A novel live intranasal TB vaccine

描述(申请人提供)：目前最广泛使用的结核病疫苗是卡介苗，一种活的牛分枝杆菌无毒变种，出生时皮内接种。除了与注射相关的固有安全和后勤问题外，保护效果通常很差，到青春期就会减弱。给免疫抑制的个体注射卡介苗也可能传播并导致严重的危及生命的感染。第二代卡介苗经过改良，可以表达结核分枝杆菌(Mtb)抗原，如Ag85B，目前正在进行人体临床试验。不幸的是，这些疫苗也被注射，并对免疫抑制人群保留了固有的安全风险。TBVac85是一种新型、活的、鼻腔减毒的结核病疫苗。它是一种低温适应的、温度受限的肖特西分枝杆菌的衍生物，其基因工程是为了表达Ag85B。由于与结核分枝杆菌的细胞壁和抗原性相似，TBVac85是天然的佐剂。鼻腔接种TBVac85具有与重组卡介苗相关的潜在好处，对温度限制生长和鼻腔(无针)免疫所提供的免疫受损的人具有更高的安全性。我们的初步研究表明，在接下来的几周内，经鼻接种并加强使用TBVac85的小鼠和豚鼠的鼻道和肺部没有毒性或致病性。我们还证明了TBVac85细菌缺乏持久性，无论是在局部还是在免疫动物的肺和脾中。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免疫的豚鼠的体液和细胞反应。TBVac85开发的下一阶段和本提案的主题是在豚鼠气溶胶感染模型中确定鼻内TBVac85对结核分枝杆菌攻击的保护效果。如果比卡介苗更具保护作用，则将在第二阶段应用中在非人类灵长类动物模型中检查TBVac85的保护效果。 公共卫生相关性：拟议研究的目标是在豚鼠气溶胶感染模型中确定鼻内TB Vac85对结核分枝杆菌攻击的保护效果。如果比卡介苗更具保护作用，则将在第二阶段应用中在非人类灵长类动物模型中检查TBVac85的保护效果。

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.