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

有效的红细胞前阶段疟疾疫苗的发现和临床前开发

基本信息

批准号：
10513808
负责人：
Socrates Herrera Valencia
金额：
$ 58.22万
依托单位：
CAUCASECO SCIENTIFIC RESEARCH CENTER
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-11-20 至 2023-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10513808
关键词：
Acceleration Affinity Chromatography Animal Model Antibodies Antibody titer measurement Antigens Aotus primate Area Attenuated B-Lymphocytes Bioinformatics Biological C57BL/6 Mouse Cells Cessation of life Clinical Complex Confocal Microscopy Country Development Eligibility Determination Enzyme-Linked Immunosorbent Assay Epitopes Erythrocytes Evaluation Experimental Animal Model Experimental Models Formulation Future Generations Glycine Goals Hepatocyte Human Immune Immune Sera Immune response Immunity Immunization Immunoglobulin G Immunologics Incidence Individual Infection Invaded Length Life Cycle Stages Malaria Malaria Vaccines Methods Molecular Conformation Monkeys Montanide ISA-51 Mus Parasites Passive Transfer of Immunity Peptide Synthesis Phase Phase I/II Clinical Trial Plasmodium Plasmodium falciparum Plasmodium vivax Plasmodium vivax vaccine Populations at Risk Process Production Prophylactic treatment Protein Microchips Proteins Public Health Radiation Recombinant Proteins Recombinants Rodent Rotation Specificity Sporozoites Standardization Sterility Structure Surface T-Lymphocyte Techniques Technology Testing Therapeutic Transgenic Organisms Vaccinated Vaccine Design Vaccinee Vaccines Variant Virus-like particle X-Ray Crystallography clinical development cost effective cytokine design disorder risk efficacy evaluation feature detection human monoclonal antibodies immunogenic immunogenicity improved in silico inhibiting antibody innovation nanoparticle novel novel vaccines passive prophylaxis preclinical development prevent protective efficacy protein aminoacid sequence protein structure rational design research clinical testing response screening self assembly synthetic peptide synthetic protein tool vaccine candidate vaccine development vaccine formulation vaccine trial volunteer

项目摘要

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.

摘要