Written by Deborah L. Ungerleider, MD, FAAP

The two leading causes of death in the world from infectious diseases are tuberculosis at number two, and COVID-19 at number one,[1] making immunization efforts for these and other infectious diseases critical to world health.

The bacille Calmette-Guérin (BCG) vaccine, developed more than 100 years ago, is the only vaccine currently licensed for prevention of tuberculosis. Although not generally administered in the United States, globally, it has been given to more people than any other vaccination against an infectious disease, with 88% of children in the world receiving BCG during year one of life in 2019.

When neonates receive this vaccine in the first year of life, they develop >70% protection against tuberculosis during their young childhood years.[2] The countries in which BCG is given routinely have a high incidence of tuberculosis (ie, India, Africa, and South America); therefore, in those countries, the vaccine is routinely administered after birth.

The BCG vaccine was developed in France at the Pasteur Institute by Albert Calmette, a physician, and Camille Guérin, a veterinarian, by attenuating bacteria (Mycobacterium bovis) that causes tuberculosis in cattle and other animals. The process began in 1906 and after 230 culture renewals between 1908 and 1920, they had a vaccine that was first administered to a neonate in 1921 via an oral route. The intradermal route began being used in 1928, as it was able to be more reliably dosed, more effective, and had less reduction of efficacy.[2]

After the success of the BCG vaccine in France, the idea of using the vaccine in other countries with a high prevalence of tuberculosis was raised; however, there were production challenges, including mutations that have produced different phenotypes. The efficacy of the BCG vaccine, therefore, varies between countries. In addition to mutations, other variables that have been considered to affect efficacy, especially in clinical trials, are age at which the vaccine was administered (more effective when given at a younger age), time since vaccination, prevalence of tuberculosis in a specific population, and geography (BCG works better at higher latitudes compared to the equator).[2,3] The efficacy of the BCG vaccine can also be affected by socioeconomic status and diet/nutritional status.[3]

In addition to its protective action against tuberculosis, BCG has been shown to decrease infant mortality, independent of its anti-tuberculosis effect. This reduction has been shown in both observational and randomized controlled trials to be secondary to the “induction of protection against unrelated infectious agents” (such as those causing neonatal sepsis and respiratory infections).[4] One study in young children showed that BCG immunization appeared to decrease the incidence of lower respiratory syncytial virus infections; another in older people, showed that BCG also reduced the number of respiratory infections compared to placebo; a third study in adolescents showed close to three times fewer respiratory infections in patients who had received the BCG vaccine.[4]

Efficacy of some vaccines (influenza, hepatitis B, and yellow fever) has also been shown to improve when the BCG vaccine was administered prior to that vaccine.[4,5] Other diseases that the BCG vaccine may (or has already been shown to) protect against or reduce the progression of are leprosy and non-tuberculous mycobacteria, in addition to two cancers (melanoma and non-muscle invasive bladder cancer). Additionally, disease severity appears to be decreased in patients with type 1 diabetes and multiple sclerosis post-vaccination with BCG.[3,6]

There are two proposed mechanisms for this effect of the BCG vaccine on immunity to other infectious agents. One is inducing heterologous lymphocyte responses and the other is innate immune memory response or trained immunity. Trained immunity is the “process of epigenetic, transcriptional, and functional reprogramming of innate immune cells (such as myeloid cells or natural killer cells), leading to an increase in the cytokine production capacity and their antimicrobial function.”[7] BCG vaccine has been demonstrated to increase the production of interleukin (IL)-1β, IL-6, and tumor necrosis factor-α by monocytes when stimulated with other infectious agents.[4,5,8]

Recent attention in the medical community has been focused on COVID-19 (SARS-CoV-2) infection and what we can do to prevent further spread and continuation of the global pandemic. Although we now have specific vaccines for COVID-19, frequent mutations with variants have arisen, making these vaccines less effective in preventing disease spread, although, with boosters, they have remained effective for protection from serious illness, hospitalization, and death, in most vaccinated individuals.[9]

To address the limitations of the specific COVID-19 vaccines, several studies have been done, or are underway. One study was a randomized, double-blinded trial from January 2020 to April 2021 looking at the BCG vaccine as possibly offering protection to patients with type 1 diabetes. The investigators found that the group studied, who had received the BCG vaccine prior to the pandemic (but had not yet received a SARS-CoV-2-directed vaccine), had fewer confirmed cases of COVID-19 than the placebo group (92% vaccine efficacy). Additionally, most individuals receiving placebo had more severe symptoms, whereas patients who received the BCG vaccine had the same or less severe symptoms than others in their household (who had not received the BCG vaccine). The BCG multi-dose vaccine was also found to be safe.[6]

Another study, ACTIVATE, looked at elderly patients who received a single dose of BCG vaccine or placebo at discharge from the hospital between 2017 to 2019. An unplanned interim analysis done looking for protection from the SARS-CoV-2/COVID-19 pandemic showed a 79% reduction of respiratory infections in the cohort of this population who had been administered the BCG vaccine.[7]

As a follow-up to the ACTIVATE study, a phase 3 placebo-controlled randomized trial (ACTIVATE-2) of the BCG vaccine against SARS-CoV-2 was conducted with positive results. The individuals vaccinated with the BCG vaccine had a 68% reduction of COVID-19 infection, retrospectively diagnosed at six months after vaccination, compared to the placebo group. Both the incidence and severity were decreased in the patients who had received the BCG vaccine. This was true after adjustment for comorbidities. The authors of this study also suggest that the BCG vaccine may boost immunity even after an individual has an asymptomatic SARS-CoV-2 infection.[10]

Three other studies focused on the potential benefit of administering the BCG vaccine to healthcare workers. Two of them did not show any benefit in terms of decreasing absenteeism or COVID-19 infection.[11,12] The third, the phase 3 BRACE trial, is ongoing and no results have been posted. The investigators propose that if there is a benefit, the BCG vaccine might be able to be used as an early intervention in future novel respiratory virus outbreaks, especially for healthcare workers and other high-risk populations.[13]

Why are these studies still needed when we have multiple COVID-19 vaccines available in the U.S.? There are several reasons. Although these vaccines are widely available here in the U.S., that is not the case in all countries;[8,10] however, those developing countries that have limited availability do have programs for neonatal BCG vaccination. Using BCG revaccination could have a great impact on the COVID-19 pandemic in those places. There have been several observational studies showing that the incidence and mortality of COVID-19 were lower in countries in which BCG vaccine was widely administered. However, other studies have not demonstrated these same results.[8]

Even in the U.S., where new variants continue to appear and escape the vaccines,[8,10] using vaccines such as the BCG vaccine may be able to be used as “bridge vaccination” for partial protection while newer, more specific vaccines are being developed.[10] Another barrier to wide acceptance of the COVID-19 vaccines is misinformation and the relatively short timeframe of the vaccine’s development, leading to vaccine hesitancy.[8] A well-established vaccine, such as BCG, may be more widely accepted by those who are hesitant.

Additionally, other viruses may cause future pandemics; if so, administration of the BCG vaccine may also be a bridge before an effective vaccine is developed, reducing the early and rapid spread that was seen at the beginning of the COVID-19 pandemic.[4,5] This could be especially crucial for those who are at higher risk of illness and death, such as young children and the elderly. It has also been suggested that this may be used for other infectious diseases; influenza-related morbidity and mortality may be decreased with this strategy, as well as preventing reactivation of latent viruses (ie, varicella, cytomegalovirus, Epstein Barr virus).[4]

So, yes, there may be a role for BCG vaccines in preventing infectious diseases other than TB. It will be important to await the results of the 56 clinical trials underway,[8] which will hopefully aid in the fight against COVID-19.