Estimating the Burden of Mycobacterium tuberculosis (Mtb) Infection in the United States and the Potential Impact of Vaccination Interventions to Prevent Tuberculosis Disease Restricted; Files Only

Abstract

Tuberculosis (TB) incidence in the United States has risen each year since 2021, with over 85% of cases resulting from reactivation of Mycobacterium tuberculosis (Mtb) infection. Vaccine candidates that prevent progression from Mtb infection to TB disease are in late-stage clinical trials, but the potential impact of targeting vaccination to high-risk populations in a low-burden setting has not been evaluated. This dissertation estimated the Mtb infection burden among high-risk U.S. populations and evaluated targeted vaccination as a strategy to prevent TB disease.

Aim 1: Estimating the reservoir of Mtb infection among high-risk populations is necessary to focus prevention efforts, but the most recent prevalence estimates were from 2015. We estimated prevalence nationally and across risk groups from 2018 to 2021 and for 2024 using updated reactivation rates and national TB surveillance data. Approximately 10.5 to 12.6 million people in the U.S. had Mtb infection during the study period, with non-U.S.-born persons accounting for most infections.

Aim 2: The number needed to vaccinate (NNV) provides a way to translate vaccine efficacy into population-level terms, but no NNV estimates existed for TB vaccination in any low-burden setting. We estimated the NNV to prevent one TB case across high-risk populations, comparing vaccination of all individuals in a risk group to vaccination restricted to those with Mtb infection. Restricting vaccination to persons with Mtb infection reduced the NNV substantially, with values within the range of other established U.S. vaccines.

Aim 3: Which populations to prioritize for vaccination is a key question for low-burden settings. We used a risk-stratified transmission model to compare strategies targeting different combinations of high-risk groups under primary (50% efficacy, strategy-specific vaccination rates) and optimistic (70% efficacy, 50% per year) vaccine assumptions. Under the primary scenario, targeting all three high-risk groups prevented 1,348 cases per year (13% reduction), while the optimistic scenario achieved reductions of 52–58%. The non-U.S.-born population drove the majority of achievable impact regardless of which clinical groups were also targeted, while persons living with HIV had the lowest NNV.

These results provide an evidence base for evaluating the potential role of TB vaccination in U.S. TB elimination efforts. As vaccine candidates advance toward licensure, these findings can inform which populations should be prioritized and how vaccination could complement existing strategies.

Table of Contents

Chapter 1 - Introduction 1

1.1 Introduction 2

1.2 TB Epidemiology in the U.S. 5

1.3 Estimating the Burden of Mtb Infection in the U.S. 9

1.4 TB Vaccine Landscape 11

1.5 Evaluating the Potential Impact of TB Vaccination in Low-Burden Settings 14

1.6 Dissertation Overview and Aims 16

Chapter 2 - Aim 1: Estimates of Mycobacterium tuberculosis (Mtb) Infection Prevalence in the United States, 2018–2021, 2024 18

2.1 Introduction 19

2.2 Methods 20

2.3 Results 24

2.4 Discussion 30

Chapter 3 - Aim 2: Estimating the Number Needed to Vaccinate with a Novel TB Vaccine Candidate to Prevent TB in a Low-TB Burden Setting 40

3.1 Introduction 42

3.2 Methods 43

3.3 Results 46

3.4 Discussion 51

Chapter 4 - Aim 3: Targeted Tuberculosis (TB) Vaccination Strategies in the United States: A Modeling Study 56

4.1 Introduction 58

4.2 Methods 59

4.3 Results 64

4.4 Discussion 71

Appendix 75

Chapter 5 - Cross-Aim Comparisons 97

5.1 Reconciling Mtb Infection Estimates Across Aims 98

5.2 Comparison of NNV Estimates Across Aims 2 and 3 101

Chapter 6 - Public Health Impact 104

Bibliography 112

About this Dissertation

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School	Laney Graduate School
Department	Epidemiology
Degree	Ph.D.
Submission	Dissertation
Language	English
Research Field	Health Sciences, Public Health Health Sciences, Epidemiology
Keyword	Mycobacterium tuberculosis infection Tuberculosis Number needed to vaccinate Vaccination United States
Committee Chair / Thesis Advisor	Kristin N. Nelson, MPH, PhD, Emory University Neel R. Gandhi, MD, Emory University
Committee Members	Benjamin A. Lopman, PhD, Emory University Kenneth G. Castro, MD, Emory University

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