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Molecular and cellular properties of broad and protective immune responses to the Plasmodium falciparum variant surface antigen responsible for severe malaria

Award Number: F31AI169993
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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Molecular and cellular properties of broad and protective immune responses to the Plasmodium falciparum variant surface antigen responsible for severe malaria - PROJECT SUMMARY Malaria remains a global health problem, with nearly half the world’s population at risk of transmission. Of the many clinical outcomes of malaria, cerebral malaria is the major cause of death in children. Cerebral malaria is caused by the accumulation of infected erythrocytes in brain capillaries, resulting in reduced blood flow, lesions, brain swelling, and ultimately coma and death. The adhesion of infected erythrocytes to host receptors found on brain endothelium is facilitated by the variant surface antigen Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1). Specifically, cysteine-rich interdomain region alpha 1 (CIDRa1) domains in PfEMP1 mediate binding to host endothelial protein C receptor (EPCR). Children in malaria-endemic regions who overcome the initial clinical complications of the disease rapidly develop immunity against cerebral malaria, resulting from the acquisition of antibodies targeting CIDRa1. Given the high sequence variation among CIDRa1 variants and the quick waning of antibody responses against other P. falciparum proteins, it is unclear how this protection is achieved and maintained over time. Our preliminary work has revealed that monoclonal antibodies from malaria- protected adults can recognize multiple CIDRa1 variants despite their sequence diversity and inhibit the binding of these CIDRa1 variants to EPCR. We also observed that a substantial percentage of CIDRa1-targeting B cells possessed an atypical B cell phenotype. Based on our preliminary data, we hypothesize that broadly reactive antibodies against CIDRa1 target diverse epitopes around the EPCR-binding site and are generated in conjunction with long-lasting B cell memory. In Specific Aim 1, we will isolate monoclonal antibodies against CIDRa1 from memory B cells of malaria protected adults to elucidate the diversity and epitopes of broad and variant specific antibodies. In Specific Aim 2, we will define the phenotype and maintenance of CIDRa1-specific B cells using high parameter spectral flow cytometry on longitudinal peripheral blood mononuclear cell samples. The results from this study will enhance our understanding of the nature and durability of protective immunity and advance the design of a vaccine that elicits broad and long-lived protection against malaria pathogenesis.


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 = -$35,140 )
2024	2023	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Allergy and Infectious Diseases Research	000	2	11/10/2023	NON-COMPETING CONTINUATION	-$27,007
2024	2023	THE UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Allergy and Infectious Diseases Research	001	2	4/24/2024	NON-COMPETING CONTINUATION	-$8,133
														Subtotal = -$35,140

Issue Date FY: 2023 ( Subtotal = $36,934 )
2023	2023	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Allergy and Infectious Diseases Research	000	2	4/25/2023	NON-COMPETING CONTINUATION	$36,934
														Subtotal = $36,934

Issue Date FY: 2022 ( Subtotal = $35,992 )
2022	2022	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Allergy and Infectious Diseases Research	001	1	5/25/2022	NEW	$716
2022	2022	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER OF SAN ANTONIO	7703 FLOYD CURL DR	SAN ANTONIO	TX	78229	BEXAR	USA	Allergy and Infectious Diseases Research	000	1	3/24/2022	NEW	$35,276
														Subtotal = $35,992

Grand Total All Awards = $37,786

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Molecular and cellular properties of broad and protective immune responses to the Plasmodium falciparum variant surface antigen responsible for severe malaria

Award Number: F31AI169993

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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