Vaccination with a candidate subunit vaccine, or revaccination with primary bacille Calmette- Guérin (BCG) vaccine, did not prevent initial tuberculosis (TB) infection among South African adolescents in a high-transmission area compared with placebo, a phase II trial found.
Neither revaccination with BCG vaccine or vaccination with H4:IC31, a candidate subunit vaccine, met primary efficacy criterion based on initial QuantiFERON-TB Gold In-tube assay (QFT) conversion rates, reported Elisa Nemes, MD, of the University of Cape Town in South Africa, and colleagues.
However, those adolescents who received either of the vaccines had a lower sustained QFT conversion rate compared to those who received placebo (6.7% for BCG versus 8.1% for H4:IC31 vs 11.6% for placebo, respectively), they wrote in the New England Journal of Medicine.
The authors cited potential drawbacks of the QFT test, namely “assay variability and uncertainty regarding the most effective assay cutoff.” However, they added that research found recent infection, including that diagnosed through QFT conversion, is linked to a higher risk of disease. Moreover, both human and animal studies suggested reversion to negative tuberculin skin test is associated with a “early containment of M. tuberculosis infection and a lower risk of tuberculosis disease.”
“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,” the authors wrote.
They examined candidate subunit vaccine, H4:IC31 — which had shown protection in preclinical models and “acceptable safety and immunogenicity in humans” — alongside revaccination with the BCG vaccine. Participants in this randomized, placebo-controlled clinical trial were adolescents, ages 12-17, who had received the BCG vaccine in infancy and tested negative for TB via QFT, as well as for HIV.
Overall, 990 participants were randomized to receive either H4:IC31 vaccine, BCG revaccination, or placebo. Median age of participants at baseline was 14, with 53% girls and about two-thirds of “Cape mixed ancestry” race or ethnic group.
Examining primary outcomes in a modified intention-to-treat population, efficacy point estimates were 9.4% (P=0.63) for H4:IC31 vaccine compared with 20.1% (P=0.29) for BCG revaccination, the authors said.
Safety was also primary outcome, with at least 550 participants who received at least one dose of trial vaccine or placebo reporting at least one adverse event. Adverse events were mostly mild-to-moderate local injection site reactions. There were four severe adverse events — one each in the H4:IC31 and BCG groups and two in the placebo group — and 19 serious adverse events, but the author said that none were judged related to the vaccine. There was one death by suicide in the placebo group.
Notably, revaccination with the BCG vaccine had an efficacy of 45.4% (P=0.03) against sustained QFT conversion, the authors said, adding “the durability of this important finding and potential public health significance for protection against tuberculosis disease warrants epidemiologic modeling and further clinical evaluation.”
The authors noted that efficacy estimates against sustained QFT conversion for the H4:IC31 vaccine (30.5%, P=0.16) did not meet standard statistical criteria for efficacy, but because a pre-specified 80% confidence interval had efficacy estimates ranging from 3.0 to 50.2%, they argued that “subunit vaccines that include few antigens against M. tuberculosis may have a biologic effect, a finding that encourages clinical evaluation of next-generation subunit vaccine candidates.”
In addition to technical limitations with QFT, the authors acknowledged their findings were limited by the fact that there is no definitive test for acquisition, persistence, or clearance of M. tuberculosis.
The study was supported by Aeras, Sanofi Pasteur, the Bill and Melinda Gates Foundation, and the Dutch and U.K. governments.
Nemes disclosed no relevant relationships with industry. Co-authors disclosed support from Sanofi Pasteur, Aeras, SATVI, SSI, GlaxoSmithKline, the Bill and Melinda Gates Foundation, the U.K. government, and the Dutch government.