Development of a novel adjuvanted Th1- and Th17-inducing subunit TB Vaccine

点击翻译按钮获取中文摘要

PROJECT SUMMARY Adjuvants included as a component of a vaccine have a major impact on vaccine efficacy via modulating and prolonging host immune responses. While vaccines are the most effective way to prevent and control infectious diseases, many pathogens that significantly impact human health remain without an effective vaccine. For example, one-fourth of the world’s population is latently infected with Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB)1, a leading infectious disease killer in the world. The currently licensed TB vaccine, M. bovis BCG (BCG) provides variable protective efficacy (0-80%) across the world2-4. In the absence of clear correlates of protection for TB vaccines, it is imperative that we explore new and effective approaches to target broad T cell responses for vaccine-induced immunity against TB. In the current proposal, we hypothesize that use of new adjuvants that drive Th1 responses (UM-1007, a novel TLR7/8 agonist) and Th17 responses (UM-1098, a novel Mincle agonist) will significantly augment vaccine-induced protection against TB. Thus, during the R61 phase of the proposal, we will optimize the use of these novel Th1- and Th17-inducing adjuvanted vaccine platforms and conduct proof-of-principle studies including detailed assessment of immunogenicity, antigen optimization, identification of prime-boost strategies that enhance lung Th1- and Th17- vaccine responses (Specific Aim 1), and test if these novel Th1- and Th17-inducing TB vaccine candidates will protect in mouse challenge models of TB (Specific Aim 2). During the R33 phase we will test the optimized Th1- and Th17-inducing TB candidate vaccines for immunogenicity, safety and protection in an aerosol challenge model in macaques (Specific Aim 3). We also propose that we will meet the following milestones. R61 phase. Milestone 1 (Month 12): Antigen selection for an optimized IM vaccine producing a Th1 response (UM-1007:TB) and a Th17 response (UM-1098:TB). Milestone 2 (Month 18): Identification of the best prime-boost strategy for a TB vaccine inducing maximal lung Th1 responses (UM-1007:TB) and Th17 responses (UM-1098:TB). Milestone 3 (Month 33): Testing efficacy of optimized UM-1007:TB and UM-1098:TB candidates against drug susceptible and drug resistant Mtb and in genetically diverse Mtb-infected mice. Milestone 4 (Month 36): Submission of R33 transition package. R33 phase. Milestone 5 (Month 60): Immunogenicity, safety and efficacy studies of optimized UM-1007:TB and UM-1098:TB vaccines in macaques and in-depth characterization of vaccine-induced immune responses. Milestone 6 (Month 60): Final selection of newly discovered Mtb vaccine. Thus, the work proposed in this grant will result in a novel, first-of-kind rationally designed Th1- and/or Th17- inducing TB vaccine for use in humans in the near future.