Enhancing efficacy of pertussis vaccines

增强百日咳疫苗的功效

• 批准号: 9158545
• 负责人: RAJENDAR K DEORA
• 金额: $ 39.11万
• 依托单位: WAKE FOREST UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9158545
• 关键词: Acellular Vaccines; Adjuvant; Adoptive Transfer; Antibodies; Antibody Response; Antigens; Blood Chemical Analysis; Bordetella; Bordetella pertussis; CD4 Positive T Lymphocytes; Cells; Clinical; Combined Vaccines; Country; Data; Developed Countries; Disease; Enhancing Antibodies; Europe; Formulation; Goals; Heart; Immune; Immune Cell Activation; Immune response; Immunity; Immunization; Immunologic Memory; Incidence; Individual; Infection; Inflammatory; Injection of therapeutic agent; Interferon Type II; Interferons; Interleukin-17; Kidney; Knockout Mice; Laboratories; Life; Liver; Longevity; Lung; Lung diseases; Membrane Proteins; Memory; Modification; Molecular; Molecular Profiling; Mus; Pertussis; Pertussis Vaccine; Phenotype; Property; Proteins; Public Health; Research; Respiratory System; Respiratory tract structure; Role; Shapes; Signal Pathway; Site; System; T cell response; T-Lymphocyte; TLR4 gene; Testing; Tissues; Treatment Efficacy; Vaccines; Whole Cell Vaccine; Work; adaptive immunity; aluminum sulfate; combat; cytokine; factor A; functional hypothalamic amenorrhea; mouse model; novel; novel vaccines; pathogen; protective efficacy; reproductive tract; research study; response; safety testing; transcriptome sequencing; vaccine efficacy; vaccine-induced immunity

Alum is the most widely used adjuvant in acellular vaccines for bacterial pathogens including Bordetella pertussis, the causative agent of pertussis or whooping cough. However, it may not be the most effective adjuvant to elicit long-term protection when the mechanism involves Th1-type immune responses, since it skews antibody and T cell responses towards Th2. Since alum activates strong antigen-specific responses and provides protection in the short term, leveraging these properties with an adjuvant that shapes the immune repertoire towards a Th1/Th17-type response may elicit a more protective response that confers life-long immunity. Despite high vaccine coverage, the incidence of pertussis is increasing in the USA, Europe and other countries. The current acellular pertussis vaccines (aPV) are only partly effective, compared with whole cell vaccines (wPV). However, the reactogenicity of wPV limits its use. We identified an outer membrane protein, Bordetella Colonization Factor A (BcfA), and show that it has adjuvant activity and enhances antibody responses to protein antigens. In an intranasal murine model of B. pertussis infection, we show that addition of BcfA to the aPV induces Th1-skewed antibody responses and provides better protection against infection. We hypothesize that the combined activity of alum and BcfA will result in synergistic enhancement of protective immune responses in mice against B. pertussis. In Specific Aim 1, we will test the signaling pathways activated by BcfA, alone and together with alum. We hypothesize that combination treatment with these adjuvants will reshape the profile of activated cytokines produced by inflammatory cells. In Specific Aim 2, we will determine how combined immunization with BcfA and alum alters the phenotype of antibody and T cell responses to B. pertussis antigens. In Specific Aim 3, we hypothesize that the Th1/Th17 skewed immune responses induced by the combination of alum and BcfA will result in better clearance of a B. pertussis challenge, and long-lived immunologic memory. This hypothesis will be tested by determining the effect of combined alum/BcfA immunization on B. pertussis clearance from the murine respiratory tract. IMPACT: We have identified a novel adjuvant, BcfA, and hypothesize that the potent responses induced by alum will be shaped to a Th1 type response by BcfA thereby providing better protection against B. pertussis infection. This adjuvant combination may be applicable to other diseases where Th1 type immunity is important for protection.

明矾是用于包括博德特氏菌在内的细菌病原体的无细胞疫苗中最广泛使用的佐剂 百日咳，百日咳的病原体。然而，它可能不是最有效的 当机制涉及Th 1型免疫应答时，佐剂可以引发长期保护，因为它 使抗体和T细胞应答偏向Th 2。由于明矾能激活强烈的抗原特异性反应， 在短期内提供保护，利用这些特性与佐剂，塑造免疫 Th 1/Th 17型反应的所有组成部分可能会引发更具保护性的反应， 免疫力 尽管疫苗覆盖率很高，但百日咳的发病率在美国，欧洲和其他国家正在增加。 国家目前的无细胞百日咳疫苗（aPV）与全细胞疫苗相比， 疫苗（wPV）。然而，wPV的反应原性限制了其使用。我们发现了一种外膜蛋白， 博德特氏菌定殖因子A（BcfA），并显示其具有佐剂活性和增强抗体 对蛋白质抗原的反应。在B的鼻内小鼠模型中。百日咳感染，我们表明，除了 针对aPV的BcfA诱导Th 1偏斜的抗体应答，并提供更好的抗感染保护。我们 假设明矾和BcfA的组合活性将导致保护性的协同增强， 小鼠对B的免疫应答。百日咳。 在具体目标1中，我们将测试BcfA单独和与明矾一起激活的信号通路。 我们假设联合使用这些佐剂将重塑激活的细胞因子谱 由炎症细胞产生。在具体目标2中，我们将确定如何与BcfA联合免疫 明矾改变了抗体的表型和T细胞对B的反应。百日咳抗原在具体目标3中，我们 假设由明矾和BcfA的组合诱导的Th 1/Th 17偏斜的免疫应答将 导致B的更好清除。百日咳激发和长期免疫记忆。这一假设将 通过确定明矾/BcfA联合免疫对B的影响来测试。百日咳疫苗接种 小鼠呼吸道。 影响：我们已经确定了一种新的佐剂，BcfA，并假设， 明矾将被BcfA定型为Th 1型应答，从而提供针对B的更好保护。百日咳 感染该佐剂组合可适用于Th 1型免疫重要的其它疾病 为了保护自己