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Biologically informed design of CD8+ T cell-dependent pre-erythrocytic stage malaria vaccines

Award Number: U01AI155335
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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Biologically informed design of CD8+ T cell-dependent pre-erythrocytic stage malaria vaccines - PROJECT SUMMARY/ABSTRACT Immunization with whole pre-erythrocytic (sporozoite and liver stage) Plasmodium falciparum (Pf) vaccines confers sterilizing immunity in human clinical trials. Replication-deficient vaccines, such as radiation- attenuated sporozoites infect the liver as sporozoites but do not develop into liver stage schizonts. Replication- competent vaccines, however, infect the liver and replicate as tissue schizonts. Multiple lines of evidence in animal models of malaria have shown that protection is dependent on antigen-specific CD8+ T cells that recognize liver stage-infected hepatocytes, leading to their elimination. Replication-competent parasite vaccination confers superior durable sterilizing immunity against infection, and this appears to be, in animal models, associated with broader and better CD8+ T cell responses. However, it remains largely unknown how the distinct molecular cell biological features of whole attenuated parasite vaccines drive differences in the priming of protective CD8+ T cells and of equal importance, which liver stage antigens are directly presented by wildtype liver stage-infected hepatocytes that are the targets of vaccine-elicited protective CD8+ T cells. We will address these critical knowledge gaps. In Aim 1, we will identify the distinct time points during which the demise of liver stage-infected hepatocytes results in optimal cross-presentation of liver stage antigens by antigen presenting cells to CD8+ T cells. For this, we will use the Plasmodium yoelii (Py) rodent malaria model to inform vaccine design of Pf, with which mechanistic host studies cannot be done. We will also determine at what time points of wildtype liver stage development infected hepatocytes are most vulnerable to effector CD8+ T cell- mediated elimination. In concert with this, we will determine dynamic liver stage transcriptomes and proteomes throughout development and down-select the subset of liver stage proteins most prone to intrahepatocytic processing and MHC class I-restricted peptide presentation. In Aim 2, we will directly determine the MHC class I peptidome of Py and Pf presented on infected hepatocytes, specifically at timepoints of highest vulnerability and test their reactivity with whole parasite-vaccine-elicited CD8+ T cells. We will then test reactive epitopes as well as nonreactive epitopes (covert epitopes) as vectored subunit vaccines in mice. As in Aim 1, mechanistic testing cannot be done in Pf and thus we will conduct studies of Py to guide our Pf work. In Aim 3, we will genetically engineer the ultimate Pf replication-competent parasite strain that is built with gene deletions and dominant negative transgenes of parasite origin and will also over-express protective CD8+ T cell epitopes that target liver stages at the point of their greatest vulnerability. Thus, in a multi-pronged approach our project will develop the next generation of pre-erythrocytic vaccines including both vectored subunit vaccine candidates and whole genetically attenuated parasite vaccine candidates, designed to generate optimal and durable protective CD8+ T cell responses against Pf infection.


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 = $1,204,933 )
2025	2025	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	000	5	12/20/2024	NON-COMPETING CONTINUATION	$1,204,933
														Subtotal = $1,204,933

Issue Date FY: 2024 ( Subtotal = $1,242,198 )
2024	2024	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	001	4	5/24/2024	NON-COMPETING CONTINUATION	$124,220
2024	2024	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	000	4	1/12/2024	NON-COMPETING CONTINUATION	$1,117,978
														Subtotal = $1,242,198

Issue Date FY: 2023 ( Subtotal = $1,242,198 )
2023	2023	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	002	3	1/6/2023	NON-COMPETING CONTINUATION	$1,242,198
2023	2022	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	001	2	12/29/2022	NON-COMPETING CONTINUATION	$0
2023	2021	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	000	1	12/28/2022	NEW	$0
														Subtotal = $1,242,198

Issue Date FY: 2022 ( Subtotal = $1,298,298 )
2022	2022	SEATTLE CHILDREN'S HOSPITAL	4800 SAND POINT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	000	2	1/31/2022	NON-COMPETING CONTINUATION	$1,298,298
														Subtotal = $1,298,298

Issue Date FY: 2021 ( Subtotal = $1,342,548 )
2021	2021	SEATTLE CHILDREN'S HOSPITAL	4800 SAND PT WAY NE	SEATTLE	WA	98105	KING	USA	Allergy and Infectious Diseases Research	000	1	2/4/2021	NEW	$1,342,548
														Subtotal = $1,342,548

Grand Total All Awards = $6,330,175

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Biologically informed design of CD8+ T cell-dependent pre-erythrocytic stage malaria vaccines

Award Number: U01AI155335

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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