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.

Keywords: BCG; VPM1002; immunity; next-generation vaccine; recombinant; tuberculosis; vaccination.

FIGURE 1

Description of the etiology of TB by Robert Koch. Agenda of the meeting of the Physiological Society in Berlin, where Robert Koch for the first time presented his data on March 24, 1882 and first page of the publication on this topic in the Berlin Clinical Weekly, April 10, 1882 (Koch, 1882). Figure also includes photo of Robert Koch from 1883 (Kaufmann and Winau, 2005).

FIGURE 2

Koch’s postulates, based on Robert Koch’s lecture on the etiology of TB and phrased in general terms by F. Loeffler (Loeffler, 1884; Kaufmann and Winau, 2005).

FIGURE 3

Report describing the clinical trials with Koch’s remedy against TB. The figure shows title page of report and photo of the principle investigator (Guttstadt, 1891; Kaufmann and Winau, 2005). Also shown is a picture from a magazine depicting vaccination of a TB patient with tuberculin in front of medical doctors.

FIGURE 4

Description of development and clinical testing of BCG. Figure shows title page of book, photo of the author, Albert Calmette, and leaflet advocating BCG vaccination of neonates from the book (Calmette et al., 1927).

FIGURE 5

Title page of the report on investigations into the so-called Lubeck disaster and photo from this report depicting lung and lymph nodes with numerous lesions caused by M. tuberculosis contamination of BCG (Moegling, 1935).

FIGURE 6

Simplified scheme of potential mechanisms induced by VPM1002 underlying a better safety and efficacy profile over BCG. Figure modified from Kaufmann (2020) and based on published data (Hess et al., 1998; Conradt et al., 1999; Decatur and Portnoy, 2000; Grode et al., 2005; Winau et al., 2006; Farinacci et al., 2012; Saiga et al., 2015; Chen et al., 2018; Nguyen et al., 2019).