Immunity; Immunization; In Vitro; Infant; Injection of therapeutic agent; Interferons; Interleukin-10; Investigation; Knockout Mice; Knowledge; Laboratories; Macaca mulatta; Modeling; Mus; Nature; Neonatal; Pattern; Phase I Clinical Trials; Pneumococcal Colonization; Pneumococcal Infections; Pneumococcal vaccine; Polysaccharides; Population; Production; Proteins; Public Health; Reagent; Refrigeration; Regulatory T-Lymphocyte; Research; Role; Serotyping; Signal Pathway; Signal Transduction; Streptococcus pneumoniae; T cell response; T-Lymphocyte; Target Populations; Testing; Time; Transgenic Mice; Vaccination; Vaccine Adjuvant; Vaccines; Whole Cell Vaccine; base; cytokine; extracellular; high risk; immunogenic; immunogenicity; inhibitor/antagonist; insight; killings; macrophage; neonatal human; neonate; nonhuman primate; novel; response; success; vaccination strategy; vaccine development; vaccine evaluation; volunteer; young adult

DESCRIPTION (provided by applicant): The overall objective of the proposed research is to evaluate the immunological response of infants to a candidate pneumococcal vaccine. Investigations in the Malley laboratory and elsewhere have revealed the role of CD4+ T cells in providing protection against pneumococcal colonization. The whole cell vaccine (WCV) developed in the Malley laboratory, which will be entering Phase I clinical trials, confers a two-pronged protection against pneumococcus: CD4+ Th17-dependent protection against colonization and non-capsular antibody-mediated protection against invasive disease. Preliminary studies have shown that while infant mice respond to the whole cell vaccine and are protected against pneumococcal colonization, they nevertheless have a reduced CD4+ T cell response and lower protection when compared to adult mice. Understanding the factors that inhibit a robust T cell response to WCV in infants will help guide development of more highly immunogenic vaccines and adjuvants, and inform immunological assessment during clinical trials. IL-10 is a potent inhibitor of Th17 responses, and we have shown that neonatal macrophages make significantly more IL-10 in response to stimulation with pneumococcal antigen than macrophages from adult mice. Therefore we propose to test the hypothesis that reduced immunogenicity and efficacy of WCV in infants is primarily due to increased production of IL-10 and other inhibitory cytokines by neonatal antigen presenting cells. In Aim 1 we will use a combination of transgenic mice and unique IL-10 reagents developed in the Horwitz laboratory to determine whether IL-10 produced by neonatal macrophages attenuates the protective Th17 response following vaccination. In Aim 2 we will determine why neonatal macrophages produce enhanced levels of IL-10 by comparing the intracellular NF-?B and ERK signaling pathways, as well as the extracellular IFN-¿/IL-27 axis that have been implicated in regulating IL-10 production. In the third and final aim, these innate and acquired immune responses will be evaluated in a nonhuman primate model. We will examine the macrophage response in neonatal, young and adult rhesus macaques, which will provide important information regarding the nature of the innate immune response to pneumococcus and this vaccine in particular. Neonatal, young and adult rhesus macaques will be immunized with Good Manufacturing Practice (GMP)-grade whole cell vaccine and their immune (T cell and antibody) responses analyzed in detail. Overall, these investigations will provide important insight into the immune response to a candidate pneumococcal vaccine in infants vs. adults and will guide further studies of this vaccine as it enters clinical trials.

描述（由适用提供）：拟议研究的总体目的是评估婴儿对候选肺炎球菌疫苗的免疫反应。在Malley实验室和其他地方进行的调查揭示了CD4+ T细胞在提供防止肺炎球菌定殖的保护中的作用。在Malley实验室开发的整个细胞疫苗（WCV）将进入I期临床试验，该试验赋予了针对肺炎球菌的两种良好保护：CD4+ TH17依赖性依赖性依赖于定殖和非囊泡抗体介导的抗体介导的防御性疾病的保护。初步研究表明，尽管婴儿小鼠对整个细胞疫苗有反应并受到肺炎球菌定殖的保护，但与成年小鼠相比，它们的CD4+ T细胞反应降低，并且降低了保护。了解抑制婴儿对WCV的强大T细胞反应的因素将有助于指导更高的免疫原性疫苗和调节器的开发，并在临床试验中为免疫学评估提供信息。 IL-10是Th17反应的潜在抑制剂，我们已经证明，新生儿巨噬细胞对肺炎球菌抗原刺激的响应比成年小鼠的巨噬细胞显着更多。因此，我们建议检验以下假设：婴儿的免疫原性和WCV的效率降低主要是由于增加。新生儿抗原呈递细胞生产IL-10和其他抑制性细胞因子。在AIM 1中，我们将使用在Horwitz实验室中开发的转基因小鼠和独特的IL-10试剂的组合来确定新生儿巨噬细胞产生的IL-10是否会减弱疫苗后受保护的TH17反应。在AIM 2中，我们将确定为什么新生儿巨噬细胞通过比较细胞内NF-？B和ERK信号传导途径以及细胞外IFN-€ /IL-27轴，这些巨噬细胞产生了增强的IL-10水平。在第三个也是最后一个目标中，这些先天和获得的免疫调查会将以非人类的私人模型进行评估。我们将研究新生儿，年轻和成人恒河猕猴的巨噬细胞反应，该猕猴将提供有关先天免疫反应对肺炎球菌尤其是这种疫苗的重要信息。新生儿，年轻和成人恒河猕猴将通过良好的制造实践（GMP）详细分析的全细胞疫苗及其免疫（T细胞和抗体）反应进行免疫。总体而言，这些投资将为婴儿与成人的候选肺炎球菌疫苗的免疫抑制反应提供重要的见解，并将在该疫苗进入临床试验时进行进一步的研究。