The centenary celebrations of the discovery of insulin have eclipsed another seminal event in the history of medicine that has had significant impact on human health - the first use of BCG (Bacillus Calmette-Guerin), the vaccine against tuberculosis (TB) in humans.
TB is caused by a bacterium called Mycobacterium tuberculosis, belonging to the Mycobacteriaceae family consisting of about 200 members. Some of these cause diseases like TB and leprosy in humans and others infect a wide range of animals. Mycobacteria are also widely dispersed in the environment. In humans, TB most commonly affects the lungs (pulmonary TB), but it can also affect other organs (extra-pulmonary TB).
TB is a very ancient disease and has been documented to have existed in Egypt as early as 3000 BC. Sadly, unlike other historically dreaded diseases like smallpox, leprosy, plague and cholera that have been either eradicated or controlled to a large extent due to advances in science and technology, TB continues to be a major public health problem in the world. According to the WHO’s Global TB Report, 10 million people developed TB in 2019 with 1.4 million deaths. India accounts for 27% of these cases.
BCG was developed by two Frenchmen, Albert Calmette and Camille Guerin, by modifying a strain of Mycobacterium bovis (that causes TB in cattle) till it lost its capacity to cause disease while retaining its property to stimulate the immune system. It was first used in humans in 1921.
Sole vaccine
Currently, BCG is the only licensed vaccine available for the prevention of TB. It is the world’s most widely used vaccine with about 120 million doses every year and has an excellent safety record. In India, BCG was first introduced in a limited scale in 1948 and became a part of the National TB Control Programme in 1962.
One intriguing fact about BCG is that it works well in some geographic locations and not so well in others. Generally, the farther a country is from the equator, the higher is the efficacy. It has a high efficacy in the UK, Norway, Sweden and Denmark; and little or no efficacy in countries on or near the equator like India, Kenya and Malawi, where the burden of TB is higher. These regions also have a higher prevalence of environmental mycobacteria. It is believed that these may interfere with the protective effect against TB. However, in children, BCG provides strong protection against severe forms of TB. This protective effect appears to wane with age and is far more variable in adolescents and adults, ranging from 0–80%. A large clinical trial between 1968-1983, by the ICMR’s National Institute for Research in Tuberculosis (then called the Tuberculosis Research Centre) in Chengalpattu district of Tamil Nadu, indicated that BCG offered no protection against pulmonary TB in adults, and a low level of protection (27%) in children.
India is committed to eliminate TB as a public health problem by 2025. To achieve this goal, we would not only need better diagnostics and drugs but also more effective vaccines. Over the last ten years 14 new vaccines have been developed for TB and are in clinical trials. Of particular interest is a Phase 3 clinical trial by the ICMR, of two vaccines; a recombinant BCG called VPM 1002 and Mycobacterium indicus pranii (MIP). MIP was identified and developed into a vaccine in India. Results of this trial are eagerly awaited.
In addition to its primary use as a vaccine against TB, BCG also protects against respiratory and bacterial infections of the newborns, and other mycobacterial diseases like leprosy and Buruli’s ulcer. It is also used as an immunotherapy agent in cancer of the urinary bladder and malignant melanoma.
In progress
Interestingly, it has been observed that in some countries that have had BCG vaccination as a national policy, the burden of SARS CoV-2 morbidity and mortality was significantly less compared to countries which did not. Clinical trials to know if this is indeed true, are underway, including in India.
In these distressing times of Covid-19, it is interesting to compare development of vaccines for Covid-19 and TB. For Covid-19 in about 18 months,17 vaccines have received emergency use authorization in various countries, and 97 are in clinical trials. For TB, a single vaccine has been in use for the last 100 years and 14 new vaccines are in clinical trials. For R&D of Covid-19 vaccines, US$ 8.5 billion have been earmarked (Global Contributions to ACT- Accelerator, Vaccines category); for TB the amount is US$ 0.117 billion (Global Funding for TB Vaccine Research, 2019). If viewed in the backdrop of the deaths caused by these two diseases (Covid-19 - 1.7 million in 2020; TB - 1.4 million in 2019), one can see the stark inequity in investment in vaccine development.
While we commemorate the centenary of BCG vaccine use in humans, we need to acknowledge that more effective vaccines are needed to reach the targets of TB elimination. The experience and success of development of new vaccines for Covid-19 have shown that this is possible if TB gets similar political, financial and pharmaceutical support.
(Dr. M S Jawahar is Former Deputy Director, ICMR-NIRT, Chennai and Dr. Lalit Kant is a former Head, Division of Epidemiology & Communicable Diseases, ICMR)
