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.

生命最初 1000 天免疫性别差异的影响以及童年和青少年时期项目摘要：男性和女性的免疫反应之间存在显着差异女性的健康和生存受到严重影响。免疫性别差异在几周内开始受孕并终生维持。但我们仍会继续采取预防措施治疗时没有考虑免疫性别差异，主要是由于缺乏对免疫性别差异的了解他们的机制。了解这些免疫性别差异的机制至关重要，因为它将提供定制疫苗和治疗方法以及改善健康结果的基本原理。我们在此寻求定义生命早期免疫性别差异的基本机制通过专注于特定免疫和感染的三个目标，一直到青春期：在目标 1 中，我们评估了对 BCG 免疫反应的免疫性别差异机制出生和 6 个月时接种麻疹疫苗。我们将不仅关注保护的具体应对措施对抗结核病和麻疹，还影响这些疫苗的非特异性免疫作用，从而减少结核病和麻疹以外的疾病造成的儿童死亡率降低了 50%。特定的和非特定的女性的反应更强。我们将研究南非性别不一致的双胞胎，以实现目标 1-2。在目标 2 中，我们研究了免疫性别差异对 HIV 暴露结果的影响子宫。先前的研究表明，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外，我们还将在夸祖鲁-纳塔尔省进行研究自 2015 年以来，我们对超过 230 对感染艾滋病毒的母子进行了追踪。最近，我们证明女性胎儿更容易因 I 型干扰素耐药而受到宫内感染病毒，尤其是当母亲在怀孕期间发生血清转化时。在目标 3 中，我们将在一项观察性研究中评估针对 SARS-CoV-2 的免疫性别差异英国 12-17 岁青少年群体的疫苗接种。免疫性别差异从出生到老年，对所有获得许可的疫苗都观察到，女性会产生更强的抗体反应但如上所述，会遭受更大的不良事件。中和抗体水平提高 76% 与 16-25 岁儿童相比，12-15 岁儿童对辉瑞 BioNTech COVID-19 疫苗的反应令人震惊证明年龄特异性对免疫力的影响，甚至在青少年与年轻人中也是如此。在这项研究中，我们提出了 TLR7-IFN-I 中性别差异的总体假设信号通路，在非常规 T 细胞（例如 MAIT 细胞和 Vd2+ gd T 细胞）的激活中，通过 DNA 甲基化、性类固醇水平和经胎盘对特定免疫基因的调节母源抗体的转移 - 所有这些因素都会驱动并影响结果的性别差异来自生命早期及以后的疫苗和感染。