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.
