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：
10434165
负责人：
PHILIP J GOULDER
金额：
$ 54.58万
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/10434165
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 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 precision medicine prenatal exposure response 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.

免疫性别差异的影响在生命的前1000天在童年和青春期项目摘要：男性的免疫反应与严重影响健康和生存的女性。免疫性别差异在几周内开始概念并在一生中保持维护。但是，我们继续管理预防和治疗而无需考虑免疫性别差异，主要是由于对他们的机制。了解这些免疫性别差异的机制至关重要，因为它将提供量身定制疫苗和治疗的理由，并改善健康结果。我们在这里寻求定义早期免疫性别差异的基本机制通过三个目的到青春期，重点关注特定的免疫和感染：在AIM 1中，我们评估了针对BCG免疫的免疫性别差异机制出生和麻疹在6个月时疫苗接种。我们不仅会专注于保护的特定响应针对结核病和麻疹，还针对这些疫苗的非特异性免疫作用除TB以外的其他疾病和麻疹以外的疾病死亡率增加了50％。具体和非特异性女性的反应更强。我们将在南非学习性爱双胞胎，以解决目标1-2。在AIM 2中，我们研究了免疫性别差异对HIV暴露结果的影响子宫。先前的研究表明，对艾滋病毒未感染儿童的免疫功能的影响很大母亲患有艾滋病毒。除了艾滋病毒未感染的双胞胎队列，我们还将在夸祖鲁 - 纳塔尔邦A学习自2015年以来，我们从出生开始就一直关注的> 230个HIV感染的母子对。我们最近有证明女性胎儿更容易通过I型干扰素感染子宫内感染病毒，尤其是当母亲在怀孕期间血清转化时。在AIM 3中，我们将在对SARS-COV-2的响应中的观察性研究中评估免疫性别差异在英国的青少年队列中，年龄12-17岁的疫苗接种。免疫性别差异已经存在从出生到老年，所有有执照的疫苗都观察到女性做出更强的抗体反应但是如上所述，遭受更大的不利事件。中和抗体的水平高76％在12-15yo中观察到的是16-25yo，响应于辉瑞-Biontech Covid-19 即使在青少年与年轻人中，也证明年龄对免疫的影响。在这项研究中，我们解决了塔尔7-IFN-I的性别差异的超级假设信号通路，在非常规T细胞（例如Mait细胞和VD2+ GD T细胞）中激活中通过DNA甲基化，性类固醇水平和移植中调节特异性免疫基因母体抗体的转移 - 所有这些因素驱动并影响结果的性别差异从早期及以后的疫苗和感染中。