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Impact of immune sex differences in the first 1000 days of life and in childhood and adolescence

Award Number: U01AI168655
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $527,932 )
2024	2024	UNIVERSITY OF OXFORD	UNIVERSITY OFFICES	OXFORD				GBR	Allergy and Infectious Diseases Research	001	3	6/11/2024	NON-COMPETING CONTINUATION	$527,932
2024	2023	UNIVERSITY OF OXFORD	UNIVERSITY OFFICES	OXFORD				GBR	Allergy and Infectious Diseases Research	000	2	12/11/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $527,932

Issue Date FY: 2023 ( Subtotal = $534,090 )
2023	2023	UNIVERSITY OF OXFORD	UNIVERSITY OFFICES	OXFORD				GBR	Allergy and Infectious Diseases Research	000	2	7/31/2023	NON-COMPETING CONTINUATION	$534,090
														Subtotal = $534,090

Issue Date FY: 2022 ( Subtotal = $545,825 )
2022	2022	UNIVERSITY OF OXFORD	UNIVERSITY OFFICES	OXFORD	OXFORDSHIRE			GBR	Allergy and Infectious Diseases Research	000	1	6/17/2022	NEW	$545,825
														Subtotal = $545,825

Grand Total All Awards = $1,607,847

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Impact of immune sex differences in the first 1000 days of life and in childhood and adolescence

Award Number: U01AI168655

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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