Using natural antibodies to improve vaccines

使用天然抗体改进疫苗

• 批准号: 8215634
• 负责人: John J Iacomini
• 金额: $ 40.69万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-15 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8215634
• 关键词: Adjuvant; Affect; Antibodies; Antibody Repertoire; Antibody Specificity; Antigen-Presenting Cells; Antigens; B-Lymphocytes; Binding; Bovine Serum Albumin; Carbohydrates; Cells; Cytotoxic T-Lymphocytes; Data; Dendritic Cells; Development; Effectiveness; Epitopes; Generations; Human; Hybridomas; ITGAX gene; Immunity; Immunization; Immunocompromised Host; Immunoglobulin M; Immunoglobulins; Immunosuppression; Immunosuppressive Agents; Individual; Infection; Knock-in Mouse; Lethal Dose 50; Light; Listeria monocytogenes; Lymphoid Follicle; MHC Class I Genes; Maintenance; Memory; Modification; Murine leukemia virus; Mus; Organ Transplantation; Ovalbumin; Play; Pongidae; Primates; Recombinants; Regimen; Role; Solid; T cell response; T-Lymphocyte; Testing; Transformed Cell Line; Vaccination; Vaccine Research; Vaccines; Virus; base; clinically relevant; immunogenic; immunogenicity; improved; in vivo; novel; novel vaccines; pathogen; public health priorities; public health relevance; response; secondary infection; vaccine efficacy; variable region gene

DESCRIPTION (provided by applicant): Natural antibodies play a major role in providing protective host immunity. A significant portion of natural antibodies present in all humans, apes and Old World primates are specific for the carbohydrate antigen Gal11-3Gal21-4GlcNAc-R, or 1Gal. Indeed, 1Gal-specific natural antibodies comprise one to eight percent of circulating immunoglobulin in humans. Based on the universal high-titer presence of these antibodies, we hypothesized that it might be possible to utilize this pre-existing antigen-specific repertoire to augment the immunogenicity of antigens in order to improve the efficacy of vaccines. To test this hypothesis, we used 1Gal-deficient mice (GT0 mice), which like humans produce 1Gal-specific natural antibodies, to analyze whether conjugation of a poorly immunogenic antigen, such as bovine serum albumin (BSA), to 1Gal could affect its immunogenicity in vivo. Immunization of GT0 mice with BSA conjugated to 1Gal (1Gal-BSA) led to a T and B cell response to BSA that was significantly greater than that observed following immunization of control mice without the need for adjuvant. The ability to produce 1Gal-specific antibodies also led to an enhanced cytotoxic T lymphocyte anti-virus response following challenge of mice with murine leukemia virus- transformed cell lines expressing 1Gal. These data suggest that pre-existing 1Gal-specific antibodies encoded for in the natural antibody repertoire can be used to increase B and T cell responses to poorly immunogenic antigens that have been modified to express 1Gal epitopes without the need for adjuvant. The central hypothesis of this proposal is therefore that this pre-existing antibody repertoire can be used to improve vaccine strategies for pathogens. The specific aims are: to determine the mechanism by which 1Gal-specific natural antibodies increase the immunogenicity of antigens modified to express 1Gal; determine if pre-existing 1Gal-specific natural antibodies can be used to improve vaccines for pathogens, and; determine the effectiveness of immunization with 1Gal-modified antigens in immunocompromised hosts. PUBLIC HEALTH RELEVANCE: The development of novel immunization strategies against emerging pathogens remains a high public health priority throughout the world. In this proposal we will examine whether pre-existing natural antibody specificities can be used to develop potentially novel vaccine strategies.

描述(申请人提供)：天然抗体在提供保护性宿主免疫方面起主要作用。存在于所有人类、猿类和东半球灵长类动物中的很大一部分天然抗体是针对碳水化合物抗原Gal11-3Gal21-4GlcNAc-R或1Gal的。事实上，1Gal特异性天然抗体占人类循环免疫球蛋白的1%至8%。基于这些抗体的普遍高效价存在，我们假设有可能利用这一预先存在的抗原特异库来增强抗原的免疫原性，以提高疫苗的效力。为了验证这一假设，我们使用了1Gal缺陷小鼠(GT0小鼠)，它们像人类一样产生1Gal特异性天然抗体，以分析免疫原性较差的抗原，如牛血清白蛋白(BSA)与1Gal的结合是否会影响其在体内的免疫原性。用1Gal-BSA(1Gal-BSA)免疫GT0小鼠后，T和B细胞对BSA的反应性明显高于不需要佐剂的对照组。在用表达1Gal的小鼠白血病病毒转化的细胞系攻击小鼠后，产生1Gal特异性抗体的能力也导致了增强的细胞毒性T淋巴细胞抗病毒反应。这些数据表明，在天然抗体库中编码的预先存在的1Gal特异性抗体可以用来增强B和T细胞对免疫原性低的抗原的反应，这些抗原已经被修改为表达1Gal表位，而不需要佐剂。因此，这一提议的中心假设是，这一预先存在的抗体库可用于改进病原体的疫苗策略。其具体目的是：确定1Gal特异性天然抗体提高表达1Gal的修饰抗原的免疫原性的机制；确定现有的1Gal特异性天然抗体是否可用于改进病原体疫苗；以及确定1Gal修饰的抗原在免疫低下宿主中的免疫效果。 公共卫生相关性：针对新出现的病原体制定新的免疫战略仍然是全世界公共卫生的高度优先事项。在这项提案中，我们将研究是否可以利用预先存在的天然抗体特异性来开发潜在的新疫苗策略。