Development of Shielded Adenovirus Vector as a Vaccine Strategy For Anthrax

开发屏蔽腺病毒载体作为炭疽疫苗策略

• 批准号: 7326325
• 负责人: Susan J Hedley
• 金额: $ 10万
• 依托单位: VECTORLOGICS, INC.
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-15 至 2008-03-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7326325
• 关键词: Address; Adenovirus Vector; Adenoviruses; Albumins; Anthrax Attack; Anthrax disease; Antibodies; Antigens; Biological; Biological Models; Biological Products; Botulism; Capsid; Capsid Proteins; Chemicals; Clinical; Development; Dose; Economics; Effectiveness; Evaluation; Exposure to; Future; Gene Delivery; Generations; Genetic; Genome; Goals; Green Fluorescent Proteins; Heterogeneity; Human; Immune; Immune response; Immune system; Immunity; In Vitro; Intoxication; Ligands; Locales; Minor; Modeling; Mus; Numbers; Oryctolagus cuniculus; Pharmaceutical Preparations; Phase; Plague; Polyethylene Glycols; Polylysine; Polymers; Population; Production; Proteins; Protocols documentation; Range; Reaction; Safety; Serotyping; Small Business Funding Mechanisms; Small Business Innovation Research Grant; Standards of Weights and Measures; System; Technology; Terrorism; Time; Transgenes; Translations; Vaccination; Vaccine Therapy; Vaccines; Validation; Variant; Virion; Virus; Work; anthrax protective factor; base; biothreat; concept; cost; crosslink; desire; gene therapy; genetic manipulation; in vivo; in vivo Model; neutralizing antibody; novel strategies; pathogen; prevent; prophylactic; response; scale up; success; transgene expression; vector; vector vaccine

DESCRIPTION (provided by applicant): The emerging threat of bio-terrorism provides a major challenge to protect the civilian population through standard prophylactic vaccine means. The recent anthrax attacks highlighted the urgent need to develop vaccine strategies that act rapidly to the threat of the biological pathogen, and which can be produced in an economically effective manner. In the context of anthrax, the protective antigen (PA) of this pathogen elicits a strong immune response and is used in the current prophylactic vaccine. However, due to the protracted protocol of the current vaccine, an alternative delivery system of PA, one of which rapidly induces the immune system to produce antibodies, in a sustained manner is necessary. One such mechanism would be gene delivery of PA using adenovirus (Ad) gene delivery vectors, which provide an ideal platform to meet both economic and vaccination requirements. Ad vectors are employed in a wide range of gene therapy and vaccine applications and have an established broad safety record in humans, with attractive features such as high titer production, structural stability, broad infectivity, established protocols for genetic manipulation and high levels of transgene expression with lack of host genome integration. Importantly, these vectors are efficient at evoking immunity against the transgene they carry. However, development of these vectors in the clinical context has highlighted that vector efficacy may be limited by the host humoral responses due to pre-existing titers of neutralizing antibodies, in humans, against the vector itself. On the basis of this caveat we have a novel strategy, termed shielding, in which we have technology to genetically modify the virion capsid to provide an uniformly shielded Ad vector. We have identified the pIX capsid protein as an ideal locale for genetic incorporation of shielding ligands, in particular self-proteins such as albumin, to conceal the Ad vector from pre-existing neutralizing antibodies. In this SBIR proposal the basic feasibility of employing a shielding protein, albumin, in the Ad capsid in a defined manner utilizing a specific capsid protein will be established in in vitro [and in vivo models and] the ability of the vector to retain PA expression will be established in vitro. We envision the creation of our shielded Ad vectors as a major progress in the development of clinically and commercially feasible [Ad drug candidates] that can be dosed multiple times for maximum effectiveness to prevent bio-terrorism provoked illness in humans. There are currently no prophylactic vaccines, which act rapidly to protect the population against the emerging threat of bio-terrorism, and this was highlighted by recent anthrax attacks. It is clear that new options are needed. The development of the proposed shielded Ad vector technology can provide an efficient, cost-effective and creative approach to combat anthrax attacks. In addition, the development of the immunologically shielded vector system approach would have further application for many biological threats such as plague and botulism.

描述（由申请人提供）：生物恐怖主义的新兴威胁为通过标准的预防性疫苗手段保护平民提供了一个重大挑战。最近的炭疽病攻击强调了迫切需要开发迅速针对生物病原体威胁的疫苗策略，并且可以以经济有效的方式生产。在炭疽的背景下，该病原体的保护性抗原（PA）引起了强烈的免疫反应，并用于当前的预防性疫苗。但是，由于当前疫苗的旷日持久，PA的替代输送系统，其中一种迅速诱导免疫系统以持续方式产生抗体。一种这样的机制是使用腺病毒（AD）基因递送向量的PA递送的基因递送，该载体提供了满足经济和疫苗接种要求的理想平台。 AD载体用于广泛的基因疗法和疫苗应用中，并具有在人类中建立的广泛安全记录，具有吸引人的特征，例如高滴度产生，结构稳定性，广泛的感染性，既定的基因操纵和高量转基因表达方案，且缺乏宿主基因组整合。重要的是，这些向量有效地唤起对携带的转基因的免疫力。但是，在临床背景下，这些向量的发展表明，由于对向量本身的中和抗体的预先存在抗体的滴度，载体疗效可能受到宿主的体液反应的限制。在此警告的基础上，我们采用了一种新颖的策略，称为屏蔽，在这种策略中，我们具有基因修改病毒粒子的技术以提供均匀屏蔽的AD载体。我们已经将PIX Capsid蛋白确定为屏蔽配体遗传掺入的理想位置，尤其是白蛋白等自蛋白，以掩盖AD载体预先存在的中和抗体。在此SBIR提案中，使用特定的衣壳蛋白在AD CAPSID中采用屏蔽蛋白Cholel的基本可行性将在体外和体内模型中建立，并且在体内模型以及载体保留PA表达的能力将在体外建立。我们设想创建屏蔽的AD载体是临床和商业上可行的[AD药物候选者]发展的主要进步，可以多次服用以防止生物恐怖主义引起人类的疾病。目前没有预防性疫苗，可以迅速采取行动，以保护人群免受生物恐怖主义的新威胁，而最近的炭疽病攻击强调了这一点。显然，需要新的选项。拟议的屏蔽AD向量技术的开发可以提供有效，成本效益和创造性的方法来打击炭疽攻击。此外，免疫学屏蔽媒介系统方法的发展将进一步应用许多生物学威胁，例如瘟疫和肉毒杆菌。