The impact of prenatal exposure to persistent organic pollutants on kinetics of immune response to vaccines and sero-protection in infants

 描述(申请人提供)：持久性有机污染物(POP)是一组化学上稳定的化合物，在环境、动物和人类中生物积累和持续存在。POP的毒性包括致癌、内分泌病变、神经毒性和免疫毒性。虽然在20世纪80年代许多国家禁止生产持久性有机污染物，但在世界各地的幼儿血液中仍然可以检测到高水平的持久性有机污染物。大量接触持久性有机污染物可在胎儿免疫系统发育的关键时期从宫内开始，而且持久性有机污染物似乎会引起许多免疫毒性效应。有具体证据表明，对疫苗效力降低的免疫接种反应减弱，但尚未对一组常规婴儿免疫接种持久性有机污染物的影响进行全面评估。相当一部分中国人接触到了广泛的持久性有机污染物，接触水平与美国人口相当。POP免疫毒性对公众健康的影响已被中国疾病预防控制中心(中国)和美国国立卫生研究院确定为优先研究事项。我们将在天津中国进行一项前瞻性队列研究，以评估产前POPs暴露对疫苗特异性免疫反应和感染风险的依赖性。具体地说，将与中国疾控中心合作，建立天津市塘沽地区580名20-30岁健康孕妇中国的队列。将在出生时采集脐带血样本，并将检测属于所有主要类别的47种化合物的脐带血浓度，以衡量产前接触持久性有机污染物。随后将对婴儿从出生到25个月大进行跟踪，收集有关接种疫苗的历史、诊断、治疗和感染结果、一般健康状况、生长和发育以及非传染性疾病(特别是与过敏、自身免疫和癌症有关的疾病)的数据。在此期间，将在多个时间点采集血液样本，分析与5种常规婴儿免疫(口服脊髓灰质炎疫苗、乙肝、甲型肝炎、白喉/百日咳/破伤风、麻疹/流行性腮腺炎/风疹)相关的10种疫苗特异性抗原的抗体滴度/浓度。将使用对每个疫苗免疫原的免疫反应的动力学参数来汇总纵向数据。将使用多元回归方法对免疫动力学参数与单独和联合暴露于47种持久性有机污染物化合物的水平之间的关系进行建模。将使用多重归因和具有交叉验证的群体套索的统计技术来识别类别内和类别之间对免疫结果最具预测性的POPs化合物的子集。在持久性有机污染物暴露和免疫反应性下降之间建立明确的联系，将对中国以及美国和全球的疾病预防工作产生重要影响。

 DESCRIPTION (provided by applicant): Persistent organic pollutants (POPs) are a group of chemically stable compounds that bioaccumulate and persist in the environment, animals and humans. POP toxicities include carcinogenicity, endocrinopathy, neurotoxicity, and immunotoxicity. Although production of POPs was banned in many countries in the 1980s, high levels can be still be detected in the blood of young children worldwide. Significant exposure to POPs can begin in utero, during critical periods of fetal immune system development, and POPs appear to induce numerous immunotoxic effects. There is specific evidence of attenuated responses to immunizations that suggest reduced vaccine efficacy however a comprehensive assessment of the effects of POPs exposure across a panel of routine infant immunizations has not yet been performed. Significant portions of the Chinese population are exposed to a broad array of POPs across a range of exposure levels that are comparable to those in US populations. The public health impact of POP immunotoxicity has been identified as a research priority by the Chinese Centers for Disease Control and Prevention (China CDC), as well as the US National Institutes of Health. We will perform a prospective cohort study in Tianjin China to assess the dependence of vaccine-specific immune responses and risk for infections on prenatal POPs exposure. Specifically, a cohort of 580 healthy pregnant women 20-30 years of age living in the TangGu Districts of Tianjin China will be established in collaboration with the China CDC. Samples of cord blood will be obtained at the time of birth, and cord blood concentrations of a panel of 47 compounds belonging to all major classes of POPs will be assayed to measure prenatal exposure to POPs. Infants will then be followed from birth to 25 months of age, capturing data regarding vaccination history, diagnosis, treatment and outcomes for infections, general health status, growth and development, and non-infectious illness (especially those related to allergic, autoimmune, and cancer). Blood specimens will be taken at multiple time points throughout this period and analyzed for antibody titers/concentrations to a panel of 10 vaccine-specific antigens associated with 5 routine infant immunizations (oral poliovirus vaccine, hepatitis B, hepatitis A, diptheria/pertussus/tetanus, measles/mumps/rubella). Kinetic parameters of the immune response to each vaccine immunogen will be used to summarize longitudinal data. Multivariate regression methods will be used to model the dependence of the immunologic kinetic parameters on levels of exposure to the 47 POPs compounds alone and in combination. The statistical techniques of multiple imputation and group LASSO with cross-validation will be used to identity subsets of POPs compounds within and between classes that are most predictive of the immunologic outcomes. The establishment of clear links between POPs exposure and degraded immune responsiveness will have important implications for disease prevention efforts in China, as well as in the US and around the globe.