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

用于疟疾疫苗开发的恶性疟原虫和间日疟原虫卷曲螺旋抗原的发现和临床前评估

• 批准号: 10323004
• 负责人: Socrates Herrera Valencia
• 金额: $ 31.95万
• 依托单位: CAUCASECO SCIENTIFIC RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-03 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10323004
• 关键词: Adjuvant; Animal Model; Animals; Antibodies; Antibody Response; Antibody titer measurement; Antibody-mediated protection; Antigens; Aotus primate; Area; Bioinformatics; Biological Assay; Blood; Cessation of life; Chemicals; Circular Dichroism; Circular Dichroism Spectroscopy; Clinical; Coiled-Coil Domain; Control Animal; Country; Data; Development; Enzyme-Linked Immunosorbent Assay; Epitopes; Erythrocytes; Evaluation; Genome; Goals; Growth; High Pressure Liquid Chromatography; Human; Immune response; Immune system; Immunity; Immunization; Immunize; Immunoglobulin G; Immunologics; In Vitro; Incidence; Individual; Infection; Malaria; Malaria Vaccines; Mass Spectrum Analysis; Methods; Monkeys; Mus; Parasitemia; Parasites; Peptide Synthesis; Peptide antibodies; Peptides; Persons; Phagocytosis; Plasmodium; Plasmodium falciparum; Plasmodium vivax; Preparation; Primates; Process; Protein Fragment; Proteins; Proteome; Public Health; Recombinants; Respiratory Burst; Risk; Rodent; Solid; Specificity; Sterility; Structure; Synthetic Antigens; Testing; Vaccines; aqueous; base; cost effective; cross reactivity; design; disorder risk; efficacy study; experience; experimental study; immunogenic; immunogenicity; improved; in silico; in vitro Assay; in vivo; inhibiting antibody; innovation; manufacturing facility; nonhuman primate; novel; novel vaccines; peptide vaccination; preclinical evaluation; protective efficacy; protein structure; screening; success; tool; vaccine candidate; vaccine development

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 α-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 α-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 α-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 α-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.

项目总结/文摘

项目成果

P. falciparum and P. vivax Orthologous Coiled-Coil Candidates for a Potential Cross-Protective Vaccine.

恶性疟原虫和疟原虫直系同源卷曲圈候选物，用于潜在的交叉保护疫苗。

• DOI: 10.3389/fimmu.2020.574330
• 发表时间: 2020
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Ayadi I;Balam S;Audran R;Bikorimana JP;Nebie I;Diakité M;Felger I;Tanner M;Spertini F;Corradin G;Arevalo M;Herrera S;Agnolon V
• 通讯作者: Agnolon V