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DISCOVERY AND PRECLINICAL DEVELOPMENT OF EFFICACIOUS P. vivax PRE-ERYTHROCYTIC STAGE MALARIA VACCINES

Award Number: U01AI155363
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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Abstract A significant global malaria incidence reduction in the last two decades has stimulated greater efforts toward its global eradication; however, this ambitious goal demands novel and highly efficacious control tools, including vaccines. Although the biological complexity of the Plasmodium life cycle has prevented faster progress towards the development of a highly efficacious malaria vaccine, recent technological and scientific developments could facilitate further progress. We propose to integrate established facilities, experimental models, and standardized and novel techniques to identify and characterize P. vivax (Pv) pre-erythrocytic (PE) antigens showing vaccine potential for further clinical development. Our general hypothesis is that “immunization with selected PvPE antigen constructs can induce protective immune responses in the vertebrate host.” The overall goal of this proposal is to accelerate Pv vaccine development by identifying and characterizing classical and novel vaccine candidates with confirmed protective efficacy that could be further advanced to clinical development. Specific aims are Aim 1: Characterization of novel PvPE antigens recognized preferentially by sporozoite-vaccinated and protected individuals; Aim 2: Evaluation of the immunogenicity and protective efficacy of novel PvPE protein constructs in animal models; Aim 3: Design of self-assembled protein nanoparticle (SAPN) constructs containing antigenically relevant Pv-CSP and novel PvPE selected proteins/fragments; Aim 4: Generation of anti-Pv-CSP human monoclonal antibodies (Hu-MABs) with protective efficacy to define their precise epitopes and conformations. Methods are 1) selection and expression of early and late PvPE antigens associated with sterile protection, using Pv protein microarrays. 2) In silico prediction of B, T and CTL epitopes, and synthesis of the corresponding peptide sequences. 3) Immunological characterization, i.e., humoral (ELISA Igs/isotypes) and CMI (FACS cytokines/cell profiles) responses. 4) Immunogenicity and protective efficacy analyses of selected antigen constructs/formulations in rodents, using transgenic parasites. 5) Monkey immunogenicity, ex-vivo inhibition of spz invasion (ISI) to liver cells, protective efficacy to wild-type spz, and durability of protection. 6) Development of SAPN constructs containing the Pv-CSP variants (VK210; VK247); 7) Evaluation of the nanoparticles´ immunogenicity and protective efficacy in mice and monkeys; 8) Development of Pv-CSP Hu-MABs and analyses of their protective efficacy and fine epitope specificity; 9) Antigen-antibody (Ag::Ab) interactions analyses by X-ray crystallography. The innovation of this proposal is the use of a comprehensive, rational, and rigorous Pv protein/epitope down-selection process using unique sera/cells from malaria vaccinated protected individuals, together with protein structural analyses leading to the rational design of protective nanoparticle formulations. The significance of this proposal is to provide rapid preclinical development of 1-2 highly efficacious PvPE vaccines for future clinical evaluation and Pv-HuMABs that could be administered passively for malaria prophylaxis.


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	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 = $582,163 )
2023	2023	CENTRO DE INVESTIGACION CIENTIFICA CAUCASECO LTDA	CARRERA 37 2 BIS 5 E 08	CALI	VALLE			COL	Allergy and Infectious Diseases Research	001	3	7/6/2023	NON-COMPETING CONTINUATION	$0
2023	2023	CENTRO DE INVESTIGACION CIENTIFICA CAUCASECO LTDA	CARRERA 37 2 BIS 5 E 08	CALI	VALLE			COL	Allergy and Infectious Diseases Research	000	3	11/9/2022	NON-COMPETING CONTINUATION	$582,163
														Subtotal = $582,163

Issue Date FY: 2022 ( Subtotal = $579,640 )
2022	2022	CENTRO DE INVESTIGACION CIENTIFICA CAUCASECO LTDA	CARRERA 37 2 BIS 5 E 08	CALI	VALLE			COL	Allergy and Infectious Diseases Research	000	2	10/22/2021	NON-COMPETING CONTINUATION	$579,640
														Subtotal = $579,640

Issue Date FY: 2021 ( Subtotal = $583,695 )
2021	2021	CENTRO DE INVESTIGACION CIENTIFICA CAUCASECO LTDA	CARRERA 37 2 BIS 5 E 08	CALI	VALLE			COL	Allergy and Infectious Diseases Research	000	1	11/19/2020	NEW	$583,695
														Subtotal = $583,695

Grand Total All Awards = $1,745,498

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DISCOVERY AND PRECLINICAL DEVELOPMENT OF EFFICACIOUS P. vivax PRE-ERYTHROCYTIC STAGE MALARIA VACCINES

Award Number: U01AI155363

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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