The BCG Vaccine Prevents Tuberculosis in Young Children, but Not in Adults

Summary (The Lancet Global Health)

Background

BCG vaccines are given to more than 100 million children each year, but there is considerable debate about the effectiveness of the BCG vaccine in preventing tuberculosis and death, especially among older children and adults. Therefore, we aimed to investigate the age-specific impact of childhood BCG vaccination on development and mortality from tuberculosis (pulmonary and extrapulmonary).

Methods

In this systematic review and meta-analysis of individual participant data, we searched MEDLINE, Web of Science, BIOSIS, and Embase without language restrictions for contact cohort studies of tuberculosis contact cases published between January 1, 1998 and January 7, 1998. April 2018 terms included “mycobacterium tuberculosis,” “TB,” “tuberculosis,” and “contact . ” Cohort studies that did not provide information on BCG vaccination or that were conducted in countries that did not recommend BCG vaccination at birth were excluded . Individual-level participant data were requested from the authors of all eligible studies for a predetermined list of variables, including characteristics of the exposed participant (contact), index case, and setting.

The primary outcome was a composite of prevalent (diagnosed on or within 90 days of onset) and incident (diagnosed more than 90 days after onset) tuberculosis in tuberculosis-exposed contacts.

Secondary outcomes were pulmonary tuberculosis, extrapulmonary tuberculosis, and mortality. We obtained adjusted odds ratios (aOR) using multivariable, binary, and mixed-effects logistic regression analyzes with random effects at the study level, adjusting for the variable of interest, baseline age, sex, previous tuberculosis, and whether data were collected. prospectively or retrospectively.

We stratified our results by age of contact and Mycobacterium tuberculosis infection status. This study is registered with PROSPERO, CRD42020180512.

Results

We identified 14,927 original records from our database searches. We included participant-level data from 26 cohort studies conducted in 17 countries in our meta-analysis.

Among 68,552 participants, 1782 (2·6%) developed tuberculosis (1309 [2·6%] of 49,686 BCG-vaccinated participants vs. 473 [2·5%] of 18,866 unvaccinated participants ).

The overall effectiveness of BCG vaccination against all tuberculosis was 18% (aOR 0.82, 95% CI 0.74–0.91). When stratified by age , BCG vaccination only significantly protected against all tuberculosis in children younger than 5 years (aOR 0.63, 95% CI 0.49–0.81).

Among contacts with a positive tuberculin skin test or IFNγ release assay, BCG vaccination significantly protected against tuberculosis among all participants (aOR 0·81, 95% CI 0·69–0·96), to participants younger than 5 years (0·68, 0·47–0·97), and participants aged 5–9 years (0·62, 0·38–0·99). There was no protective effect among those with negative tests, unless they were younger than 5 years (0·54, 0·32–0·90).

14 cohorts reported whether tuberculosis was pulmonary or extrapulmonary (n=57,421). BCG vaccination significantly protected against pulmonary tuberculosis among all participants (916 [2.2%] in 41,119 vaccinated participants vs 334 [2.1%] in 16,161 unvaccinated participants; aOR 0.81, 0. 70–0.94) but not against extrapulmonary tuberculosis (106 [0·3%] in 40,318 vaccinated participants vs 38 [0·2%] in 15,865 unvaccinated participants; 0·96, 0·65–1· 41).

In the four studies with mortality data , BCG vaccination was significantly protective against death (0·25, 0·13–0·49).

BCG vaccination at birth and risk of death, stratified by age. Each stratified model used separate, mixed-effects, binary, and multivariable logistic regression analyzes with random effects at the study level. We assume a conditional Bernoulli distribution of the response given the random effects. Models were adjusted for the variable of interest, baseline age, sex, previous tuberculosis, and whether data were collected prospectively or retrospectively. Age was adjusted within each age stratum. 

Interpretation

Our results suggest that BCG vaccination at birth is effective in preventing tuberculosis in young children, but is ineffective in adolescents and adults. Therefore, it is necessary to strengthen immunoprotection in older populations.

Comments

Amid the long-running debate over the effectiveness of the tuberculosis vaccine, a new study suggests that the vaccine protects against TB in children under 5 years of age, but adolescents and adults in high-burden countries may need additional protection to maintain immunity beyond childhood.

The tuberculosis (TB) vaccine, bacillus Calmette-Guérin (BCG), is one of the most widely administered vaccines worldwide. Almost 100 years old, it is the only vaccine ever administered to treat TB, which affects more than 10 million people each year.

Despite the age and widespread use of the BCG vaccine, there is still considerable debate about its effectiveness in preventing TB and how long immunity can last after it is administered in childhood. And as experts study and propose new TB vaccines to complement the BCG vaccine, an important consideration is the age at which these new vaccines should be administered to high-risk populations.

Now, a new study led by a Boston University School of Public Health (BUSPH) researcher provides new perspective and clarity on these issues.

Published in The Lancet Global Health , the study found that BCG vaccination at birth provides significant protection against tuberculosis disease, but only among children under 5 years of age . The vaccine did not provide protection among adolescents or adults in this study.

These results suggest that BCG vaccine protection may begin to wane as children age, and therefore children over 10 years of age and adults should receive a BCG booster vaccine and eventually a new follow-up vaccine. , as researchers note that the BCG vaccine booster may also have limited effectiveness for TB immunity beyond childhood. Unfortunately, a BCG booster has limited effectiveness, so new vaccines are needed.

"Unlike many of the mRNA COVID-19 vaccines, which we know are very effective , there is widespread debate about the effectiveness and duration of protection of the BCG vaccine, as well as whether the vaccine only works in selective environments," says the study’s lead author, Dr. Leonardo Martínez, assistant professor of epidemiology at BUSPH. “Our findings indicate that the BCG vaccine is effective in preventing tuberculosis in young children. Since tuberculosis in children is a very debilitating and serious disease, the BCG vaccine should continue to be used.”

However, since the results show that the vaccine was not effective in adolescents and adults, “immunoprotection needs to be increased for older populations,” says Martínez. “New vaccines are urgently needed to complement BCG vaccination in high-burden settings.”

These findings provide updated assessments of TB vaccine effectiveness, as most previously published studies on this topic were conducted more than 50 years ago, with variable results and primarily in settings with a relatively low disease burden. . This new analysis presents data from the last 10 years, from high-burden environments in 17 countries, including South Africa, China, Vietnam, Indonesia, Uganda, Gambia and Brazil.

For the study, Martinez and her colleagues analyzed individual-level data from 26 longitudinal studies that included nearly 70,000 participants exposed to TB between 1998 and 2018. The researchers examined the impact of the BCG vaccine for all TB diseases, as well as as specifically for pulmonary and extrapulmonary disease . The analysis examined variability between studies, including the use of skin and blood TB infection tests, and took into account potentially confounding factors such as HIV, exposure status, and previous TB history, among others.

Among all children under 5 years of age, BCG vaccination was 37 percent effective. The researchers found no conclusive evidence that the vaccine protected children over 10 years of age or adults. When focusing only on pulmonary TB, BCG vaccination was 19 percent effective, however, this effect was also only among young children.

Although the BCG vaccine is not widely administered in the United States, Martinez says this new information has important implications for the U.S. and other wealthy countries.

“The vast majority of tuberculosis cases in the US and other high-income countries occur in immigrants who recently traveled to the US from places with a high burden of tuberculosis,” he says. “Several cost-effectiveness studies and mathematical models have found that dedicating resources to countries with a high burden of tuberculosis outside the US is one of the most effective interventions to control tuberculosis within the US. So, “Although our results are primarily in high-TB burden settings, they are also relevant to low-burden settings.”

The researchers emphasize that substantial investment in the development of TB vaccines is critical to controlling global TB. “We urgently need vaccines that are effective against TB in adults,” says study co-author Dr. C. Robert Horsburgh, professor of epidemiology. “There are several promising TB vaccine candidates under study and we hope that one or more of them will prove effective.”