In a recent phase 2 trial, an investigational tuberculosis vaccine, H4:IC31, and the bacille Calmette-Guérin, or BCG, vaccine both lacked efficacy against initial Mycobacterium tuberculosis infection.
However, BCG revaccination in adolescents who were first vaccinated during infancy was associated with a significant reduction in sustained M. tuberculosis infection, according to researchers.
“The efficacy of the primary BCG vaccine against disease is highly variable in the different populations; efficacy is thought to be greatest in persons without previous mycobacteria exposure and may last for 10 years,” Elisa Nemes, PhD, senior research officer in the South African Tuberculosis Vaccine Initiative at the University of Cape Town, and colleagues wrote in The New England Journal of Medicine. “Our findings suggest that BCG revaccination of [M. tuberculosis-negative] adolescents may provide additional benefit.”
For the trial, Nemes and colleagues randomly assigned 990 adolescents from South Africa in a 1:1:1 ratio to receive H4:IC31 (Aeras, Sanofi Pasteur), BCG revaccination or placebo. All the participants underwent neonatal BCG vaccination and were negative for M. tuberculosis and HIV upon enrollment.
The trial was designed to test vaccine efficacy based on the prevalence of asymptomatic M. tuberculosis infection. This is unique for TB vaccine trials, which typically base efficacy on clinical TB disease occurrence, one of the researchers said previously.
There are barriers to testing participants for asymptomatic infection, Nemes and colleagues reported. Although the acquisition, persistence and clearance of M. tuberculosis infection may be important indicators of vaccine efficacy, they cannot be directly measured with available tests. The test used in the current study — QuantiFERON-TB Gold In-tube assay (QFT, Qiagen) — has no optimal threshold for infection, according to the researchers. However, assessing for asymptomatic infection instead of disease occurrence can accelerate the time to receiving clinical results.
“Although the clinical significance of QFT reversion remains to be established, we propose that sustained QFT conversion more likely represents sustained M. tuberculosis infection and a higher risk of progression to disease than transient QFT conversion,” Nemes and colleagues wrote.
After a 2-year follow-up period, QFT conversion occurred in 14.3% of participants who received H4:IC31, 13.1% of those who received BCG and 15.8% who received placebo. Sustained conversion was reported in 8.1% of participants who received H4:IC31, 6.7% of those who received BCG and 11.6% who received placebo.
Neither vaccine met the primary endpoint of initial QFT conversion prevention. Vaccine efficacy against initial conversion was 9.4% for the H4:IC31 vaccine and 20.1% for the BCG vaccine. Although both vaccines reduced sustained conversion, only BCG had a significant impact, preventing 45.4% of conversions (95% CI, 6.4-68.1; P = .03). H4:IC31 was 30.5% effective against sustained conversion (95% CI, –15.8-58.3; P = .16) and did not differ significantly from placebo, according to Nemes and colleagues.
Adverse events occurred in 550 participants. Most were reported among those who received BCG revaccination; however, these were predominately mild to moderate in severity.
Because there is no definitive test for M. tuberculosis infection, Nemes and colleagues said the clinical implications of the findings are limited. However, their study illustrates the value of measuring sustained QFT conversion rather than initial QFT reversion alone when using M. tuberculosis prevalence as an indicator of vaccine efficacy.
“Our results raise important questions with respect to the prevention of M. tuberculosis infection for the control of tuberculosis disease and provide a promising signal for BCG vaccine,” the researchers concluded. “These encouraging findings provide an impetus to reevaluate the use of BCG revaccination of populations that are free of M. tuberculosis infection for the prevention of disease.” – by Stephanie Viguers
Disclosures: Nemes reports no relevant financial disclosures. Please see the study for all other authors’ relevant financial disclosures.