Protective versus deleterious immune responses that impact vaccine efficacy against Staphylococcus aureus bloodstream infection

影响金黄色葡萄球菌血流感染疫苗功效的保护性免疫反应与有害免疫反应

• 批准号: 10358530
• 负责人: M Javad Aman
• 金额: $ 72.75万
• 依托单位: INTEGRATED BIOTHERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-12 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10358530
• 关键词: Acquired Immunodeficiency Syndrome; Adjuvant; Affect; Antibiotic Resistance; Antibiotics; Antigens; Bacteremia; CD4 Positive T Lymphocytes; Cardiac Surgery procedures; Cessation of life; Clinical; Clinical Research; Clinical Trials; Consequentialism; Cutaneous; Development; Disease; Endothelial Cells; Epithelial Cells; Exposure to; Future; Generations; Goals; HLA-DR4 Antigen; Human; Immune; Immune Evasion; Immune response; Immunity; Immunization; Immunize; Immunologics; Immunotherapy; Incidence; Individual; Infection; Infectious Skin Diseases; Interferon Type II; Interleukin-17; Interleukin-2; Iron; Lead; Life; Macaca fascicularis; Mediating; Membrane Proteins; Modeling; Morbidity - disease rate; Multiple Organ Failure; Mus; Operative Surgical Procedures; Outcome; Parents; Pathogenicity; Patient-Focused Outcomes; Patients; Persons; Phenotype; Pilot Projects; Placebo Control; Placebos; Pre-Clinical Model; Prevalence; Public Health; Recurrence; Role; Sepsis; Serum; Staphylococcal Vaccines; Staphylococcus aureus; Staphylococcus aureus infection; Stromal Cells; Superantigens; Surface; Surface Antigens; Systemic infection; T cell anergy; T cell response; T-Lymphocyte; Testing; Time; Toxin; Toxoids; Transgenic Mice; Transgenic Organisms; Treatment Failure; Vaccinated; Vaccination; Vaccine Adjuvant; Vaccinee; Vaccines; Virulence; Virulence Factors; Whole Cell Vaccine; Wild Type Mouse; base; cell injury; cell mediated immune response; clinical care; cytokine; efficacy testing; human pathogen; humanized mouse; immunopathology; insight; methicillin resistant Staphylococcus aureus; mortality; mutant; nonhuman primate; novel; operation; premature; prevent; response; vaccination outcome; vaccine development; vaccine efficacy; vaccine failure; vaccine immunogenicity; vaccine platform; vaccine-induced immunity

Staphylococcus aureus (SA) is a major human pathogen that can cause life threatening systemic infections. In fact, S. aureus is the most common cause of nosocomial bacteremia with a prevalence of 26%. Despite improvements in clinical care, SA bloodstream infection (BSI) continues to pose a major challenge due to high rate of treatment failure and mortality. Infections that are caused by methicillin-resistant SA (MRSA) strains are becoming increasingly resistant to antibiotics, leading to treatment failures and poor patient outcomes. If host- directed therapies such an effective SA vaccine can provide an alternative to antibiotics, a greater understanding of immune mechanisms that promote protection is essential. This is especially important since all SA vaccination attempts over the past two decades have failed in human trials. Notably, in a recent trial, a vaccine targeting SA iron surface determinant B (IsdB) against SA infections following cardiothoracic surgery had the opposite effect and patients who were vaccinated and suffered a SA infection had a 2-fold higher rate of multiorgan failure and a 5-fold higher mortality than placebo controls. While reasons for this catastrophic outcome are still unknown, a post-hoc study suggested that absent or low serum T cell cytokine levels (IL-2 and IL-17) at the time of vaccination predisposed them for treatment failure. There is therefore an urgent need to understand the underlying immunological mechanisms that lead to these deleterious outcomes. Our preliminary findings in mice recapitulate deleterious immune responses triggered by immunizing mice with a lethally irradiated whole cell vaccine or by intradermal exposure to SA that led to exacerbated disease and mortality upon SA BSI challenge. This phenotype was associated with a CD4 T cell mediated, IFNγ-dependent immunopathology and likely an imbalance of Th1/Th17 responses. The goal of this proposal is to test the overarching hypothesis that prior exposure to SA antigens and virulence factors or cutaneous SA infection impact natural- and vaccine-elicited CD4 T cell responses during a subsequent SA BSI. To this end, using mice we will fully characterize the T cell responses to two vaccine platforms and will evaluate how the initial response to SA surface antigens or to a toxoid vaccine differentially regulate the CD4 T cell response, and consequently the vaccine-elicited immunity against subsequent SA BSI and if these responses can be influenced by different vaccine adjuvants (Aim 1). Using WT mice and human HLA-DR4 transgenic mice as well as several WT and isogenic mutant SA strains we will investigate how pore forming toxins and superantigens modulate CD4 T cell responses that affect natural and vaccine induced immunity against SA BSI (Aim 2). We will also establish and use a novel nonhuman primate model of SA BSI and evaluate the impact of pre-exposure on vaccine immunogenicity, with a focus on CD4 T cell responses, and efficacy of our multivalent toxoid vaccine (Aim 3). The ultimate goal of this proposal is to understand protective vaccine-induced immunity against SA BSI in complementary pre-clinical models to deepen our understanding of immunity to SA BSI to help guide more effective vaccines to prevent disastrous outcomes in future clinical trials.

金黄色葡萄球菌（SA）是一种主要的人类病原体，可能导致威胁生命的全身感染。在 事实，金黄色葡萄球菌是医院细菌的最常见原因，患病率为26％。尽管 临床护理的改善，SA血液感染（BSI）继续构成重大挑战 治疗率失败和死亡率。由耐甲氧西林SA（MRSA）菌株引起的感染是 变得越来越对抗生素具有抗药性，导致治疗衰竭和患者结局差。如果主持人 - 这种有效的SA疫苗的定向疗法可以提供抗生素的替代方法，更了解 促进保护的免疫机制至关重要。这尤其重要，因为所有SA疫苗接种 在过去的二十年中，尝试在人类试验中失败了。值得注意的是，在最近的一项试验中，靶向SA的疫苗 心胸外科手术后针对SA感染的铁表面确定剂B（ISDB）具有相反的作用 接种疫苗并遭受SA感染的患者的多机器人衰竭率高2倍和 比安慰剂对照高5倍。虽然这种灾难性结果的原因仍然未知，但 事后研究表明，缺乏或低血清T细胞细胞因子水平（IL-2和IL-17） 疫苗接种使它们患有治疗失败。因此，迫切需要了解 导致这些有害结果的基本免疫机制。我们在老鼠中的初步发现 概括性删除的免疫反应是由用致命的全细胞免疫小鼠触发的 疫苗或通过皮内暴露于SA，导致SA BSI挑战时加剧的疾病和死亡率。 该表型与介导的IFNγ依赖性免疫病理学的CD4 T细胞有关，并且可能 TH1/TH17响应的不平衡。该提议的目的是检验先验的总体假设 暴露于SA抗原和病毒因子或皮肤SA感染会影响自然和疫苗吸收的影响 随后的SA BSI期间的CD4 T细胞反应。为此，使用小鼠，我们将完全表征T细胞 对两个疫苗平台的响应，并将评估对SA表面抗原或对A的初始反应 毒素疫苗会差异调节CD4 T细胞反应，因此疫苗引起的免疫功能 反对随后的SA BSI，如果这些反应可能会受到不同疫苗调节器的影响（AIM 1）。 使用WT小鼠和人HLA-DR4转基因小鼠以及几种WT和等源性突变体菌株 将研究如何形成毒素和超抗原的孔调节影响自然的CD4 T细胞反应 疫苗可诱导对SA BSI的免疫力（AIM 2）。我们还将建立和使用一种新颖的非人类灵长类动物 SA BSI的模型并评估暴露前对疫苗免疫原性的影响，重点是CD4 T 细胞反应和我们多价毒素疫苗的效率（AIM 3）。该提议的最终目标是 了解受保护的疫苗诱导的对SA BSI的免疫力，以完整的临床前模型加深 我们对SA BSI免疫的理解，以帮助指导更有效的疫苗以防止灾难结果 在以后的临床试验中。