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SARS-CoV-2 Vaccine Responses in children with genetic or acquired B cell deficiencies

Award Number: R01AI174303
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/02/2022
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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SARS-CoV-2 Vaccine Responses in children with genetic or acquired B cell deficiencies - PROJECT SUMMARY Emergence of the highly transmissible SARS-CoV-2 B.1.617.2 (Delta) variant and return to in-person learning is rapidly increasing the COVID-19 disease incidence and transmission rate in children. Therefore, it is critical to protect younger children. Toward this goal, ongoing COVID-19 vaccine clinical trials aim to reach those as young as 6 months old. Because pediatric trials involve fewer participants and children have a lower rate of symptomatic infection, pediatric vaccine efficacy will be initially based on in vitro immunological parameters virus neutralization and antibodies to the receptor-binding domain (RBD) or S1 fragment of the SARS-CoV-2 spike protein. However, whether these same metrics reflect an effective vaccine response in a developing immune system (<5 years old) remains to be determined. Immune responses to vaccines are influenced by age-associated physiological changes, particularly in the first 5 years of life when changes occur in B and T cell differentiation and effector functions, affinity maturation of B cell responses, and myeloid subpopulations and their cytokine production. Additionally, in very young children mucosal lgA rapidly reach adult levels, while serum lgA only reaches adult levels in adolescence. This difference may account for the disparate COVID-19 disease incidence, transmission, and severity in children. How evolving changes in pediatric mucosal and systemic immune ontogeny affect SARS-CoV-2 infection- and mRNA vaccination-elicited immune responses are incompletely understood. The overall obiective here is to define mucosal and systemic SARS-CoV-2 infection- and mRNA vaccine- elicited molecular and immune cellular responses in healthy pediatric maturing immune systems and in pathological B cell states (inborn or acquired). In a Pfizer-vaccinated adult cohort, compared to healthy adults, we have found that B cell depleted adult multiple sclerosis patients exhibited a significantly increased RBD-specific CD8 T cell response, despite negligible production of anti-RBD lgG. Interestingly, in children homeostatic and induced lgA levels are minimally affected by B cell depleting therapies. Our central hypothesis is that mRNA vaccination within the pediatric population augments mucosal (IFN and lgA) and CD8 T cellular immune parameters in the youngest children (<5yo) relative to older children (>5yo). We predict that such immune profile will i) correlate with vaccine- and infection-elicited responses, supporting their limited infection pathology (Aim 1); and ii) become enhanced in those children with B cell deficiencies (Aim 2). To test this hypothesis and its predictions, we will i) establish a prospective longitudinal cohort of SARS-CoV-2 infected/vaccinated healthy and B cell deficient children across age groups; and ii) apply transcriptomic, immune phenotypic, and antigen-specific humoral and cellular studies to compare SARS-CoV-2 vaccine- and infection-elicited molecular and cellular signatures in healthy children and those with inborn and acquired B cell defects. Resulting insights will define metrics of infection/vaccine immunity, constituting an initial step toward establishing correlates of protection in immunocompetent/B deficient children.


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: 2025 ( Subtotal = $604,346 )
2025	2025	THE REGENTS OF THE UNIV. OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Allergy and Infectious Diseases Research	000	4	6/13/2025	NON-COMPETING CONTINUATION	$604,346
														Subtotal = $604,346

Issue Date FY: 2024 ( Subtotal = $604,346 )
2024	2024	THE REGENTS OF THE UNIVERSITY OF COLORADO	13001 E 17TH PL STE F428	AURORA	CO	80045	ADAMS	USA	Allergy and Infectious Diseases Research	000	3	5/8/2024	NON-COMPETING CONTINUATION	$604,346
														Subtotal = $604,346

Issue Date FY: 2023 ( Subtotal = $613,169 )
2023	2023	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Allergy and Infectious Diseases Research	000	2	6/1/2023	NON-COMPETING CONTINUATION	$613,169
														Subtotal = $613,169

Issue Date FY: 2022 ( Subtotal = $621,860 )
2022	2022	REGENTS OF THE UNIVERSITY OF COLORADO, THE	13001 E 17TH PLACE F428	AURORA	CO	80045	ADAMS	USA	Allergy and Infectious Diseases Research	000	1	6/2/2022	NEW	$621,860
														Subtotal = $621,860

Grand Total All Awards = $2,443,721

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SARS-CoV-2 Vaccine Responses in children with genetic or acquired B cell deficiencies

Award Number: R01AI174303

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/02/2022

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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