Disclaimer: These are personal views of the writer. They do not necessarily reflect the opinion of www-business-standard-com-nalsar.knimbus.com or the Business Standard newspaper
Tuberculosis (TB) is a curable disease, affecting people of all ages, gender and socio-economic status. It is also the largest killer among communicable diseases in the age group of 15 to 49, when people are most productive in life. Recently concluded, the largest National TB Prevalence survey (NTBPS) estimates the prevalence of confirmed pulmonary TB cases to be 312 per 1,00,000 Indian population, the second highest in the world. Under-nutrition, diabetes, alcohol and tobacco use impair the immune response of an individual and act as a driver of the TB epidemic. TB has a devastating socio-economic impact on individuals, families and communities as it remains the topmost reason for workdays lost, creating poverty and malnutrition, which in turn increases the likelihood of someone falling sick. Ending TB will require breaking this vicious cycle. We have to do much more than newer diagnostics like handheld X-rays, newer rapid nucleic acid tests and treatment regimens and have to do it faster to reach our “End TB” targets. One such intervention will be prevention of TB. Besides cough hygiene and airborne infection control, the TB preventive vaccine is an important tool in this fight against TB. Mass vaccination of adults and adolescents in high TB burden countries with an effective vaccine will be a key to elimination of the disease.
With few newer TB vaccines in the pipeline, the Bacillus Calmette Guerin (BCG) vaccine remains the only one recommended by the World Health Organization against the disease (WHO) even after 100-years of its existence. Following its first administration in 1921, the BCG vaccine has had a long journey and is routinely administered in many countries at birth. The classic large south Indian “Chingleput BCG vaccine” trial comparing BCG vaccine and placebo showed a low but consistent protection in those vaccinated at less than 15 years of age at 15 years of follow-up.
BCG revaccination has recently been reconsidered for the protection of adolescents. In addition, there is growing interest in the broader applications of BCG for its beneficial ‘off-target’ effects on the immune system that protect against a variety of infections, including Covid-19 and bladder cancer. While waiting for a specific Covid-19 vaccine it was shown that by stimulating trained immunity, BCG was able to prevent severity of the disease, need for hospitalisation, and thus possibly Covid-related death. As we wait for newer TB vaccines, there has been a renewed interest in adult BCG vaccination or revaccination for the prevention of TB.
Several studies across the globe have shown variable results at the effect of BCG revaccination in children and adolescents or adult BCG vaccination in the prevention of TB infection or TB disease. The WHO does not recommend revaccination of BCG in any individual as there is no strong evidence to support protection against TB. Some studies have shown the boosting effect of immune responses. When given for the second time in young adults, researchers at the Indian Institute of Science, Bengaluru, have shown that it could boost the host's first line of defence, including immune cells critical for vaccine induced immunity without any adverse effects.
BCG revaccination of 170,000 Brazilian school children did not show effectiveness against TB in the REVAC trial. However, the extended follow-up suggested BCG revaccination might offer protection in a selected subpopulation, like in children who were revaccinated before the age of 11 years, those with longer follow-up and in site with proximity to equator. Another study of BCG revaccination of 46,000 participants in a Malawian community did not show significant efficacy. The protective effect of BCG revaccination was only seen in those vaccinated at younger than 15 years of age, and followed up for at least 20 year and against HIV-negative tuberculosis. Earlier meta-analyses of multiple studies have shown that on average, BCG vaccine significantly reduces the risk of TB by 50 per cent, with protection against TB death, meningitis, and disseminated disease higher than for total TB cases. Sixteen countries continue to give an additional BCG vaccination – known as a booster vaccination – after the initial. Kazakhstan, Belarus, Uzbekistan, and Turkmenistan recommend three BCG vaccinations, with the third given between the ages of 12 and 15. Protection observed from BCG is highly variable across many populations, study designs, and forms of TB; and is thought to be greatest in persons without previous mycobacteria exposure and may last for 10 years.
Many persons in high TB burden countries are already infected with M.tb by early adulthood, a condition called Latent TB Infection (LTBI). The NTBPS estimated that around 30 per cent of the population above 15 years of age in the country were latently infected with TB infection. Also, many of them would have been vaccinated with BCG vaccine in infancy, yet those with LTBI are at risk for developing TB disease later. This opens the speculation that LTBI may prevent optimal immune response to BCG vaccine. Hence pre-vaccination treatment of LTBI, might allow alteration of immune response and a better response following revaccination.
Among individuals with LTBI, those with recent infection, as diagnosed by a positive skin test or quantiferon blood test, are associated with a higher risk of progression to TB disease than those not infected or infected earlier than 2-years. Studies have suggested that reversion to a negative skin test is associated with early containment of M.tb infection and a lower risk of progression to TB disease and BCG vaccination may have a significant role in this.
The Indian Council of Medical Research (ICMR) has undertaken a large multi-centre trial to look at the efficacy of a live recombinant form of BCG and a heat-killed suspension of mycobacterium to prevent TB among household contacts of patients. ICMR along with the National TB Elimination Programme will begin to give adult BCG revaccination to adolescents and adults for the prevention of TB in selected states of the country.
Studies have also shown that BCG revaccination is safe, well tolerated, and reactogenicity is similar to that of primary BCG vaccination irrespective of previous M.tb infection. BCG revaccination may be associated with development of a BCG local adverse reaction or a local lymph node swelling than initial BCG vaccination. Most local reactions self-resolve within a month.
BCG revaccination of adolescents and adults can be considered as a low-cost and globally acceptable future pandemic preparedness plan to enhance population immunity. Unfortunately, there are no reliable correlates of vaccine-induced protection in those vaccinated. Hence, long-term studies are required to evaluate the vaccine efficacy and the need for revaccination or booster shots in different subgroups of population. If proven to be effective, this can be scaled up by rolling it out in the adolescent vaccination programme throughout the country either as a revaccination strategy or an adolescent vaccine.
All this will be possible as we have a strong political commitment from the highest leadership to address the multiple challenges including procurement of drugs and diagnostics. This commitment from the topmost leadership of the country has further strengthened our resolve to end TB.
C Padmapriya is director, ICMR National Institute for Research in Tuberculosis. Balram Bhargava is chief cardiothoracic centre, AIIMS, and immediate past director general of ICMR.
These are the personal opinions of the writer. They do not necessarily reflect the views of www-business-standard-com-nalsar.knimbus.com or the Business Standard newspaper.