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Exploiting cross-reactive, conserved epitopes in Plasmodium vivax to develop a vaccine against falciparum placental malaria.

Award Number: R01AI150944
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY/ABSTRACT A vaccine is urgently needed to protect pregnant women from malaria infection and the devastating effects of this disease on maternal and child health. Two vaccines are in early stage clinical trials and both target domains within the protein VAR2CSA, which is the major surface antigen expressed by Plasmodium falciparum placental isolates. This protein binds to receptors in the placenta and mediates sequestration of infected red blood cells (iRBCs), underpinning the pathogenesis of placental malaria. However, VAR2CSA is under strong immune selection and is highly polymorphic; this compromises vaccine efficacy by limiting the breadth of protection against diverse alleles. Polymorphic antigens present a ubiquitous challenge in the development of malaria subunit vaccines. The long-term goal of this project is to develop an alternative approach to a vaccine against pregnancy-associated malaria that targets highly conserved, subdominant (even cryptic) epitopes. What is unique about this approach is that it exploits a mechanism of cross- species immunity, where epitopes from one Plasmodium species elicit robust, broadly neutralizing antibodies against structurally related antigens from another species. This mechanism was discovered recently in Colombian and Brazilian populations where VAR2CSA antibodies can be acquired outside of pregnancy following infection with P. vivax, and these antibodies blocked sequestration of iRBCs using in vitro correlates of placental malaria. The cross-reactive epitope in P. vivax was mapped to subdomain (SD1) in PvDBP and human SD1-purified antibodies blocked parasite adhesion. The objective of this project is to develop a vaccine to protect pregnant women from falciparum placental malaria that is based on the cross- reactive epitope in vivax SD1. This will be achieved through synthesis of three complementary Specific Aims. Epitopes required to elicit functional, cross-reactive antibodies will be identified in Aim 1 through conformationally constricted peptide microarrays screened with mouse monoclonal antibodies (mAbs) and human mAbs to SD1 isolated from Colombian study populations. Epitopes will be synthesized as peptide- conjugates or within engineered recombinant domains, and immunogenicity will be optimized in Aim 2 to produce antibodies with functional activity against parasites that express diverse alleles of var2csa. In the third Aim, the cryptic epitopes in VAR2CSA recognized by these antibodies will be mapped to identify the targets of antibodies elicited by an SD1-derived vaccine. The integration of these findings will provide important insight into the mechanism of cross-species epitope recognition, which will serve as the basis for a vivax vaccine against falciparum placental malaria and could be applied more broadly to vaccines against other malaria antigens.


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 = $0 )
2024	2023	THE GOVERNORS OF THE UNIVERSITY OF ALBERTA	114 STREET AND 89 AVENUE	EDMONTON	AB			CAN	Allergy and Infectious Diseases Research	000	4	4/11/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $334,505 )
2023	2023	THE GOVERNORS OF THE UNIVERSITY OF ALBERTA	114 STREET AND 89 AVENUE	EDMONTON	AB			CAN	Allergy and Infectious Diseases Research	000	4	3/28/2023	NON-COMPETING CONTINUATION	$334,505
														Subtotal = $334,505

Issue Date FY: 2022 ( Subtotal = $334,505 )
2022	2022	GOVERNORS OF THE UNIVERSITY OF ALBERTA, THE	116 ST & 85 AVE	EDMONTON	AB			CAN	Allergy and Infectious Diseases Research	000	3	3/3/2022	NON-COMPETING CONTINUATION	$334,505
														Subtotal = $334,505

Issue Date FY: 2021 ( Subtotal = $491,792 )
2021	2021	GOVERNORS OF THE UNIVERSITY OF ALBERTA, THE	116 ST & 85 AVE	EDMONTON	AB			CAN	Allergy and Infectious Diseases Research	000	2	3/1/2021	NON-COMPETING CONTINUATION	$491,792
														Subtotal = $491,792

Issue Date FY: 2020 ( Subtotal = $490,848 )
2020	2020	GOVERNORS OF THE UNIVERSITY OF ALBERTA, THE	116 ST & 85 AVE	EDMONTON	AB	T6G 2R3		CAN	Allergy and Infectious Diseases Research	000	1	3/10/2020	NEW	$490,848
														Subtotal = $490,848

Grand Total All Awards = $1,651,650

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Exploiting cross-reactive, conserved epitopes in Plasmodium vivax to develop a vaccine against falciparum placental malaria.

Award Number: R01AI150944

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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