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Assessing the determinants of durable protective immunity in SARS-CoV-2 infected human subjects

Award Number: U01AI142001
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: COOPERATIVE AGREEMENT
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/16/2019
PERIOD OF PERFORMANCE END DATE: 12/31/2023

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Assessing the determinants of durable protective immunity in SARS-CoV-2 infected human subjects - PROJECT SUMMARY Coronavirus disease 2019 (COVID-19) caused by the SARS-CoV-2 virus has already resulted in nearly 3 million laboratory diagnosed infections and over 200,000 deaths worldwide. There is no known pre-existing immunity to SARS-CoV-2 in humans or licensed therapeutics to combat or limit infection. In the absence of these pharmacological interventions, governments around the world have implemented stringent measures to that curb the spread of SARS-CoV-2 to populations at risk of serious complications from infection. Efforts to identify efficacious therapies and develop vaccines to counter infection and disease require time and ultimately need to be guided by deep knowledge about this novel pathogen. Immune-directed therapies in particular require a detailed understanding of the immune responses generated not only in severe COVID-19 disease but also in the vast majority of individuals who develop non-severe disease. Innate immunity serves as the frontline response to counter the early stages of infection and but is also critical for regulating the ensuing adaptive immune response. In humans, anti-SARS-CoV-2 humoral immunity has gained significant attention while roles for innate immunity and memory T cell responses have not been extensively studied. However, knowledge gained from SARS-CoV-1 studies indicate that T cell immunity is critical in virus control. In these SARS-CoV-1 infected mice, the induction of the innate type I Interferon signaling cascade is delayed. Yet mice lacking this innate immune response exhibited greater numbers of virus specific T cells in their lungs. Thus, this dysregulated innate immune response impairs anti-SARS-CoV-1 T cell memory. Whether SARS-CoV-2 infection induces protective memory T cells and if the durability of anti-SARS-CoV-2 T cell memory is influenced by innate immunity are all currently unexplored. In humans, the innate immune response induced in non-severe COVID-19 disease is not well characterized. However, preliminary studies in cultured cells and animal models indicate that upon SARS-CoV-2 infection, there is a restricted and delayed induction of innate immunity resulting in limited induction of cytokines and chemokines critical for immune cell recruitment. We predict that the vast majority of COVID-19 infected individuals will exhibit a dysregulated innate immune response typified by delayed and limited inflammatory signaling. If true, such a compromised innate immune response could in turn induce limited short-lived adaptive immunity. Indeed, studies from SARS-CoV-1 infections indicate that humoral responses are short-lived in recovered patients. To our knowledge, no studies have examined memory durability in COVID-19 subjects. In this proposal, we will interrogate samples from a prospective longitudinal cohort of Seattle residents to examine if aberrant T cell memory is induced during SARS-CoV-2 infection and importantly if this impaired memory stems from dysregulated innate immunity. Furthermore, mechanistic studies in the hACE2 transgenic mouse model, where SARS-CoV-2 infection results in mild disease, will identify how innate immunity shapes anti-SARS CoV-2 T cell responses.


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 = -$17,069 )
2024	2023	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	000	5	5/14/2024	NON-COMPETING CONTINUATION	$0
2024	2022	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	001	4	8/15/2024	SUPPLEMENT FOR EXPANSION	-$17,069
														Subtotal = -$17,069

Issue Date FY: 2023 ( Subtotal = $802,689 )
2023	2023	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	000	5	12/12/2022	NON-COMPETING CONTINUATION	$802,689
2023	2022	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	001	4	5/18/2023	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $802,689

Issue Date FY: 2022 ( Subtotal = $1,169,993 )
2022	2022	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	001	4	1/21/2022	SUPPLEMENT FOR EXPANSION	$367,304
2022	2022	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	000	4	1/4/2022	NON-COMPETING CONTINUATION	$802,689
2022	2021	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	002	3	8/18/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,169,993

Issue Date FY: 2021 ( Subtotal = $1,515,510 )
2021	2021	SEATTLE CHILDREN'S HOSPITAL	4800 SAND PT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	001	3	1/28/2021	NON-COMPETING CONTINUATION	$802,689
2021	2021	SEATTLE CHILDREN'S HOSPITAL	4800 SAND PT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	002	3	2/2/2021	SUPPLEMENT FOR EXPANSION	$712,821
2021	2020	SEATTLE CHILDREN'S HOSPITAL	4800 SAND PT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	000	2	11/6/2020	NON-COMPETING CONTINUATION	$0
														Subtotal = $1,515,510

Issue Date FY: 2020 ( Subtotal = $1,149,143 )
2020	2020	SEATTLE CHILDREN'S HOSPITAL	4800 SAND PT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	002	2	9/2/2020	SUPPLEMENT FOR EXPANSION	$160,801
2020	2020	SEATTLE CHILDREN'S HOSPITAL	4800 SAND PT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	001	2	7/6/2020	SUPPLEMENT FOR EXPANSION	$177,764
2020	2020	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	000	2	1/13/2020	NON-COMPETING CONTINUATION	$810,578
														Subtotal = $1,149,143

Issue Date FY: 2019 ( Subtotal = $839,196 )
2019	2019	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	001	1	6/5/2019	NEW	$0
2019	2019	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	000	1	1/15/2019	NEW	$839,196
														Subtotal = $839,196

Grand Total All Awards = $5,459,462

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Assessing the determinants of durable protective immunity in SARS-CoV-2 infected human subjects

Award Number: U01AI142001

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: COOPERATIVE AGREEMENT

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

PERIOD OF PERFORMANCE START DATE: 01/16/2019

PERIOD OF PERFORMANCE END DATE: 12/31/2023

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