Antigen processing of pneumococcal conjugate vaccines

肺炎球菌结合疫苗的抗原处理

• 批准号: 8113117
• 负责人: John R. Schreiber
• 金额: $ 25.65万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-03-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8113117
• 关键词: Affect; Age; Antibodies; Antibody Formation; Antigen Presentation; Antigen-Presenting Cells; Antigens; B-Lymphocytes; Bacteria; Bacterial Polysaccharides; Carrier Proteins; Cell physiology; Cell surface; Cells; Charge; Child; Childhood; Conjugate Vaccines; Data; Development; Diphtheria Toxin; Dose; Encapsulated; Enhancing Antibodies; Event; Generations; Glycopeptides; Goals; Healthcare Systems; Immune system; Immunity; Immunization; Immunization Programs; Infant; Infection; Investigation; Link; Location; Memory; Peptides; Pneumococcal conjugate vaccine; Polysaccharides; Process; Proteins; Research; Serotyping; Streptococcus pneumoniae; T-Independent Antigens; T-Lymphocyte; United States; Vaccines; Work; antigen processing; cross reacting material 197; cytokine; design; immunogenic; immunogenicity; improved; mouse model; pathogen; response; success; uptake

DESCRIPTION (provided by applicant): Pneumococcal (Pn) capsular polysaccharides (PS) are T independent antigens that do not induce memory responses and are poor immunogens in infants. Conjugate vaccines, in which the Pn capsular PS is covalently linked to a protein, enhance the antibody titer made to the PS and are highly successful through pediatric immunization programs in reducing invasive infections caused by Pn. Despite the success of conjugate vaccines, multiple doses are required for protection, and they are expensive to produce reducing their utility in the developing world. The mechanism by which the conjugation of protein enhances PS specific antibody production remains poorly defined, making design of second generation conjugate vaccines empiric. One of the first immunological events that occurs when an antigen is introduced after immunization is uptake by an antigen presentation cell (APC), processing of the protein portion of the conjugate and presentation of peptides with MHC II to T cells. The T cell help produced is crucial for the enhanced immunogenicity of conjugate vaccines. We have been investigating the effect of the Pn PS that is covalently attached to the carrier protein on antigen processing of the carrier protein. Using the seven valent Pn capsular PS that is covalently linked to CRM197 (a non toxic form of diphtheria toxin) that is widely used in the United States, we have found that the PS transits the APC with the carrier protein peptide and co-localizes with MHC II on the APC surface. We have also found that the serotype of the PS greatly affects antigen processing efficiency of the carrier protein and that the most efficiently processed is the most immunogenic. These data imply that the PS affects the T cell help produced by the conjugate vaccine. Our goals are to determine the fate of the Pn PS attached to the carrier protein inside the antigen presenting cell (APC). We will determine the effect of antigen processing efficiency on carrier protein specific or glycopeptide specific T cell help, and antibody titer and function. Finally we will determine if altering the charge of the Pn PS attached to the carrier protein affects antigen processing, induction of T cell help and subsequent immunogenicity. These data will provide a rationale for second generation Pn conjugate vaccines with enhanced ability to induce protective antibodies with fewer doses. PUBLIC HEALTH RELEVANCE: Vaccines called "conjugates" against the serious pediatric pathogen Streptococcus pneumoniae (pneumococcus) have greatly reduced infections in children. Unfortunately four expensive doses are needed to fully protect each child making the vaccine expensive to our health care system and difficult to use in the developing world. This proposal will investigate how the immune system sees this vaccine and lay the ground work for new information to design second generation vaccines that will protect children with fewer doses.

描述（由申请方提供）：肺炎球菌（Pn）荚膜多糖（PS）是不诱导记忆反应的T非依赖性抗原，是婴儿的不良免疫原。其中Pn荚膜PS与蛋白质共价连接的缀合物疫苗增强了针对PS的抗体滴度，并且通过儿科免疫程序在减少由Pn引起的侵入性感染方面非常成功。尽管结合疫苗取得了成功，但需要多次剂量才能提供保护，而且生产成本高昂，降低了其在发展中国家的效用。蛋白质的缀合增强PS特异性抗体产生的机制仍然不清楚，使得第二代缀合物疫苗的设计是经验性的。当在免疫后引入抗原时发生的第一免疫事件之一是被抗原呈递细胞（APC）摄取，缀合物的蛋白质部分的加工和具有MHC II的肽向T细胞的呈递。产生的T细胞辅助对于增强缀合物疫苗的免疫原性至关重要。我们一直在研究的Pn PS是共价连接到载体蛋白的载体蛋白的抗原加工的效果。使用与在美国广泛使用的CRM 197（白喉毒素的无毒形式）共价连接的七价Pn荚膜PS，我们发现PS与载体蛋白肽一起转运APC，并与APC表面上的MHC II共定位。我们还发现PS的血清型极大地影响载体蛋白的抗原加工效率，并且最有效加工的是最具免疫原性的。这些数据暗示PS影响由缀合物疫苗产生的T细胞辅助。我们的目标是确定的命运的Pn PS附着到抗原呈递细胞（APC）内的载体蛋白。我们将确定抗原加工效率对载体蛋白特异性或糖肽特异性T细胞帮助以及抗体滴度和功能的影响。最后，我们将确定改变连接到载体蛋白的Pn PS的电荷是否影响抗原加工、T细胞辅助的诱导和随后的免疫原性。这些数据将为第二代Pn缀合物疫苗提供基本原理，该第二代Pn缀合物疫苗具有增强的能力，以更少的剂量诱导保护性抗体。 公共卫生相关性：被称为“结合物”的疫苗可以对抗严重的儿科病原体肺炎链球菌（肺炎球菌），大大减少了儿童的感染。不幸的是，需要四剂昂贵的疫苗才能充分保护每个儿童，这使得疫苗对我们的卫生保健系统来说很昂贵，而且很难在发展中国家使用。这项提案将调查免疫系统如何看待这种疫苗，并为设计第二代疫苗奠定基础，这种疫苗将用更少的剂量保护儿童。