HUMAN T CELL RESPONSE TO PNEUMOCOCCAL CONJUGATE VACCINES

针对不同致病血清型肺炎球菌荚膜多糖类(PNPs)的抗体提供了免受感染的保护，但纯PNPs是T细胞无关的抗原，对儿童和老年人来说免疫原很差。PNPs与载体蛋白的结合提高了PNPs特异性抗体(Ab)的反应，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，无论这是由于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抗原处理的影响，在人类随后的T细胞帮助中产生变化。我们将用实验性的7价PNPs-CRM/197疫苗免疫50名成年志愿者，并检测针对每种血清型的抗体水平以及CRM/197。我们还将确定针对某些CRM/197表位的供者外周CD4+T细胞是否与PNPs更好的免疫原性有关。接下来，我们将检查每个捐献者中PNPs特异性B细胞前体细胞的频率，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PNPs抗体V区基因在低应答者血清型中的使用是否不同。最后，我们将研究PNPs的血清类型是否会影响人类抗原处理细胞对载体蛋白衍生表位的处理和呈现，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免疫反应的了解，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.