Development of Efficacious Vaccine Against UTI's

开发针对尿路感染的有效疫苗

• 批准号: 7473060
• 负责人: Soman N Abraham
• 金额: $ 23.4万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-04-01 至 2010-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7473060
• 关键词: Adherence; Adhesions; Adjuvant; Adverse effects; Agent 48-80; Antibiotic Resistance; Antibiotics; Antibodies; Antibody Formation; Antigen Targeting; Antigens; Bacterial Adhesins; Bacterial Infections; Binding; Bladder; Cells; Cholera Toxin; Dendritic Cells; Development; Drug Formulations; Employee Strikes; Failure; Genitourinary system; Goals; Human; Immune; Immune response; Immunity; Immunization; Immunoglobulin A; Immunoglobulin G; Infection; Liquid substance; Lymphocyte; Lymphoid Tissue; Mannose; Mediating; Mus; Needles; Nose; Outpatients; Patients; Peptide Vaccines; Personal Satisfaction; Play; Prevention strategy; Proteins; Public Health; Recurrence; Research; Rodent; Role; Safety; Serum; Site; Surface; T-Lymphocyte; Toxic effect; Treatment Protocols; United States Food and Drug Administration; Urinary tract infection; Uropathogenic E. coli; Vaccine Adjuvant; Vaccine Antigen; Vaccines; Virulence; Virulence Factors; aluminum sulfate; bacterial resistance; base; community-acquired UTI; human subject; immunogenic; immunogenicity; interest; lymph nodes; man; mast cell; migration; nonhuman primate; prophylactic; response; small molecule; trafficking

DESCRIPTION (provided by applicant): UTIs is one of the most frequent bacterial infections of man with over 85% of the outpatient community acquired UTIs caused by E.coli. Since antibiotic resistance among uropathogenic E.coli is growing, prophylactic approaches are increasingly being sought. The virulence of E.coli is attributable to expression of fimbrial adhesion FimH that mediates bacterial adherence and subsequent bacterial invasion of the bladder uroepithelium. Vaccines comprising of FimH or FimH fragments have proven highly effective in protecting mice against UTIs. However, when these FimH vaccines were administered intramuscularly with alum as adjuvant in humans, the levels of FimH specific antibodies in the serum and mucosal surfaces were low and not sustainable. Currently, a major limitation in the use of FimH vaccine in the humans is the absence of effective and safe adjuvants capable of achieving high levels of specific antibodies in serum and mucosal secretions. Recently, we discovered that mast cells (MCs) play a hitherto unrecognized role at sites of infection in orchestrating the trafficking of dendritic cells and B and T cells, Key immune cells critical for the development of adaptive immune responses. These observations led us to investigate whether co-administering antigens along with MC activators would result in elevated antigen-specific immune response. Preliminary studies revealed administering different vaccine antigens along with compound 48/80 in the nasal regions of mice evoked a highly elevated IgG response in the serum as well as IgA responses in various mucosal fluids. These studies revealed that mast cell activators have the potential to serve as potent adjuvants. Here, we hypothesized that if FimH or FimH fragments were nasally co-administered into mice with a mast cell activator, we would evoke highly protective immunity against UTI. The goals of this study are to (1) ) Evaluate the immunogenicity and protective capacity against UTIs of a FimH1-25 peptide vaccine when co administered nasally with compound 48/80. (2) Compare the efficacy and safety of compound 48/80 as a vaccine adjuvant with other known MC activators (3) Confirm that the adjuvant activity demonstrated with mast cell activators acts through specific activation of resident MCs. PUBLIC HEALTH RELEVANCE: Vaccines comprising of Fim H or FimH fragments have proven highly effective in protecting mice against UTIs. However, when these FimH vaccines were administered intramuscularly with alum as adjuvant in humans, the levels of FimH antibodies in the serum and mucosal were low and not sustainable. Currently a major limitation in the use of Fim H vaccines in humans is the absence of effective and safe adjuvants capable of achieving high levels of specific antibodies in serum and mucosal secretion. Preliminary studies have revealed that administering different vaccine antigens along with a mast cell activator in the nasal regions of mice evoked a high level of IgG antibodies in the serum as well as IgA antibodies in various mucosal fluids. The primary goal of this study is therefore to evaluate the immunogenisity and protective capacity against UTIs of a FimH peptide vaccine when co-administered nasally with mast cell activator.

描述（由申请人提供）：UTI是男性最常见的细菌感染之一，超过85％的门诊社区被e.coli引起的UTI。由于尿道病大肠杆菌之间的抗生素耐药性正在增长，因此越来越多地寻求预防性方法。大肠杆菌的毒力归因于介导细菌粘附和随后的细菌侵袭膀胱肠uro上elim的表达。由FIMH或FIMH碎片组成的疫苗已被证明在保护小鼠免受UTI的保护方面非常有效。但是，当这些FIMH疫苗被肌肉内用明矾作为辅助剂在人类中时，血清和粘膜表面中的FIMH特异性抗体水平较低且不可持续。当前，在人类中使用FIMH疫苗的主要局限性是缺乏能够在血清和粘膜分泌中获得高水平的特定抗体的有效辅助物。 最近，我们发现肥大细胞（MCS）在策划树突状细胞和B和T细胞的运输方面在感染部位起着无法识别的作用，这对于自适应免疫反应的发展至关重要。这些观察结果导致我们研究了辅助抗原以及MC激活剂是否会导致抗原特异性免疫反应升高。初步研究表明，在小鼠的鼻部鼻区使用不同的疫苗抗原以及化合物48/80，诱发了血清中高度升高的IgG反应以及各种粘膜液中的IgA反应。这些研究表明，肥大细胞活化剂有可能充当有效的佐剂。在这里，我们假设，如果FIMH或FIMH片段与肥大细胞激活剂鼻鼻子共同管理，我们将唤起对UTI的高度保护性免疫。这项研究的目标是（1））评估与化合物48/80鼻腔施用时，对FIMH1-25肽疫苗的UTI的免疫原性和保护能力。 （2）将化合物48/80作为疫苗辅助的功效和安全性与其他已知的MC激活剂的功效（3）确认，用肥大细胞激活剂证明的辅助活性通过居民MC的特异性激活作用。公共卫生相关性：由FIM H或FIMH碎片组成的疫苗已证明在保护小鼠免受UTI的保护方面非常有效。但是，当这些FIMH疫苗被肌肉内用明矾作为人类辅助剂施用时，血清和粘膜中的FIMH抗体水平很低，并且不可持续。目前，在人类中使用FIM H疫苗的主要局限性是缺乏能够在血清和粘膜分泌中获得高水平的特定抗体的有效和安全佐剂。初步研究表明，在小鼠的鼻区域内施用不同的疫苗抗原以及肥大细胞活化剂，引起了各种粘膜液中血清中高水平的IgG抗体以及IgA抗体。因此，这项研究的主要目的是评估当与肥大细胞激活剂鼻腔辅助管理时，针对FIMH肽疫苗的UTI的免疫原性和保护能力。