Elsevier

Vaccine

Volume 32, Issue 26, 30 May 2014, Pages 3162-3168
Vaccine

Review
Therapeutic vaccines for tuberculosis—A systematic review

https://doi.org/10.1016/j.vaccine.2014.03.047Get rights and content

Highlights

  • We identified 5 potential therapeutic TB vaccines—Mycobacterium vaccae, RUTI, Mycobacterium smegmatis, Mycobacterium indicus pranii and V5.

  • M. vaccae and RUTI appeared most advanced, with most safety data in humans for M. vaccae.

  • Addition of therapeutic vaccine candidates in MDR-TB treatment should be tested for safety and efficacy in clinical trials.

  • Testing TB vaccine candidate products in TB patients provides a novel platform for TB vaccine development.

  • New clinical trial research platforms need to be developed to further test current and future TB vaccine product candidates.

Abstract

For eradication of tuberculosis (TB) by 2050, the declared aim of the Stop TB Partnership, novel treatment strategies are indispensable. The emerging epidemic of multi-drug resistant (MDR) TB has fuelled the debate about TB vaccines, as increasing numbers of patients can no longer be cured by pharmacotherapy. Of several proposed modalities, TB vaccines administered in therapeutic manner represents a promising alternative, despite the controversial history due to the occurrence of exacerbated immune response. A modified concept of immunotherapy is required in order to justify further exploration. In this paper we systematically reviewed the most advanced therapeutic vaccines for TB. We address the rationale of immunotherapeutic vaccination combined with optimized pharmacotherapy in active TB. We summarize preclinical and patient data regarding the five most advanced therapeutic vaccines currently in the pipeline. Of the five products that have been tested in animal models and in humans during active or latent TB, the quality of the published clinical reports of two of these products justify further studies in patients with active TB. This systematic review fuels further clinical evaluation eventually including head-to-head comparative studies.

Introduction

With 1.3 million deaths annually, tuberculosis (TB) has remained a tremendous infectious threat around the world [1]. Following the identification of Mycobacterium tuberculosis (Mtb) as a causative agent of TB in 1884, and the development of a highly effective treatment with multi-drug short-course therapy the battle seemed to be won until hopes were shattered with the emergence of drug-resistant TB [2]. Currently, an estimated 630,000 TB cases worldwide are multi-drug resistant (MDR), with 84 countries reporting at least one case of extensively-drug resistant (XDR)-TB [3]. The paucity of novel therapeutic agents is an important set-back to fight TB [4].

Powdered sputum was used as a remedy for haemoptysis in China in the 16th century [5]. Despite lack of a detailed description, this is the earliest record of immunotherapy in TB. Robert Koch was the first to inoculate TB patients with semi-purified culture supernatants of Mtb – the old tuberculin – as a therapeutic vaccination [6]. The exacerbated immune response that subsequently occurred has continued to fuel the discussion about the safety and efficacy of TB immunotherapy [7]. Although the adverse events of the old tuberculin have been widely publicized, very little published evidence is available to substantiate the secondary literature [8], [9]. Over 50 years ago, South African researchers used anti-TB drugs in combination with tuberculin [10]. Although their study had low sample size and many drop-outs and was underpowered to detect a difference in survival, sputum culture conversion at six months tended to be better in the immunotherapy group compared to the group receiving standard care alone, with no major adverse events detected.

Current TB immunotherapy modulates immunity, tipping the balance between T-helper (Th)-2 and Th-1 to a Th-1 response, or targeting dormant, persister, slowly replicating Mtb bacilli [11]. TB disease results in a pathological immune response, and reversing this provides an important asset and might be regarded as a novel approach [12], [13]. Decreasing inflammation by inhibiting LPS biosynthesis leads to an increased survival in Acinetobacter baumannii infected mice, suggesting a survival benefit from immune intervention [14]. A similar notion was also observed in Koch's tenth experiment, when rats were fed with TB-infected meat, protecting the animals against subsequent Mtb challenges [12]. These data together provide experimental evidence of a potential benefit of immune therapy in TB.

Several novel promising TB immunotherapeutic vaccine candidates are in the pipeline.

RUTI vaccine is composed of detoxified Mtb cellular fragments expressing a wide range of latency antigens with proven safety and immunogenicity [15]. Heat-killed Mycobacterium vaccae is an inactivated environmental mycobacterium with completed phase III trials [16]. Two other NTM – Mycobacterium smegmatis and Mycobacterium indicus pranii – and V5 have been studied in animal and human models. The immunotherapeutic potential of several TB vaccines, such as DNA vaccines, has been demonstrated although these compounds were initially designed for prevention of primary infection [17], [18], [19], [20]. In contrast, attempts using a viral-vectored TB vaccine for therapeutic purpose failed in a mouse model due to toxicity, probably reflecting an exacerbated immune response [19]. Here, we discuss the most advanced TB vaccines specifically designed for therapeutic application and we systematically analyse the relevant studies of the available candidate therapeutic vaccine products.

Section snippets

Search strategy and selection criteria

We searched PubMed and EMBASE databases in September 2013 to identify relevant non-clinical as well as clinical studies for TB vaccines intended for therapeutic use. We identified five candidates, namely RUTI, M. vaccae, V5, M. smegmatis, and M. indicus pranii. Additionally, we searched the national database of CNKI (Chinese National Knowledge Infrastructure) to detect relevant studies on M. smegmatis. We consulted the World Health Organization International Clinical Trials Registry Platform

The RUTI vaccine

The RUTI candidate vaccine has been designed at the Hospital Universitari Germans Trias i Pujol in Catalonia, Spain [22]. It is composed of detoxified and liposomal cellular fragments of Mtb bacilli from the company Archivel Farma in Badalona, Catalonia, Spain. It is cultured under stress conditions (intra-granulomatous conditions) to induce latency antigens which would normally be hidden from the immune system [23], [24]. It is detoxified to decrease the risk of the exacerbated immune response

Conclusions—The way ahead

Several therapeutic vaccine products discussed hold promise—immune modulation, as demonstrated by M vaccae and targeting the persister Mtb, as exemplified by RUTI, represent the two major approaches in TB immunotherapy. M vaccae has passed Phase III clinical trials, including MDR-TB and HIV co-infected individuals, while the RUTI candidate vaccine has only been tested in individuals with LTBI with and without HIV co-infection. MDR-TB represents an important subset of patients as therapeutic

Other candidates

Apart from those two vaccine candidates, the therapeutic efficacy of the two NTMs – M. smegmatis and MIP – should also be further investigated (see electronic appendix for details). M. smegmatis induces two-way immune modulation response, while MIP might be applied in aerosol route, which would be advantageous in the context of TB immunotherapy. In the case of V5, the authors suggest that it induces immune tolerance, thereby ameliorating the patients’ condition. Oral administration of antigens

Author contributions

M.I.G. and S.A.P. equally contributed to the literature search, Jadad scoring, drafts, and revisions of the manuscript. P-J.C. and J.L.S. critically reviewed consecutive revisions of the manuscript, contributed to content of the manuscript, but did not participate in selection of papers reviewed, nor in Jadad scoring. T.S.W. supervised the design of the review, the search, Jadad scoring, taking the lead in discussions, and supervised the final draft.

Conflict of interest statement

Matthias I Gröschel, Satria A Prabowo, and Tjip S van der Werf declare no conflict of interest. Pere-Joan Cardona holds an advisory position with Archievel, producer of RUTI. John L Stanford acts an advisory role with Immodulon, producer of the inactivated M. vaccae product; he owns stocks in that company.

Acknowledgements

We thank Dr. Aldar S. Bourinbaiar for supplying several full-text manuscripts for the systematic analysis and quality assessment.

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