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.
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.
|Gupta, Tuhina; LaGatta, Monica; Helms, Shelly et al. (2018) Evaluation of a temperature-restricted, mucosal tuberculosis vaccine in guinea pigs. Tuberculosis (Edinb) 113:179-188|