The Drug Controller General of India’s (DCGI) Special Subject Expert Committee (SEC) on Vaccines last month found that major studies had failed to clearly demonstrate that recombinant BCG (rBCG -VPM1002) was effective, according to minutes of the meeting reviewed by Mint.
The recombinant BCG vaccine is a genetically modified version of the traditional TB vaccine that is based on a weakened strain of Mycobacterium bovis.
The regulator found the specialized later-stage Serum Institute of India (SII) analysis unreliable and asked the company to conduct a new, larger study to get clear and convincing evidence that the vaccine works before seeking approval for public use.
Tuberculosis (TB), caused mainly by Mycobacterium tuberculosis in humans, is the biggest killer among communicable diseases in India, with about 2.6 million new cases and 321,095 deaths reported in 2024, according to the Union Health Ministry’s report on TB in India. While the country aims to eliminate the disease by the end of this year, five years ahead of the 2030 deadline of the UN’s Sustainable Development Goals (SDGs), the task has become challenging because there is no protective TB vaccine.
“There is a critical need for a new and effective TB vaccine because the effectiveness of the standard BCG vaccine is limited outside of early childhood,” said Dr. Soumya Swaminathan, Senior Advisor, National TB Elimination Programme. “The TB control program will definitely get a big boost if we have an effective and safe vaccine.”
Queries emailed to spokespersons of the Union Ministry of Health and Family Welfare, DCGI and Serum Institute remained unanswered on Friday.
Serum vaccine
SII first applied to the DCGI for emergency use authorization for this vaccine in March 2022. The SII vaccine was designed to provide better protection against pulmonary and extrapulmonary TB in individuals aged six years and older, a group where the current BCG vaccine does not show consistent efficacy.
SII submitted two studies for approval, according to the minutes of the committee meeting held on October 15.
“The committee thoroughly discussed the proposal and recommended that the data from the study with post hoc analysis is not adequate and conclusive to make an informed decision about the application of the new drug. The company should plan an adequately powered study based on the result of the secondary end point of the ICMR study for the final decision,” the minutes read.
The committee believed the data was insufficient and lacked effectiveness, said the first government official cited above, who spoke on condition of anonymity about the regulatory process.
Other TB vaccines are in development worldwide, including the M72 vaccine (supported by the Gates Foundation), as well as mRNA vaccines from Gennova and BionTech and MTBVac from the Biovac group.
“While the primary outcome of the (Serum Institute) study showed no significant difference, subgroup analysis showed a positive trend in children aged 6-14 years, with recombinant BCG suggesting a lower incidence of both pulmonary and extrapulmonary TB compared to placebo,” said Swaminathan, who was previously a chief scientist at the World Health Organization. “These findings were based on a small sample size and require confirmation through larger trials.”
In Study 1, which focused on preventing disease recurrence in successfully treated patients with pulmonary TB, the vaccine failed to meet its primary endpoint, according to the committee. A post-hoc analysis showed that the difference in efficacy between the vaccine and placebo groups for all recurrences was not statistically significant, the commission said, noting that the analysis was unrelated to this application.
Study 1 found that the Serum Institute vaccine reduced the recurrence of TB in bacteriologically confirmed and clinically diagnosed cases by 13.5% and by 7.8% in bacteriologically or diagnostically confirmed infections only.
In a large Phase III study conducted by the Indian Council of Medical Research (ICMR) 2 study in healthy sputum-positive TB patients at home, the vaccine failed to meet its primary objective of assessing efficacy over three years. This study tested the Serum Institute’s rBCG vaccine as one of three arms against placebo. The overall effectiveness of the vaccine against all microbiologically confirmed TB (pulmonary and extrapulmonary) was found to be 16.9%, which the committee considered to be statistically insignificant.
“The statistically insignificant result was interpreted and concluded as statistically significant based on the calculation of the two-arm data instead of the three-arm data of the ICMR study,” the minutes of the meeting read, adding, “The primary objective of the study was not met and no conclusions were drawn by the company.
The second government official cited above, who also spoke on condition of anonymity, said: “Rejection rates vary widely depending on the complexity of the vaccine, the stage of the trial and the standard of data submitted. Large confirmatory trials typically take several years to complete.”
According to Swaminathan, also a former director general of the ICMR, the recombinant BCG vaccine has the key advantage of a positive safety profile. “However, definitive efficacy requires larger studies, as requested by the DCGI, to ensure the safety and efficacy of the vaccine before public use.”
The threat of drug-resistant tuberculosis
TB in India accounts for an estimated 26% of the global TB burden and contributes to drug-resistant infections.
“Since TB is an infectious disease, a preventive vaccine is crucial because if a person is sick, there is a good chance that someone in close contact with them will also catch the infection and develop active TB,” said Dr. Randeep Guleria, former director of the All India Institute of Medical Sciences, Delhi and former Indian Covid czar.
“Current TB treatment is long, and even if it has been shortened to a few months, patients often stop taking their drugs, which can lead to the development of multidrug-resistant TB (MDR-TB),” said Guleria, currently a pulmonologist at Gurgaon-based Medanta Hospital.
According to India’s TB report, the National TB Elimination Program diagnosed 63,939 MDR-TB cases and 114 extensively drug-resistant (XDR-TB) cases in 2024.
“We already use the BCG vaccine in children, but it offers only very modest protection. The ICMR is conducting further trials in adults who are at high risk of developing active TB. The Serum Institute data did not show statistically significant efficacy, so the committee did not approve it,” Guleria said.
According to Dr. Rajeev Jayadevena, a public health expert, “Despite extensive screening, testing and treatment, TB remains a formidable foe.”…If a truly effective vaccine becomes available, it will be a major breakthrough. Unfortunately, the new recombinant BCG vaccine showed only 16.9% overall efficacy in a recent study, which is not optimal for widespread use.”
While subsequent analysis showed 50.4% effectiveness against extrapulmonary TB – which infects organs other than the lungs – the regulator was right to call for larger studies, he said. “With drug-resistant tuberculosis on the rise, multifaceted efforts must continue.”
