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Principal Investigator: PHILIP J GOULDER
Organization: UNIVERSITY OF OXFORD
Fiscal Year: 2024
Award: $527,932
Funding agency: National Institute of Allergy and Infectious Diseases
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.
Terms: <0-11 years old><12-20 years old><2019-nCoV vaccine><21+ years old><65 and older><65 or older><65 years of age and older><65 years of age or more><65 years of age or older><65+ years><65+ years old><> 65 years><AIDS Virus><Acquired Immune Deficiency Syndrome Virus><Acquired Immunodeficiency Syndrome Virus><Address><Adolescence><Adolescent><Adolescent Youth><Adult><Adult Human><Adverse Experience><Adverse event><Affect><Age><Aged 65 and Over><Agonist><Androgenic Agents><Androgenic Compounds><Androgens><Antibody Response><Autoimmune Diseases><BCG immunization><BCG vaccination><BCG-vaccinated><BNT 162b2><BNT162b2><Bacille Calmette-Guerin vaccinated><Bacille Calmette-Guerin vaccination><Bacillus Calmette-Guerin vaccination><Bacillus Calmette-Guérin vaccination><Birth><COVID crisis><COVID epidemic><COVID pandemic><COVID-19 crisis><COVID-19 epidemic><COVID-19 era><COVID-19 global health crisis><COVID-19 global pandemic><COVID-19 health crisis><COVID-19 pandemic><COVID-19 period><COVID-19 public health crisis><COVID-19 vaccination><COVID-19 vaccine><COVID-19 years><Cell Body><Cells><Cellular Immune Function><Child><Child Youth><Childhood><Children (0-21)><Cohort Studies><Conceptions><Concurrent Studies><DNA><DNA Methylation><Deoxyribonucleic Acid><Diet><Differences between sexes><Differs between sexes><Disease><Disorder><Environment><Epigenetic><Epigenetic Change><Epigenetic Mechanism><Epigenetic Process><Ethnic Origin><Ethnicity><Evaluation><Female><Fetus><Genes><Gestation><Gonadal Steroid Hormones><HIV><Health><Human Immunodeficiency Viruses><IFN><Immune><Immune response><Immunes><Immunity><Immunization><Immunization Schedule><Immunological response><Immunomodulation><Individual><Infection><Inflammatory><Innate Immunity><Interferon Type I><Interferons><Investigation><LAV-HTLV-III><Licensing><Life><Long COVID><Long COVID-19><Long coronavirus disease><Long coronavirus disease 2019><Lymphadenopathy-Associated Virus><M tuberculosis infection><M. tb infection><M. tuberculosis infection><M.tb infection><M.tuberculosis infection><MTB infection><Maternal antibody><Measles><Measles Vaccine><Medical><Mothers><Mycobacterium tuberculosis (MTB) infection><Mycobacterium tuberculosis infection><Native Immunity><Natural Immunity><Nature><Non-Specific Immunity><Nonspecific Immunity><Observation research><Observation study><Observational Study><Observational research><Outcome><Parturition><Pattern><Pfizer covid19 vaccine><Pfizer-BioNTech COVID-19 vaccine><Pfizer-BioNTech coronavirus disease 2019 vaccine><Pfizer/BioNTech vaccine><Predisposition><Pregnancy><Preventative strategy><Prevention><Prevention strategy><Preventive strategy><Production><RNA Viruses><Regulation><Resistance><Role><Rubeola><SARS-CoV-2 epidemic><SARS-CoV-2 global health crisis><SARS-CoV-2 global pandemic><SARS-CoV-2 pandemic><SARS-CoV-2 vaccination><SARS-CoV-2 vaccine><SARS-coronavirus-2 epidemic><SARS-coronavirus-2 pandemic><SARS-coronavirus-2 vaccine><Serious Adverse Event><Severe Acute Respiratory Syndrome CoV 2 epidemic><Severe Acute Respiratory Syndrome CoV 2 pandemic><Severe Acute Respiratory Syndrome CoV 2 vaccine><Severe Adverse Event><Severe acute respiratory syndrome coronavirus 2 epidemic><Severe acute respiratory syndrome coronavirus 2 pandemic><Severe acute respiratory syndrome coronavirus 2 vaccination><Severe acute respiratory syndrome coronavirus 2 vaccine><Sex Differences><Sex Hormones><Sex Steroid Hormones><Sexual differences><Signal Pathway><Site><South Africa><Susceptibility><T-Cells><T-Lymphocyte><TB infection><TLR7><TLR7 gene><Therapeutic Androgen><Toll-Like Receptor 7><Tuberculosis><Twin Multiple Birth><Twin Studies><Twins><Vaccination><Vaccines><Virus><Virus-HIV><above age 65><adaptive immunity><adolescence (12-20)><adult youth><adulthood><after age 65><age 65 and greater><age 65 and older><age 65 or older><age > 65><age associated><age correlated><age dependent><age linked><age of 65 years onward><age related><age specific><aged><aged 65 and greater><aged 65+><aged ≥65><ages><autoimmune condition><autoimmune disorder><autoimmunity disease><chronic COVID><chronic COVID-19><chronic novel coronavirus disease 2019><cohort><coronavirus disease 2019 crisis><coronavirus disease 2019 epidemic><coronavirus disease 2019 global health crisis><coronavirus disease 2019 global pandemic><coronavirus disease 2019 health crisis><coronavirus disease 2019 pandemic><coronavirus disease 2019 public health crisis><coronavirus disease 2019 vaccination><coronavirus disease 2019 vaccine><coronavirus disease crisis><coronavirus disease epidemic><coronavirus disease pandemic><coronavirus disease-19 global pandemic><coronavirus disease-19 pandemic><coronavirus disease-19 vaccine><death risk><diets><disseminated TB><disseminated tuberculosis><epigenetically><exposed in utero><fetal exposure><gonadal steroids><high risk><host response><human old age (65+)><immune function><immune modulation><immune regulation><immune system response><immunologic reactivity control><immunomodulatory><immunopathology><immunoregulation><immunoregulatory><immunoresponse><improved><in utero><in utero exposure><infection due to Mycobacterium tuberculosis><intra-uterine environmental exposure><intrauterine environmental exposure><juvenile><juvenile human><kids><long haul COVID><long haul COVID-19><long haul coronavirus disease><long haul coronavirus disease 2019><long-hauler COVID><long-hauler COVID-19><long-hauler coronavirus disease 2019><long-hauler syndrome><long-term COVID><long-term COVID-19><long-term coronavirus disease><long-term coronavirus disease 2019><longterm COVID><longterm COVID-19><longterm coronavirus disease><longterm coronavirus disease 2019><male><methylome><morbilli><mortality><mortality risk><nCoV vaccine><nCoV-19 vaccine><nCoV19 vaccine><neutralizing antibody><old age><outcome following vaccination><outcome following vaccine><over 65 years><pediatric><persistent COVID-19><placental transfer><post COVID syndrome><post COVID-19 syndrome><post acute COVID syndrome><post acute COVID-19><post acute COVID-19 syndrome><post acute SARS-CoV-2><post acute coronavirus disease 2019><post acute coronavirus disease 2019 syndrome><post acute coronavirus disease syndrome><post acute severe acute respiratory syndrome coronavirus 2><post coronavirus disease 2019 syndrome><post coronavirus disease syndrome><post-acute phases of COVID-19><precision medicine><precision-based medicine><prenatal exposure><prenatally exposed><prolonged COVID-19 symptoms><resistant><response><result following vaccination><result following vaccine><serious adverse experience><serious adverse reaction><seroconversion><severe acute respiratory syndrome coronavirus 2 global health crisis><severe acute respiratory syndrome coronavirus 2 global pandemic><sex><sex based differences><sex steroid><sex-dependent differences><sex-related differences><sex-specific differences><social role><thymus derived lymphocyte><treatment strategy><tuberculosis infection><tuberculous spondyloarthropathy><vaccinate against COVID-19><vaccinate against SARS-CoV-2><vaccinate against coronavirus disease 2019><vaccinate against severe acute respiratory syndrome coronavirus 2><vaccination adverse event><vaccination against COVID-19><vaccination against SARS-CoV-2><vaccination against Severe acute respiratory syndrome coronavirus 2><vaccination against coronavirus disease 2019><vaccination associated adverse event><vaccination induced adverse event><vaccination outcome><vaccination related adverse event><vaccination result><vaccine adverse event><vaccine against 2019-nCov><vaccine against COVID-19><vaccine against SARS-CoV-2><vaccine against SARS-coronavirus-2><vaccine against Severe Acute Respiratory Syndrome CoV 2><vaccine against Severe acute respiratory syndrome coronavirus 2><vaccine associated adverse event><vaccine candidates against SARS-CoV-2><vaccine for novel coronavirus><vaccine induced adverse event><vaccine outcome><vaccine related adverse event><vaccine result><vaccines preventing COVID><vaccines to prevent COVID><virtual><young adult><young adulthood><youngster><≥65 years>