Oral Delivery of DNA Vaccines

DNA 疫苗的口服给药

• 批准号: 6557378
• 负责人: FRANK M ORSON
• 金额: $ 7.53万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-15 至 2004-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6557378
• 关键词: DNA; aerosols; antigens; cellular immunity; cytotoxic T lymphocyte; drug delivery systems; drug screening /evaluation; flow cytometry; gene expression; immunization; immunoglobulin E; immunotherapy; interleukin 12; intravenous administration; laboratory mouse; oral administration; plasmids; reporter genes; vector vaccine

DESCRIPTION (provided by applicant): Biological warfare pathogens (BWP) will potentially have severe toxicity and broad antigenic variation from deliberate manipulations and may be transmissible by numerous routes of entry, thus requiring successful vaccines to induce a much higher degree of immune protection than is needed for most ordinary pathogens. Pulmonary, gastrointestinal, and cutaneous surfaces have the highest risk of exposure. Since systemic immunity often develop responses independently of the common mucosal immune system, vaccines must be designed to elicit the mucosal effector cells that can disseminate after sensitization in one compartment to other surface tissues, enabling vaccination at an accessible site to induce immunologic resistance at other sites as well. Unlike other vaccine targets, for which substantial local pathogen replication may be tolerable before the systemic immune response controls and eradicates the infection, the immune response induced by a BWP vaccine should ideally prevent toxicity or infection entirely, or rapidly kill any pathogens or infected cells in the mucosa before extensive replication occurs. The skin, lung, and gut contain the largest surface areas of potential exposure, and are thus the natural targets that must be protected with vigorous immune responses to microbial pathogens or pathogenic products. To achieve this goal, vaccine strategies must be devised that are highly flexible antigenically and can be delivered in such a way that the mucosal immune system is strongly stimulated. Unfortunately, traditional vaccine methods using purified peptides, protein subunits, and/or attenuated or inactivated pathogens do not have all these immunological features. Furthermore, since the nature of BWP will not be precisely predictable, a general method for rapidly producing an effective vaccine for any newly modified pathogen is needed, and genetic vaccines have exactly this potential, if methods for induction of strong mucosal immune responses can be developed. We propose to investigate the properties of oral delivery methods for DNA vaccines using plasmids encoding model antigens, a fragment of anthrax lethal toxin, and the cytokine IL12 to enhance the development of immune responses in mice, with particular emphasis on eliciting antibody and cytotoxic T cell responses in both mucosal and systemic sites.

描述（申请人提供）：生物战病原体（BWP）可能具有严重的毒性和广泛的抗原变异，可通过多种途径传播，因此需要成功的疫苗诱导比大多数普通病原体更高程度的免疫保护。 肺部、胃肠道和皮肤表面的暴露风险最高。由于全身性免疫反应通常独立于常见的粘膜免疫系统，因此疫苗必须设计为引发粘膜效应细胞，这些细胞在一个区室中致敏后可以扩散到其他表面组织，从而使在可接近部位接种疫苗也能够在其他部位诱导免疫抗性。与其他疫苗靶标不同，在全身免疫应答控制和根除感染之前，大量的局部病原体复制可能是可耐受的，由BWP疫苗诱导的免疫应答理想地应完全防止毒性或感染，或在广泛复制发生之前快速杀死粘膜中的任何病原体或感染细胞。皮肤、肺和肠道含有最大的潜在暴露表面积，因此是必须通过对微生物病原体或致病产物的强烈免疫反应来保护的天然目标。为了实现这一目标，必须设计出抗原性高度灵活的疫苗策略，并且可以以强烈刺激粘膜免疫系统的方式递送。不幸的是，使用纯化肽、蛋白质亚基和/或减毒或灭活病原体的传统疫苗方法不具有所有这些免疫学特征。 此外，由于BWP的性质无法精确预测，因此需要一种快速生产针对任何新修饰病原体的有效疫苗的通用方法，如果能够开发出诱导强粘膜免疫应答的方法，则基因疫苗正好具有这种潜力。我们建议调查使用质粒编码的模型抗原，炭疽致死毒素的片段，和细胞因子IL 12的DNA疫苗的口服递送方法，以提高小鼠的免疫反应的发展，特别强调在粘膜和全身部位引起抗体和细胞毒性T细胞反应的属性。