Pneumococcal immunization through a novel mechanism

通过新机制进行肺炎球菌免疫

• 批准号: 7338688
• 负责人: RICHARD MALLEY
• 金额: $ 40.25万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-15 至 2010-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7338688
• 关键词: Address; Adjuvant; Adoptive Cell Transfers; Adoptive Transfer; Antibodies; Antigens; Bacteria; CD4 Positive T Lymphocytes; Carrier Proteins; Cell Wall; Cells; Characteristics; Charge; Chemicals; Child; Complement; Confocal Microscopy; Conjugate Vaccines; Coupling; Data; Disease; Encapsulated; Goals; Histopathology; Immune response; Immunity; Immunization; Invasive; Knock-out; Knockout Mice; Knowledge; Lead; Life; Ligands; Light; Mediating; Methodology; Modification; Mucosal Immunity; Mus; Nasopharynx; Nature; Otitis Media; Pneumococcal Colonization; Pneumococcal Infections; Polymers; Polysaccharides; Preparation; Prevention; Property; Proteins; Resistance; Role; Route; Serotyping; Specificity; Streptococcus pneumoniae; Structure; Synthetic Vaccines; Systemic disease; T-Lymphocyte; TLR4 gene; Teichoic Acids; Thinking; Time; Toll-like receptors; Toxoids; Vaccination; Vaccines; Wild Type Mouse; acquired immunity; base; chemical synthesis; cytokine; ear infection; extracellular; memory CD4 T lymphocyte; middle ear; neutrophil; novel; novel strategies; pathogen; prevent; research study; response; success

The capsular polysaccharide-protein conjugate vaccine is effective in prevention of invasive disease by Streptococcus pneumoniae (pneumococci) of the serotypes included but is costly to make and administer, minimally effective against otitis media, and subject to serotype replacement (in which non-included serotypes become more prevalent). Therefore, novel approaches to immunization are needed. We found unexpectedly that mice immunized intranasally with the pneumococcal cell wall polysaccharide (CWPS, an antigen commonto all serotypes) develop long-lasting resistance to nasopharyngeal colonization and middle ear infection with pneumococci of different serotypes. Strikingly, protection by the vaccine(i.e. CWPS + mucosal adjuvant) is independent of antibody and dependent on the presence of CD4+ T cells. This polysaccharide-induced, cell-mediated mucosal immunity against colonization by an "extracellular" encapsulated bacterium has not, to our knowledge, been previously demonstrated and therefore represents a novel approachto vaccination. We hypothesize that the zwitterionic property of CWPS is critical in eliciting this T-cell-dependent response. Our first goal is to determine the structural basis of protection by CWPS by further purification, polymer synthesis, chemical modifications to alter the zwitterionic motif, auto-coupling, or coupling to a protein carrier. Thus either the zwitterion hypothesis will be confirmed and/or the minimal protective structure will be defined. Secondly, we will examine in more detail the mechanisms whereby CD4+ T cells confer protection against pneumococcal colonization. Adoptive transfer experiments will characterize the nature of the protective T cell responses. Further approaches will include polarization of T cell responses by use of knockout mice or administration of cytokines, neutrophil depletion experiments, and histopathology with confocal microscopy. In a third aim, we will evaluate the role of innate immune responses in modulating acquired immunity to colonization, by use of Toll-like receptor (TLR) knockout mice and co-administration of TLR ligands as adjuvants at the time of immunization. Our studies will increase basic understanding of immunity to pneumococcal colonization and could lead to a simple, defined, and possibly synthetic vaccine that would complement or replace the multivalent capsular conjugates in vaccination against this, highly prevalent pathogen of children.

荚膜多糖蛋白结合疫苗是一种有效预防侵袭性疾病的疫苗