Transgenic Plant-Derived CMV Glycoprotein B Vaccine

转基因植物源 CMV 糖蛋白 B 疫苗

• 批准号: 7230286
• 负责人: Mark R. Schleiss
• 金额: $ 21.77万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-15 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7230286
• 关键词: Adjuvant; Animal Model; Animals; Antibodies; Antibody Formation; Antigens; Arabidopsis; Baculoviruses; CMV glycoprotein B; Cavia; Cells; Cholera Toxin; Clinical; Clinical Trials; Communicable Diseases; Cytomegalovirus; Cytomegalovirus Infections; Cytomegalovirus Vaccines; Data; Disease; Engineering; Enzyme-Linked Immunosorbent Assay; Evaluation; Face; Genetic Recombination; Glycoproteins; Guinea pig cytomegalovirus; Head; Health Priorities; Human; Immunity; Immunization; Immunologics; Investigation; Licensing; Licensure; Mediating; Modeling; Mucosal Immune Responses; Numbers; Oral; Oral Administration; Personal Satisfaction; Plants; Post-Translational Protein Processing; Pregnancy; Procedures; Process; Production; Proteins; Public Health; Recombinant Proteins; Recombinants; Relative (related person); Resources; Rhizobium radiobacter; Risk; Route; Seeds; Subunit Vaccines; Surface; System; Technology; Testing; Tissues; Transgenic Plants; Vaccination; Vaccines; Work; base; concept; congenital cytomegalovirus; congenital infection; efficacy evaluation; expression cloning; fetal; human TYRP1 protein; immunogenic; immunogenicity; improved; innovation; mucosal site; neutralizing antibody; novel strategies; numb protein; oral vaccine; pathogen; response; vaccine efficacy

DESCRIPTION (provided by applicant): An innovative vaccine strategy that has been promoted in recent years is the concept of oral immunization, using transgenic plants as vaccines. The rationale for transgenic plant vaccines is based on the potential for mass productive of such vaccines; lower expense; improved mucosal immune responses; and ease of administration. Although such vaccines have been shown in animal models and in human trials to be immunogenic, there is very little data about the protective efficacy of this immunization strategy. There is similarly little information about the relative immunogenicity and efficacy of following oral administration of transgenic plant material compared with oral administration of recombinant proteins generated by more traditional expression systems. Because of perceived differences in antigen stability (conferred by the presence of a plant cell well) and immunologic processing in the gut, plant vaccines are hypothesized to be superior for oral administration. This study proposes to test this hypothesis in an animal system in which the protective immunogen is well defined. The system to be studied is the guinea pig cytomegalovirus (GPCMV) model, and the protein is the glycoprotein B (gB) protein. The rationale for choosing this protein is that this protein is clearly effective in vaccine-mediated protection against CMV disease, thus providing a valuable opportunity for testing "proof of concept" of oral vaccination. In this model, we have shown that humoral responses generated against the gB protein, when expressed as an adjuvanted subunit vaccine in baculovirus, are critical in protection of the maternal-placental-fetal unit. Furthermore, since CMV infections are typically acquired at mucosal surfaces, evaluation of recombinant gB vaccine administered at an oral vaccine, at a mucosal site, warrants investigation. Using Agrobacteria tumefaciens-mediated recombination in transgenic plant expression systems, we have engineered an Arabidopsis plant transgenic for GPCMV gB, which will be utilized to immunize guinea pigs, orally, with adjuvant (cholera toxin B), followed by GPCMV challenge during pregnancy. Oral vaccination will also be conducted with baculovirus-purified gB. We will test the hypothesis that plant-derived vaccine is more immunogenic and protective than baculovirus-derived protein when administered by an oral route. The immunogenicity and protective efficacy against congenital infection and disease of this vaccine will be evaluated. These studies will advance the field of HCMV vaccines, an important public health priority. Moreover, these studies will provide data regarding the potential efficacy of oral transgenic plant vaccination, a concept which has been subjected to relatively few efficacy analyses. Based on the rationale that gB is a key immunogen in the CMV model in guinea pigs, there is a compelling rationale to evaluate this protein as an oral plant-based vaccine, compared to oral immunization with proteins purified by other approaches. These studies will advance the fields of plant and CMV vaccines.

描述（申请人提供）：近年来推广的一种创新疫苗策略是口服免疫的概念，使用转基因植物作为疫苗。转基因植物疫苗的基本原理是基于大规模生产此类疫苗的潜力；降低费用；改善粘膜免疫反应；和易于管理。尽管此类疫苗已在动物模型和人体试验中显示出具有免疫原性，但有关这种免疫策略的保护功效的数据很少。与口服更传统表达系统产生的重组蛋白相比，关于口服转基因植物材料的相对免疫原性和功效的信息同样很少。由于抗原稳定性（由植物细胞孔的存在所赋予）和肠道免疫加工的明显差异，植物疫苗被认为更适合口服给药。本研究拟在保护性免疫原明确的动物系统中检验这一假设。所研究的系统为豚鼠巨细胞病毒（GPCMV）模型，蛋白为糖蛋白B（gB）蛋白。选择这种蛋白质的理由是，这种蛋白质在疫苗介导的针对 CMV 疾病的保护中明显有效，从而为测试口服疫苗的“概念验证”提供了宝贵的机会。在该模型中，我们表明，当在杆状病毒中表达为佐剂亚单位疫苗时，针对 gB 蛋白产生的体液反应对于保护母体-胎盘-胎儿单位至关重要。此外，由于 CMV 感染通常是在粘膜表面获得的，因此对在粘膜部位口服疫苗施用的重组 gB 疫苗进行评估值得研究。利用转基因植物表达系统中根癌农杆菌介导的重组，我们设计了 GPCMV gB 转基因拟南芥植物，该植物将用于口服佐剂（霍乱毒素 B）对豚鼠进行免疫，然后在怀孕期间进行 GPCMV 攻击。还将使用杆状病毒纯化的 gB 进行口服疫苗接种。我们将测试以下假设：当通过口服途径施用时，植物源疫苗比杆状病毒源蛋白更具免疫原性和保护性。将评估该疫苗的免疫原性和针对先天性感染和疾病的保护功效。这些研究将推动 HCMV 疫苗领域的发展，这是一个重要的公共卫生优先事项。此外，这些研究将提供有关口服转基因植物疫苗接种潜在功效的数据，这一概念受到的功效分析相对较少。基于 gB 是豚鼠 CMV 模型中关键免疫原的基本原理，与使用其他方法纯化的蛋白质进行口服免疫相比，有令人信服的理由将该蛋白质评估为口服植物疫苗。这些研究将推动植物和 CMV 疫苗领域的发展。