Status of Tuberculosis Vaccines Development in Clinical Trials

Abstract

Objectives

Tuberculosis (TB) is the leading cause of death worldwide before the corona virus pandemic, but the only licensed vaccine to date is Bacillus Calmette–Guérin (BCG). This manuscript aims to introduce the current status and trends of clinical research on TB vaccines, one of the most difficult vaccines to develop.

Methods

To identify the current status of clinical development, we reviewed the literature on TB vaccine candidates currently in the clinical pipeline and the World Health Organization (WHO) reports on the introduction of new vaccine developments.

Results

As of September 2024, 15 TB vaccines candidates are in the clinical pipeline. Across vaccine platforms, six whole-cell, five recombinant protein, two viral vector-based, and two mRNA vaccines are in clinical development, with the largest number of candidates being whole-cell-based vaccines. As of 2024, two mRNA vaccines are also in Phase 1 clinical trials. WHO predicts that a new TB vaccine will be available within five years. The recombinant protein-based M72/AS01_E vaccine has been mentioned as a potential vaccine, and is currently recruiting subjects for a Phase 3 clinical trial. In addition, recombinant protein-based GemTBvac and whole cell-based MIP, MTBVAC, and VPM1002 are in Phase 3 clinical trials.

Conclusions

While several platform-based TB vaccine candidates are in clinical trials; however, the antigens contained in these candidates are often redundant and limited. To diversify the TB vaccine clinical pipeline, it is necessary to continue research to identify new antigens, the development of preclinical animal models for efficacy evaluation, and the identification of valid endpoints through the analysis of clinical trial results are necessary.

Key messages

① What is known previously?

Vaccine candidates based on a variety of platforms are in clinical trials, with whole-cell-based candidates being the most common in Phase 3.

② What new information is presented?

A 2024 World Health Organization report predicts that a new vaccine could be introduced within three to five years. Recently, M72/AS01E, which has been shown to reduce the incidence of tuberculosis by more than 50% in adolescents and adults, has been cited as a potential vaccine candidate and is currently recruiting for Phase 3 clinical trials in Africa and elsewhere. Fifteen vaccines are in development, but the clinical pipeline is still very limited compared to other infectious diseases.

③ What are implications?

To ensure pipeline diversity, it is necessary to continue research on the discovery of valid antigens, development of evaluation models for vaccine development purposes, and development of efficacy evaluation indicators. Research collaboration from basic to clinical is needed to develop vaccines for adolescents and adults as well as for infants and recurrence prevention.

Introduction

Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis. Transmitted via the respiratory route, it is, aside from coronavirus disease 2019 (COVID-19), the leading cause of death from a single infectious agent worldwide. According to the 2024 TB report, among HIV (human immunodeficiency virus)-negative individuals, the mortality rate due to tuberculosis is higher than the mortality rate due to HIV. Based on this, some researchers have stated that tuberculosis is a more dangerous pathogen than HIV [1]. The sole existing vaccine for TB, the Bacillus Calmette–Guérin (BCG), was developed in 1921. Although it offers some protection in infants, its effectiveness in adolescents and adults is minimal. Consequently, there is a global demand for the development of new TB vaccines that could either replace or enhance the efficacy of BCG. However, no such vaccine has yet been developed.

In 2023, the global incidence of TB was 134 per 100,000 people, marking a 4.8% increase from 2020 [1]. According to WHO, the proportion of people infected with tuberculosis is one-fourth of the world’s population, which is approximately 2 billion [2]. Notably, 87% of TB cases are concentrated in 30 high-burden countries, with eight countries (India, Indonesia, China, Philippines, Pakistan, Nigeria, Bangladesh, and Congo) accounting for two-thirds of these cases [1]. Although both TB incidence and mortality were on a decline until 2019, the advent of COVID-19 saw a rise in TB mortality by 5.6% in 2020, reverting to the levels of 2017 [3].

In 2018, the WHO introduced the preferred product characteristics (PPC) for new TB vaccines [2-4], highlighting the need for vaccines that can demonstrate at least 50% efficacy in preventing TB infection and offer protection for a duration of 10 years [2,4]. By 2024, the WHO anticipated the introduction of vaccines for adolescents and adults within 3–5 years [1,2], predicting that these would offer greater health and economic benefits than vaccines for infants (Figure 1) [5-7]. These assertions are supported by modeling predictions that indicate higher advantages of vaccination in high-incidence countries over those with lower incidences [5-7]. GSK’s recombinant protein-based vaccine, M72/AS01_E, which consists of antigens Mtb32A and Mtb39A and the adjuvant AS01_E, demonstrated a 54% efficacy in preventing active TB among individuals with latent TB in Phase 2b trials [8]. This result aligns with WHO’s PPC for new TB vaccines. Enrollment for Phase 3 clinical trials is currently ongoing. Considering WHO’s predictions of additional Phase 3 TB vaccine candidates and the potential introduction of new vaccines within the next 3–5 years [1,2], this paper briefly introduces the current status and research trends in TB vaccines currently undergoing clinical trials.

Figure 1. Predicted reduction in tuberculosis incidence rate by 2050 following the introduction of new vaccines.

This figure presents the predicted reduction in tuberculosis incidence rate with the introduction of a new vaccine that has an efficacy of over 50% and provides protection for up to 10 years. The results suggest that introducing vaccines for adolescents and adults is more effective in reducing incidence compared to the introduction of infant vaccines. Reused from the article of Knight et al. (Proc Natl Acad Sci U S A 2014;111:15520-5) [5]; Clark et al. (Lancet Glob Health 2023;11:e546-55) [6]; and TechNet [7].

Methods

We categorized 15 TB vaccines currently in the clinical pipeline based on their platforms: whole-cell-based, recombinant protein-based, viral vector-based, and nucleic acid-based. We reviewed clinical trial results from published literature and reports by the WHO [1,3,8-15].

Results

1. Clinical Research Status by TB Vaccine Platform

As of September 2024, there are 15 TB vaccine candidates in the clinical pipeline, distributed across various platforms, with 12 currently undergoing clinical trials (Figure 2) [14]. Six of these candidates are in Phase 3 clinical trials; four are whole-cell-based, including BCG revaccination, and two are recombinant protein-based vaccines. Phase 2 candidates consist of two whole-cell-based vaccines, two recombinant protein-based vaccines, and one viral vector-based vaccine. Phase 1 trials include one viral vector-based vaccine, one recombinant protein-based vaccine, and two mRNA vaccines (Figure 2) [14].

Figure 2. TB vaccine pipeline.

There are currently 15 vaccine candidates in the clinical pipeline, 12 of which are in clinical trials. Of the six vaccines in Phase 3, four are whole cell-based and two are recombinant protein-based. Recombinant protein-based M72/AS01_E is expected to enter Phase 3 in 2024 and H107/CAF10b entered Phase 1. Two mRNA-based candidates are also currently in Phase 1. Data from the Stop TB Partnership [14].

1) Whole-cell-based vaccines: VPM1002, MIP, MTBVAC, RUTI, DAR-901

While whole-cell-based vaccine candidates include BCG revaccination, this manuscript focuses on five other candidates, excluding BCG revaccination (Table 1). Whole-cell vaccines are categorized into recombinant live vaccines and inactivated vaccines. VPM1002 and MTBVAC are classified as recombinant live-attenuated vaccines [8]. VPM1002, a recombinant BCG strain, has been engineered by introducing two genes (urease C and listeriolysin O) into the BCG strain. Phase 2 clinical trial results have shown improved safety compared to BCG in neonates, and it is currently in Phase 3 clinical trials for adolescents and adults [9]. MTBVAC, which is a recombinant strain of M. tuberculosis lacking two key virulence genes (phoP and fadD26), demonstrated higher efficacy than BCG in Phase 1 and 2 trials among adults and neonates. It is now in Phase 3 trials among infants and young children in high TB-incidence countries [8]. The inactivated whole-cell-based TB vaccine candidates include RUTI and DAR-901. RUTI, containing detoxified fragments of M. tuberculosis cell walls combined with liposomes, is undergoing Phase 2 trials as an adjunct therapeutic vaccine for drug-sensitive and antibiotic-resistant TB [8]. DAR-901, an inactivated vaccine derived from Mycobacterium obuense, showed no protective efficacy against initial TB infection in a Phase 2b trial conducted in Tanzania, leading to the discontinuation of further clinical trials [9].

Table 1. Antigens of vaccine candidates in clinical trials.

Platform	Candidates	Antigens
Live attenuated	VPM1002	rBCG(△ureC∷hly)
	MIP	Mycobacterium indicus pranii
	MTBVAC	Mycobacterium tuberculosis Mt103(△phoP, △fadD26)
Inactivated cell	RUTI	Heat-inactivated, purified, and fragmented M. tuberculosis
	DAR-901	Inactivated Mycobacterium obuense
Protein subunit	GemTBvac	Ag85A(fbpA), ESAT6(esxA)-CFP10(esxB)
	M72/AS01E	Mtb32A(PepA), Mtb39A(PPE18)
	AEC/BC02	Ag85B(fbpB), CFP10(esxB)-ESAT6(esxA)
	ID93+GLA-SE	Rv1813, Rv2608(PPE42), Rv3619(esxV), Rv3620(esxW)
	H107/CAF10b	PPE68, ESAT6, EspI, EspC, EspA, MPT64, MPT70, MPT83
	H56:IC31	Ag85B(fbpB), ESAT6(esxA), Rv2660
Viral vectored	ChAdOx.1.85A	Ag85A(fbpA)
	MVA85A	Ag85A(fbpA)
	TB/Flu-05E	TB10.4(esxH), HspX(acr)

2) Recombinant protein-based TB vaccine: GemTBvac, M72/AS01_E, AEC/BC02, ID93/GLA-SE, H107/CAF10b

Recombinant protein-based TB vaccines are composed of TB antigen proteins combined with immune adjuvants, as proteins alone do not elicit sufficiently robust immune responses. The antigens included in each TB vaccine candidate are summarized in Table 1.

GemTBvac is a recombinant protein vaccine consisting of the single protein antigen Ag85A and the fusion protein ESAT6-CFP10, along with adjuvants dextran and nucleic acid (CpG). It is currently in Phase 3 clinical trials targeting TB-naïve adults [8]. M72/AS01_E, which began enrolling participants for Phase 3 clinical trials in March 2024, includes two TB antigen proteins, Mtb39A and Mtb32A, combined with a liposome-based adjuvant. Results from Phase 2 clinical trials in adults have shown 54% efficacy in preventing active pulmonary TB, with no safety concerns and sustained protection for 3 years [8]. These results meet the PPC outlined by WHO, indicating a strong potential for development as an adolescent and adult TB vaccine. AEC/BC02, another recombinant protein vaccine, features the antigens Ag85B and ESAT6-CFP10. It uses a nucleic acid-based adjuvant and is currently undergoing Phase 2 clinical trials targeting adults exposed to TB [9]. ID93/GLA-SE consists of four proteins (Rv2608, Rv3619, Rv3620, Rv1813) and an immune adjuvant. It is being developed by a domestic company through technology transfer. A Phase 2a clinical study among healthy adults previously vaccinated with BCG showed a significant enhancement in immune responses [10]. Additionally, a Phase 1 clinical trial is underway to confirm its safety and immunogenicity in middle-aged and older adults [9]. H107/CAF10b, which is newly entering clinical trials, combines eight antigens with a liposome-based immune adjuvant. In mouse models, when co-administered with BCG, it demonstrated higher preventive efficacy than BCG alone [11]. It is currently in Phase 1 trials targeting adults regardless of their TB infection status. Although not currently in the clinical trial pipeline, H56:IC31, a recombinant protein-based vaccine, was in Phase 2b clinical trials for TB prevention and Phase 1 as a therapeutic vaccine as of October 2022. It was excluded from the pipeline after demonstrating a relapse prevention rate of only 5.4% [12].

3) Viral vector-based vaccines: ChAdOx.1.85A+MVA85A, TB/FLU-05E

Viral vector-based TB vaccine candidates employ various viruses as delivery vehicles for vaccine antigens. The primary viral vectors used in clinical trials for TB vaccine development include chimpanzee adenovirus (ChAdOx.1), modified vaccinia virus Ankara (MVA), and influenza virus (Table 1). ChAdOx.1.85A, a viral vector-based TB vaccine candidate, uses chimpanzee adenovirus to express the antigen Ag85A(fbpA). When combined with MVA85A, it has shown increased immunogenicity compared to BCG vaccination in Phase 1 and 2a clinical trials [9]. TB/FLU-05E, another viral vector-based candidate, utilizes an attenuated influenza virus vector to deliver two TB antigens (TB10.4 and HspX) and is administered intranasally. A 2021 report indicated that it demonstrated protective efficacy against infection in both mouse and guinea pig models [11].

4) mRNA-based vaccines: BNT164a1, BNT164b1

mRNA vaccines work by delivering antigen-specific mRNA into cells, which then induces diverse immune responses against the targeted antigen. The first successful application of mRNA vaccines in preventing an infectious disease was with COVID-19. This breakthrough has opened up possibilities for using mRNA technology against other infectious diseases. BioNTech, the company behind the COVID-19 vaccine, has developed two TB vaccine candidates, BNT164a1 and BNT164b1, which are currently in Phase 1 clinical trials in adults.

2. Research Trends for Diversification of the TB Vaccine Clinical Pipeline

As of September 2024, the clinical pipeline includes a total of 15 TB vaccine candidates, 12 of which are currently undergoing clinical trials (Figure 2) [14]. This number is significantly lower compared to candidates for other infectious diseases, and there is often redundancy in the antigens used (Table 1). Moreover, it is uncertain whether all TB vaccine candidates currently in Phase 3 trials will be successfully developed. To mitigate the risks of clinical trial failures, continuous research is essential. This research should focus not only on vaccines for adolescents and adults but also on those that could potentially replace BCG and prevent the reactivation of latent TB [1,9].

1) Identification of effective antigens

For COVID-19, there are currently 183 vaccine candidates in the clinical pipeline. In contrast, the number of TB vaccine candidates is 15, which represents approximately 9% of the number of COVID-19 vaccines. This is a relatively small number compared to vaccines for other infectious diseases, which limits alternative options in the event of clinical trial failures. The genome of M. tuberculosis is known to consist of approximately 4,000 genes. However, only a very small fraction of these genes are targeted for TB vaccine development, and six candidates among the recombinant and viral vector-based TB vaccines in clinical trials contain overlapping antigens (Table 1). To identify effective antigens capable of inducing diverse immune responses beyond conventional immunity, ongoing research utilizes AI-based predictive modeling, immunopeptidomics, and single-cell sequencing technologies [10,11]. Recently, mRNA-based TB vaccine candidates employing antigens identified through T-cell profiling techniques on clinical trial samples have been included in the preclinical pipeline [12]. Additionally, as a strategy to diversify vaccine development, proposals are being made to apply various vaccine formulations and delivery methods to previously identified antigens [11,13].

2) Development of preclinical models

Evaluating the efficacy of identified antigens through diverse assessment models is critical for advancing clinical research. However, the lack of suitable preclinical animal models for TB vaccine research has become a significant barrier to vaccine development. To address the shortage of appropriate preclinical animal models, human challenge models using BCG strains and humanized mouse models are currently being employed [11,15]. Moreover, the development of suitable in vitro assessment models and genetically diverse animal models tailored to the objectives of TB vaccine development is essential. These models are necessary to understand the complex infection and immune mechanisms of TB and to identify effective vaccine candidates with high clinical potential [11,15]. For this purpose, research is ongoing into the development of animal models that reverse-apply outcomes from clinical trials [11,15].

3) Identification of valid efficacy endpoints based on clinical trial results

Selecting highly promising vaccine candidates before proceeding to large-scale clinical trials is crucial. However, there is a significant shortage of applicable endpoints for selection in TB vaccine development. Comparative studies are currently being conducted to identify meaningful efficacy endpoints by analyzing samples from ongoing or planned Phase 2b and Phase 3 clinical trials. These studies focus on indicators that are consistently observed across different studies and those that vary according to the phases of the clinical trials. Additionally, research aimed at understanding the correlations between vaccine development objectives and efficacy endpoints through comprehensive comparisons of individual vaccine candidate trial results has been reported [11,15]. Applying these identified efficacy endpoints to preclinical efficacy evaluations will enable the selection of valid vaccine candidates and enhance the efficiency of clinical trials for vaccine development 2024 [11,15].

Conclusion

To diversify TB vaccine candidates, it is essential to identify effective antigens, develop genetically diverse animal models, and secure reliable evaluation indicators. Additionally, translational research that bridges the gap between basic and clinical studies is crucial. Ongoing research and collaboration between basic and clinical disciplines are required to develop vaccines that are tailored to their specific intended purposes.