Enhancing neonatal immunity to Streptococcus pneumoniae

增强新生儿对肺炎链球菌的免疫力

• 批准号: 8446269
• 负责人: RICHARD MALLEY
• 金额: $ 37.27万
• 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/8446269
• 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(由申请人提供)：拟议研究的总体目标是评估婴儿对候选肺炎球菌疫苗的免疫学反应。Malley实验室和其他地方的研究揭示了CD4+T细胞在提供对肺炎球菌定植的保护作用方面的作用。Malley实验室开发的全细胞疫苗(WCV)将进入第一阶段临床试验，它提供了对肺炎球菌的双管齐下的保护：依赖于CD4+Th17的对定植的保护和对侵袭性疾病的非囊膜抗体介导的保护。初步研究表明，虽然幼鼠对全细胞疫苗有反应并受到保护，不受肺炎球菌定植的影响，但与成年鼠相比，它们的CD4+T细胞反应和保护作用较低。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免疫原性疫苗和佐剂的开发，并为临床试验期间的免疫学评估提供信息。IL-10是Th17反应的有效抑制物，我们已经证明，新生儿巨噬细胞在肺炎球菌抗原刺激下产生的IL-10显著高于成年小鼠的巨噬细胞。因此，我们建议检验这一假设，即WCV在婴儿中的免疫原性和有效性降低主要是由于新生儿抗原提呈细胞产生IL-10和其他抑制性细胞因子增加所致。在目标1中，我们将使用霍维茨实验室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是否会减弱疫苗接种后的保护性Th17反应。在目标2中，我们将通过比较细胞内的NF-β和ERK信号通路，以及与调节IL-10产生有关的细胞外干扰素/IL-27轴，来确定新生儿巨噬细胞产生IL-10水平升高的原因。在第三个也是最终目标中，这些先天和后天免疫反应将在非人类灵长类动物模型中进行评估。我们将检测新生儿、幼年和成年恒河猴的巨噬细胞反应，这将提供有关肺炎球菌特别是这种疫苗的先天免疫反应性质的重要信息。将用GMP级全细胞疫苗对新生、幼年和成年恒河猴进行免疫，并详细分析它们的免疫(T细胞和抗体)反应。总体而言，这些研究将为婴儿和成人对候选肺炎球菌疫苗的免疫反应提供重要的洞察力，并将指导这种疫苗进入临床试验的进一步研究。