The potential health and economic impact of new tuberculosis vaccines in India

By Dr. Liji Thomas, MDJul 14 2023Reviewed by Danielle Ellis, B.Sc.

India is among the countries with the heaviest burden of tuberculosis globally, accounting for almost one in three. As recently as 2021, there were almost three million cases in the country, with over 500,000 deaths. The need for better preventative and therapeutic measures is urgent.

*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

A new preprint on medRxiv* discusses how novel tuberculosis vaccines for adolescents and adults could mitigate this problem.

Introduction

The government of India has long attempted to control tuberculosis in India, with the latest plan being the National Strategic Plan to End Tuberculosis in India 2020–2025, developed by the National Tuberculosis Elimination Programme (NTEP). The goals include reducing disease transmission, preventing TB, and improving social factors that promote the disease.

The coronavirus disease 2019 (COVID-19) pandemic threw a spanner into the works, with adverse effects on both TB prevention and care. The mortality due to TB rose for the first time since 2007 during the pandemic, while notifications dropped by almost a third in 2021.

The NTEP promotes better diagnosis, screening, and preventive treatment on a broader scale, as well as vaccine development. This aligns with the efforts of the World Health Organization (WHO) and other international bodies.

The WHO reported the results of its study showing that vaccine development deserves more investment because of its potential to improve both the health and economic aspects of countries burdened with TB.

At present, there are 16 candidate vaccines at various stages of development. One of them is M72/ASO1E, which has completed its phase IIb trial. This showed it to be effective in preventing disease in adolescents and adults, reducing the risk of TB by half after a follow-up period of three years.

Another phase IIb trial looked at the effectiveness of providing a second dose of the primary TB vaccine, Bacille Calmette-Guerin (BCG), to people in their teens who have not yet been infected. This showed a comparable preventive efficacy of ~45% against long-term infection.

This is being re-tested in another phase IIb trial, the results being expected around the middle of 2024. An earlier trial, when data from uninfected participants at the time of BCG vaccination, reported 36% protective efficacy. If an additional BCG dose is confirmed to confer protection, it would be an easy step to introduce a revaccination policy since the vaccine is already licensed.

The current preprint aimed to provide modeling predictions about the India-specific health and economic impacts of either of these approaches (BCG-2 and M72/ASO1E vaccination) on the TB profile. This type of data is key to understanding how different vaccines and vaccination policies could affect the outcome with respect to this country.

What did the study show?

The current situation would result in approximately 72 million new cases and ~14 million deaths from TB during the period from 2025-2050. Conversely, the corresponding figures in the case of stronger current interventions alone would be 36 million and 7.6 million, that is, a risk reduction by half.

Assuming the introduction of M72/AS01E for all those aged 15 and above, in 2030, with a second campaign in 2040, at a price of $2.50 per dose and with 50% protective efficacy, irrespective of infection status at the time of vaccination, almost 13 million cases could be prevented, and two million deaths, during the same period.

While a more effective vaccine, at 70% efficacy, could increase averted cases and deaths still further, this would entail delayed vaccine introduction until 2036. This would push up cases and deaths by ~5 million and ~ 970,000, respectively. If the M72/AS01E vaccine worked only when the individual was infected at the time of vaccination, it could avert about 6 million cases and 900,000 deaths.

If BCG revaccination for all those aged 10 or above was modeled with 45% efficacy and ten years of protection in people uninfected at the time of vaccination at a price of $0.17 per dose (i.e., per course), it could reduce cases and deaths by 9 million and 1.5 million, respectively. If it helped avoid infection as well as clinical disease, this would bring down the numbers by 3.4 million and 600,000, respectively, below the baseline.

The M72/AS01E would be more effective than BCG revaccination at improving health, averting about 40% more cases and deaths compared to the latter by 2050. But if current interventions were applied more stringently along with the vaccination strategy, the two vaccines would reduce cases and deaths by 8% vs. 5% and 6.7% vs 4.5%, respectively.

While M72/AS01E vaccination for all people aged 60 or above was shown to be inefficient, the impact of the vaccine, when given by the age of 55 years, was cost-effective.

The additional cost of M72/AS01E, if introduced along with current interventions, was estimated to be $5.3 billion. In turn, this averted about 37 million disability-adjusted life years (DALYs) by this step alone out of the total 4 billion DALYs predicted.  

If given to all those aged 15 or above, with additional targeting of those between 16-34 years, M72/AS01E vaccination was cost-effective.

With BCG revaccination, cost-effective strategies involved all those delivering the vaccine at the age of ten and above, up to the age of 34. The cost was $656 million, considerably lower than with the M72/AS01E, averting 29 million DALYs. Like M72/AS01E, BCG revaccination was cost-effective if given to all above ten and targeting those aged 11-18.

While the mean vaccination cost per year for M72/AS01E was $250 between 2025-2050, this would save an average of $60 million per year on diagnosis and treatment. With BCG revaccination, an average yearly investment of $67 per dose saved $43 million per year over 2025-2050. Thus, the second vaccine was about a fourth of the cost of the first.

Similarly, the mean cost of introducing M72/AS01E would be eight-fold that of introducing BCG revaccination, at $190 million per year vs $23 million per year. Over a five-year period, until maximum coverage was achieved, the former would cost $638 million per year for vaccination vs $121 million for the latter.

A repeat campaign was envisaged in 2040 for M72/AS01E at a cost of $2.2 billion. Conversely, two repeat campaigns were planned in 2035 and 2045, for the BCG revaccination program, at a cost of $377 million and $272 million, respectively.

 What are the implications?

The results of this study showed that a repeat dose of BCG and M72/ASO1E vaccination are potentially effective in reducing the burden of tuberculosis in India at an affordable rate. The models predicted greater cost-effectiveness for BCG revaccination, with incremental programs costing about eight times more for M72/AS01E per year.

Health-wise, the M72/AS01E vaccine was predicted to prevent tuberculosis in both infected and uninfected people effectively, provided they did not have active disease. In contrast, BCG revaccination would work only in uninfected people and would prevent infection.

The greater spectrum of coverage of M72/AS01E, and the faster results obtained, gave it a 40% higher impact on health compared to BCG revaccination, which would show results only after a longer period, corresponding to the period required for active disease to set in following first vaccination and then infection.

This is consistent with previous work showing more rapid impact on disease of a vaccine that prevents disease directly in those currently infected.”

On the other hand, the evidence lacks robustness. It is not known if M72/AS01E works well in uninfected individuals or if BCG revaccination protects against disease in adults. Further studies are required to elucidate these key points and to understand the mechanism of action of these vaccines.

Moreover, the actual efficacy of these vaccines is still unclear, which may have led to inflated estimates of their impact on health and economic outcomes. Multiple assumptions made during the modeling process may also have limited the accuracy of the predictions.

We cannot solely rely on M72/AS01E and BCG-revaccination in case the realized characteristics differ considerably from expectations. Investment in multiple vaccine developments and delivery should be increased to raise the probability of success.”

*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.