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（Staphylococcus aureus，SA）是一种主要的人类病原体，可引起危及生命的全身性感染。在 事实上，S。金黄色葡萄球菌是医院内菌血症的最常见原因，患病率为26%。尽管 随着临床护理的改善，SA血流感染（BSI）继续构成一个重大挑战， 治疗失败率和死亡率。由耐甲氧西林金黄色葡萄球菌（MRSA）菌株引起的感染是 对抗生素的耐药性越来越强，导致治疗失败和患者预后不良。如果主持人- 这种有效的SA疫苗可以提供抗生素的替代品， 促进保护的免疫机制至关重要。这一点尤其重要，因为所有SA疫苗接种 过去二十年的尝试在人体试验中失败了。值得注意的是，在最近的一项试验中，一种针对SA的疫苗 铁表面决定子B（IsdB）对心胸外科手术后SA感染具有相反的作用 接种疫苗并感染SA的患者多器官衰竭的发生率高出2倍， 死亡率是安慰剂对照组的5倍。虽然这种灾难性后果的原因仍然未知， 事后研究表明，治疗时血清T细胞细胞因子水平（IL-2和IL-17）缺失或较低 接种疫苗使他们容易治疗失败。因此，迫切需要了解 导致这些有害结果的潜在免疫机制。我们在老鼠身上的初步发现 概括了用致死性辐照的全细胞免疫小鼠所引发的有害免疫应答 疫苗或通过皮内暴露于SA，导致SA BSI攻击后疾病加重和死亡。 这种表型与CD 4 T细胞介导的IFNγ依赖性免疫病理学有关， Th 1/Th 17反应失衡。该提案的目标是测试首要假设，即 暴露于SA抗原和毒力因子或皮肤SA感染影响自然和疫苗引起的 在随后的SA BSI期间的CD 4 T细胞应答。为此，我们将使用小鼠来全面表征T细胞 反应，并将评估如何初始反应SA表面抗原或 类毒素疫苗差异性地调节CD 4 T细胞应答，从而调节疫苗引起的免疫 针对随后的SA BSI，以及这些应答是否可以受到不同疫苗佐剂的影响（目的1）。 使用WT小鼠和人HLA-DR 4转基因小鼠以及几种WT和同基因突变SA株， 将研究如何孔形成毒素和超抗原调节CD 4 T细胞反应，影响自然 和疫苗诱导的抗SABSI的免疫（目的2）。我们还将建立并使用一种新的非人类灵长类动物 SA BSI模型，并评价预暴露对疫苗免疫原性的影响，重点是CD 4 T 细胞应答和我们的多价类毒素疫苗的功效（目的3）。这项建议的最终目的是 在补充临床前模型中了解针对SA BSI的保护性疫苗诱导免疫，以加深 我们对SA BSI免疫力的理解有助于指导更有效的疫苗预防灾难性后果 在未来的临床试验中。