Mechanisms Involved in, and Development of, FcR-Enhanced Mucosal Vaccination

FcR 增强粘膜疫苗的参与机制和开发

• 批准号: 8261081
• 负责人: Edmund J Gosselin
• 金额: $ 38.47万
• 依托单位: ALBANY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8261081
• 关键词: Adjuvant; Antibodies; Antigen Presentation; Antigen Targeting; Antigen-Presenting Cells; Antigens; Area; B-Lymphocytes; Binding; CD4 Positive T Lymphocytes; CD8B1 gene; Categories; Cells; Cellular Immunity; Communicable Diseases; Complex; Development; Dose; Event; Fc Receptor; Flow Cytometry; Formaldehyde; Francisella tularensis; Generations; Human; Humoral Immunities; Immune; Immune response; Immunity; Immunization; Immunofluorescence Immunologic; Immunoglobulin G; Infection; Inflammation; Interferon Type II; Knockout Mice; Knowledge; Label; Life; Lymphoid Tissue; Measures; Mediating; Monitor; Mono-S; Monoclonal Antibodies; Mucosal Immune Responses; Mucosal Immunity; Mus; Organism; Peripheral; Play; Production; Public Health; Radiolabeled; Role; Route; Series; Streptococcus pneumoniae; Subunit Vaccines; Surface; T-Lymphocyte; Testing; Vaccines; Virulent; Work; aluminum sulfate; antigen binding; base; biothreat; extracellular; flexibility; improved; in vivo; interferon-alpha B; mucosal site; mucosal vaccination; mucosal vaccine; neonatal Fc receptor; pathogen; radiotracer; receptor function; vaccine development

SUMMARY: F. tularensis is a gram-negative Category A intracellular mucosal pathogen. Cellular immunity is critical for protection against this organism, while antibodies (Abs) delay the progression of infection. Targeting antigen (Ag) to Fc receptors (FcR) on Ag presenting cells (APC) can enhance humoral and cellular immunity. We hypothesize targeting infectious disease Ag, such as inactivated F. tularensis (iFt), to FcR at mucosal sites will enhance protection against mucosal challenge. In Aim 1, we will investigate the ability of preformed mAb-iFt complexes and mAb plus iFt mixtures, to enhance binding, internalization, and presentation of iFt by APC to Ag-specific T cells, key events in initiating a protective immune response. We will: 1) Examine the impact of mAb:iFt ratio on mAb-iFt-binding, internalization, and Ag presentation by mouse APC; 2) Determine, using mouse APC, if mAb plus iFt mixtures can be used in place of preformed mAb-iFt; 3) Determine if the above FcR-targeting strategies also enhance IFt-binding, internalization, and presentation by human APC. In Aim 2, we will determine in mice, the ability of mAb-iFt complexes and/or mAb plus iFt mixtures administered i.n., i.d., i.m., or s.c. to enhance protection against i.n. or i.d challenge with live F. tularensis, and identify the humoral and/or cellular components critical to the observed protection. We will: 1) Verify optimal FcR-mediated binding, internalization, and presentation observed in Aim 1, correlates with optimal protection generated by FcR-targeted immunogens administered i.n.; 2) Determine the role of CD8 and CD4 T cells, B cells, FcR, Ab, and IFN-gamma in FcR-dependent protection, using mice lacking these immune components; 3) Determine if FcR-targeted iFt preferentially localizes to lymphoid tissues, versus non-targeted iFt; 4) Determine if protection against i.n. and i.d. challenge can be generated following peripheral (i.d., i.m., or s.c.) immunization; 5) Determine if inclusion of CTB (i.n.) and Alum (i.d., i.m., or s.c.) further enhances protection generated by FcR- targeted immunogens. In Aim 3, we will validate the flexibility and the multi-pathogen potential of this vaccine platform. Specifically, we will generate an FcR-targeted subunit vaccine (Fc-PspA) against S. pneumoniae, an extracellular mucosal pathogen of significant public health concern. PspA is a surface component of S. pneumoniae, which generates Ab-dependent protection in the presence of adjuvant. We will investigate the ability of mono- and multivalent Fc-PspA conjugates containing variable amounts of PspA, and administered via mucosal and peripheral routes, to protect against i.n. challenge with S. pneumoniae. The significance of the above studies is substantial: 1) New and safer vaccine platforms, which generate both humoral and cellular immunity are needed; 2) The latter is particularly evident in the case of mucosal vaccines; 3) There is an urgent need for an effective mucosal vaccine against F. tularensis, and a more efficacious vaccine against S. pneumoniae; 4) Knowledge regarding the role of FcR in mucosal immunity, and the generation of protection against mucosal pathogens, is lacking. The proposed studies will fill significant gaps in all the above areas.

摘要：土拉菌是一种革兰氏阴性的a类细胞内粘膜病原体。细胞免疫是