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Impact of immune sex differences in the first 1000 days of life and in childhood and adolescence

生命前 1000 天以及儿童期和青少年期免疫性别差异的影响

基本信息

批准号：
10649515
负责人：
PHILIP J GOULDER
金额：
$ 53.41万
依托单位：
UNIVERSITY OF OXFORD
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-17 至 2027-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10649515
关键词：
Address Adolescence Adolescent Adult Adverse event Affect Age Agonist Androgens Antibody Response Autoimmune Diseases Bacille Calmette-Guerin vaccination Birth COVID-19 pandemic COVID-19 vaccination COVID-19 vaccine Cells Child Childhood Cohort Studies Conceptions DNA DNA Methylation Diet Disease Environment Epigenetic Process Ethnic Origin Evaluation Female Fetus Genes Gonadal Steroid Hormones HIV Health Immune Immune response Immunity Immunization Immunization Schedule Individual Infection Inflammatory Interferon Type I Interferons Investigation Licensing Life Long COVID Maternal antibody Measles Measles Vaccine Medical Mothers Natural Immunity Nature Observational Study Outcome Pattern Pfizer-BioNTech COVID-19 vaccine Predisposition Pregnancy Prevention Prevention strategy Production RNA Viruses Regulation Resistance Role Serious Adverse Event Sex Differences Signal Pathway Site South Africa T-Lymphocyte TLR7 gene Tuberculosis Twin Multiple Birth Twin Studies Vaccination Vaccines Virus adaptive immunity aged cohort high risk human old age (65+)immune function immunopathology immunoregulation improved in utero male methylome mortality mortality risk neutralizing antibody placental transfer precision medicine prenatal exposure response seroconversion sex treatment strategy vaccination outcome vaccine adverse event virtual young adult

项目摘要

IMPACT OF IMMUNE SEX DIFFERENCES IN THE FIRST 1000 DAYS OF LIFE AND IN CHILDHOOD AND ADOLESCENCE PROJECT SUMMARY: Substantial differences exist between the immune responses made by males and females that critically impact on health and survival. Immune sex differences start within weeks of conception and are maintained throughout life. However, we continue to administer preventions and treatments without taking immune sex differences into account, largely through a lack of understanding of their mechanism. Understanding mechanisms of these immune sex differences is essential because it will provide the rationale to tailor vaccines and treatments and improve health outcomes. We seek here to define the fundamental mechanisms underlying immune sex differences in early life through to adolescence via three aims that focus on specific immunizations and infections: In Aim 1, we evaluate mechanisms of immune sex differences in response to BCG immunization at birth and measles vaccination at 6 months. We will focus not only on the specific responses protecting against tuberculosis and measles but also on the non-specific immune effects of these vaccines that reduce childhood mortality from diseases other than TB and measles by 50%. Both specific and non-specific responses are stronger in females. We will study sex-discordant twins in South Africa to address Aims 1-2. In Aim 2, we investigate the impact of immune sex differences on outcome from HIV exposure in utero. Previous studies have shown strong effects on immune function in HIV-uninfected children born to mothers living with HIV. In addition to the HIV-uninfected twin cohort we will also study in KwaZulu-Natal a cohort of >230 HIV-infected mother-child pairs we have followed from birth since 2015. We have recently demonstrated that female fetuses are more susceptible to in utero infection via type I interferon-resistant viruses, especially when the mothers have themselves seroconverted during the pregnancy. In Aim 3, we will evaluate in an observational study immune sex differences in response to SARS-CoV-2 vaccination in an adolescent cohort aged 12-17 years in UK. Immune sex differences have been observed to all licensed vaccines, from birth to old age, with females making stronger antibody responses but suffering greater adverse events, as described above. The 76% higher levels of neutralising antibodies observed in 12-15yo compared to 16-25yo in response to the Pfizer-BioNTech COVID-19 vaccine is striking in demonstrating the age-specific effects on immunity even among adolescents versus young adults. In this study, we address the over-arching hypotheses that sex differences in the TLR7-IFN-I signalling pathway, in the activation of nonconventional T-cells such as MAIT cells and Vd2+ gd T-cells, in the regulation of specific immune genes by DNA methylation, in sex steroid levels, and in the transplacental transfer of maternal antibody - all of these factors drive and have an impact on sex differences in outcome from vaccines and infections in early life and beyond.

免疫性别差异对生命最初1000天的影响儿童和青少年项目总结：男性和女性的免疫反应之间存在实质性差异，对健康和生存产生重大影响的女性。免疫的性别差异开始于概念，并在整个生命中保持。然而，我们继续实施预防措施，没有考虑免疫性别差异的治疗，主要是由于缺乏对免疫系统的了解。他们的机制。了解这些免疫性别差异的机制是至关重要的，因为它将为定制疫苗和治疗方法以及改善健康结果提供理论依据。我们在此试图阐明生命早期免疫性别差异的基本机制通过三个目标，重点是特定的免疫接种和感染：在目的1中，我们评估了在不同年龄段对BCG免疫应答的免疫性别差异的机制。婴儿出生后6个月接种麻疹疫苗。我们将不仅关注具体的应对措施，预防结核病和麻疹，而且还对这些疫苗的非特异性免疫作用，结核病和麻疹以外疾病的儿童死亡率降低50%。特异性和非特异性女性的反应更强烈。我们将研究南非的性别不一致双胞胎，以解决目标1-2。在目标2中，我们研究了免疫性别差异对HIV暴露结局的影响，子宫。以前的研究表明，在出生时未感染艾滋病毒的儿童的免疫功能受到强烈影响，感染艾滋病毒的母亲。除了未感染艾滋病毒的双胞胎队列，我们还将在夸祖鲁-纳塔尔a进行研究。自2015年以来，我们从出生起就跟踪了超过230对艾滋病毒感染母婴的队列。我们最近研究表明，女性胎儿更容易通过I型干扰素耐药的子宫内感染，病毒，特别是当母亲在怀孕期间血清转化时。在目标3中，我们将在一项观察性研究中评估对SARS-CoV-2反应的免疫性别差异英国12-17岁青少年队列的疫苗接种。免疫的性别差异从出生到老年，观察到所有许可的疫苗，女性产生更强的抗体反应但是如上所述遭受更大的不良事件。中和抗体水平高出76% 与16- 25岁相比，12- 15岁对辉瑞-BioNTech COVID-19疫苗的反应是惊人的在证明特定年龄对免疫力的影响，甚至在青少年与年轻人。在这项研究中，我们解决了过度假设，TLR 7-IFN-I的性别差异，信号通路，在非常规T细胞如MAIT细胞和Vd 2 + gd T细胞的活化中，通过DNA甲基化调节特异性免疫基因，在性类固醇水平和经胎盘母体抗体的转移-所有这些因素都驱动并影响结果的性别差异从早期的疫苗和感染中恢复过来。