Vaccine Development Against Tuberculosis Over the Last 140 Years: Failure as Part of Success

Abstract

The year 2020 was shaped by the COVID-19 pandemic which killed more people than any other infectious disease in this particular year. At the same time, the development of highly efficacious COVID-19 vaccines within less than a year raises hope that this threat can be tamed in the near future. For the last 200 years, the agent of tuberculosis (TB) has been the worst killer amongst all pathogens. Although a vaccine has been available for 100 years, TB remains a substantial threat. The TB vaccine, Bacille Calmette-Guérin (BCG), has saved tens of millions of lives since its deployment. It was the best and only choice available amongst many attempts to develop efficacious vaccines and all competitors, be they subunit vaccines, viable vaccines or killed whole cell vaccines have failed. Yet, BCG is insufficient. The last decades have witnessed a reawakening of novel vaccine approaches based on deeper insights into immunity underlying TB and BCG immunization. In addition, technical advances in molecular genetics and the design of viral vectors and adjuvants have facilitated TB vaccine development. This treatise discusses firstly early TB vaccine developments leading to BCG as the sole preventive measure which stood the test of time, but failed to significantly contribute to TB control and secondly more recent attempts to develop novel vaccines are described that focus on the genetically modified BCG-based vaccine VPM1002, which has become the frontrunner amongst viable TB vaccine candidates. It is hoped that highly efficacious vaccines against TB will become available even though it remains unclear whether and when this ambition can be accomplished. None the less it is clear that the goal of reducing TB morbidity and mortality by 90% or 95%, respectively, by 2030 as proposed by the World Health Organization depends significantly on better vaccines.

Therapeutic Vaccines for Tuberculosis: An Overview

“…In the two years of follow-up, a total of 34 patients in the MIP arm and 26 in the placebo arm relapsed, which again, was not statistically significant (15). There is an ongoing phase III efficacy and safety trial for preventing pulmonary TB among healthyhousehold contacts of sputum positive TB patients in India and first results are expected soon (18). In summary, MIP has shown robust evidence of immunostimulation.…”

Research Advances for Virus-vectored Tuberculosis Vaccines and Latest Findings on Tuberculosis Vaccine Development

“…One of the most promising TB vaccines may provide an alternative. The genetically modified BCG-based vaccine VPM1002, in which the gene encoding urease C was replaced by the listeriolysin encoding gene from Listeria monocytogenes , showed the potential to replace the current BCG vaccine and is now undergoing three phase III clinical efficacy trials ( 19 ).…”

After 100 Years of BCG Immunization against Tuberculosis, What Is New and Still Outstanding for This Vaccine?

“…In 2021, Mycobacterium bovis Bacille Calmette-Guérin (BCG), reached a century since its first application to humans. Quite comprehensive reviews have already been published this year [1,2]. On the other hand, on celebrating the 100 years since BCG's first administration to humans, experts in the TB field already gave us an account of what specific and unspecific benefits and shortcomings have been discovered in this century of use [3,4].…”

“…On the other hand, on celebrating the 100 years since BCG's first administration to humans, experts in the TB field already gave us an account of what specific and unspecific benefits and shortcomings have been discovered in this century of use [3,4]. Therefore, this work does not consider several aspects related to vaccine development, for which the reader may refer to other publications [1,2,4,5]. Also, topics such as innate trained immunity or the effect of BCG on cancer, which were comprehensively discussed by renowned experts in other publications in 2021 [4,[6][7][8], are outside the scope of this work.…”