From the Journals

Primary efficacy not met by new M. tuberculosis vaccine strategies



Vaccination may have reduced the rate of sustained Mycobacterium tuberculosis infection in a recent randomized, placebo-controlled clinical trial conducted in a high-risk setting for tuberculosis transmission, despite not meeting the primary endpoint of the study.

Mycobacterium tuberculosis infection (Pulmonary Tuberculosis) Stockdevil/Thinkstock

In adolescents who had received the bacille Calmette-Guérin (BCG) vaccine in infancy, BCG revaccination reduced the rate of sustained conversion of QuantiFERON-TB Gold In-Tube assay (QFT), a test that is thought to reflect sustained M. tuberculosis infection.

The study also evaluated a candidate subunit vaccine, H4:IC31, which also reduced the rate of sustained QFT conversion, though the efficacy estimate did not reach statistical significance, investigators reported.

Neither H4:IC31 nor BCG revaccination prevented initial QFT conversion, the primary endpoint of the study; however, both vaccines were immunogenic, they said.

Moreover, the significantly reduced rate of sustained conversion with BCG revaccination provides a “promising signal,” study authors said in the New England Journal of Medicine.

“The durability of this important finding and potential public health significance for protection against tuberculosis disease warrants epidemiologic modeling and further clinical evaluation,” wrote Elisa Nemes, PhD, of the South African Tuberculosis Vaccine Initiative, which is part of the Institute of Infectious Disease and Molecular Medicine at the University of Cape Town (South Africa), and her coauthors.

Similarly, the nonsignificantly reduced rate of sustained QFT conversion seen with H4:IC31 suggested that subunit vaccines can have a biologic effect in this setting, which may inform development of new tuberculosis vaccines, Dr. Nemes and her colleagues added.

The phase 2 trial included 990 adolescents in South Africa who had undergone neonatal BCG vaccination. They were randomly assigned to receive BCG revaccination, H4:IC31 vaccine, or placebo.

Neither vaccine met the primary efficacy criterion based on initial QFT conversion rates, which were 13.1% for BCG revaccination, 14.3% for H4:IC31 vaccine, and 15.8% for placebo.

For the secondary endpoint of sustained QFT conversion, the efficacy of BCG revaccination was 45.4% (95% confidence interval, 6.4%-68.1%; P = .03), while the efficacy of H4:IC31 vaccine was 34.2% (95% CI, –10.4% to 60.7%; P = .11).

“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,” Dr. Nemes and her coauthors wrote in their report.

Revaccination with BCG was associated with more adverse events, compared with the other groups, although adverse events in the trial were predominantly injection-site reactions that were mild to moderate in severity, investigators reported. There were no serious adverse events judged by investigators to be related to trial vaccine.

Taken together, these results raise important questions regarding the potential benefits of vaccine-mediated prevention of M. tuberculosis infection for control of tuberculosis disease, according to Dr. Nemes and her coauthors.

However, interpretation of the findings is limited because there is no definitive test for M. tuberculosis infection.

Recent infection diagnosed by tuberculin skin test or QFT conversion has been associated with higher risk of disease, compared with nonconversion, according to investigators, while reversion to a negative tuberculin skin test correlates with infection containment and lower risk of tuberculosis.

“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,” they wrote.

The study was supported by Aeras, Sanofi Pasteur, the Bill & Melinda Gates Foundation, the Government of the Netherlands Directorate-General for International Cooperation and Development, and the United Kingdom Department for International Development. Study authors reported disclosures related to GlaxoSmithKline, Sanofi Pasteur, and Aeras.

SOURCE: Nemes E et al. N Engl J Med. 2018;379:138-49.

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