Antigen processing of pneumococcal conjugate vaccines

肺炎球菌结合疫苗的抗原处理

• 批准号: 8230494
• 负责人: John R. Schreiber
• 金额: $ 19.63万
• 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/8230494
• 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; public health relevance; 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.

说明书(申请人提供)：肺炎球菌(PN)荚膜多糖(PS)是T非依赖性抗原，不会引起记忆反应，对婴儿来说是免疫原性差。PN囊膜PS与蛋白质共价连接的结合疫苗可提高PS的抗体效价，并通过儿科免疫计划在减少PN引起的侵袭性感染方面非常成功。尽管结合疫苗取得了成功，但需要多次接种才能起到保护作用，而且它们的生产成本高昂，降低了它们在发展中国家的效用。蛋白质的结合增强PS特异性抗体产生的机制仍然不清楚，这使得第二代结合疫苗的设计具有经验性。当免疫后引入抗原时，首先发生的免疫学事件之一是被抗原提呈细胞(APC)摄取，处理结合物的蛋白质部分，并将带有MHC II的多肽递呈给T细胞。产生的T细胞辅助对于增强结合疫苗的免疫原性至关重要。我们一直在研究共价连接到载体蛋白上的PN PS对载体蛋白抗原处理的影响。利用与美国广泛使用的CRM197(白喉毒素的一种无毒形式)共价连接的七价PN壳PS，我们发现PS与载体蛋白肽一起穿过APC，并与APC表面的MHC II共定位。我们还发现PS的血清型对载体蛋白的抗原处理效率有很大影响，处理最有效的PS是最具免疫原性的。这些数据表明PS影响结合疫苗产生的T细胞辅助功能。我们的目标是确定附着在抗原提呈细胞(APC)内载体蛋白上的PN PS的命运。我们将确定抗原处理效率对载体蛋白特异性或糖肽特异性T细胞帮助以及抗体效价和功能的影响。最后，我们将确定改变附着在载体蛋白上的PN PS的电荷是否会影响抗原处理、T细胞Help的诱导和随后的免疫原性。这些数据将为第二代PN结合疫苗提供理论基础，使其以更少的剂量诱导保护性抗体的能力增强。 公共卫生相关性：针对严重的儿科病原体肺炎链球菌(肺炎球菌)的疫苗被称为“结合物”，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完全保护每个儿童，这使得疫苗对我们的卫生保健系统来说很昂贵，而且在发展中国家很难使用。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的新信息奠定基础，这些疫苗将以较少的剂量保护儿童。