Keywords

1 Introduction

Leprosy is an age-old infectious disease that continues to be endemic in some regions of the Americas, Africa, and South-east Asia [1]. It is caused by the bacterium called Mycobacterium leprae, discovered by Gerhard Armauer Hansen in 1874 [2]. Hence, leprosy is also called Hansen’s disease. Leprosy primarily affects the skin and peripheral nerves. Every year, over 200,000 new leprosy cases are reported globally [1]. In 2019, India, Brazil, and Indonesia accounted for 79% of the 202,166 newly registered leprosy cases [1]. A third of the diagnosed patients experience disabilities because of nerve damage (Fig. 4.1). Consequently, leprosy is the leading infectious cause of disability worldwide [3, 4], and an estimated three to four million people are living with disabilities caused by leprosy [5].

Fig. 4.1
A photo of the hands of two persons. The person on the left has normal hands, and the person on the right has a hand affected with leprosy.

The hand of a leprosy patient (right) with terminal phalanges examined by a health worker (left) in Bhutan. (Image source: Wellcome Collection. The Leprosy Mission International. Attribution 4.0 International (CC BY 4.0))

Multi-drug therapy (MDT)Footnote 1 introduced by the World Health Organization (WHO) in 1981 remains highly effective to cure leprosy, but early diagnosis and treatment are paramount to preventing permanent nerve damage that can progressively lead to deformity and disability. Alarmingly, cases of drug resistance and disease relapses have been reported [6,7,8]. There have been many leprosy vaccine candidates and a leprosy vaccine does exist: in 2018, the WHO recommended one dose of the Bacille Calmette-Guérin (BCG) vaccine for healthy neonates at the earliest opportunity to reduce the risk of leprosy in countries or settings where it is common [9] (Fig. 4.2). However, meta-data analyses of clinical trials found that the BCG vaccine has variable protection ranging from 18% to 90% against leprosy [10,11,12].

Fig. 4.2
Two photographs. Left is a box of leprosy vaccine and right of B C G vaccine. Two vials outside the box are B C G vaccine, freeze-dried and diluent, buffered saline.

Photographs of vaccines. Left: a leprosy vaccine of unknown composition produced by the Wellcome Physiological Research Laboratories in London, United Kingdom, circa 1978. (Image source: Wellcome Collection. Attribution 4.0 International (CC BY 4.0)). Right: a BCG vaccine to prevent tuberculosis, manufactured by Aventis Pasteur Canada in 2002. (Image source: Sanofi Pasteur Canada Archives)

In the next decade, the WHO Global Leprosy Strategy, 2021–2030, boldly aims ‘towards zero leprosy’ [5], focusing on interrupting transmission and achieving zero autochthonous cases. To ultimately bring leprosy to zero, an effective leprosy vaccine is essential and pivotal as part of the global strategic effort to eradicate the debilitating disease in the twenty-first century. In this chapter, we highlight the leprosy vaccine successes and investigate current leprosy vaccine developments and strategies.

2 The BCG Vaccine Has Variable Protection Against Leprosy

A misconception is that there is no leprosy vaccine. Studies show that the BCG vaccine used to prevent tuberculosis caused by M. tuberculosis, a bacterium closely related to M. leprae, offers more protection against leprosy than against tuberculosis [12, 13]!

The BCG vaccine is live attenuated M. bovis BCG strain. It was originally developed by Jean-Marie Camille Guérin and Léon Charles Albert Calmette in the early 1900s using attenuated M. bovis, a bacterium more closely related to M. tuberculosis, as an experimental vaccine to protect cattle from bovine tuberculosis [14]. In 1921, BCG was administered for the first time to a newborn baby in Paris to prevent human tuberculosis [15]. Now, BCG is one of the most widely used vaccines worldwide. In 1987, the Brazilian Ministry of Health recommended BCG vaccination or repeat vaccination of contacts to reduce the incidence of leprosy [16]. However, it was only in 2018 that leprosy was included in the WHO BCG vaccine program. Why did it take so long?

BCG vaccination against leprosy was first suggested by J. M. M. Fernandez in 1939 [17], who reported leprominFootnote 2 conversation among children following BCG administration. It was postulated that BCG may confer some protection against leprosy due to possible common antigens between M. bovis BCG and M. leprae. The finding initiated five early small-scale trials in the 1950s in Brazil [18], India [19], Argentina [20], Venezuela [21], and Japan [22]. The trials showed that BCG vaccine has partial or wide protection (26–96%) against leprosy, but they had inadequate controls to draw any definitive conclusion. Furthermore, because leprosy has a long incubation period, on average of 5 or more years before the disease manifests in a clinically diagnosable form [5], long follow-ups and large-scale trials are needed to provide the necessary robust data. A plethora of clinical trials and community surveys then followed from the 1960s to the 2000s in Uganda [23,24,25], New Guinea [26, 27], India [11, 28,29,30,31,32,33], Myanmar (Burma) [34,35,36,37,38], Malawi [39,40,41], Kenya [42], Venezuela [43], Vietnam [44, 45], Brazil [46,47,48,49,50,51,52,53], and Indonesia [54]. Interestingly, the trial data in BCG protection were heterogeneous but showed protection wherever they were studied. To make sense of the heterogeneity, Setia et al. [10], Zodpey [11], and Merle et al. [12] carried out meta-data analyses and found that BCG protection against leprosy remained variable, between 18% and 90%. While the extrema are wide and with no definitive reasons for the heterogeneity, the authors agreed the trials consistently showed that BCG protects against leprosy. The authors commented that the variability between studies was due to several factors: study population (genetics, household contact, geography), environmental bacteria (cross-reaction), BCG dose number, M. bovis BCG diversity of sub-strains (genotype, phenotype, and vaccine manufacturer), nutrition, economic background, study bias, publication bias, and data collection/methodology.Footnote 3 These are ongoing factors to consider and to address for future studies.

In 2013, the WHO published new recommendations for manufacturing and evaluating BCG vaccine (for tuberculosis) [55]. In 2018, the WHO officially included leprosy in the single-dose BCG vaccination recommendation [9]. The inclusion of leprosy for BCG vaccination has huge implications for public health and research moving forward. It recognises that the BCG vaccine is important to prevent both tuberculosis and leprosy.

Generally, a single dose of BCG showed higher protection against leprosy in young individuals. The BCG protection wanes over time but can last for 10–30 years [12, 13].

3 The Recombinant BCG Vaccines to Improve Efficacy Against Leprosy

Strategies to increase BCG vaccine immunogenicity include mixed vaccine with the addition of killed M. leprae or killed M. vaccae (an environmental mycobacterium) and recombinant BCG (rBCG) that expresses foreign molecules.

In three large clinical trial studies in Venezuela [56], Malawi [57], and India [58] comparing the efficacy between BCG and BCG + killed M. leprae, no significant difference in protection was found in Venezuela (56% vs. 54%) after 5-year follow-up and in Malawi (49% vs. 49%) after 6- to 9-year follow-up. However, an improvement was found in the Indian study (34% vs. 64%), after 4- to 7-year follow-up.

There are contradictory conjectures and a lack of studies on the premise that pre-sensitisation to environmental mycobacteria may improve, diminish, or mask BCG immunogenicity [59,60,61,62,63,64,65]. In a small population vaccination trial of children in close contact with leprosy in Vietnam [66], BCG + killed M. vaccae was found to have a modest improvement in protection at 66%, compared to BCG (58%) and M. vaccae alone (55%). Further studies are needed but killed M. leprae is a scare material. M. leprae cannot be cultured with an artificial growth medium and is therefore difficult to isolate in large quantities for experimental studies. Currently, M. leprae cultivation requires animals such as mice [67,68,69] or armadillos [70,71,72], which is costly, with months of maintenance and growth time required to isolate sufficient bacterial samples.

The rBCG was first introduced by Stover et al. in 1991 [73] and enabled the expression of foreign antigens in BCG. In essence, BCG is immunogenic and is used as a vector to elicit specific immune responses guided by the foreign antigen. Since then, a repertoire of antigenic rBCG candidates have shown promise, in improving immunogenicity not only against tuberculosis [74] but also against viruses (respiratory syncytial virus [75, 76], human metapneumovirus [77], measles [78], human immunodeficiency virus type 1 [79, 80]); bladder cancer [81, 82]; the protozoa parasites Leishmania [83], Plasmodium spp. [84, 85], and Toxoplasma gondii [86]; and the bacteria Streptococcus pneumoniae [87], Borrelia burgdorferi [88], and Bordetella pertussis [89,90,91].

Several rBCG candidates have been developed for leprosy. Ohara et al. [92, 93] first constructed the rBCG/85A vaccine with M. leprae antigen Ag85A and then the rBCG/BA51 vaccine with M. leprae antigen Ag85 and M. tuberculosis major protein MBP51. They found that a repeat immunisation in C57BL/6 mice with rBCG/85A vaccine drastically inhibited the multiplication of M. leprae in the mouse footpads compared to control and BCG. This was improved with the rBCG/BA51 vaccine with one-dose immunisation inhibiting multiplication of M. leprae in the mouse footpads, compared to control and BCG in C57BL/6 and BALB/c mice. Furthermore, M. leprae lysate stimulated a higher level of interferon-γ (IFN-γ) production in spleen cells from rBCG/BA51 immunised C57BL/6 mice than BCG and rBCG/85A, an indication of improved host immune defence against M. leprae.

Makino et al. [94,95,96] constructed the rBCG-SM vaccine secreting M. leprae major membrane protein II (MMP-II). MMP-II is an antigen that can stimulate dendritic cells (DC) to produce interleukin (IL)-12 p70 and activate T cells to produce IFN-γ during the pro-inflammatory response important for adaptive and innate immunity. In the initial in vitro and ex vivo studies, the rBCG-SM-infected DC stimulated BCG-vaccinated donor naïve and memory type CD4+ and CD8+ T cells, to produce significantly higher levels of IFN-γ than the rBCG-vector and killed rBCG-SM. A similar outcome was found for IFN-γ production by splenic T cells of C57BL/6 mice infected with rBCG-SM. This was also later confirmed by Maeda et al. [97]. Furthermore, Makino et al. [95] found that rBCG-SM-infected DC increased intracellular production of perforin in CD8+ T cells. Perforin is a pore-forming cytolytic protein produced by cytotoxic T cells that allows passive diffusion of pro-apoptotic proteases to enter target cells to control infection [98]. In a subsequent study, rBCG-SM-stimulated macrophages induced granulocyte-macrophage colony-stimulating factor (GM-CSF) cytokine production and inhibited the production of IL-10 [96]. The T cell activation was found to be dependent on GM-CSF production. IL-10 can block the reactivation of memory T cells. Therefore, the inhibition can potentially benefit anti-mycobacterial immune responses. This has been found in IL-10-deficient mice with a decreased bacterial burden [99].

Tabouret et al. [100] designed the rBCG::PGL-1 vaccine to study the role of PGL-1 in the pathogenesis of leprosy. PGL-1 is a species-specific phenolic glycolipid 1 from M. leprae with virulence, protective, and immunomodulatory properties. They found that rBCG::PGL-1 enhanced invasion via the complement receptor 3 (CR3) of human monocyte-derived macrophages, increased uptake by DCs, and impaired inflammatory responses. Recently, Doz-Deblauwe et al. [101] found that rBCG::PGL-1 enhanced CR3-mediated non-opsonic phagocytosis in polymorphonuclear neutrophils and DCs and activated Syk-calcineurin/nuclear factor of activated T cells signalling to rewire host cytokine responses to M. leprae. Although no M. leprae infection challenge was carried out, the insights on the PGL-1 could help rBCG vaccine development, by considering immune responses during leprosy pathogenesis and the mechanisms of nerve damage causation.

Horwitz et al. [102] designed the rBCG30 vaccine to overexpress M. tuberculosis 30 kDa major secretory protein antigen 85B, which they found to offer better protection than BCG against M. tuberculosis and M. bovis challenge in animal models. Gillis et al. [103] further evaluated rBCG30 and found that it could stimulate CD4+ and CD8+ in cytokine responses from BCG-immunised BALB/c mice and needed boosting with purified M. tuberculosis 30 kDa antigen 85B to reduce M. leprae burden in mouse footpads.

Now, there is only one rBCG vaccine in clinical trials, the VPM1002 vaccine. The clinical trial evaluations are in phases II and III for tuberculosis (ClinicalTrials.gov Identifier: NCT03152903, NCT04351685), in phases I and II for recurrent non-muscle invasive bladder cancer (ClinicalTrials.gov Identifier: NCT02371447), and in phase III for SARS-CoV-2 infectionFootnote 4 (ClinicalTrials.gov Identifier: NCT04439045, NCT04387409). The VPM1002 vaccine has not been evaluated as a vaccine candidate for leprosy. The VPM1002 is a genetically modified BCG that has the urease C encoding gene replaced by the listeriolysin O encoding gene from Listeria monocytogenes [115,116,117]. Urease C neutralises phagosomes that contribute to mycobacteria survival, whereas listeriolysin O forms transmembrane β-barrel pores in the phagolysosome membrane. Therefore, VPM1002 can effectively release mycobacterial antigens into the cytosol to trigger immunogenic responses. The VPM1002 system can potentially be used and further modified as a leprosy vaccine. Now that BCG is more widely recognised as a vaccine for leprosy, this offers promise for rBCGs such as VPM1002, rBCG/85A, rBCG-SM, rBCG::PGL-b, and rBCG::PGL-1 and the tuberculosis rBCGs as leprosy vaccine candidates in clinical studies.

4 The Cross-Reactivity and Subunit Leprosy Vaccines

Other leprosy vaccine candidates besides the M. bovis BCG and rBCGs include (1) non-pathogenic or closely related M. leprae mycobacterium species to induce cross-reactivity such as the ICRC (Indian Cancer Research Centre bacilli), M. vaccae, M. duvalii, M. welchii (M. w) or M. indicus pranii (MIP) [118],Footnote 5 and M. habana and (2) recombinant protein subunits, such as the LEP-F1 + GLA-SE (LepVax), to induce target-specific immune responses. M. vaccae, as previously discussed, is like BCG in leprosy protection. M. duvalii is an early vaccine candidate proposed in 1974 [119] that showed some cross-reactivity. However, Shepard et al. in 1976 [120] later found that M. duvalii and M. duvalii + BCG offered less protection and no change in protection, respectively, when compared to BCG in mice footpad immunisation studies.

The M. habana vaccine was reported by Singh et al. [121, 122] to reduce M. leprae counts better than BCG in mice footpad immunisation studies. Furthermore, Singh et al. [123] found that M. habana induced a positive Mitsuda reaction in monkeys. Additionally, Chaturvedi et al. [124] identified M. habana proteins in the cell wall and cell membrane fractions that were recognised by leprosy antisera, and the 65 kDa protein [125] and 23 kDa proteins [126] were found to induce cell-mediated immune responses. The latest study identified two additional M. habana proteins, an enoyl-coenzyme A hydratase and antigen 85B, both recognised by leprosy antisera [127]. These proteins can be used in vaccine studies and as serodiagnosis tools. However, the M. habana efficacy as a leprosy vaccine remains uncertain. A small vaccination study of 31 lepromatous leprosy patients and 36 household contacts found positive lepromin reaction only after 15 weeks, but also had systemic side effects [128]. It is a short time frame to draw a conclusion considering that leprosy has a long incubation period. Therefore, further studies are required to understand the efficacy and the safety profile.

The ICRC vaccine is a gamma-radiation inactivated group of leprosy-derived cultivable slow-growing mycobacteria belonging to the M. avium complex isolated in 1958 from a leprosy patient [129,130,131]. Early immunological studies from 1974 to 1978 all demonstrated reactivity [132,133,134]. Bhide et al. [135] reported in 1978 that ICRC offered protection against M. leprae infection in the mouse footpad model. This led to small trials by Deo et al. [136] and Bhatki et al. in the early 1980s [137] that continued to show promising outcomes. ICRC resulted in negative to positive lepromin conversion in 58% of lepromatous leprosy patients and 91% of borderline lepromatous patients. Chaturvedi et al. [138] reported that ICRC has a dose-dependent lepromin conversion at eighth week (high dose and 1/30th dose resulted in 79% and 46% lepromin conversion, respectively) and resulted in >90% lepromin conversion in healthy subjects from household contacts of leprosy patients and non-contacts in a general population in Bombay at the end of 1 year; patients remained stable up to 3 years; and no nerve toxicity was reported, as hypersensitivity to M. leprae antigens can lead to nerve damage. In a large-scale comparative study in India, Gupte et al. [58] reported 66% protection by ICRC versus 34% protection by BCG after 4–7-year follow-up. Interestingly in the same comparative study, BCG combined with killed M. leprae offered 64% protection, similar to ICRC. A recent ICRC formula evaluation found that ICRC candidate strain C-44 is coated with human immunoglobulin G that may play a role in the immune responses [139].

The MIP vaccine was developed in the National Institute of Immunology, India, and showed promising early initial outcomes. Chaudhuri et al. [140] and Talwar et al. [141] reported that 20 of the 32 patients had negative to positive lepromin reaction conversion after 4–6 weeks from a single administration and remained stable after 6–11 months. However, in the large-scale comparative study in India reported by Gupte et al. [58], MIP only offered 26% protection compared to 66% protection by ICRC, 34% protection by BCG, and 64% protection by BCG + killed M. leprae, after 4–7-year follow-up. In a double-blind immunoprophylactic trial conducted in an endemic area of Kanpur Dehat, Uttar Pradesh, Sharma et al. [142] showed that the low MIP protection was attributable to a decrease in protection over time and offered greater protection for contacts. They found that MIP had protective efficacy of 69%, 59%, and 39% at, 3-, 6-, and 9-year follow-up, respectively, for household contacts after the initial vaccination. Similarly, the protective efficacy was 68%, 60%, and 28% at 3-, 6-, and 9-year follow-up, respectively, for both patients and contacts after the initial vaccination. The MIP vaccine was less effective for patients: the protective efficacy was 43%, 31%, and 3% at 3-, 6-, and 9-year follow-up, respectively. However, smaller studies have found that MDT and MIP as immunotherapy for multibacillary leprosy patients could shorten recovery time, reduce bacterial load, clear granuloma, and reduce neuritis [143,144,145,146,147]. The MIP vaccine has received approval by the Drugs Controller General of India and the US Food and Drug Administration [148]. In 2017, the Indian Council for Medical Research launched a vaccine programme to eradicate leprosy in leprosy endemic districts [149,150,151]. The patients, family members, and contacts will receive two doses of autoclaved MIP at 6 months intervals. Studies are ongoing to evaluate the efficacy of MDT and MIP immunotherapy.

LepVax is the latest vaccine candidate moving in the clinical trial pipeline [152] (Fig. 4.3). LepVax is a defined subunit vaccine containing a chimeric recombinant protein (LEP-F1) consisting of a tandem linkage of M. leprae antigens ML2531, ML2380, ML2055, and ML2028 and a synthetic Toll-like receptor 4 (TLR4) agonist glucopyranosyl lipid adjuvant-stable emulsion (GLA-SE). In the M. leprae mouse challenge studies, LepVax raised an immune response not affected by prior BCG immunisation. Additionally, immunised mice infected with M. leprae had significantly fewer bacteria recovered in the mouse footpad experiments, compared to unimmunised control mice. After 12 months, the bacterial burden in immunised mice was approximately 85% lower than mice immunised with GLA-SE adjuvant formulation alone. Importantly, LepVax immunisation delayed motor nerve function impairment in M. leprae-infected nine-band armadillos, demonstrated as post-exposure immunoprophylaxis. LepVax dosage, safety, and immunogenicity parameters were evaluated in the phase 1a clinical trial on 24 healthy adult volunteers in the United States [153]. The study outcome published in 2020 concluded that LepVax was safe and immunogenic and LepVax will start phase 1b/2a clinical trial in 2022 to carry out the same evaluation in leprosy endemic regions (ClinicalTrials.gov Identifier: NCT03947437).

Fig. 4.3
A photo of a vial of L E P, F 1.

A vial of LepVax (LEP-F1). The vaccine development is a partnership between the American Leprosy Missions and the Infectious Disease Research Institute (now Access to Advanced Health Institute) in Seattle, Washington, that started in 2002. (Image source: American Leprosy Missions)

5 Vaccine and Drug Combinatory Therapy

The combination of immunotherapy and chemotherapy can shorten leprosy treatment time and potentially improve the treatment outcome. When the WHO recommended MDT for leprosy in 1981, patients were required to be on the regimen for at least 2 years.Footnote 6 An early evaluation of the MIP vaccine candidate by Talwar et al. [154] found there was more rapid bacterial clearance in vaccinated patients who were also receiving MDT. Zaheer et al. [155] investigated if chemotherapy in combination with immunotherapy, i.e. MDT + MIP, could reduce the treatment time by inducing cell-mediated immune responses. They reported that MIP helped overall in the treatment; 13 of 31 BL and LL patients or multibacillary leprosy patients who received MDT and MIP were bacteriologically negative within 2 years, compared to 5 of 25 controls. The vaccinated patients had either upgraded in disease spectrum or were completely cleared of granuloma. Furthermore, 80% of vaccinated BL and LL patients had lepromin conversions, compared to 14% of the controls.

Sharma et al. [156] also reported a faster bacterial clearance for patients receiving both MDT and MIP within 2 or 3 years. They found that 90% of the vaccinated patients had negative to positive lepromin conversions compared to 38% of the placebo group, and the patients released from treatment had no incidence of relapses in a 5-year follow-up. They concluded that the addition of MIP to MDT could reduce treatment time from 4–5 years to 2–3 years. Kaur et al. [145] and Kamal et al. [144] have similarly reported that MDT + MIP improves treatment outcomes. Due to the long incubation period of leprosy, long-term follow-up is needed for the safety and efficacy of shortening the treatment time.

Katoch et al. [157] reported a comparative study between MIP and BCG with MDT. They found that the patient groups receiving MDT and MIP, or BCG, had no detectable viable bacilli in the local and distal sites by mouse footpad analysis, whereas viable bacilli were detected in the patients on MDT alone within 2 years. Additionally, patients receiving MDT and MIP, or BCG, also had accelerated granuloma clearance. As with the previous studies, they also concluded that the addition of immunotherapy to achieve negative bacteriology could reduce treatment time by about 40% and found no relapses in the 10–12 years post-treatment follow-up. Interestingly, MIP did perform slightly better than BCG in bacterial and granuloma clearance. In contrast, Narang et al. [147] found that although MIP or BCG improved clinical outcomes, BCG performed better than MIP. However, immunisation by BCG on its own of close contacts of leprosy patients has been reported to precipitate PB leprosy on potentially asymptomatic infected or previously exposed individuals [158,159,160].

The addition of immunotherapy to patients under MDT generally shows positive clinical outcomes. What about close contacts of leprosy patients and transmission? It has been shown that a single dose of rifampicin (one of the drugs in the leprosy MDT) to close contacts of patients is 57% effective at preventing leprosy within 2 years, but with no effect after 2 years [161, 162]. Richardus et al. [163, 164] investigated whether chemoprophylaxis with rifampicin and immunoprophylaxis with BCG on contacts of leprosy patients could reduce transmission. Although they found a 42% reduction in PB leprosy cases of close contacts of leprosy patients in the first year, they noted that it was not statistically significant, due to low patient cases. Thus, more studies are needed to understand the clinical benefits of the combination of MIP or BCG with MDT on reducing transmission.

The Leprosy Post-Exposure Prophylaxis (LPEP) programme (Fig. 4.4), funded and coordinated by Novartis Foundation, launched in 2015, and ended in 2018, was established to explore contact tracing and to evaluate single-dose rifampicin post-exposure prophylaxis (SDR-PEP) to reduce and curb transmission in Brazil, Cambodia, India, Indonesia, Myanmar, Nepal, Sri Lanka, and Tanzania [165,166,167]. The programme outcome varied in countries that showed an increase in the number of detected cases in the first year but followed by a reduction in cases, indicating a reduction in leprosy incidence. Furthermore, a 2040 projection model indicates that LPEP could have a huge impact in interrupting M. leprae transmission. Future programmes to include immunotherapy may demonstrate greater impact.

Fig. 4.4
A photo of people seated in the courtyard of a house. A person stands amidst them and speaks to them.

Health education in Nepal about leprosy and SDR-PEP for the contacts of a leprosy patient (household contacts and neighbours) to get their consent before screening and SDR-PEP administration in the community. (Photograph: Tom Bradley/Netherlands Leprosy Relief)

Overall, the studies indicate that a combination of chemotherapy and immunotherapy is a powerful therapeutic intervention to treat leprosy patients and potentially as a control strategy to reduce transmission.

6 Conclusion and Vaccine Outlook

The current BCG vaccine for leprosy offers only partial protection. Leprosy is not eliminated, despite early ‘elimination’ declaration by WHO defined as ‘the reduction of prevalence to a level below one case per 10,000 population’ [168]. This has drawn major criticism, because it changed public perception and shifted away the resources and financial support needed to carry out fundamental and long-term epidemiological studies [169,170,171,172]. M. leprae remains a bacterium that requires animals for cultivation. We still do not exactly know how M. leprae transmission occurs, how it induces immune responses, and what is the mechanism underlying the nerve damage.

The recognition that BCG is a leprosy vaccine by the WHO is a critical admission that can help push current vaccine research forwards and support social changes. Historically, leprosy sufferers are stigmatised and discriminated against by their community [5, 173]. Unfortunately, stigma and discrimination are still happening today. According to the WHO, there are 127 discriminatory laws in 22 countries based on leprosy [5]. A widely recognised leprosy vaccine that is already in use can change the dialogues within communities and perceptions about the disease. Table 4.1 summarises the leprosy vaccines and strategies to reduce treatment time and transmission discussed in this chapter. The development of rBCGs, killed related mycobacteria, and subunit recombinant vaccine candidates is showing promise in clinical trials for the future, with an improved and effective leprosy vaccine as immunoprophylaxis, a supplement to chemotherapy, and post-exposure immunoprophylaxis.

Table 4.1 A list of leprosy vaccine candidates and treatment and transmission reduction strategies