Human Immunity to Vaccinia Virus

目前保护美国人免受天花侵袭的政策要求接种NATve和之前的疫苗 用活牛痘病毒(VV)接种成人疫苗。对W的获得性免疫知识仅限于 中和抗体、细胞毒性T淋巴细胞(CTL)活性和淋巴细胞增殖的描述 这在很大程度上是因为在当前分子免疫学时代之前就停止了广泛的疫苗接种。 该项目的研究将检查新接种和重新接种的W-特异性记忆T细胞的进化 (增强的)成年人。W特异性获得性免疫与病毒载量和先天因素的关系 豁免权将结合项目7和9确定。具体目标是： 1.鉴定诱导CD8？T细胞记忆的免疫优势Vv表位。人工神经网络和 首先将使用计算算法来选择多肽表位，然后对多肽进行评估 与人类白细胞抗原I类等位基因的结合及多肽刺激干扰素的能力评估和IL-2反应 通过人类白细胞抗原相合和不相合的初级疫苗接种者和成人给予加强剂量的W。 2.测定CD8？细胞在适应性诱导和记忆阶段的功能表型 免疫W.HLAI类四聚体-多肽复合体将用于鉴定和量化CD8细胞 在接种前和接种后9天、6个月、12个月和24个月携带W表位特异性TCR。 淋巴细胞产生可能的免疫介质(干扰素、穿孔素、MIP-LCC)和记忆 标志物(CD45RO、CD45RA、CCR7)将在初级疫苗接种者中进行前瞻性评估和加强 成年人。 3.评估VV特异性CD8细胞在初次接种和加强免疫后的克隆库 以前接种过疫苗的成年人。TCR VI3的使用和CDR3的长度和序列多态性将是 在选定的人类白细胞抗原A2+和人类白细胞抗原A11+个体中进行前瞻性评估。

Current policy to protect Americans against smallpox mandates immunization of naTve and previously vaccinated adults with live vaccinla virus (VV). Knowledge of adaptive immunity to W is limited to descriptions of neutralizing antibodies, cytotoxic T lymphocyte (CTL) activity, and lymphocyte proliferation responses, largely because widespread vaccination ceased before the current era of molecular immunology. Research in this project will examine the evolution of W-specific memory T cells in newly vaccinated and revaccinated (boosted) adults. The relationship of W-specific adaptive immunity to viral load and innate immunity will be determined in conjunction with projects 7 and 9. The specific aims are to: 1. Identify immunodominant VV epitopes that induce CD8 ¿ T cell memory. Artificial neural networks and computational algorithms will initially be used to select peptide epitopes, followed by evaluation of peptide binding to HLA class I alleles and assessment of the ability of peptides to stimulate IFN-? and IL-2 responses by HLA-matched and HLA-mismatched primary vaccinees and adults given booster doses of W. 2. Determine the functional phenotype of CD8 ¿ cells during the inductive and memory phases of adaptive immunity to W. HLA class I tetramer-peptide complexes will be used to identify and quantify CD8 ¿ cells bearing TCR specific for W epitopes before vaccination and 9 days, 6, 12, and 24 months post-vaccination. Lymphocytes producing putative mediators of immunity (IFN-?, perforin, MIP-lcc) and bearing memory markers (CD45RO, CD45RA, CCR7) will be evaluated prospectively in primary vaccinees and boosted adults. 3. Evaluate the clonotypic repertoire of Vv-specific CD8 ¿ cells following primary vaccination and boosting of previously vaccinated adults. TCR VI3 usage and CDR3 length and sequence polymorphism will be evaluated prospectively in selected HLA-A2+ and HLA-A11+ individuals.