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Discovery and preclinical evaluation of Plasmodium falciparum and P. vivax coiled coil antigens for malaria vaccine development

Award Number: R01AI148843
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 Despite the great global public health importance, malaria vaccine development has been slow with only a handful of candidates under development and the most advanced displaying modest efficacy. The current use of bioinformatics for genome/proteome screening, animal models, and more efficient manufacturing facilities for recombinant/synthetic antigens could significantly accelerate the development of novel vaccines. We propose to use these advances to identify and develop vaccine candidates targeting both, Plasmodium falciparum and P. vivax parasites, responsible for >99% of the malaria cases worldwide. Alpha-helical coiled-coil motifs, protein structures widely distributed in the Plasmodium proteomes known to spontaneously fold in aqueous solution, are able to induce antibodies that inhibit parasite growth in vitro. We previously in silico identified 220 proteins in both parasite proteomes, 170 of which were synthesized and tested. High antigenicity with human sera from endemic areas, and immunogenicity in mice led to selection of 145 fragments. Several of them displayed significant P. falciparum/P. vivax cross reactivity, and importantly in vitro parasite inhibition activity, which correlated with malaria clinical immunity. Furthermore, mice immunization with a P. falciparum poly-epitope construct (Pf-181) maintained individual epitopes specificity and parasite inhibitory activity. Our general hypothesis is that “Plasmodium poly-epitope constructs containing cross-reacting a-helical coiled-coil motifs induce protection in monkey against homologous and heterologous parasite challenges. The overall goal is to determine the vaccine potential of P. falciparum and P. vivax erythrocytic synthetic poly-epitope constructs containing a-helical coiled-coil motifs. This goal will be approached through the following specific aims: 1) Design, synthesis and characterization of P. falciparum and P. vivax poly-epitope constructs containing a-helical coiled-coil motifs; 2) Evaluation of the immunogenicity and protective efficacy of selected P. falciparum and P. vivax poly-epitope constructs against homologous and heterologous parasite challenges in Aotus monkeys; 3) In vitro characterization of a-helical coiled-coil fragments/constructs and immune responses elicited by animal immunization. Methods proposed are: a) F-moc peptide synthesis of poly-epitope constructs, followed by HPLC purification, mass spectrometry (MS) and circular dichroism (CD) analyses; b) Monkey immunization with selected poly-epitope constructs and evaluation of protective efficacy to homologous and heterologous challenges using P. falciparum (Santa Lucia) and P. vivax (Sal-I) parasite strains; c) ELISA and IFAT test of sera from immunized animals; d) antibody functional in vitro assays (GIA, ADRB,OPA).The innovation of this study is the highly efficient and cost-effective approach, using a comprehensive rational and rigorous epitope down- selection of hundreds of protein fragments from in silico epitope identification in Plasmodium proteomes for poly- epitope design and evaluation of their protective efficacy studies in monkeys. It will accelerate the development of malaria vaccines for human use.


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	2022	CENTRO DE INVESTIGACION CIENTIFICA CAUCASECO LTDA	CARRERA 37 2 BIS 5 E 08	CALI	VALLE			COL	Allergy and Infectious Diseases Research	000	3	3/29/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	CENTRO DE INVESTIGACION CIENTIFICA CAUCASECO LTDA	CARRERA 37 2 BIS 5 E 08	CALI	VALLE			COL	Allergy and Infectious Diseases Research	000	3	7/6/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $319,458 )
2022	2022	CENTRO DE INVESTIGACION CIENTIFICA CAUCASECO LTDA	CARRERA 37 2 BIS 5 E 08	CALI	VALLE			COL	Allergy and Infectious Diseases Research	000	3	1/11/2022	NON-COMPETING CONTINUATION	$319,458
														Subtotal = $319,458

Issue Date FY: 2021 ( Subtotal = $382,571 )
2021	2021	CENTRO DE INVESTIGACION CIENTIFICA CAUCASECO LTDA	CARRERA 37 2 BIS 5 E 08	CALI	VALLE			COL	Allergy and Infectious Diseases Research	000	2	12/31/2020	NON-COMPETING CONTINUATION	$382,571
														Subtotal = $382,571

Issue Date FY: 2020 ( Subtotal = $458,622 )
2020	2020	CENTRO DE INVESTIGACION CIENTIFICA CAUCASECO LTDA	CARRERA 37 2 BIS 5 E 08	CALI	VALLE			COL	Allergy and Infectious Diseases Research	000	1	1/3/2020	NEW	$458,622
2020	2020	CENTRO DE INVESTIGACION CIENTIFICA CAUCASECO LTDA	CARRERA 37 2 BIS 5 E 08	CALI	VALLE			COL	Allergy and Infectious Diseases Research	001	1	7/29/2020	NEW	$0
														Subtotal = $458,622

Grand Total All Awards = $1,160,651

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Discovery and preclinical evaluation of Plasmodium falciparum and P. vivax coiled coil antigens for malaria vaccine development

Award Number: R01AI148843

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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