Host SNPs and Altered Responses to Influenza Vaccine

描述（由申请方提供）：灭活流感病毒疫苗在过去几十年中得到了逐步改进，以降低反应原性并使抗原含量标准化。尽管取得了这样的进展，一些原本健康的个体要么免疫反应较差，要么对疫苗接种产生不良反应，这强烈表明宿主因素可能在决定对流感疫苗的反应方面发挥作用。多种宿主免疫遗传多态性通过编码改变的基因产物或通过影响转录调控与宿主易感性和一些感染性疾病的临床表现相关。本研究将关联三个宿主免疫遗传因子的多态性：甘露糖结合凝集素（MBL）基因，肿瘤坏死因子（TNF）-α和白细胞介素10（IL-10）启动子，与宿主对灭活流感疫苗的免疫应答。将参与先前进行的灭活流感疫苗试验的志愿者与免疫应答活跃且未发生与疫苗接种相关的不良事件的志愿者进行比较。 受试者的年龄、性别和人种将匹配。将从先前由NIH资助的大型流感疫苗田间试验中获得的冷冻存档血清标本中提取基因组DNA。将通过基于PCR的技术确定MBL外显子1基因组以及TNF-α和IL-10启动子区域中的宿主多态性。确定流感疫苗免疫原性和不良事件的宿主分子决定因素可能有助于制定策略，以提高疫苗在大量患者人群中的有效性和安全性。人们充分认识到，对这三种宿主多态性的分析可能过于有限，无法确定疫苗诱导应答变异性的遗传基础，但从拟议研究中产生的存档基因组DNA将用于检查未来其他尚待鉴定的宿主多态性。

DESCRIPTION (provided by applicant): Inactivated influenza virus vaccines have been progressively improved over the past several decades to decrease reactogenicity and standardize antigenic content. Despite such progress, some otherwise healthy individuals either develop poor immune responses or experience adverse reactions to vaccination, strongly suggesting that host factors may play a role in determining responses to influenza vaccine. Various host immunogenetic polymorphisms are associated with host susceptibility and clinical manifestations of some infectious diseases, either by encoding altered gene products or by affecting transcriptional regulation. The present study will correlate polymorphisms of three host immunogenetic factors: the mannose binding lectin (MBL) gene, the tumor necrosis factor (TNF)-alpha and interleukin10 (IL-10) promoters, with host immune responses to inactivated influenza vaccines. Volunteers participating in previously conducted inactivated influenza vaccine trials who developed either decreased immune responses or increased adverse events to vaccination will be compared with those who developed brisk immune response and suffered no adverse events associated with vaccination. Subjects will be matched for age, gender and race. Genomic DNA will be extracted from frozen archived serum specimens obtained in a large previously conducted NIH-funded influenza vaccine field trial. The host polymorphisms in the MBL exon 1 genome and in the TNF-alpha and IL-10 promoter regions will be determined by PCR-based techniques. Defining host molecular determinants of influenza vaccine immunogenecity and adverse events may foster strategies to enhance vaccine effectiveness and safety in large patient populations. It is fully realized that the analysis of these three host polymorphisms may be too limited to pinpoint the genetic basis of variability in vaccine-induced responses, but the archived genomic DNA generated from the proposed studies will be used to examine additional, yet to be identified, host polymorphisms in the future.