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TB vaccines ineffective against initial infection

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July 12, 2018

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.

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The BCG vaccine has been around for a long time, having been first developed in France in 1921 from an attenuated strain of Mycobacterium bovis by Albert Calmette and Camille Guérin. It is one of the most commonly used vaccines in the world, given to over 100 million infants annually in over 150 countries.

BCG vaccine was evaluated in 21 randomized controlled trials between 1927 and 1968. The efficacy of BCG vaccine in those studies ranged from 0% to 80%, with considerable geographic variability. In 1995, meta-analyses showed the efficacy of BCG vaccine in preventing TB disease (ie, pulmonary TB) was about 50%, modest efficacy by today’s standards.  In case-control studies, BCG showed efficacy of 75% to 83% in preventing TB meningitis and disseminated TB in infants and young children. There was no evidence that BCG prevented TB infection. Hence, there is a reasonable rationale to continue to use BCG in resource-limited settings. Importantly, it also serves as a “gateway” to immunization programs that also provide highly effective measles-mumps-rubella-varicella, diphtheria-pertussis-tetanus and poliovirus vaccines to prevent other serious childhood illnesses.

In many countries, children and adolescents used to be revaccinated with BCG, with the hope of boosting immune responses for better protection. Often a negative tuberculin skin test was used as the indicator for revaccinating. This was a common practice in Eastern Europe and Asia, where, in a few countries, as many as six vaccines were given between birth and age 19. In 1995, WHO recommended against revaccination to prevent TB, because there were no data that definitively showed that revaccination conferred additional protection. WHO recommended that BCG vaccine should continue to be administered in the first year of life. A subsequent large-cluster randomized trial in Brazil showed minimal efficacy of BCG revaccination. Through 2011, 33 countries discontinued their revaccination practices, and 16 still revaccinated.

Fast-forward 20 plus years — we now have a better understanding of specific antigens of M. tuberculosis and the immunopathogenesis of TB, which allow a more nuanced scientific approach and better tools for vaccine development. However, despite these advances, a new safe, more effective vaccine than BCG has not yet emerged. There have been numerous phase 1 and 2 studies testing novel subunit vaccines and adjuvants to BCG; these studies have failed to show meaningful additional protection against TB.

The current study is novel because its primary endpoint is TB infection rather than TB disease, unlike the prior studies discussed earlier, which require expensive trials with very large sample sizes. The marker for TB infection was the QuantiFERON Gold Test, which unlike the tuberculin skin test, is not affected by prior BCG vaccination. The study compared the new H4:1C31 vaccine, BCG revaccination and placebo with a modest sample size of 990 in a high-incidence setting. Unfortunately, neither the investigational vaccine or BCG revaccination protected against initial infection. The unique finding of the study was that BCG revaccination might confer some protection as indicated by its effect on reversion of the QuantiFERON test, albeit as a secondary endpoint with a modest treatment effect. And it is unknown if this metric is a true indicator of vaccine efficacy

So, what does this all mean? This is an interesting study because of its design, but once again, vaccine efficacy for the prevention of TB has not been demonstrated. Although it requires further investigation, I think it is unlikely that BCG revaccination is a viable strategy to impact TB control in a meaningful way. This and other studies indicate we still have a way to go before we achieve the Holy Grail of an effective new TB vaccine. For the foreseeable future to enhance global TB control, we must rely upon the trifecta of improved case detection to diagnose TB; effective treatment with it is hoped better and shorter regimens for both drug-sensitive and drug-resistant TB; and treatment of latent TB infection with isoniazid and shorter, more potent, rifamycin-based regimens.

David L. Cohn, MD

Professor of medicine
Division of infectious diseases
University of Colorado School of Medicine
Infectious Disease News Editorial Board member

Disclosure: Cohn reports no relevant financial disclosures.