Enhancing neonatal immunity to Streptococcus pneumoniae

增强新生儿对肺炎链球菌的免疫力

• 批准号: 8299197
• 负责人: RICHARD MALLEY
• 金额: $ 41.5万
• 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/8299197
• 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. PUBLIC HEALTH RELEVANCE: The proposed research is highly relevant to public health because Streptococcus pneumoniae is an important cause of childhood disease in the US and throughout the world. This research will examine the neonatal immune response to a candidate pneumococcal vaccine that is entering clinical trials. Knowledge gained from this study will inform future vaccine development for the most susceptible population, infants and children.

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反应。 Malley 实验室和其他地方的研究揭示了 CD4+ T 细胞在防止肺炎球菌定植方面的作用。 Malley 实验室开发的全细胞疫苗 (WCV) 将进入一期临床试验，可对肺炎球菌提供双管齐下的保护：CD4+ Th17 依赖性的针对定植的保护和非荚膜抗体介导的针对侵袭性疾病的保护。初步研究表明，虽然幼年小鼠对全细胞疫苗有反应并免受肺炎球菌定植，但与成年小鼠相比，它们的 CD4+ T 细胞反应减弱，保护作用也较低。了解婴儿中抑制 T 细胞对 WCV 的强烈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 反应的有效抑制剂，我们已经证明，与成年小鼠的巨噬细胞相比，新生巨噬细胞在受到肺炎球菌抗原刺激时会产生明显更多的 IL-10。因此，我们建议检验以下假设：WCV 在婴儿中的免疫原性和功效降低主要是由于新生儿抗原呈递细胞产生的 IL-10 和其他抑制性细胞因子增加所致。在目标 1 中，我们将结合使用转基因小鼠和 Horwitz 实验室开发的独特 IL-10 试剂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 NF-κB 和 ERK 信号通路，以及参与调节 IL-10 产生的细胞外 IFN-K/IL-27 轴，确定为什么新生儿巨噬细胞产生更高水平的 IL-10。在第三个也是最后一个目标中，这些先天性和后天性免疫反应将在非人类灵长类动物模型中进行评估。我们将检查新生儿、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。新生儿、幼年和成年恒河猴将使用良好生产规范 (GMP) 级全细胞疫苗进行免疫，并详细分析它们的免疫（T 细胞和抗体）反应。总体而言，这些研究将为婴儿与成人对候选肺炎球菌疫苗的免疫反应提供重要的见解，并将指导该疫苗进入临床试验时的进一步研究。 公共卫生相关性：拟议的研究与公共卫生高度相关，因为肺炎链球菌是美国和全世界儿童疾病的重要原因。这项研究将检查新生儿对正在进入临床试验的候选肺炎球菌疫苗的免疫反应。从这项研究中获得的知识将为未来针对最易感人群、婴儿和儿童的疫苗开发提供信息。