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

产前接触持久性有机污染物对婴儿疫苗免疫反应动力学和血清保护的影响

• 批准号: 8945760
• 负责人: STEVEN G. SELF
• 金额: $ 61.46万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8945760
• 关键词: 2 year old; Address; Affect; Age-Months; Age-Years; Allergic; Animals; Antibodies; Antibody Response; Antigen-Presenting Cells; Antigens; Area; Attenuated; Autoimmune Process; Binding; Biological Assay; Birth; Blood; Blood specimen; Centers for Disease Control and Prevention (U.S.); Chemicals; Child; Childhood; China; Chinese People; Cohort Studies; Collaborations; Communicable Diseases; Complex Mixtures; Country; Data; Dependence; Diagnosis; Dioxins; Effector Cell; Enrollment; Environment; Evaluation; Exposure to; Frequencies; Furans; Growth and Development function; Health Status; Hepatitis A; Hepatitis B; Human; Immune; Immune response; Immune system; Immunization; Immunologics; Individual; Infant; Infection; Kinetics; Life; Link; Malignant Neoplasms; Maternal antibody; Measles; Measurement; Measures; Methods; Modeling; Mothers; Mumps; Nature; Newborn Infant; Oral Poliovirus Vaccine; Outcome; Pattern; Period Analysis; Polychlorinated Biphenyls; Population; Pregnant Women; Production; Property; Public Health; Receptor Signaling; Recording of previous events; Recruitment Activity; Research Priority; Risk; Rubella; Sampling; Severities; Systems Development; Techniques; Tetanus; Time; Toxic effect; Treatment outcome; Umbilical Cord Blood; United States National Institutes of Health; Vaccination; Vaccine Antigen; Vaccines; Validation; Variant; base; carcinogenicity; cohort; critical period; disorder prevention; early childhood; fetal; follow-up; immunotoxicity; in utero; in vivo; neurotoxicity; organochlorine pesticide; persistent organic pollutants; predictive modeling; prenatal; prenatal exposure; prospective; public health relevance; receptor; response; vaccine efficacy

 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.

 描述（申请人提供）：持久性有机污染物（POP）是一组化学性质稳定的化合物，可在环境、动物和人类中进行生物累积并持久存在。持久性有机污染物的毒性包括致癌性、内分泌病、神经毒性和免疫毒性。尽管许多国家在20世纪80年代禁止生产持久性有机污染物，但世界各地幼儿的血液中仍然可以检测到高含量的持久性有机污染物。在胎儿免疫系统发育的关键时期，大量接触持久性有机污染物可在子宫内开始开始，持久性有机污染物似乎可诱发多种免疫毒性效应。有具体证据表明，对免疫接种的反应减弱，表明疫苗效力降低，但尚未对接触持久性有机污染物对一组常规婴儿免疫接种的影响进行全面评估。中国人口中有相当一部分暴露于各种各样的持久性有机污染物，其暴露水平与美国人口相当。持久性有机污染物免疫毒性的公共卫生影响已被中国疾病预防控制中心（中国CDC）和美国国立卫生研究院确定为研究重点。我们将在中国天津进行一项前瞻性队列研究，以评估疫苗特异性免疫应答和感染风险对产前持久性有机污染物暴露的依赖性。具体而言，将与中国疾病预防控制中心合作，建立一个由580名年龄在20-30岁之间的健康孕妇组成的队列。将在婴儿出生时采集脐带血样本，并对属于持久性有机污染物所有主要类别的47种化合物的脐带血浓度进行分析，以测量产前对持久性有机污染物的接触情况。然后将对婴儿从出生到25个月大进行随访，收集有关疫苗接种史、感染的诊断、治疗和结果、一般健康状况、生长和发育以及非感染性疾病（特别是与过敏、自身免疫和癌症相关的疾病）的数据。在此期间的多个时间点采集血液样本，并分析与5种常规婴儿免疫（口服脊髓灰质炎病毒疫苗、乙型肝炎B、甲型肝炎、白喉/百日咳/破伤风、麻疹/腮腺炎/风疹）相关的10种疫苗特异性抗原的抗体滴度/浓度。对每种疫苗免疫原的免疫应答的动力学参数将用于总结纵向数据。将采用多变量回归方法模拟免疫动力学参数对47种持久性有机污染物化合物单独和混合接触水平的依赖性。多重插补和交叉验证的组LASSO的统计技术将用于识别类别内和类别之间最能预测免疫学结局的POP化合物子集。在持久性有机污染物暴露和免疫反应下降之间建立明确的联系，将对中国、美国和地球仪的疾病预防工作产生重要影响。