A novel live intranasal TB vaccine

一种新型鼻内结核活疫苗

基本信息

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
项目类别：
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

项目摘要

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）：目前最广泛使用的结核病疫苗是卡介苗（BCG），它是牛分枝杆菌的一种活的无毒力变种，在出生时皮内注射。除了与注射相关的固有安全性和后勤问题外，保护效果通常很差，并且到青春期就会减弱。对免疫抑制个体施用卡介苗也可能传播并导致严重危及生命的感染。经过修饰以表达结核分枝杆菌 (Mtb) 抗原（例如 Ag85B）的第二代 BCG 疫苗正在进行人体临床试验。不幸的是，这些疫苗也是注射的，对免疫抑制人群仍然存在固有的安全风险。 TBVac85 是一种新型鼻内结核减毒活疫苗。它是一种冷适应、温度限制的肖氏分枝杆菌衍生物，经过改造可表达 Ag85B。由于细胞壁和抗原与 Mtb 的相似性，TBVac85 具有天然佐剂作用。鼻内 TBVac85 具有与重组 BCG 疫苗相关的潜在益处，通过温度限制生长和鼻内（无针）免疫增强了免疫功能低下者的安全性。我们的初步研究表明，在随后几周内鼻内接种 TBVac85 并加强接种的小鼠和豚鼠的鼻道和肺部不存在毒性或致病性。我们还证明了 TBVac85 细菌在局部以及免疫动物的肺和脾中缺乏持久性。最后，我们通过检测血清抗体以及对 Ag85B 和结核菌素的阳性皮试反应，证明了 TBVac85 免疫豚鼠的体液和细胞反应性。 TBVac85 的下一阶段开发和本提案的主题是确定鼻内 TBVac85 对豚鼠气溶胶感染模型中 Mtb 攻击的保护功效。如果TBVac85比BCG更具保护性，则将在II期应用中在非人灵长类动物模型中检查其保护功效。公共卫生相关性：本研究的目的是确定鼻内 TBVac85 对豚鼠气溶胶感染模型中 Mtb 攻击的保护功效。如果TBVac85比BCG更具保护性，则将在II期应用中在非人灵长类动物模型中检查其保护功效。