PROJECT SUMMARY/ABSTRACT Tuberculosis (TB) is a major cause of ill health and was the leading infectious cause of death in 2019, a burden felt disproportionately in low- and middle-income countries. To accelerate progress towards the World Health Organization’s ambitious goal to cut TB deaths by 95% and cases by 90% by 2035, new tools to prevent TB are essential. New and repurposed vaccines against TB hold promise to fill this gap: after decades of research, two TB vaccines have emerged from Phase II clinical trials with positive efficacy results. The existing BCG vaccine, currently given at birth, is being reconsidered for use (‘revaccination’) in adults after a Phase IIb trial showed 50% efficacy in preventing TB infection in adolescents. In a separate Phase IIb trial, subunit vaccine M72-AS01e was shown to be 50% efficacious in preventing TB disease in adults. The overarching objectives of this K01 are to (1) estimate the potential epidemiologic impact of new and repurposed TB vaccines; and (2) identify and assess potential vaccination strategies targeting high-risk groups. We will do this using data from the GlobalMix study, which will provide detailed country-specific social contact and mobility data from four countries – Mozambique, Guatemala, India, and Pakistan – with diverse TB epidemic profiles. Understanding potential differences in vaccine impact across countries can guide the design of further vaccine trials and inform strategies for introducing new and repurposed TB vaccines into immunization programs. This K01 project will provide Dr. Nelson with skills in conducting international field work as well as building, fitting, and analyzing TB transmission models to address questions with practical implications for TB vaccine policy and implementation. The mentoring team, Drs. Ben Lopman (Primary Mentor), Neel Gandhi (co-Mentor), Ted Cohen (co-Mentor), and Rob Breiman (co-Mentor), will provide Dr. Nelson with training in how to build and analyze models of TB transmission to estimate vaccine impact, the design and conduct of vaccine trials, and the role of modeling in development of evidence-based national and global vaccine policy. Home to the Emory Vaccine Center and the Center for TB Research, Emory University offers abundant resources for young investigators engaged in TB vaccine research, providing an ideal setting to carry out the proposed work. The TB vaccine modeling framework developed in this K01 will form the basis of a future NIH R01 proposal aiming to quantify country-level vaccine impact and develop country-specific recommendations for TB vaccine implementation in conjunction with TB vaccine experts and policymakers. The skills Dr. Nelson will develop have broad applicability to other infectious diseases, building a foundation for a career in infectious disease dynamics which will address vaccine implementation challenges for emerging and endemic infections.

NARRATIVE Tuberculosis is the leading cause of death worldwide. New and repurposed vaccines against TB offer immense promise to reduce TB-related morbidity and mortality, especially in low- and middle-income countries. This project will estimate the potential impact of introducing TB vaccines in four key countries and identify specific vaccination strategies that will maximize population benefit.