SCIENCE TODAY

Clinical study to evaluate the non-specific protection conferred by Bacillus Calmette-Guerin bacteria

Tuberculosis (TB) continues to be the bacterial disease that affects the most people worldwide, with about 10 million new cases each year, as well as the unfortunate death of 1.5 million people annually. Due to the ravages that TB continues to wreak worldwide, there are several efforts to replace or to boost the only vaccine available today against this disease: the attenuated bacteria (does not cause disease in immunocompetent people) Mycobacterium bovis Bacillus Calmette-Guerin, better known as BCG.

BCG vaccine protects against the most deadly forms of TB during early infancy and childhood, such as disseminated and cerebral manifestations. However, BCG does not appear to be able to maintain good protection against the pulmonary form, which usually occurs in 8 out of 10 patients and results in transmission to others in the environment of those affected by TB. In addition to the protective effect, even if limited against the pulmonary form of BCG against TB, attention has recently been drawn to the fact that this vaccine promotes, in a non-specific manner, a response that reduces complications of various diseases, especially of the respiratory type (so much so that there are several clinical studies to evaluate whether it helps to protect against COVID-19).

In particular, studies have found that the BCG vaccine:

1. In adults, decreased peak yellow fever vaccine viremia and improved resistance to malaria infection.

2. In addition, the BCG vaccine increases the antibody response to concomitantly or subsequently administered vaccines such as hepatitis B, H. influenzae type B, pneumococcal, tetanus toxoid, and influenza vaccines.

Due to these properties, the results of a randomized, placebo-controlled clinical trial were recently reported to verify the ability of BCG, in 3 different schedules, to promote an ex vivo immune response against various pathogens, both Mycobacterium tuberculosis and different from this one, including Escherichia coli, Staphylococcus aureus and Candida albicans (1). The schemes evaluated were: 1) to apply one regular dose (0.75 mg/mL of Danish BCG, applying 0.1 mL per person) to adults not previously vaccinated with BCG; 2) to apply a high dose (1.5 mg/mL of Danish BCG, applying 0.1 mL per person) to adults not previously vaccinated with BCG, and 3) revaccination with regular dose to persons who had already been vaccinated during childhood with BCG.

The latter scheme was proposed because of a recent report showing that the revaccination of adolescents with BCG promoted a reduction in Quantiferon® conversion from negative to positive, which was taken as evidence of protection against TB (2).

In this work it is mentioned that revaccination with BCG or the administration of high doses of BCG does not contribute to improve the capacity to induce cytokines in the face of non-specific stimulation beyond that induced by a standard dose of BCG, ex vivo. These results even represent an advance in the sense that, at least in the case of vaccinating adults for the first time with BCG, with standard or regular doses, protection against other diseases could be maintained without the need to increase the amount of vaccine applied.

Of course, there is a long way to go in defining whether these effects vary in the case of BCG vaccination of infants or toddlers, whether the strain used for vaccination would have any effect on the induction of nonspecific protection, and whether different populations have different capacities to respond to such nonspecific challenges.

Mario Alberto Flores Valdez, PhD

Senior Researcher C at CIATEJ, A.C. in Medical and Pharmaceutical Biotechnology. Doctor of Science with a specialty in Biochemistry from the UNAM. Research Member of the international network VALIDATE “Vaccine development for complex intracellular neglected pathogens.”

References

Debisarun, P., Kilic, G., L. de Bree, C., Pennings, L., van Ingen, J., Benn, C., Aaby, P., Dijkstra, H., Lemmers, H., Domínguez-Andrés, J., van Crevel, R., G. Netea, M. (2023) The impact of BCG dose and revaccination on trained immunity. Clinical Immunology. Volume 246, Retrieved from: https://doi.org/10.1016/j.clim.2022.109208.

Nemes, E., Geldenhuys, H., Rozot, V., Rutkowski, K., Ratangee, F., Bilek, N., Mabwe, S., Makhethe, L., Erasmus, M., Toefy, A., Mulenga, H., Hanekom, W., Self, S., Bekker, L., Ryall, R., Gurunathan, S., Diaz-Granados, C., Andersen, P., Kromann, I., Evans, T.,... Mark Hatherill. (2018) Prevention of M. tuberculosis infection with H4:IC31 vaccine or revaccination with BCG. The New England Journal of Medicine; 379:138-149. Retrieved from: http://doi.org/10.1056/NEJMoa1714021