Targeted Tuberculosis (TB) Vaccination Strategies in the United States: A Modeling Study

A modeling study demonstrates that targeted vaccination strategies focusing on high-risk groups in the United States, particularly non-U.S.-born persons and people living with HIV, could substantially reduce tuberculosis incidence, preventing up to 51.8% of annual cases under optimistic scenarios.

The Gist

Imagine the United States as a large, mostly dry forest. In this forest, a dangerous fire called Tuberculosis (TB) occasionally breaks out. Unlike forests where fires spread quickly from tree to tree, most fires in this U.S. forest don't start from new sparks. Instead, they start from old, smoldering embers hidden deep underground that suddenly flare up.

About 85% of these fires come from embers that have been burning slowly for years, waiting for the right conditions to ignite.

This study is like a computer simulation run by a team of epidemiologists to answer a big question: If we invent a new "fire shield" (a vaccine) for adults, who should we give it to first to stop the most fires?

The Problem: Where the Embers Are

The study found that these smoldering embers aren't spread evenly across the forest. They are concentrated in specific groups of people:

1. People born outside the U.S.: They make up about 77% of the fires. They likely picked up the "ember" in their home countries before moving here.
2. People living with HIV: Their immune systems are weaker, making it easier for the ember to turn into a full fire.
3. People with other health issues: Conditions like diabetes or kidney disease also make the embers more likely to flare up.

The Experiment: Testing Different "Fire Shield" Strategies

The researchers built a model to test different ways of handing out this new vaccine. They imagined two scenarios:

• The "Dream Team" Scenario (Optimistic): The vaccine is super effective (70% shield), and we manage to vaccinate half of the eligible people every year.
• The "Real World" Scenario (Plausible): The vaccine is decent (50% shield), and we only manage to reach a small slice of the eligible people each year (about 5%).

They tested strategies like "Vaccinate only HIV patients," "Vaccinate only immigrants," or "Vaccinate everyone with embers."

The Findings: Who Needs the Shield Most?

1. The "All-High-Risk" Strategy Wins the Most
The most effective strategy was to vaccinate all three high-risk groups (Immigrants, HIV patients, and those with other medical conditions).

• In the Dream Scenario: This approach would stop over 5,000 fires a year, cutting the total number of TB cases in half.
• In the Real World Scenario: Even with a weaker vaccine and lower reach, this strategy would still stop about 1,350 fires a year.

2. The "Efficiency" Surprise
If you look at how many people you need to vaccinate to stop just one fire (called the "Number Needed to Vaccinate"), vaccinating only HIV patients is the most efficient. Because there are fewer of them and they are at very high risk, you get a big bang for your buck.

• However, because the HIV group is small, stopping fires only in this group wouldn't lower the total number of fires in the whole forest very much. It's like putting a shield on the most flammable tree but ignoring the whole forest around it.

3. The "Immigrant" Factor is Key
The study makes it clear: You cannot solve the TB problem in the U.S. without including people born outside the country. Since they carry the majority of the smoldering embers, any strategy that leaves them out misses the biggest opportunity to stop the fires.

4. The "Ripple Effect"
The vaccine works by stopping the ember from turning into a fire inside the person who gets it (Direct Effect). But it also helps unvaccinated people. When fewer people get sick, there are fewer sparks flying around to start new fires in others (Indirect Effect).

• Even people who didn't get the vaccine (like U.S.-born people without other health issues) would see their risk drop by about 22% in the best scenario, simply because the fire was contained in the high-risk groups.

The Bottom Line

The paper concludes that to make a real dent in TB in the U.S., we need a "fire shield" strategy that casts a wide net over the specific groups carrying the most embers: Immigrants, HIV patients, and those with other serious health conditions.

If we can get a vaccine that works well (around 50-70% effective) and keep giving it to these groups, we could potentially cut the number of TB cases in the U.S. by half, even if we aren't vaccinating the entire population. The study emphasizes that this is a modeling exercise based on current data and potential future vaccines, not a clinical recommendation for immediate use.

Technical Summary

Technical Summary: Targeted Tuberculosis Vaccination Strategies in the United States

Problem Statement
Tuberculosis (TB) incidence in the United States has remained elevated above pre-pandemic levels since 2021, with 10,388 cases reported in 2024. As a low-burden setting, over 85% of U.S. TB cases result from the reactivation of latent Mycobacterium tuberculosis (Mtb) infection acquired years prior, rather than recent transmission. The burden is disproportionately distributed: non-U.S.-born persons account for approximately 77% of cases, while individuals with immunocompromising conditions (including persons living with HIV [PLWH], end-stage renal disease, and diabetes) face significantly elevated risks of progression from infection to disease. While new "prevention of disease" (POD) vaccines are advancing in clinical trials (e.g., M72/AS01E), the potential health impact of deploying such vaccines specifically within U.S. high-risk subgroups has not been quantitatively evaluated. The central policy question addressed is which population subgroups should be prioritized for vaccination to maximize both absolute impact and programmatic efficiency.

Methodology
The authors developed a deterministic compartmental transmission model stratified by four mutually exclusive clinical and demographic populations:

1. Persons living with HIV (PLWH).
2. Persons with non-HIV medical comorbidities increasing TB progression risk.
3. Non-U.S.-born persons (without HIV or specific comorbidities).
4. U.S.-born persons (without HIV or specific comorbidities).

Individuals overlapping multiple risk categories were assigned to the stratum with the highest progression risk (hierarchy: PLWH > Medical Comorbidities > Non-U.S.-Born > U.S.-Born). The model tracks Mtb infection dynamics through five main compartments: Susceptible (S), Fast Latent (Lf), Slow Latent (Ls), Infectious (I), and Recovered (R). It incorporates partial protection against reinfection and allows for waning vaccine immunity.

The model was calibrated to 2024 U.S. TB surveillance data (n=10,388 cases) to estimate transmission rates and infection prevalences. The authors evaluated multiple vaccination strategies targeting Mtb-infected individuals within specific strata under two scenarios:

• Optimistic: Vaccine efficacy (VE) of 70%, 10-year protection duration, and a 50% annual vaccination rate for all strategies.
• Plausible: VE of 50%, 10-year protection duration, and strategy-specific annual vaccination rates (5% for most groups, 10% for PLWH, 2% for broad "All Mtb-Infected" strategies).

Outcomes measured at equilibrium included annual cases prevented, percent reduction in TB incidence, and the Number Needed to Vaccinate (NNV). Uncertainty was quantified using 500 Latin Hypercube Sampling draws across 12 parameters.

Key Contributions and Results
The study provides the first estimates comparing TB vaccination strategies across clinically and demographically defined high-risk populations in a low-burden setting.

• Impact of Broad High-Risk Targeting: Under the optimistic scenario, vaccinating all high-risk groups (PLWH, non-U.S.-born, and medical comorbidities) prevented 5,385 cases annually (a 51.8% reduction in incidence) with an NNV of 366. Under the plausible scenario, this same strategy prevented 1,348 cases (13.0% reduction) with an NNV of 510.
• Critical Role of Non-U.S.-Born Persons: Strategies excluding non-U.S.-born persons failed to achieve substantial population-level impact. Strategies including this group prevented 8.9–13.0% of cases in the plausible scenario, compared to only 1.0–5.9% for strategies targeting only clinical risk groups (PLWH and medical comorbidities).
• Efficiency vs. Impact Trade-offs: While vaccinating only PLWH was the most efficient strategy per dose (lowest NNV of 68 in the plausible scenario), it prevented only 100 cases annually (1.0% reduction) due to the small size of the population. Conversely, the "All Mtb-Infected" strategy prevented the most cases (739 in the plausible scenario) but had a higher NNV (507) and lower effective coverage.
• Direct vs. Indirect Effects: Direct effects (preventing progression in vaccinated individuals) accounted for 77–89% of total impact. Indirect effects (reduced transmission) were modest but non-negligible, providing unvaccinated U.S.-born persons with a 5.5% (plausible) to 22.4% (optimistic) reduction in cases.
• Vaccine Characteristics: To achieve a ≥20% reduction in annual cases under the optimistic scenario, a vaccine with 30% efficacy and 10-year duration was required. Halving annual cases required 70% efficacy. Extending protection duration to 20 years reduced the minimum required efficacy by 5–20 percentage points.

Significance and Claims
The paper claims that targeted vaccination of persons with Mtb infection in recognized high-risk subgroups can substantially reduce TB incidence in the United States. The authors assert that strategies must include non-U.S.-born persons and PLWH to be both efficient and impactful; excluding non-U.S.-born persons forfeits the majority of achievable vaccine impact.

The study concludes that while no single strategy is optimal on both absolute impact and efficiency simultaneously, a combined approach targeting non-U.S.-born persons and PLWH captures the majority of the potential benefit. The authors note that their NNV estimates fall within the range of other recommended adult vaccines in the U.S. (e.g., influenza, pneumococcal). They emphasize that the feasibility of these strategies depends on the capacity of existing clinical and community platforms to screen for and vaccinate eligible individuals, and that future research should evaluate the cost-effectiveness of these strategies relative to existing Tuberculosis Preventive Treatment (TPT) programs. The authors explicitly state that their analysis assumes the vaccine prevents progression but does not clear existing infection or prevent new infection.