Table 1.
A comprehensive compilation of the vaccine approaches and analyses tested against Leishmania.
| VACCINE CANDIDATE | STRAIN (CHALLENGE) | ROI | ADJUVANT | OUTCOME | DRAWBACK(S) | REF |
|---|---|---|---|---|---|---|
| 1ST GENERATION VACCINES | ||||||
| Leishmanization (LZ) | L. major | S.C | -- | Higher success rate in Uzbekistan & Iran | Loss of infectivity, safety & ethical issues | [17] |
| Killed but metabolically active | L. major & L. infantum chagasi | S.C | -- | Treating them with amotosalen and low dose of UV radiation | Shown promise in murine model but failed in human trials | [18] |
| Killed but metabolically active | L. major (Alum ppt. Autoclaved L. major) | -- | BCG | Shown promise in VL and PKDL patients | Chances of relapse | [19] |
| 2ND GENERATION VACCINES | ||||||
| FML (Fucose Mannose Ligand) | L. donovani | S.C, I.P | Saponin, Al(OH)3, QuilA IL-12, BCG | Protective efficacy in BALB/C, Swiss albino, Hamster & dogs | Not shown promise in human | [20,21] |
| Leishmune | L. chagasi | S.C | -- | No parasites were detected in blood, Skin and Lymph node | No trials in humans | [22] |
| Leishmune® |
L. donovani
L. chagasi |
S.C | Saponin | Have transmission blocking property | Partial protection | [23] |
| LAG (L. donovani promastigote membrane antigens) | L. donovani | I.P | Liposome | Shown promise in mice and hamster | Failed in higher animal models | [24] |
| SLA (Soluble Leishmanial Antigen) | L. donovani | I.P, S.C | Liposome, MPL-TDM, non-coding pDNA+ISS | Prophylactic and therapeutic effect in mice model | Free or negatively charged liposome confers partial protection | [25,26,27] |
| gp36 | L. donovani | S.C | Saponin | Protective effect in murine model | Not reached human trials | [28] |
| Ld91, Ld72, Ld51, Ld31 | L. donovani | I.P | Liposome | Reduce parasite burden in visceral organ | Protective efficacy only in mice models | [29] |
| dp72 and gp70-2 | L. donovani | I.P | Corynebacterium parvum | Decrease in parasitemia in visceral organ | Gp70-2 were not promising in mice | [30] |
| SA (Soluble Antigen) | L. donovani | I.M | CpG-ODN | Decrease in parasite load | Ag alone show mixed response in mice models | [31] |
| Ribosomal P0 protein | L. major | S.C | CpG-ODN | Shown promise in C57BL/6 mice | Failure in BALB/C mice | [32] |
| F2 subfraction (97.4-68 kda) | L. donovani | I.D | BCG | Th1 mediated cellular response in cured VL patients and hamsters | Not tested in clinical studies | [33] |
| F2 sub-fraction (89.9-97.1 kDa) | L. donovani | I.D | BCG | 99% parasite inhibition were observed in hamsters | Specific characterization of antigen is needed for higher trials | [34,35] |
| LPG and Phlebotomus duboscqi salivary gland lysates (SGLs) | L. major | S.C | -- | LPG alone provide protection in BALB/C mice | LPG+SGLs failed to provide protection | [36] |
| LPG | Phlebotomus duboscqi sandflies | -- | -- | Block the transmission of Leishmania | -- | [37] |
| gp63 (leishmanolysin) | L. donovani | I.P | Cationic (DSPC) liposomes | Protective effect in BALB/C mice | Mixed responses | [38] |
| Recombinant.gp63 | L. major | -- | -- | Recognition of fusion protein | Fusion protein did not protect the mice | [39] |
| gp63 | L. major | I.V, S.C | -- | BCG expressing gp63 only provide Protection | Limited up to mice only | [40] |
| gp63 | L. major | S.C | CpG ODN + Liposome | Th1 type response | Adjuvant is needed for protection | [41] |
| gp63 | L. donovani | I.M, S.C | CpG ODN | Evoke cellular and humoral response | No trials on higher animal | [42] |
| H2B (Histone protein) | L. major | S.C | CpG | Th1 type response | Only amino-terminal region confer protection | [43] |
| H2B |
L. major, L. infantum patients |
-- | -- | Whole H2B protein induces Th1 profile in individuals | Not reached clinical trials | [44] |
| rORFF + BT1 | L. donovani | S.C | CFA, ICFA | Detection of high levels of anti-ORFF and anti-BT1 antibodies | Partial protection | [45] |
| rORFF | L. donovani | I.M | CpG ODN | Combination of CpG ODN with rORFF induces reduction in parasite load | Partial protection | [46] |
| ORFF |
L. donovani (antimony sensitive & resistant) |
I.M | -- | UBQ-ORFF induces cellular & humoral response | Ubiquitin is required for protective effect | [47] |
| Elongation factor 2 (LelF-2) | L. donovani | I.D | -- | Shown promise in Hamster | Not reach clinical trials | [48] |
| rF14 | L. donovani | I.M | MPL | Reduce in parasite burden in spleen and liver | Partial protection | [49] |
| HASPB1 | L. donovani | S.C | IL-12 | Induces DC to produce IL-12 | rHASPB1 immunization induces Th2 response | [50] |
| 78kDa | L. donovani | S.C | MPL-A, Liposome rIL-12, ALD, FCA |
Enhanced DTH response, reduction in infection rate of peritoneal macrophages | Antigen alone induces IgG1 isotypes | [51] |
| LCR1 | L. chagasi | I.P, S.C | -- | Protective effect in BALB/C mice | BCG-LCR1 I.P administration did not show protection | [52] |
| Meta1 antigen | L. major | I.M, S.C | IFA | MCP-3/meta 1 fusion partially shift towards Th1 type | Rec. protein Meta1 antigen induces Th2 response | [53] |
| LirCyP1 | L. infantum | I.P | IL-12 | Promote differentiation of helper and memory T cell | Partial protection | [54] |
| Maxadilan (MAX) | L. major | S.C, I.P | CFA IFA |
Vaccination against Max elicits Th1 type response | MAX enhance blood flow and inhibit the immune response of the host | [55] |
| LJM19 | L. infantum chagasi | I.D | -- | Induces low parasite load and high IFN-γ/TGF-β ratio | Not reached clinical trials | [56] |
| A2 protein | L. donovani | I.P | Propianibacterium acnes | Production of IFN-ϒ response | Mixed Responses | [57] |
| rLdγGCS | L. donovani | S.C | NIV | Induces humoral response | Mixed Responses | [58] |
| FUSION, HYBRID AND POLYPROTEIN VACCINES | ||||||
| Chimeric Q protein | L. infantum | S.C | -- | Clearance of parasites from majority of the dogs | Studies during natural infection condition are required | [59] |
| Amastigote cysteine proteases | L. major | S.C | -- | Hybrid CPA/B elicits protective response | Partial protection | [60] |
| TAT-antigen fusion protein | L. major | I.D | CpG ODN 1826 | CD8+ T cells rapidly proliferate, activate Leishmania-specific Tc1 cells | Protective effect is observed in C57BL/6 mice | [61] |
| rLeish-111f | L. major | S.C | rIL-12 MPL-SE |
Protective efficacy in BALB/C mice | Mixed IgG2a/IgG1 Ab response | [62] |
| Leish-111f | L. infantum | S.C | MPL-SE | 99.6% reductions in parasite loads, completed phase 1 and 2 safety human trial | -- | [63] |
| LEISH-F1 | L. donovani | S.C | MPL-SE | Vaccine is safe, immunogenic in healthy subjects | Further trials are needed | [64] |
| LIVE, ATTENUATED (GENETICALLY) VACCINES | ||||||
| dhfr-ts− null mutant | L. major | I.V, S.C, I.M | -- | Unable to cause disease in susceptible and immune deficient (nu/nu) BALB/C mice | Need to be tested on animal higher models | [65] |
| dhfr-ts−L. major knock out mutant | L. amazonensis | S.C, I.V | -- | Cross- Protection was observed in both BALB/C and C57BL/6 mice | Partial degree of protection | [66] |
|
LdCen1(−/−)
L. donovani centrin null mutants |
L. donovani
L. braziliensis |
I.M I.C |
-- | No parasites were seen in spleen, liver in BALB/C, SCID mice and Hamster, Cross protection against L. braziliensis | Not reach clinical trials | [67] |
|
(BT1−/−)
Biopterin transporter null mutant |
L. donovani | I.V | -- | Th1 mediated response were observed in BALB/C mice | Need to be tested on higher animal models | [68] |
|
LiSIR2(+/−)
L. infantum SIR2 single knockout |
L. infantum | I.P | -- | Reversion of T cell anergy, increased IFN-γ/IL-10 ratio | Mixed response in BALB/C mice | [69] |
| Ldp27(−/−) |
L. donovani
L. infantum chagasi |
I.C | -- | less COX (Cytochrome C oxidase complex) activity and ATP synthesis | Safety efficacy need to be tested on higher animal models | [70] |
| ΔHSP70-II | L. major | I.P, I.V, S.C | -- | Promise protection in BALB/C model, consider safe in SCID mice and hamster | Need to be tested on higher animal models | [71] |
| LiΔHSP70-II null mutant | L. major | I.V, S.C | -- | Promise protection in BALB/C and C57BL/6 mice | Limited only to mice models | [72] |
| Δlpg2 | L. major | S.C | CPG-ODN | Shown promise in C57BL/6 mice | Antigen alone is not sufficient to provide protection | [73] |
| lpg2− | L. major | Foot pad | -- | Suppress IL-4 and IL-10 responses | Very low IFN-ϒ response were observed | [74] |
|
Leishmania tarentolae
(Non-pathogenic) |
L. donovani | I.P | -- | Activates DC, Induces IFN-ϒ, Th1 phenotype in BALB/C mice | Further testing is needed | [75] |
|
A2-recombinant
L. tarentolae |
L. infantum | I.P, I.V | -- | Th1 response in BALB/C mice | I.V route elicits Th2 response | [76] |
| A2-expressing Lactococcus lactis | L. donovani | S.C | -- | Antigen-specific humoral response was observed | Only in BALB/C mice | [77] |
| 3RD GENERATION VACCINES | ||||||
| LACK | L. major | S.C | +rIL-12 -rIL-12 |
Protective response in BALB/C mice | Need to be tested on higher animal models | [78] |
| pCIneo-LACK | L. chagasi | I.N Intranasal |
-- | Reduce parasite burden in liver and spleen | Limited up to BALB/C mice | [79] |
| LACK-DNA | L. chagasi | I.N | -- | Cellular and humoral response were observed | Not reached clinical trials | [80] |
| p36 (LACK) DNA | L. donovani | I.D, S.C | IL-12 | Robust Th1 response, highly immunogenic | No protection | [81] |
| gp63 and Hsp70 | L. donovani | S.C | -- | Significantly reduce the parasite burden | Need to be tested on higher animal models | [82] |
| A2+E6 | L. donovani | I.M | -- | Induce cellular and humoral response, inhibit cellular p53 response | Limited to mice model | [83] |
| A2 (Expressed in adenovirus) | L. chagasi | S.C | -- | Reduced parasitism in spleen and liver, production of high level of IFN-ϒ | Low antibody response | [84] |
| ORFF | L. donovani | I.M | -- | Induces both cellular and humoral response | Limited to BALB/C mice | [85] |
| rORFF | L. donovani | I.M | IL-12 | Higher levels of IFN-γ were observed | Need to be tested on higher animal models | [86] |
| KMP-11 | L. donovani | I.M | -- | Reversal of T-cell anergy with functional IL-2 generation | Mixed response | [87] |
| KMP-11 | L. major | I.M, S.C | IL-12 | Robust IFN-ϒ production, polarized Th1 response | Require adjuvant for complete protection | [88] |
| ϒ GCS | L. donovani | I.M | -- | Elevated humoral and cell mediated response | Limited to mice model only | [89] |
| H2A, H2B, H3, H4, LACK | L. donovani | I.M, I.D | IL-12 GM-CSF |
Induce DTH response, reduction in parasite burden | Unable to induce parasite-specific antibody response | [90] |
| N-terminal domain of proteophosphoglycan (PPG) | L. donovani | I.M | -- | Induce IFN-ϒ, TNF-α, IL-12 and downregulate TGF-β, IL-4, IL-10 | Need further trials ahead of hamster model | [91] |
| Single antigen Gp63, polytope and polytope HSP70 | L. donovani | I.M, I.P | -- | Strong Th1 response | Limited to mice only | [92] |
| NH36 |
L. chagasi
L. mexicana |
I.M, S.C | -- | Reduction in parasite load, Th1 mediated response, cross-protection | No differences were observed after infection with L. mexicana | [93] |
| NH36 | L. chagasi | I.M, I.P | -- | Reduction in parasite burden in liver | Clinical trials not done | [94] |
| KMP11, TSA, elongation factor P74, CPA and CPB, HASPB, A2 LEISHDNAVAX | L. donovani | I.D | -- | Induce CD4+ and CD8+ T cell responses in genetically diverse human populations | Require clinical trials | [95] |
| KMPII, TRYP, LACK and GP63 | L. infantum | I.D | -- | Vaccine was safe and well tolerated for dogs | No protection in dogs | [96] |
| papLe22 | L. infantum | I.M | -- | Downregulate Th2 type response in hamsters | Low antibody response | [97] |
| HbR | L. donovani | I.M | -- | Complete protection in both BALB/C and Hamsters | Clinical trials not done | [98] |
| Tuzin | L. donovani | I.M | -- | higher levels of IFN-γ and IL-12 production | Limited only to BALB/C mice | [99] |
| HETEROLOGOUS PRIME-BOOST (HPB) VACCINES | ||||||
| ORFF | L. donovani | I.M | Alum | 75%–80% reduction in parasite load, enhanced production of IgG2a and IFN-γ in BALB/C mice | Need to be tested on higher animal models | [100] |
| Cysteine proteinases type I and II | L. infantum | S.C | CpG ODN and Montanide 720 | Antigen-specific immune response was observed | Need to be tested on higher animal model | [101] |
| rLdP1 | L. donovani | I.M | FCA | 75.68% decrease in splenic parasite burden in hamsters, | Challenge by other Leishmania species needed for evaluation | [102] |
| A2-CPA-CPB (CTE) recombinant L. tarentolae | L. infantum | Foot pad | cationic solid lipid nanoparticle (cSLN) | High NO production, and low parasite burden | Mixed responses | [103] |
| LACK-WR or LACK-MVA | L. infantum | I.D, I.P | -- | High levels of protection in the draining lymph node | Low protection observed in Spleen and Liver | [104] |
| AlphaGalCer + DNAp36+ VVp36 | L. major | I.D, I.P | αGalCer | 20-fold reductions in parasite burdens | Limited to mice only | [105] |
| DNA/MVA TRYP | L. Viannia panamensis | I.D | α-GalCer, LPS, CpG, Pam3CSK4, MALP-2 | TLR1/2 activation, antigen specific CD8 cells | Need to be tested on higher animal model | [106] |
| pORT-LACK/MVA-LACK | L. infantum | S.C | -- | increase in expression of Th1 type cytokines in PBMC and target organs | Limited to canine model only | [107] |
| LdPxn-1 (L. donovani Peroxidoxin-1) | L. major | I.M S.C |
m-GMCSF | Induction of multipotent CD4+ cells | Mixed responses | [108] |
| DENDRITIC CELL(DC)-BASED VACCINES | ||||||
| DCs pulsed with peptide L1 of gp63 (SPL) & pulsing with peptide L2 of gp63 | L. major | I.V | -- | Reduce lesion and parasite load, Th1 phenotype in BALB/C mice with L1 peptide | Partial protection with L1 peptide, whereas L2 peptide switch towards Th2 profile | [109] |
| Plasmacytoid DCs | L. major | I.V | CpG-ODN | Induce T cell-mediated protection | IFN-α production could not be detected | [110] |
| SLDA-pulsed DCs | L. donovani | I.V | IL-12 | Live parasites were not detected in the liver of mice, 1-3 log lower parasite burdens | Granuloma formation were found in SLDA-pulsed, non-transduced DCs BALB/C mice | [111] |
| BM-DCs pulsed with KMP-11 (12–31aa) peptide | L. infantum | I.V | CpG-ODN | Induced the differentiation of peptide-specific Th17 cells | Mixed responses | [112] |
| SLDA-pulsed syngeneic BM-DCs | L. donovani | I.V, I.M | -- | Complete clearance of parasites from spleen and liver | Need to be tested on higher animal models | [113] |
| Hybrid cell vaccine (HCV) | L. donovani | I.V | -- | Strong antigen-specific CTL generation | Expression of IL-4 and IL-13 get elevated at both transcription and translational levels | [114] |
ABBREVIATIONS: ALD (Autoclaved Leishmania antigen), BCG (Bacille Calmette Guerin), CFA (Complete Freund’s Adjuvant), CpG-ODN (CpG- oligodeoxynucleotides), DSPC (Distearoyl phosphatidylcholine), FCA (Freund’s adjuvant), I.D (Intradermal), I.M (Intramuscular), I.N (Intranasal), I.P (Intraperitoneal), I.V (Intravenous), ICFA (Incomplete Freund’s adjuvant), IFA (Incomplete Freund’s Adjuvant), ISS (Immunostimulatory sequences), LPS (Lipopolysaccharide), m-GMCSF (murine granulocyte-macrophage colony-stimulating factor), MPL-SE (Monophosphoryl lipid A plus squalene), MPL-TDM (Monophosphoryl lipid-trehalose dicorynomycolate), NIV (non-ionic surfactant vesicle), S.C (Subcutaneous).