Enhancing protective immunity against RSV by inhibitors of sphingolipid synthesis

通过鞘脂合成抑制剂增强对 RSV 的保护性免疫力

• 批准号: 10354486
• 负责人: Stefan Worgall
• 金额: $ 26.94万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-09 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10354486
• 关键词: Active Immunization; Adjuvant; Adult; Affect; Age; Aluminum; Antibodies; Antibody Response; Antigen-Presenting Cells; Antigens; B cell differentiation; B-Lymphocytes; Biological; Cells; Characteristics; Child; Coenzyme A-Transferases; Data; Dendritic Cells; Development; Disease; Exposure to; Formalin; Genetic; Health; Helper-Inducer T-Lymphocyte; Human; Immune; Immune response; Immunity; Immunization; Inactivated Vaccines; Infection; Inflammatory; Intramuscular; Lead; Lower respiratory tract structure; Lung; Lung diseases; Lymphocyte; Mediastinal lymph node group; Mediator of activation protein; Memory B-Lymphocyte; Methods; Morbidity - disease rate; Mucous Membrane; Mus; Neonatal; Outcome; Palmitoyl Coenzyme A; Phenotype; Plasma Cells; Play; Population; Populations at Risk; Property; Pulmonary Inflammation; Respiratory Syncytial Virus Vaccines; Respiratory System; Respiratory Tract Diseases; Respiratory syncytial virus; Respiratory syncytial virus RSV F proteins; Risk; Role; Route; Salts; Secondary to; Serine; Shapes; Sphingolipids; Spleen; T-Lymphocyte; Testing; Time; Toll-like receptors; Vaccinated; Vaccination; Vaccines; Viral; Viral Antigens; Virus Diseases; Virus Inhibitors; adaptive immune response; airway hyperresponsiveness; cell motility; experimental study; global health; high risk; immune activation; immunogenicity; improved; infant infection; inhibitor; innate immune mechanisms; lymph nodes; mortality; neutralizing antibody; novel; pathogenic virus; respiratory; respiratory challenge; respiratory pathogen; response; secondary lymphoid organ; serine palmitoyltransferase; sex; sphingosine 1-phosphate; success; thermozymocidin; tool; trafficking; vaccination strategy; vaccine development; vaccine response

PROJECT SUMMARY Infections with respiratory syncytial virus (RSV) are a considerable global health threat with high morbidity and mortality in populations at risk, especially young children. Despite decades of intense efforts, a safe and effective vaccine against RSV is not available. The development of an active immunization strategy has been hampered by the risk for severe lung disease. Severe RSV lung disease first occurred in small children who had been vaccinated with a formalin- inactivated vaccine upon infection with RSV. Lessons learned from studying severe RSV disease, and responses to RSV antigens point to the need for a successful vaccine to induce robust Th1-biased immune response and potent neutralizing antibodies. We found that simultaneous inhibition of sphingolipid de novo synthesis and mucosal administration RSV induces a robust, Th1 biased and protective immune responses. We hypothesize that inhibitors of serine-palmitoyl CoA transferase (SPT), the rate-limiting step of sphingolipid synthesis, can function as potent adjuvants to enhance and favorably shape the immunogenicity of an RSV vaccine. Further, the mechanism of this novel adjuvant strategy might differ substantially from the pro-inflammatory and TLR-activating properties of other adjuvants. The aims of this exploratory proposal are two-fold: First, to confirm the adjuvant effect of SPT-inhibitors for a variety or biological relevant variables and targets for a RSV vaccine, most importantly the capacity to enhance Th1 immunity and to lower the risk for vaccine-enhanced disease. Second, to elucidate the innate immune mechanisms that trigger the increased adaptive immune responses. Given the early stage of this project, we will focus mostly on lung dendritic cells and potential alterations in immune cell trafficking induced by changes in pulmonary mucosal sphingolipid synthesis. These results could then inform further detailed immune characterization of other potentially affected cells, such as T follicular helper and regulatory cells and further development of SPT-inhibitors as potential adjuvants for vaccines against other respiratory pathogens.

项目摘要 呼吸道合胞病毒（RSV）的感染是巨大的全球健康威胁 人口处于危险中的发病率和死亡率，尤其是幼儿。尽管数十年 不可用的努力，对RSV的安全有效的疫苗。发展的发展 严重肺部疾病的风险阻碍了主动免疫策略。严重 RSV肺部疾病首先发生在接受福尔马林疫苗接种的小孩中 感染RSV后灭活疫苗。从研究严重的RSV中学到的经验教训 疾病以及对RSV抗原的反应表明，成功疫苗需要诱导 强劲的Th1偏置免疫反应和有效的中和抗体。我们发现 同时抑制从头合成和粘膜给药RSV 诱导强大的Th1偏见和保护性免疫反应。我们假设抑制剂 丝氨酸 - 甲状腺素COA转移酶（SPT）的鞘脂合成速率步骤 充当有效的佐剂，可增强和塑造RSV的免疫原性 疫苗。此外，这种新颖的佐剂策略的机制可能与 其他佐剂的促炎和TLR激活特性。这个目的 探索性提案是两个方面：首先，确认SPT抑制剂的辅助作用 RSV疫苗的多样性或生物学相关变量和目标，最重要的是 增强Th1免疫力并降低疫苗增强疾病风险的能力。第二， 阐明触发自适应免疫的先天免疫机制 回答。鉴于该项目的早期阶段，我们将主要关注肺树突状细胞和 肺粘膜变化引起的免疫细胞运输的潜在改变 鞘脂合成。这些结果然后可以告知进一步详细的免疫特征 其他潜在受影响的细胞，例如T卵泡辅助器和调节细胞，以及进一步 开发SPT抑制剂作为疫苗对其他呼吸道的潜在佐剂 病原体。