Two New TB Vaccines Prove Safe but Fall Short of Broad Protection in Large India Trial

Two new tuberculosis vaccines are safe but do not offer broad protection against all forms of the disease, according to a large Phase 3 trial in India — a sobering result in the century-long effort to improve on the ageing BCG shot.

The PreVenTB trial, run by the Indian Council of Medical Research, tested VPM1002 and Immuvac against placebo in 12,717 household contacts of TB patients aged 6 and up, across 18 sites in 6 Indian states, with 38-month follow-up. Results were published in The BMJ.

Why TB needs a new vaccine

BCG, the only licensed TB vaccine, dates to the 1920s and remains among the most widely administered vaccines in the world. Its performance is genuinely strange.

It protects young children well against the most severe forms — disseminated TB and TB meningitis — which is why it remains in routine infant immunisation across high-burden countries. Against pulmonary TB in adults, which is the form that spreads the disease, its efficacy has ranged from substantial to nil across trials in different populations, for reasons never fully resolved.

Since adult pulmonary TB drives transmission, a vaccine failing there cannot control the epidemic however well it protects infants.

Why household contacts

The trial population reflects how TB spreads. Household contacts of active cases face sustained, close exposure and represent one of the highest-risk groups available — which allows a trial to accumulate enough cases in a reasonable period.

It is also where a vaccine would be deployed first in practice: preventive treatment of household contacts is already standard policy, so a vaccine fitting that pathway has a clear route into use.

The mixed results

VPM1002 showed about 50.4% effectiveness against extrapulmonary TB overall, rising to 79.5% in adults aged 36–60, and protected across all TB forms in children aged 6 to under 14.

Immuvac protected only against extrapulmonary TB in children aged 6 to under 10.

The pattern — protection against extrapulmonary disease, less against pulmonary — unfortunately echoes BCG’s limitation. Extrapulmonary TB, affecting lymph nodes, bones, the abdomen or the central nervous system, is serious and worth preventing. It is also not what sustains transmission.

The finding that matters most

Neither vaccine protected underweight individuals.

This is the most consequential result and the least discussed. Undernutrition is among the strongest risk factors for progressing from TB infection to active disease — malnutrition impairs the cell-mediated immunity that contains the bacterium, and in high-burden countries the two conditions overlap heavily.

A vaccine failing precisely in the population at greatest risk has limited public health value regardless of what it achieves elsewhere. It also raises a mechanistic concern: if undernutrition prevents mounting an effective vaccine response, that limitation may apply to other TB vaccine candidates, since they all depend on the same impaired immunity.

Reading the subgroup findings carefully

79.5% efficacy in adults aged 36–60 is a striking number and should be treated cautiously.

When a trial reports overall effectiveness of about 50% and a specific age band at 79.5%, the subgroup figure is generated by dividing the population — and subgroups produce extreme values by chance routinely. Unless that band was pre-specified with a stated rationale, it is a hypothesis rather than a result.

The children’s finding is somewhat more interesting because protection extended across all TB forms rather than only extrapulmonary disease, suggesting the vaccines may work differently in younger immune systems — which is also what BCG does.

What was achieved

Both vaccines were safe, which is not nothing. A large Phase 3 in a high-burden setting establishing safety clears a real hurdle, and the protective signals in specific groups are genuine even if narrower than hoped.

The trial infrastructure matters too: 18 sites across 6 states with 38-month follow-up in 12,717 participants is capability that persists and can be used for subsequent candidates.

Where the field stands

Tuberculosis remains among the world’s deadliest infectious diseases, and a shot reliably preventing it across all forms and populations remains elusive. These results add useful data without delivering the broad, robust protection the field is chasing.

Why TB vaccine development is so slow

A century after BCG, the absence of a better vaccine reflects genuine scientific difficulty rather than neglect alone.

The central problem is that nobody knows what protective immunity against tuberculosis looks like. For most vaccines, a measurable immune marker predicts protection — an antibody level that can be checked in a blood sample. Tuberculosis has no established correlate of protection.

The consequence is that candidates cannot be screened efficiently. A vaccine cannot be judged promising on immune measurements and advanced with confidence; it must be tested against actual disease, in large trials, in high-burden settings, over years, because TB progresses slowly and only a fraction of infected people develop active disease at all.

That makes every candidate expensive and slow to evaluate, and it means failures like this one consume resources that could have supported several attempts in a disease with better surrogate endpoints. It is also why the underweight finding matters beyond this trial — each large trial is a rare opportunity, and lessons about who fails to respond should shape the next one.

The underweight finding in particular should shape how subsequent candidates are designed and evaluated — a vaccine that works in well-nourished trial participants and fails in the malnourished is testing the wrong population. Clinical trial news, not medical advice.