Infection-blocking antibody targets for malaria

疟疾感染阻断抗体靶点

• 批准号: 9890993
• 负责人: Stefan HI Kappe
• 金额: $ 82.61万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9890993
• 关键词: ART protein; Active Immunization; Animal Model; Anopheles Genus; Antibodies; Antibody Repertoire; Antibody Response; Antibody-mediated protection; Antigen Targeting; Antigens; Antimalarials; B-Lymphocytes; Bite; Blocking Antibodies; Blood; Cessation of life; Clinical; Clinical Trials; Clone Cells; Culicidae; Dermis; Development; Disease; Economics; Ensure; Erythrocytes; Evaluation; Exhibits; Falciparum Malaria; Goals; Hepatocyte; Human; Humoral Immunities; Immune response; Immunity; Immunization; In Vitro; Infection; Infection prevention; Life Cycle Stages; Liver; Malaria; Malaria Vaccines; Mediating; Modeling; Mus; Outcome; Parasites; Parasitic infection; Pathway interactions; Phase; Plasmodium; Plasmodium falciparum; Plasmodium yoelii; Population; Production; Protein Subunits; Proteins; Proteome; Proteomics; Recombinant Proteins; Rodent; Rodent Model; Scheme; Serological; Skin; Sporozoites; Sterility; Stream; Subunit Vaccines; Surface; System; T-Lymphocyte; Techniques; Technology; Testing; Transgenic Organisms; Vaccination; Vaccine Design; Vaccines; Wild Type Mouse; analysis pipeline; base; circumsporozoite protein; cost effective; data modeling; design; disorder prevention; evidence base; falls; gene replacement; global health; human pathogen; humanized antibody; humanized monoclonal antibodies; humanized mouse; immunogenicity; improved; innovation; liver infection; malaria infection; malaria transmission; mouse model; neutralizing antibody; next generation; novel; novel vaccines; polyclonal antibody; prevent; protective efficacy; protein expression; public health relevance; response; vaccine candidate; vaccine development; vaccine efficacy; vaccine evaluation; vaccine trial

 DESCRIPTION (provided by applicant): A vaccine capable of targeting and neutralizing sporozoites, the infectious stage of the malaria parasites injected by mosquito bite, remains a promising target for preventing malaria infection and transmission. Analysis of malaria vaccine trials has shown that antibodies can neutralize the sporozoite and prevent infection of the liver. However, the most clinically advanced pre-erythrocytic vaccine candidate based on the circumsporozoite protein (CSP) confers only partial protection, indicating that it is necessary to add new antigen targets to increase vaccine efficacy. The overall goal of this proposal is to evaluate novel Plasmodium falciparum pre-erythrocytic antigen candidates that can elicit protective immunity from infection. Building on our recent unprecedented characterization of the P. falciparum sporozoite surface/secreted proteome, we have identified a number of promising surface/secreted antigens that warrant interrogation as new vaccine candidates. Based on this evidence, we will develop 15 P. falciparum sporozoite surface/secreted antigens in a state-of-the-art recombinant protein expression platform and evaluate whether they can elicit protective immunity against mosquito bite sporozoite infection. We will employ an innovative combination of transgenic Plasmodium parasite technology, B cell cloning techniques and humanized rodent models to develop a comprehensive pre-erythrocytic antigen development pipeline for analysis of antibody-mediated protection. In addition, we will evaluate the mechanisms of vaccine-elicited protective humoral immunity against the parasite and deepen our understanding of B cell-mediated protective immunity. Our experimental systems to study the human pathogen P. falciparum in a fully humanized humoral immunogenicity mouse model and a liver- humanized mouse challenge model will ensure our results provide the closest possible approximation of vaccination-elicited responses in humans. The outcomes of our aims will provide an evidence-based selection of novel vaccine candidates and will accelerate their pathway toward human clinical trials using the P. falciparum challenge model. If successful, novel non-CSP vaccine immunogens identified can be considered for inclusion into next generation multi-antigen subunit malaria vaccines.



项目成果

A method for the isolation and characterization of functional murine monoclonal antibodies by single B cell cloning.

• DOI: 10.1016/j.jim.2017.05.010
• 发表时间: 2017-09
• 期刊: Journal of immunological methods
• 影响因子: 2.2
• 作者: Carbonetti S;Oliver BG;Vigdorovich V;Dambrauskas N;Sack B;Bergl E;Kappe SHI;Sather DN
• 通讯作者: Sather DN

Anti-TRAP/SSP2 monoclonal antibodies can inhibit sporozoite infection and may enhance protection of anti-CSP monoclonal antibodies.

• DOI: 10.1038/s41541-022-00480-2
• 发表时间: 2022-05-26
• 期刊: NPJ vaccines
• 影响因子: 9.2

Plasmodium yoelii S4/CelTOS is important for sporozoite gliding motility and cell traversal.

约氏疟原虫 S4/CelTOS 对于子孢子的滑动运动和细胞穿越很重要。

• DOI: 10.1111/cmi.12817
• 发表时间: 2018
• 期刊: Cellular microbiology
• 影响因子: 3.4
• 作者: Steel,RyanWJ;Pei,Ying;Camargo,Nelly;Kaushansky,Alexis;Dankwa,DorenderA;Martinson,Thomas;Nguyen,Thao;Betz,Will;Cardamone,Hayley;Vigdorovich,Vladimir;Dambrauskas,Nicholas;Carbonetti,Sara;Vaughan,AshleyM;Sather,DNoah;Kappe,S
• 通讯作者: Kappe,S