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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：
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.

出生后1000天免疫性别差异的影响