Leishmania, a protozoan parasite, causes a complex form of disease called leishmaniasis. This disease is prevalent in 98 countries with major occurrence in the developing world (India, Bangladesh, Nepal, Ethiopia, Sudan, and Brazil) (1). Approximately 20,000–30,000 deaths and 0.7–1 million new cases of leishmaniasis occur per annum. The clinical forms include visceral (the most serious form of the disease, also known as kala-azar), cutaneous and mucocutaneous leishmaniasis (ML) (WHO, 2017). Leishmania parasites are transmitted in the mammalian host by infected sandfly. These flies mostly belong to the genus Phlebotomus and Lutzomyia (2). The control of leishmaniasis mainly relies on chemotherapy while other measures include sleeping under nets treated with insecticide, and spraying insecticides to kill sandflies. The current therapy against leishmaniasis depends on the use of the drugs such as pentavalent antimonials and amphotericin B. Other treatment options include miltefosine and paromomycin. The lacunae suffered by these drugs are inherent toxicity and requirement of long-term treatment. In addition, the expansion of human immunodeficiency virus (HIV) has influenced the epidemiology of the leishmaniasis. 35 out of the 70 countries, endemic for visceral leishmaniasis (VL), have documented cases of Leishmania–HIV coinfection (3). One of the unfavorable complications amalgamated with HIV coinfection is that it lowers the plausibility of a therapeutic response to treatment against Leishmania infantum and it also greatly boosts the possibility of a relapse (4). Furthermore, the problem of high cost and the emergence of resistant parasites to these drugs have frustrated the situation of leishmaniasis control (5). These issues necessitate alternative to chemotherapy like developing new non-toxic antileishmanials or different interventions like prophylactic and therapeutic vaccine. Interestingly, development of resistance to reinfection in individuals cured of Leishmania encourages the feasibility of protective vaccine. Moreover, application of cytokines and immunomodulators as immunotherapeutic agents that can direct curative immune response provides promising approach to immunotherapy against leishmaniasis. Since the sequencing of complete Leishmania genome has been achieved, advancement toward understanding the disease pathogenesis along with its defense by the host has paved new opportunities in the way for Leishmania vaccine and immunotherapy research. This review will discuss the development in the field of prophylactic and therapeutic vaccine and the challenges encountered as alternatives to chemotherapy against leishmaniasis.

The basic necessity for developing any form of interventions against the disease is the better understanding of the host–pathogen interaction. The characteristic that allows the parasite to establish chronic infection lies in its ability to dampen as well as evade both the innate and adaptive machinery of the host’s immune system. The major innate immune cells that play a significant role in defense against Leishmania are neutrophils, macrophages, and dendritic cells (DCs). When the female sandfly sucks blood meal from the vertebrate hosts, flagellate metacyclic forms of Leishmania are delivered along with sandfly salivary ingredients into the skin of the hosts (6). Initially, the promastigotes are taken up by the neutrophils at the site of infection. Following apoptosis in these infected neutrophils, the released parasites infect neighboring macrophages (7, 8). These macrophages are recruited by the chemotactic properties of the proteophosphoglycans, delivered to the infection site by the vector at the time of its blood meal (9, 10). Binding of Leishmania parasites to C3b accelerates phagocytosis after which promastigotes get converted to the amastigote form (11). Following phagocytosis in macrophages, establishment of infection is determined by several survival strategies of the parasites, most prominent of which is the modulation and attenuation of immune responses. Leishmania parasite suppresses the release of Th1 associated cytokines like interleukin (IL)-12 from these cells. This, in turn, restrains DCs to present the parasite-specific antigens to the T cells. Thus preventing the activation of the acquired immunity, this is very crucial for the containment of the disease (12, 13). Influence of Th1/Th2 cytokine has been observed to vary in the progression of disease in VL compared with cutaneous leishmaniasis (CL). Although the classical Th1/Th2 paradigm of resistance/susceptibility appears to be valid during CL, a mixed Th1/Th2 response is required for disease control during VL (14). However, it is yet to establish a clear Th1/Th2 paradigm for curative and preventive response against both CL and VL. Moreover, for ML, the disease manifestation is largely due to inflammatory response than due to parasite burden. Therefore, conventional Th1/Th2 paradigm does not apply to ML. It has been found that Treg (CD4⁺CD25⁺ regulatory T cells) as well as Th17 (other subsets of T cells) cells, play a significant role in disease outcome in both CL and VL, their role in ML is much more complicated. Studies with Leishmania major and L. infantum have shown a protective role of IL-17 as well as IL-22 (Th17 cytokines) against intracellular parasites (15, 16). Recently it was shown that when recombinant IL-17 or IL-23 was administered to mice it caused a considerable containment of parasite load in infected organs with significant production of factors such as IFN-γ, nitric oxide, etc. Thus, this study demonstrated the association of Th17-based cytokines in providing protection against the disease (17). As an important constituent of the immune system, Treg cells are known to regulate immune response of other cells. These cells were observed to be present in human cutaneous lesions (18). Increased expression of lesional FoxP3 and IL-10 during progressive L. major infection in a murine model and similarly during Leishmania braziliensis infection in human patients suggest the disease-promoting role of these regulatory cytokines (19). The preliminary data suggest that despite Th1 polarization production of IL-10 and Treg cells is associated with delayed healing of CL (20). Apart from T-cell subsets (Treg and Th17) other than conventional T cells, the role of innate immune response has been essentially linked to disease outcome. In fact, engagement of the macrophage toll-like receptors (TLRs) by the parasites has not only shown to improve phagocytosis but also lead to the killing of the parasites due to triggering of NF-κB transactivation and concomitant production of the downstream mediators including pro-inflammatory cytokines. For instance, TLR9 activation has been found to be beneficial for the host against these parasites. But this situation may not be true for all the TLRs. Lipophosphoglycan, a TLR2 agonist has been shown to have antagonizing effect on TLR9 mediated signal cascade in host macrophage, which in turn facilitates parasite survival (21, 22). Studies showed that treatment with TLR4 and TLR9 agonists decreased the disease severity following challenge infection with L. major in BALB/c mice (23). However, in human VL, comparison of mRNA expression levels between pretreatment and posttreatment splenic aspirate samples showed considerably more TLR2 and TLR4 expression but no change in TLR9 expression during Leishmania donovani infection (24). Despite advances, achieving a comprehensive and clear picture of the immunobiology of leishmaniasis is still required to develop effective interventions such as type-specific vaccine and immunotherapy for leishmaniasis.

Chemotherapy is the key intervention to control leishmaniasis. The existing drugs for the treatment of leishmaniasis in the market are pentavalent antimonials, amphotericin B, miltefosine, paromomycin, and amphotericin B in liposomal forms. But the major setback of these drugs include toxicity, cost, route of injection, treatment duration, and the predominant one being blooming of drug-resistant parasites (5). Pentavalent antimonials are the first line course of medication for leishmaniasis worldwide except Indian subcontinent. In India, about 90% of all infections are resistant to pentavalent antimonials (25). Accordingly, amphotericin B has been used as the leading drug to treat patients infected with Leishmania. But high toxicity and reports of drug-resistant parasites have narrowed down their use (26). Miltefosine, an oral medication, came up with promising results in the beginning but there is increasing occurrence of relapses in cases prescribed with this drug (27–29). Lately, in a multicentric clinical trial, it was found that Ambisome (liposomal amphotericin B) was effective enough in a single-dose treatment with a lesser degree of toxicity compared with mainstream treatments (30). However, this line of medication protocol raises the possibility of advancement in the development of drug-resistant parasites. Consequently, there is a development of combinatorial drug therapy for use in endemic regions (31, 32). Nevertheless, mouse model studies imply that even the combinatorial drug treatment can develop drug resistance L. donovani (33). Regardless of the advances in antileishmanial chemotherapeutics, it is implausible that chemotherapy solely will facilitate disease eradication. Since leishmaniasis is predominantly a disease of the poverty-stricken community, chemotherapy proves inadequate and less acceptable. This socioeconomic concern calls for a preventive and/or immunotherapeutic alternative to chemotherapy. Hence there is an imperative need for an effective prophylactic and therapeutic vaccine if enduring ambition of managing and eliminating this disease are to be accomplished.

Even though the global share of leishmaniasis is limited to selective parts of the world, the number of individuals being affected and are at risk is noteworthy. The ongoing scope to deal with this concern includes vector control, development of technologies for easy and quick diagnosis, refinement of drugs for improved treatment and developing vaccine approaches both prophylactically and therapeutically.

Following success of a number of vaccine candidates at laboratory evaluation, a few have been tested in the field and are listed in Table 3. Notably, Canileish, recently licensed for prophylaxis against canine VL has demonstrated Th1 biased persistent antileishmanial immunity (72, 97, 98). The success of other two licensed canine vaccines: Leish-Tec (L. donovani A2 protein-adenovirus) and Leishmune (FML-saponin formulation) have persuaded researchers to develop human leishmaniasis vaccine. LEISH-F1 (formerly Leish-111F), comprising of a fusion of three relatively conserved L. major antigens (TSA, LmStI1, and Leishmania elongation initiation factor) formulated as stable emulsions of MPL-A in squalene oil, is the first among defined vaccines for leishmaniasis to be clinically evaluated (99, 100). It has been reported that in animal models LEISH-F1 + MPL-SE stimulated partial protection against VL. However, Phase III trial of LEISH-F1 + MPL-SE showed unsuccessful results in defending dogs against infection (101). Human phase I trials of LEISH-F1 + MPL-SE targeting VL and CL were conducted in Colombia (2007), Brazil (2007), Peru (2007), and India (2008) demonstrating the formulation to be safe, immunogenic, and well tolerated in people irrespective of their serostatus (102). Moreover, the LEISH-F1 + MPL-SE was also found to have therapeutic significance when used with chemotherapy in patients with ML (100). The noteworthy early success of the LEISH-F1 + MPL-SE has encouraged IDRI researchers to redesign this vaccine candidate into a new construct LEISH-F2. The new candidate has a deleted N-terminal histidine tag so as to keep the recombinant molecule close to its original form with replacement of a residue Lys274, a potential site for proteolytic activity, with Gln (102). Promising phase I trial of LEISH-F2 + MPL-SE has lead to a phase II trial where the safety, immunogenicity, and efficacy were studied in evaluation with standard chemotherapy in adolescent and adults participants infected with CL [www.ClinicalTrials.gov. A study of the efficacy and safety of the LEISH-F2 + MPL-SE vaccine for treatment of CL; 2013]. A third candidate LEISH-F3 under investigation by IDRI, a tandemly fused polypeptide of open reading frame of two Leishmania proteins: L. infantum/donovani nonspecific nucleoside hydrolase protein (aa 1–314) and L. infantum sterol 24-c-methyltransferase protein (aa 2–353), is in a phase I trials in USA. These trials aims to assess the safety and immunogenicity of unadjuvanted LEISH-F3 with variety of adjuvants likely to be glucopyranosyl lipid A formulated as stable emulsion (GLA-SE), MPL-SE, second generation lipid adjuvant stable emulsion (SLA-SE) in different studies [www.ClinicalTrials.gov. Phase 1 LEISH-F3 vaccine trial in healthy adult volunteers; 2014, LEISH-F3 + GLA-SE and the LEISH-F3 + MPL-SE Vaccine; 2016, Phase 1 LEISH-F3 + SLA-SE Vaccine Trial in Healthy Adult Volunteers; 2016] (103).

Other group has explored the safety, tolerability, and immunogenicity of vaccine candidate ChAd63-KH for human VL and post kala azar dermal leishmaniasis (PKDL) in Phase I clinical trials. ChAd63-KH is a simian adenoviral vaccine with defective replication, which expresses a novel synthetic gene (KH) encoding two Leishmania proteins kinetoplastid membrane protein 11 and hydrophilic acylated surface protein B. Phase I trial showed induced innate response characterized by activation of DCs and production of IFN-γ along with robust CD8⁺ T-cell response, which suggests the further development of ChAd63-KH as vaccine for VL and PKDL (105).

For the effective control and complete eradication of any infectious disease, the potential approach that can be exploited as an economical means is vaccination. Over the past two decades, immunotherapy, either alone or in combination with chemotherapy, has been developed as an additional approach to combat leishmaniasis. Lifetime immunity against reinfection manifests possibility of developing an effective vaccine (prophylactic and therapeutic) against leishmaniasis. Nevertheless, an antileishmanial vaccine for human administration is still unavailable. Therefore, the present scenario augments questions concerning the issues or limitations in the advancement of effective interventions against eradication of leishmaniasis. Some of the major challenges that need to be addressed are as follows:

Vaccines against leishmaniasis, malaria, schistosomiasis and a number of other bacterial and viral diseases are unappealing to the industry considering limits of financial benefits (300–800 million US dollars) (1). According to the G-Finder, over US$ 66 million has been granted for research and development of vaccine, preventative, and therapeutic, against leishmaniasis largely from chief public sector and charitable trusts (from the year 2007 to 2013). Some of the major funding sources are Carlos Slim Foundation, Bill & Melinda Gates Foundation, Wellcome Trust, Indian Council of Medical Research, European Commission, Institute Pasteur, German Federal Ministry of Education and Research (BMBF), and the U.S. National Institutes of Health (Policy Cures. G-Finder; 2015). In addition, new and enhanced funding from public–private joint ventures and pharmaceutical companies will be encouraging to boost vaccine (preventive and therapeutic) research.

Most conventional treatment option for leishmaniasis is highly expensive and toxic drugs. Vaccination (prophylactic and/or therapeutic), if possible, can be considered to be the most efficient strategy to control this infectious disease. Leishmaniasis is not an exception as patients cured of the disease become impervious to further infection. A plethora of vaccine candidates against leishmaniasis has been explored ranging from live vaccine to recombinant polyprotein and multiantigenic T-cell epitope-based vaccines. Moreover, chemotherapy along with immunotherapy that can elicit protective immune response can clear infection more effectively providing better possibility of recovery in patients. Subunit vaccine candidates—Leish-F1, Leish-F2, Leish-F3, and ChAd63-KH—are currently in different stages of clinical trials have kept alive the optimism for a licensed human vaccine (prophylactic and/or therapeutic) in near future. Although, licensed vaccines for canine leishmaniasis are available, the scope for improvement with newer approaches remains undaunted. With the rapid progress in understanding the propagation of protective immunity during leishmaniasis, development of better correlates of immunity to evaluate vaccines, novel delivery systems, immunotherapy with or without drugs, immunomodulators and adjuvant together with updated revelation in genetic information about the parasite have opened up opportunities for advanced research in the vaccine field. Moreover, if funding trust can lead the long road of vaccine development, the unmet goal of alternative approaches to chemotherapy will be achieved very soon.

ND collected literature and drafted the manuscript. MS, AS, and NA edited the manuscript. NA finalized the manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.