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Role of cytolytic ZEB2+ memory CD4+ T cells in protection against liver stage malaria

Award Number: R21AI188626
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: 01/14/2025
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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Role of cytolytic ZEB2+ memory CD4+ T cells in protection against liver stage malaria - Abstract Malaria remains a major human parasitic disease with over half a million deaths and 247 million cases every year. The WHO approved vaccines, RTS,S/AS01 (MosquirixTM) and R21/Matrix-M target the major Plasmodium falciparum (Pf) pre-erythrocytic stage circumsporozoite protein (CSP) antigen (Ag). They have limited efficacy and fall short of the global Malaria Vaccine Technology Roadmap goal of developing a 75%- effective vaccine. The mechanisms underlying both vaccines are poorly understood. There was only very limited analysis of the cellular responses associated with RTS,S/AS01 vaccination, partially due to the lack of sufficiently powerful high dimensional flow cytometry analyses at the time of the study. In contrast to protection afforded by vaccines, natural immunity provides long lived, robust protection from severe disease and death and infection is associated with minimal to no clinical symptoms. Thus, there is a pressing need to understand the cellular immune determinants associated with clinical immunity, to inform second generation vaccines. To gain insights into clinical immunity, we conducted a prospective study in a malaria endemic region in Malawi, with clinically immune and clinically susceptible individuals, using high dimensional flow cytometry phenotyping and single cell transcriptomic. We discovered in the blood of Pf-infected patients, a population of clonally expanded memory CD4+ T cells that express a robust cytolytic signature and reacted to the Pf-derived CSP Ag that is also the target of RTS,S/AS01 and R21 vaccines. We hypothesize that CSP-specific cytolytic memory CD4+ T cells could represent important mediators of natural and vaccine-induced immunity against malaria by limiting sporozoite and liver stage pre-erythrocytic infection. Here we propose to use murine models of radiation arrested sporozoites (RAS) immunization and sporozoite mosquito infection to explore the kinetics, differentiation requirements, functions and protective capacity of CSP-specific cytolytic CD4+ T cells during malaria.


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: 2026 ( Subtotal = $210,000 )
2026	2026	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	000	2	12/29/2025	NON-COMPETING CONTINUATION	$210,000
														Subtotal = $210,000

Issue Date FY: 2025 ( Subtotal = $244,440 )
2025	2025	ALBERT EINSTEIN COLLEGE OF MEDICINE	1300 MORRIS PARK AVE	BRONX	NY	10461	BRONX	USA	Allergy and Infectious Diseases Research	000	1	1/14/2025	NEW	$244,440
														Subtotal = $244,440

Grand Total All Awards = $454,440

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Role of cytolytic ZEB2+ memory CD4+ T cells in protection against liver stage malaria

Award Number: R21AI188626

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: 01/14/2025

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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