Towards a Vaccine to Prevent Toxoplasmosis

开发预防弓形虫病的疫苗

基本信息

批准号：
8290398
负责人：
Rima L McLeod
金额：
$ 81.08万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-07-24 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8290398
关键词：
Acute Address Adjuvant Antibodies Antigens Attenuated Binding Bioterrorism Breeding CD4 Positive T Lymphocytes CD8B1 gene Cellular Immunity Chicago Complementary DNA Congenital Toxoplasmosis DNA DNA Vaccines Data Drug resistance Engineering Epitopes Fetus Foundations Funding Future Goals Hand Human Immune response Immunization Inbred Strains Mice Infection Injection of therapeutic agent Interleukin-12 Interleukin-15 Interleukin-18 Interleukin-2 Life MHC Class I Genes Malaria Methods Modeling Mus Oocysts Organism Parasites Pathway interactions Peptides Population Process Proteins Recombinants Recommendation Sporozoites Suggestion Surface Antigens System T-Lymphocyte Testing Toxoplasma Toxoplasma gondii Toxoplasmosis Transgenic Mice Transgenic Organisms Vaccinated Vaccination Vaccines Vaccinia Vaccinium Vertical Disease Transmission Viral Virginia Virulence Virulent Washington Work anthrax lethal factor antigen challenge base congenital infection cytokine design experience immunogenicity improved microorganism multicatalytic endopeptidase complex pathogen prevent programs promoter protective effect research study stem tool vaccine development vaccine evaluation vector

项目摘要

DESCRIPTION (provided by applicant): The long term goal is to develop a vaccine that prevents toxoplasmosis, including transmission from mother to child and reduction or elimination of organisms during initial acute infection. Work toward this goal will be accomplished using a rational approach based on understanding and using only epitopes that induce a protective immune response, without extraneous epitopes that may be harmful, and optimizing adjuvants. Specific aims are: 1. Identify optimal adjuvants and delivery, characterizing and optimizing peroral bilosome delivery systems for DMA vaccines; 2.Characterize protective effect, and when there is protection, immune responses produced by SAG1 or ROP2 or GRA2 or 3 or 6 or 7 or a bradyzoite antigen (BLKAg), and for oocyst challenge a sporozoite antigen (SpAg) vaccination. HLA A2.1, HLA A3/11 and HLA B7 mice, will be vaccinated with DMA constructs containing parasite antigens, with and without adjuvant(s) or bilosomes or MVA for boost; 3. Create multiepitope vaccines based on epitopes identified from those proteins which confer protection; 4. In later studies, test the most promising constructs in (a) peroral bradyzoite or oocyst challenges, (b) challenges with hypervirulent, recombinant and a Brazilian strain of T. gondii, and (c) in congenital and ocular models. Studies initially will define the best adjuvant(s) of 6 cytokine eliciting or cytokine encoding constructs or delivery with bilosomes or MVA boost construct using T. gondii SAG1. These will be used to vaccinate HLA A2 transgenic mice with DNA from clonal type 1 or II parasites and challenge with the homologous clonal type of parasite. Adjuvants that will be tested include DNA constructs which encode each of the following separately: IL -1Beta,-2,-12,-15,and -18; delivery within an attenuated vaccinia construct following an injection within the DNA construct; and delivery in bilosomes. Then, vaccines will be tested with DNA encoding T. gondii proteins that are candidates for protection with the best adjuvant(s) or means of delivery in HLA supermotif transgenic B7, and A*201 and A3/11 mice (HLA supermotifs present in ~90% of humans). Proteins were selected based on data available about peptides that enter MHC Class I pathways and confer protection in inbred strains of mice, including SAG1, ROP2, GRA2, GRA3, GRA6, GRA7, BLKAG, and SpAg. When protective proteins in each HLA supertype mouse are identified, epitope-encoding constructs will be designed following the principles of vaccine optimization defined by the Sette/Alexander group. This work will provide a foundation to develop a vaccine protective against toxoplasmosis for humans as well as a paradigm for vaccines to protect against other pathogens.

描述（由申请人提供）：长期目标是开发一种预防弓形虫病的疫苗，包括母婴传播以及在初始急性感染期间减少或消除微生物。实现这一目标的工作将使用一种合理的方法来完成，该方法基于理解和仅使用诱导保护性免疫反应的表位，而不使用可能有害的外来表位，并优化佐剂。具体目标是： 1. 确定最佳佐剂和递送，表征和优化 DMA 疫苗的口服胆汁体递送系统； 2.表征保护作用，当有保护作用时，由SAG1或ROP2或GRA2或3或6或7或缓殖子抗原（BLKAg）产生的免疫反应，以及针对卵囊攻击的子孢子抗原（SpAg）疫苗接种。 HLA A2.1、HLA A3/11 和 HLA B7 小鼠将用含有寄生虫抗原的 DMA 构建体进行疫苗接种，使用或不使用佐剂或胆汁体或 MVA 进行加强接种； 3. 根据从那些具有保护作用的蛋白质中鉴定出的表位，创建多表位疫苗； 4. 在以后的研究中，在 (a) 经口缓殖子或卵囊挑战，(b) 高毒力、重组体和巴西弓形虫菌株挑战，以及 (c) 先天性和眼部模型中测试最有前途的构建体。研究最初将确定 6 种细胞因子引发或细胞因子编码构建体或使用弓形虫 SAG1 的胆汁体或 MVA 加强构建体递送的最佳佐剂。这些将用于用 1 型或 II 型克隆寄生虫的 DNA 给 HLA A2 转基因小鼠接种疫苗，并用同源克隆型寄生虫进行攻击。将测试的佐剂包括分别编码以下各项的DNA构建体：IL -1Beta、-2、-12、-15和-18；在DNA构建体中注射后，在减毒痘苗构建体中递送；和胆汁体中的递送。然后，将用编码刚地弓形虫蛋白的 DNA 测试疫苗，这些蛋白是在 HLA 超基序转基因 B7、A*201 和 A3/11 小鼠（HLA 超基序存在于〜 90%的人类）。根据有关进入 MHC I 类途径并为近交系小鼠提供保护的肽的可用数据来选择蛋白质，包括 SAG1、ROP2、GRA2、GRA3、GRA6、GRA7、BLKAG 和 SpAg。当每只 HLA 超型小鼠的保护性蛋白被识别后，表位编码结构将按照 Sette/Alexander 小组定义的疫苗优化原则进行设计。这项工作将为开发人类弓形虫病疫苗奠定基础，并为预防其他病原体的疫苗提供范例。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

CD4+ T Cell Responses to Toxoplasma gondii Are a Double-Edged Sword.

CD4 T 细胞对弓形虫的反应是一把双刃剑。

DOI：
发表时间：
2023-09-14
期刊：
影响因子：
7.8
作者：
El Bissati, Kamal;Krishack, Paulette A;Zhou, Ying;Weber, Christopher R;Lykins, Joseph;Jankovic, Dragana;Edelblum, Karen L;Fraczek, Laura;Grover, Harshita;Chentoufi, Aziz A;Singh, Gurminder;Reardon, Catherine;Dubey, J P;Reed, Steve;Alexander
通讯作者：
Alexander

Oral oocyst-induced mouse model of toxoplasmosis: effect of infection with Toxoplasma gondii strains of different genotypes, dose, and mouse strains (transgenic, out-bred, in-bred) on pathogenesis and mortality.

口腔卵囊诱导的弓形体病小鼠模型：不同基因型、剂量和小鼠品系（转基因、远交、近交）的弓形虫菌株感染对发病机制和死亡率的影响。

DOI：
发表时间：
2012-01
期刊：
影响因子：
2.4
作者：
Dubey, J P;Ferreira, L R;Martins, J;McLeod, Rima
通讯作者：
McLeod, Rima

Global initiative for congenital toxoplasmosis: an observational and international comparative clinical analysis.

先天性弓形虫病全球倡议：观察性和国际比较临床分析。

DOI：
发表时间：
2018-09-27
期刊：
影响因子：
13.2
作者：
El Bissati, Kamal;Levigne, Pauline;Lykins, Joseph;Adlaoui, El Bachir;Barkat, Amina;Berraho, Amina;Laboudi, Majda;El Mansouri, Bouchra;Ibrahimi, Azeddine;Rhajaoui, Mohamed;Quinn, Fred;Murugesan, Manoradhan;Seghrouchni, Fouad;Gómez
通讯作者：
Gómez

Evidence for finely-regulated asynchronous growth of Toxoplasma gondii cysts based on data-driven model selection.

基于数据驱动模型选择的弓形虫包囊精细调节异步生长的证据。

DOI：
发表时间：
2013
期刊：
影响因子：
4.3
作者：
Sullivan, Adam M;Zhao, Xiaopeng;Suzuki, Yasuhiro;Ochiai, Eri;Crutcher, Stephen;Gilchrist, Michael A
通讯作者：
Gilchrist, Michael A

IL-2 produced by CD8+ immune T cells can augment their IFN-γ production independently from their proliferation in the secondary response to an intracellular pathogen.

CD8 免疫 T 细胞产生的 IL-2 可以增强其 IFN-γ 的产生，独立于其在对细胞内病原体的二次反应中的增殖。