A novel live intranasal TB vaccine

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，一种M.在出生时皮内注射的牛。沿着与注射相关的固有安全性和后勤问题，保护效力通常较差，并在青春期减弱。免疫抑制者接种卡介苗也可传播并导致严重的危及生命的感染.第二代BCG疫苗，经修饰以表达结核分枝杆菌（Mtb）抗原，如Ag85B，正在人体临床试验中。不幸的是，这些疫苗也是注射的，并且对免疫抑制人群保留了固有的安全风险。TBVac85是一种新型鼻内结核减毒活疫苗。它是一种冷适应性、温度限制性的肖氏分枝杆菌衍生物，经工程改造可表达Ag85 B。TBVac85由于细胞壁和抗原与Mtb的相似性而天然具有佐剂性。鼻内TBVac85具有与重组BCG疫苗相关的潜在益处，通过温度限制性生长和鼻内（无针）免疫接种，对免疫功能低下者具有增强的安全性。我们的初步研究表明，在随后的几周内，鼻内接种TBVac85并加强接种的小鼠和豚鼠的鼻道和肺中缺乏毒性或致病性。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和对Ag85B和结核菌素的阳性皮肤试验反应，证明了TBVac85免疫豚鼠的体液和细胞反应性。TBVac85开发的下一阶段和本提案的主题是确定鼻内TBVac85在豚鼠气溶胶感染模型中对Mtb攻击的保护功效。如果TBVac85的保护性高于BCG，则将在II期申请中在非人灵长类动物模型中检查TBVac85的保护效力。

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.