A novel live intranasal TB vaccine

一种新型鼻内结核活疫苗

• 批准号: 8315003
• 负责人: FREDERICK D QUINN
• 金额: $ 30万
• 依托单位: PATHENS, INC.
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8315003
• 关键词: Address; Adolescence; Aerosols; Animals; Antibodies; Antigens; Attenuated; Attenuated Vaccines; Autopsy; BCG Vaccine; Bacteria; Birth; Body Temperature; Body Weight decreased; Caliber; Cavia; Cell Wall; Cells; Clinical Trials; Companions; Detection; Development; Diagnostic; Disease; Engineering; Generations; Genus Mycobacterium; Goals; Growth; Human; Humanities; Hypersensitivity skin testing; Immune response; Immunization; Immunocompromised Host; Immunoglobulin G; Individual; Infection; Interferons; Lead; Life; Link; Liver; Lung; Mammals; Marketing; Microscopic; Modeling; Monitor; Mus; Mycobacterium tuberculosis; Mycobacterium tuberculosis antigens; Nebulizer; Needles; Nose; Organ Survival; Pathogenicity; Pathology; Pharmacologic Substance; Phase; Population; Reading; Recombinants; Regimen; Research; Risk; Safety; Serum; Small Business Technology Transfer Research; Spleen; Staging; Temperature; Test Result; Testing; Tissues; Toxic effect; Tuberculin; Tuberculin Test; Tuberculosis; Tuberculosis Vaccines; Vaccinated; Vaccination; Vaccines; Variant; base; design; dosage; humane endpoint; immunosuppressed; improved; killings; nonhuman primate; novel; particle; pathogen; protective efficacy; response; vaccine delivery

DESCRIPTION (provided by applicant): The most-widely used vaccine for TB currently is BCG, a live avirulent variant of M. bovis that is given intradermally at birth. Along with the inherent safety and logistical problems associated with being injected, protective efficacy is generally poor and wanes by adolescence. BCG administration to an immunosuppressed individual also can disseminate and lead to serious life- threatening infection. Second-generation BCG vaccines, modified to express Mycobacterium tuberculosis (Mtb) antigens, such as Ag85B, are in human clinical trials. Unfortunately, these vaccines also are injected and retain the inherent safety risk to the immunosuppressed population. TBVac85 is a novel, live, attenuated intranasal TB vaccine. It is a cold-adapted, temperature-restricted derivative of Mycobacterium shottsii engineered to express Ag85B. TBVac85 is naturally adjuvantic due to cell wall and antigenic similarities to Mtb. Intranasal TBVac85 possesses the potential benefits associated with recombinant BCG vaccines, with enhanced safety for the immunocompromised afforded by temperature-restricted growth and intranasal (needle-free) immunization. Our preliminary studies demonstrated a lack of toxicity or pathogenicity in the nasal passages and lungs of mice and guinea pigs intranasally vaccinated and boosted with TBVac85 over subsequent weeks. We also have demonstrated lack of persistence by TBVac85 bacteria, both locally and in the lungs and spleens of the immunized animals. Finally, we demonstrated humoral and cellular responsiveness in TBVac85-immunized guinea pigs through the detection of serum antibodies and positive skin test responses to Ag85B and tuberculin. The next stage of development of TBVac85 and the subject of this proposal is to determine the protective efficacy of intranasal TBVac85 against Mtb challenge in the guinea pig aerosol infection model. If more protective than BCG, TBVac85 will be examined for protective efficacy in a non-human primate model in the phase II application. PUBLIC HEALTH RELEVANCE: The goal of the proposed research is to determine the protective efficacy of intranasal TBVac85 against Mtb challenge in the guinea pig aerosol infection model. If more protective than BCG, TBVac85 will be examined for protective efficacy in a non-human primate model in the phase II application.

描述（由申请人提供）：当前使用最宽敞的结核病疫苗是BCG，BCG是BCG，它是Bovis的活节无毒变体，在出生时在皮内给予。除了注射的固有安全性和后勤问题外，保护性效能通常很差，并且在青春期时会减弱。 BCG对免疫抑制的人进行管理也可以传播并导致严重威胁生命的感染。第二代BCG疫苗，被修饰以表达结核分枝杆菌（MTB）抗原，例如AG85B，是在人类临床试验中。不幸的是，这些疫苗也被注射并保留了免疫抑制人群的固有安全风险。 TBVAC85是一种新颖的，活的，减弱的鼻内结核病疫苗。这是一种易冷的，温度限制的衍生物，用于表达AG85B的shottsii。由于细胞壁和与MTB的抗原相似性，TBVAC85自然是辅助的。鼻内TBVAC85具有与重组BCG疫苗相关的潜在益处，并具有增强的安全性，可通过温度限制的生长和鼻内（无针头）免疫来提供免疫功能低下。我们的初步研究表明，在随后的几周内，鼻腔和鼻猪肠内疫苗接种并用TBVAC85促进的小鼠和豚鼠缺乏毒性或致病性。我们还表明，在当地和免疫动物的肺和脾脏中，TBVAC85细菌缺乏持久性。最后，通过检测血清抗体和对AG85B和结核蛋白的皮肤测试阳性反应，我们证明了TBVAC85豚鼠的体液和细胞反应性。 TBVAC85的下一个阶段和该提案的主题是确定豚鼠气雾剂感染模型中鼻内TBVAC85对MTB挑战的保护性疗效。如果比BCG更具保护性，则将检查TBVAC85在II期应用中非人类灵长类动物模型中的保护功效。 公共卫生相关性：拟议的研究的目的是确定豚鼠气雾剂感染模型中鼻内TBVAC85针对MTB挑战的保护作用。如果比BCG更具保护性，则将检查TBVAC85在II期应用中非人类灵长类动物模型中的保护功效。