Bacterial Commensal Vector Delivery/Smallpox Vaccine

细菌共生载体递送/天花疫苗

• 批准号: 7051706
• 负责人: DENNIS E. HRUBY
• 金额: $ 49.14万
• 依托单位: SIGA TECHNOLOGIES, INC.
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-01 至 2007-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7051706
• 关键词: Poxviridae; Poxviridae disease; Streptococcus; antibody; antigens; bioterrorism /chemical warfare; birth; clinical research; human; immunization; model; vaccinia virus; virus antigen; virus protein

DESCRIPTION (provided by applicant): Smallpox is widely considered to be the most serious threat for use as a potential agent of biowarfare. There is an effective vaccine available (vaccinia virus), but because of a small but significant risk of serious complications (including death) associated with vaccinia virus, mass immunization is not currently advisable. This leaves the populace at risk to the deliberate or accidental introduction of a pathogenic poxvirus into our environment. The focus of this proposal is to develop an alternative vaccine with improved safety for use in preventing human disease caused by pathogenic orthopoxviruses such as variola virus. To accomplish this goal we will utilize our newly-developed BCV (bacterial commensal vector) technology. BCV utilizes gram-positive commensal bacteria, such as Streptococcus gordonii, to express heterologous antigens of interest on its external surface. Phase I human clinical trials indicate that this S. gordonii strain is safe and well-tolerated in humans. Mucosal immunization of mice with S. gordonii expressing either the vaccinia virus A27L protein or DSL elicited protection against lethal vaccinia challenge. We believe that the delivery of selected vaccinia virus antigens via this live bacterial vector system will provide an effective and safe method for prevention of smallpox in humans. The following specific aims are proposed 1) To construct recombinant S. gordonii strains that express conserved vaccinia antigens anchored to the bacterial surface, and 2) To test the immunogenicity of S. gordonir.W recombinants when delivered topically into mice, measuring antibody response (IgG and IgA), antigen-specific CTL responses, viral neutralization and/or killing, and protection against a live viral challenge in a murine model. Successful completion of the proposed  experiments will identify a BCV smallpox vaccine candidate suitable for subsequent preclinical validation and development.

描述（由申请人提供）：天花被广泛认为是用作生物战潜在制剂的最严重威胁。有一种有效的疫苗（痘苗病毒），但由于与痘苗病毒相关的严重并发症（包括死亡）的风险虽小但显着，因此目前不建议进行大规模免疫。这使得民众面临着故意或意外地将致病性痘病毒引入我们的环境的风险。该提案的重点是开发一种安全性更高的替代疫苗，用于预防由天花病毒等致病性正痘病毒引起的人类疾病。为了实现这一目标，我们将利用我们新开发的 BCV（细菌共生载体）技术。 BCV 利用革兰氏阳性共生细菌（例如戈登链球菌）在其外表面表达感兴趣的异源抗原。 I 期人体临床试验表明，这种 S. gordonii 菌株在人类中是安全且耐受性良好的。用表达痘苗病毒 A27L 蛋白或 DSL 的戈登沙门氏菌对小鼠进行粘膜免疫，可引发针对致命痘苗攻击的保护作用。我们相信，通过这种活细菌载体系统传递选定的牛痘病毒抗原将为预防人类天花提供有效且安全的方法。提出以下具体目标 1) 构建表达锚定在细菌表面的保守痘苗抗原的重组戈登沙门氏菌菌株，以及 2) 测试戈登沙门氏菌.W 重组体局部递送至小鼠时的免疫原性，测量抗体反应（ IgG 和 IgA）、抗原特异性 CTL 反应、病毒中和和/或杀灭，以及在小鼠模型中针对活病毒攻击的保护。成功完成拟议的实验将确定适合后续临床前验证和开发的 BCV 天花候选疫苗。