Bacillus Calmette–Guérin (BCG), the only vaccine proven to be effective against tuberculosis (TB), is the most commonly used vaccine globally. In addition to its effects on mycobacterial diseases, an increasing amount of epidemiological and experimental evidence accumulated since its introduction in 1921 has shown that BCG also exerts non-specific effects against a number of diseases, such as non-mycobacterial infections, allergies and certain malignancies. Recent Corona Virus Disease 2019 (COVID-19) outbreak has put BCG, a classic vaccine with significant non-specific protection, into the spotlight again. This literature review briefly covers the diverse facets of BCG vaccine, providing new perspectives in terms of specific and non-specific protection mechanisms of this old, multifaceted, and controversial vaccine.

Bacillus Calmette–Guérin (BCG), a live-attenuated bacterial vaccine derived from Mycobacterium bovis was originally isolated in 1902 from a cow with tuberculosis (TB). The isolate was cultured continuously for >230 generations for 13 years (1908–1921) to generate a mutant strain with weakened virulence but with high immunogenicity. First used in humans in 1921, BCG vaccine has been included in the infant immunization programs by the World Health Organization (WHO) since 1974. As of 2018, BCG has been used within the national vaccination program of 180 countries or territories in Asia, Africa, Europe, and America, with a coverage range of over 90%. Since the 1920s, the original BCG strain has been shipped to 20 different international sites, where the vaccine was repeatedly sub-cultured under different conditions. This has given rise to diverse licensed BCG formulations that are distinct in live mycobacteria content and in genetic composition. Currently, the most widely used strains for BCG vaccine production globally include French Pasteur strain (Pasteur 1173P2), Denmark 1331 strain (Danish 1331), Brazil strain (BCG Mearou RJ), Russian strain (Moscow-368), Bulgarian substrain (Sofia SL222), and the Japan 172 strain (Tokyo 172-1).

As one of the oldest and most widely used vaccines in the world, BCG has been administered for nearly a century, with more than four billion of BCG-vaccinated individuals globally. In most countries, BCG is administered to newborns a few hours or days after birth, and it has been shown to exhibit a protective efficacy of 73% and 77%, respectively, against TB meningitis and miliary TB. Although BCG was specifically developed as a vaccine for TB, numerous studies have shown that BCG has the ability to induce the so-called Non-Specific Effects (NSEs) that provide effective protection against other infectious diseases. Several epidemiological studies conducted in TB endemic countries have demonstrated that immunization of neonates with BCG can lower neonatal mortality by 50%, which may be attributed to the decreased likelihood of sepsis and respiratory infections observed in children after receiving BCG vaccination. Clinical evidence also suggests that BCG may be effective against infections caused by viral pathogens, such as respiratory syncytial virus, human papilloma virus, and herpes simplex virus26. Moreover, an increasing number of animal studies using mouse models have demonstrated the effects of BCG on secondary viral infections. In two separate studies, mice immunized with BCG have been shown to exhibit a significantly lower titer of influenza A virus (H1N1), resulting in a decreased level of inflammation and lung injury, compared with those without BCG immunization. Furthermore, other studies have reported that BCG-vaccinated animal models or humans appeared to be more resistant to various viruses, including herpes simplex virus types 1 and, sendai virus, Japanese encephalitis virus, encephalomyocarditis virus, and ectromelia virus, or to non-communicable diseases, such as leukemia, allergy, and childhood diabetes.

Remarkably, BCG can be used as an expression vector for recombinant antigens to develop novel vaccines for pathogenic bacteria and viruses, as well as for cancer immunotherapy. Clearly, BCG cannot be regarded as a vaccine with only “Specific Effects” for unilateral prevention of TB. Hence, further understanding on the possible “NSEs” of BCG is required.

Conclusion

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