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A Novel Self-Adjuvanting cc Particle-Based Tuberculosis Vaccine


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Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, remains a major public health threat worldwide, yet effective Mtb vaccines remain elusive. Mtb antigens ESAT-6 and Ag85B have shown promise as the basis of vaccines. However, developing effective immune responses to such antigens requires co-administration of immune boosters known as adjuvants, which complicates vaccine development. Another limitation of many current Mtb vaccines is the need for multiple immunizations to induce strong immunity. This proposal seeks to develop a unique Ebola virus-like particle-(eVLP)-based approach comprised of Ebola virus proteins and built-in adjuvanting activity that has several advantages over existing Mtb vaccine candidates. First, the introduction of the 2CARD signaling domains from the pattern recognition receptor RIG-I confers self-adjuvanting activity to the eVLPs, such that they elicit vigorous immune responses as compared to standard eVLPs. Second is the inclusion of proven Mtb antigens that can elicit beneficial immunity into the 2CARD-eVLP platform. To date, we have successfully produced highly purified eVLPs that incorporate the ESAT-6 Mtb antigen, and that have shown that 2CARD-ESAT-6-eVP40 causes robust activation of innate immune signaling when expressed in cells, and that infection of cells with VLPs containing this construct also activates innate immune responses. This puts us in good position to progress to the proposed in vivo (mouse) immunogenicity studies in year 2.



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