HUMAN T CELL RESPONSE TO PNEUMOCOCCAL CONJUGATE VACCINES

针对肺炎球菌荚膜多糖（PnPs）的各种致病性血清型的抗体可提供感染保护，但纯PnPs是T细胞独立抗原，在儿童和老年人中是较差的免疫原。PnPs与载体蛋白结合可改善PnPs特异性抗体（Ab）反应，并引起T细胞的帮助。实验性肺炎球菌-蛋白结合疫苗使用纯化的PnPs特异性B细胞前体，或者是由于PnPs特异性B细胞前体的血清型的影响，还是由于PnPs的血清型对CRM197抗原加工的影响，从而在随后的人类T细胞帮助中产生改变。我们将用实验性的7价PnPs- CRM/197疫苗对50名成年志愿者进行免疫，并测量每种血清型和CRM/197的Ab水平。我们还将确定供体外周CD4+ T细胞对某些CRM/197表位的特异性是否与PnPs更好的免疫原性相关。接下来，我们将检查每个供体中PnPs特异性B细胞前体的频率，并确定PnPs特异性B细胞频率是否与PnPs抗体滴度相关。我们还将确定低应答血清型的PnPs抗体V区基因使用是否不同。最后，我们将研究血清型PnPs是否会影响人类抗原加工细胞对载体蛋白衍生表位的加工和呈递，从而在随后的T细胞帮助中产生差异。这些数据将大大增加我们对结合疫苗的免疫反应的理解，并可能为第二代疫苗的设计提供有用的信息。

Antibodies against the various pathogenic serotypes of pneumococcal capsular polysacharides (PnPs) provide protection from infection , but pure PnPs are T cell independent antigens and are poor immunogens in children and elderly. Conjugation of PnPs to a carrier protein improves the PnPs-specific antibody (Ab) response and elicits T cell help. The experimental pneumococcal-protein conjugate vaccine uses purified PnPs-specific B cell precursors or whether it is due to the effect of the serotype of the PnPs-specific B cell precursors or whether it is due to the effect of the serotype off the PnPs on the antigen processing of CRM197 yielding alterations in subsequent T cell help in humans. We will immunize fifty adult volunteers with the experimental 7 valent PnPs- CRM/197 vaccine and measure Ab levels against each serotype as well as CRM/197. We will also determine if donor peripheral CD4+ T cells specific for certain CRM/197 epitopes are associated with better immunogenicity of PnPs. Next, we will examine the frequency of PnPs- specific B cell precursors in each donor and determine if PnPs-specific B cell frequency correlates with PnPs Ab titer. We will also determine if PnPs antibody V region gene usage is different for low responder serotypes. Finally, we will examine whether the serotype of PnPs affects processing and presentation of carrier protein-derived epitopes by human antigen processing cells, yielding differences in subsequent T cell help. These data will significantly add to our understanding of the immune response to conjugate vaccines and may provide information useful to the design of second-generation vaccines.