British researchers led by Dr Punam Mangtani of the London School of Hygiene and Tropical Medicine have shown that BCG, the world’s only licensed tuberculosis (TB) vaccine, may offer protection against the disease for nearly twice as long as previously thought. Writing in the latest issue of the International Journal of Epidemiology, they noted that “Evidence of protection from childhood Bacillus Calmette-Guerin (BCG) against tuberculosis (TB) in adulthood, when most transmission occurs, is important for TB control and resource allocation.”
Is there a benefit in vaccinating children who were left out earlier?
Thus far, scientists knew that BCG vaccination is effective for 10-15 years; the new case-control study found that if given in early teenage years (12-13), the Bacillus Calmette-Guérin (BCG) vaccine protected over 50% of UK children against TB for at least 20 years, then the immunity waned.
“Although some studies in countries such as Brazil and Norway have indicated that BCG might be effective for longer than first thought, this study provides the most robust evidence to date,” they clarified.
Researchers invited cases and controls to take part in face-to-face interviews. Experienced field interviewers carried out Computer- assisted Personal Interviews (CAPIs), following training specific to the study including inspecting both arms of all subjects to identify BCG vaccination scars. BCG was a vaccine given in school at about 12–13 years and usually caused a pustule and then a scar. Researchers considered that recall by cases and controls is likely to be good. (I recall that because of the possibility of a permanent scar, many in my generation did not go for vaccinations and ran away when vaccinators visited their homes!)
Researchers assessed protection from BCG vaccination administered to children 10–30 years previously, 5-year intervals after vaccination and tested for trends over time by analyzing time since vaccination, on a continuous scale. The study covered only UK born White subjects
The study covered 677 cases and 1170 controls. Researchers reported that confounding by deprivation, education and lifestyle factors was slight 10–20 years after vaccination, and more evident after 20 years. Vaccination Effectiveness (VE) 10–15 years after vaccination was 51%; 57% at 15–20 years. At 20–25 years, VE was 25%; it was 1% at 25-29years.
“With no new vaccine for TB imminently available, the researchers say their findings highlight the important role BCG is playing in preventing the spread of the disease, and provide an argument for uptake to be higher in areas where TB risk is high but vaccination coverage is low, such as parts of Central and Western Africa, East Asia and the Pacific – important new evidence for agencies like the World Health Organization (WHO) advising on vaccines,” the press release on the British study asserted.
The British study applies to children who were vaccinated while they were aged 12-13 years. The study addressed protection against TB occurring 10-29 years later. The press release on the study stated that in most countries BCG vaccination is carried out during infancy. Environmental and genetic factors also may play a role. Dr Punam Mangtani, the lead author stated that “we do not know the duration of protection in different populations.”
“Is there not a need to conduct country-specific study to generate such data?”
“I agree that it would be good to have more information on the durability of the BCG after BCG vaccination in infancy and in other settings especially where the burden is highest and sensitization by environmental mycobacterium is more likely,” Dr Mangatani responded in my e-mail message.
“The paper does note other studies e.g.: in Saudi Arabia and Brazil where longer than expected protection is seen. Certainly having further confirmation will be useful,” she added.
The researchers listed the following key messages from the study:
- “It is unclear whether protection by school-aged Bacillus Calmette-Guerin (BCG) vaccination against TB continues into adulthood, when most transmission occurs.”
- “Using a case–control study design based on 677 cases and 1170 controls, we found about 50% protection that lasted 20 years and then waned.”
- “That BCG attributable protection against tuberculosis lasts longer than previously thought affects its cost-effectiveness and has implications for the evaluation of new TB vaccines.”
In the press release, Dr Mangtani stated that health officials should consider recommending childhood BCG vaccination where TB risk is high and where infant vaccination has not been given. To me, this is indeed the key message for most developing countries. I believe that this message should have been included as one of the “key messages” in the main text.
I sought Dr Mangtani’s reaction to my suggestion.
“Your point … is well taken and I hope that message can be made to come over more strongly,” she agreed.
To my query whether there is a mechanism that explains the attenuation of the efficacy of the vaccine in the vaccinated individual over time, Dr Mangtani responded thus:
“There are competing theories of why there is attenuation of BCG over time, not just the usual immunological memory waning as with most vaccines. The oldest is masking where by those not vaccinated get some protection from being sensitised by environmental mycobacteria so that BCG can add little. The other is blocking, so prior infection or sensitisation by environmental mycobacteria reduces the effect of BCG. It is unclear and could of course be a mixture of both especially as there is some evidence that BCG can prevent infection.”
She also referred to some correspondence on a recent systematic review of the randomized controlled trials of BCG efficacy she was involved in that gives more details and one or two references (Paper 1 and Paper 2) for the masking and blocking theories . These papers amply revealed how difficult it is to get clarity on the correct mechanisms.
The WHO in its “Global Tuberculosis Report -2016” stated that the TB epidemic is larger than previously estimated, reflecting new surveillance and survey data from India. The agency also noted that the number of TB deaths and the TB incidence rate continue to fall globally and in India.
However, some of the WHO data reveal a chilling reality. “In 2015, there were an estimated 10.4 million new (incident) TB cases worldwide, of which 5.9 million (56%) were among men, 3.5 million (34%) among women and 1.0 million (10%) among children. People living with HIV accounted for 1.2 million (11%) of all new TB cases. Six countries accounted for 60% of the new cases: India, Indonesia, China, Nigeria, Pakistan and South Africa.”
Besides the TB Patients living with HIV, Multi Drug Resistant TB (MDR-TB) added a new dimension to the problem.
A large scale community-based double blind randomized controlled trial carried out in Chingleput district of south India to evaluate the protective effect of BCG against bacillary forms of pulmonary tuberculosis gave the following results:
- “BCG offered no overall protection in adults and a low overall protection in children…”
- “The findings at 15 years show that in this population with high infection rates and high nonspecific sensitivity, BCG did not offer any protection against adult forms of bacillary pulmonary tuberculosis”.
- “This lack of protection could not be explained by methodological flaws or the influence of prior sensitisation by non-specific sensitivity or because most of the cases arose as a result of exogenous re-infection”, the study concluded
A telling editorial titled “BCG revisited” in The Indian Journal of Tuberculosis concluded thus:
- “Since the first use of BCG in 1921, in the randomized controlled clinical trials of BCG vaccine carried out, its protective efficacy against tuberculosis has varied from 0 to 80%, in different populations”
- “In general, the protective efficacy was found to be greater in trials conducted in northern latitudes, where tuberculosis prevalence is low compared with studies elsewhere”
- “Variability in protective efficacy has been observed not only in the different trials but also between sites of the disease. However, a meta-analysis has shown that summary BCG protective effect against miliary tuberculosis or tuberculous meningitis in randomized control trials was 86%, and in case control studies it was 75%. Further, case control studies carried out in India (not included in the quoted meta-analysis) also show a protective efficacy of BCG against tuberculous meningitis of not less than 75%”.
The British paper did not refer to the Indian study presumably because the Indian study was carried out nearly 20 years ago.
“The efficacy of BCG in preventing TB varies geographically, particularly for pulmonary TB, with limited evidence of protection in many tropical areas, ” the British researchers conceded.
Under ideal conditions, each country should have specific information on the efficacy of BCG vaccination to its population including how long the immunity lasts. This is a very expensive proposition. Specialists and health policy makers should decide whether BCG vaccination of children not vaccinated in infancy must be included now in light of the British study.