Management of visceral leishmaniasis with therapeutic vaccines

Figures & data

Table 1 A summary of therapeutic vaccines evaluated against VL

Vaccine, dose, (schedule)/ route of administration	Model system	Causative organism/stage	Drugs (dose, schedule/route of administration)	Intervention on day postinfection	Day of assessment postvaccination	Assessment criteria	Rem ar ks/refe ren ces
Therapeutic vaccine alone
UR6 (live/sonicated), 10^8 parasites ×3 (monthly)/sc	Hamster	L donovani! amastigote (AG83)	–	D30	D135	Splenic and hepatic parasite burden by LDU	Reduced parasite burden in spleen (95/93%) and liver (94/93%)^Citation66
UR6 (live/sonicated), 10^9 parasites ×3 (monthly)/sc	BALB/c mice	L donovani/ amastigote (AG83)	–	D30	DI65	Splenic and hepatic parasite burden by LDU	Reduced parasite burden in spleen (97/95%) and liver (82/84%)^Citation65
Attenuated L. donovani promastigotes irradiated @ 100 Gy and 150 Gy, 5×10^6 parasites ×3 (15-day intervals)/im	BALB/c mice	L. donovani/ promastigote (AG83)	–	D75	DI20	Splenic and hepatic burden by LDU NO, ROS, as well as cytokine and antibody response Proliferation and cytokine rpcnnncp	Reduced parasite burden in spleen (77%-80%) and liver (84%-93%) NO and ROS↑, IFN-γ↑, IL-10-↓- and lgG2/lgGI ↑^67 T-cell proliferation↑, with iNOS↑ TGF-β level↓^Citation68
Therapeutic vaccine in combination with adjuvant				1 CoUUI IC	anci i or-p ιενειψ
FML + saponin, 150pg+ 100μg ×3 (weekly)/sc	BALB/c mice	L. donovani! amastigote (LD-IS)	–	DI5	D45	Liver parasite load by LDU DTH, cell proliferation, and antibody response	Reduced burden (94.7%) DTH↑, IgGI↑, lgG2a↑, lgG2b levels↑, and cell proliferation↑^Citation71
FML + saponin, 1.5 mg + 1.0 mg x3 (20-30 days’ interval)/sc	Mongrel dogs (experimental; Brazil)	L donovani! amastigote (LD-IS)		DI27	D365	Clinical symptoms Parasitic burden in dab smears of skin, spleen, liver, lymph nodes, and bone marrow DTH, antibody response, and PBMC analysis	Asymptomatic Amastigotes are absent DTH↑, IgG2 levels↑, normal levels of CD4, CD8, and CD21^Citation72
Leishmune® (FML + saponin), 1.5 mg + 1.0 mg x3 (20-30 days’ interval)/sc	Mongrel dogs (experimental; Brazil)	L. chagasil amastigote (BH46)		DI80	D450	Clinical symptoms Parasite burden in dab smears of spleen, liver, lymph nodes and bone marrow Antibody response and T-cell subset analysis	Lower clinical scores Lower percentage of evidence of parasite lgG2↑, IgG1↓, and normal CD4+ counts^Citation73
NH-DNA, 100 Mg or 20 Mg x2 (15 days’ interval)/im + aqueous garlic extract (8 mg/kg) x7 days/ip	BALB/c mice	L. chagasil amastigote (BH46)		DI4	D38	Parasite load in liver by LDU Survival DTH, antibody level, and cytokine response	Reduction in parasite load (91%) 100% DTH↑, lgG2↑, IL-4-↓-, and IL-10-↓·^Citation74
rLdccys 1 + P. acnes, 500 pg each ×3 (monthly)/sc	Naturally infected dogs (Brazil)	L chagasi			D90	Clinical symptoms Splenic parasite burden by limiting dilution Survival DTH, antibody level, and cytokine response	Lower clinical scores Reduced splenic burden Up to 12 months posttreatment DTH↑, lgG2↑, IgG1↓-, IFN-γ↑, and 1L-10↓^Citation75
Therapeutic vaccines in combination with antileishmanial drugs
Alum/ALM + BCG, 100 μg ×4 (weekly)/im	Human PKDL patients (field trial in Sudan)	L. donovani	Sb, 20 mg/kg/d ×40/iv	–	D60	Clinical symptoms	87% of patients cured by D60 posttreatment
ALM + M. vaccae, 100 μg ×3	Dogs	L. infantum/	Meglumine	D60	D270	Cytokine response Parasite burden in dab smear of	IFN-γ/IL-10↑^77Parasite number reduced and
(monthly)/id	(experimental; Iran)	amastigote	antimoniate, 100 mg/ kg/d ×30/im			bone marrow, spleen, and liver Survival	animal becomes serologically negative Relapsed^Citation76
CSA (from attenuated parasite), 100 μg ×2 (15 days’ interval)/sc	BALB/c mice	L. donovani/ promastigote (AG83)	Sodium antimony gluconate, 25 mg/kg/d ×5/im	D15 (acute) and D120 (chronic)	D60 (acute) and D165 (chronic)	Hepatic and splenic parasite burdens by LDU/limiting dilution Cytokine response	Complete and 99% protection in acute and chronic stages IFN-γ↑ and IL-10↓^Citation78
SLA (25 μg/mL)-pulsed DC, 10^5 cells ×3 (weekly)/iv	BALB/c mice	L. donovani/ amastigote (AG83)	Sodium stibogluconate (50 mg/kg ×3 (weekly))/im	D30	D70	Splenic and liver parasite burdens by LDU Cytokine response	Complete clearance IL-12↑ and IFN-γ↑^Citation79
LiF2 (50 μg ×3 (weekly)/im	Naturally infected dogs (France)	L. infantum (France)	Glucantime, 300 mg/ kg ×20 (2 days’ interval)/im	–	D90 and D180	Clinical symptoms Parasite burden in dab smear of bone marrow	Symptoms disappeared 100% parasitological cure on combined therapy^Citation80
Leishmune, 1.5 mg + 1.0 mg ×3 (20–30 days’ interval)/sc	Naturally infected dogs (Brazil)	L. chagasi	Allopurinol (10 mg/kg/12 h for 15 months) or amphotericin B 0.5 mg/kg ×16 (3 day’ intervals)/iv	–	D90 and D240	Parasitic burden in dab smears of aspirates of popliteal lymph nodes DTH response	Reduces symptomatic cases with decreased CVL deaths DTH↑^Citation82
GRP78 + MPLA, 10 μg + 40 μg ×2 (15 days’ interval)/sc	BALB/c mice	L. donovani/ promastigote (Dd8)	Cisplatin (0.5 mg/kg ×5 days) ×2 (14 days’ interval)/ip	D30	D55, D70, and D85	Parasitic burden in liver and spleen by LDU DTH, antibody level, and cytokine response	Reduction in liver (84%–93%) and spleen (87%–93%) burden DTH↑, IgG2a↑, IgG1↓, IFN-γ↑, IL- 2↑, IL-10↓, and IL-4↓ levels^Citation85
Leish-110f + MPL-SE, 20 μg + 25 μg ×3 (21 days’ interval)/sc	Naturally infected mongrel dogs (Brazil)	L. chagasi	Glucantime (100 mg/ kg× 10 days) ×2 (10 days’ interval)/im	–	D180	Clinical symptoms Parasite burden in bone marrow aspirates and skin biopsies Survival Antibody response	Improvement in clinical response Reduced number of deaths Higher survival Increased antibody titers^Citation87
Leish-111f + MPL-SE, 20 μg + 25 μg ×4 (weekly intervals)/sc	Naturally infected dogs (Brazil)	L. chagasi	Glucantime, 20 mg/kg ×30 days/im	–	D180	Clinical symptoms Antibody response	75% of vaccinated dogs were cured Antibody titer↑^Citation88
LEISHDNAVAX, 100 μg/200 μg/id	C57BL/6J mice	L. donovani/ amastigote (HU3)	AmBisome 0.8 mg/kg ×2 (14 days’ interval)/iv	D7	D31	Parasite burden in spleen and liver by LDU	Reduction in spleen (~75%) and liver (~68%) burden^Citation89
Delivery of therapeutic vaccines using carrier system
Positively charged liposome containing SLA (15 μg ×3 (14 days’ interval)/ip	BALB/c mice	L. donovani/ promastigote (AG83)	–	D60	D100	Parasite load in liver and spleen by LDU Antibody and cytokine response	Reduction in liver (91%) and spleen (95%) burden IgG2↑, IgG1↓, DTH↑, IFN-γ↑, IL-12↑, with IL-4↓ and IL-10↓^Citation92
HASPB + KMP-11/sc	BALB/c mice	L. donovani/ amastigotes (LV9)	–	D21	D31	Splenic parasite burden by LDU Cytokine and antibody response	Reduction in spleen (66%) burden IFN-γ↑ and CD8+ cells↑, particularly to HASPB, and IgG1↓ and IgG2a↑^Citation93

Notes: Numbers separated by / indicate reduction in parasite burden by live/sonicated parasites. ↑, Increase; ↓, decrease.

Abbreviations: ALM, autoclaved Leishmania major; BCG, Bacillus Calmette–Guérin; CD, cluster of differentiation; CSA, complete soluble antigen; CVL, canine visceral leishmaniasis; DTH, delayed type hypersensitivity; DC, dentritic cell; FML, fucose–mannose ligand; GRP78, glucose-regulated protein 78; HASPB, hydrophilic acylated surface protein B; id, intradermal; IFN, interferon; IgG, immunoglobulin G; IL, interleukin; im, intramuscular; iNOS, inducible nitric oxide synthase; ip, intraperitoneal; iv, intravenous; KMP-11, kinetoplastid membrane protein-11; L. chagasi, Leishmania chagasi; L. donovani, Leishmania donovani; LDU, Leishman Donovan Units; LiF2, L. infantum-derived fraction 2, 94–67 kDa; MPLA, monophosphoryl lipid A; MPL-SE, monophosphoryl lipid A plus squalene emulsion; NH, nucleoside hydrolase; NO, nitric oxide; PBMC, peripheral blood mononuclear cell; PKDL, post kala azar dermal leishmaniasis; rLdccys1, recombinant cysteine proteinase from L. (L.) infantum chagasi; ROS, reactive oxygen species; sc, subcutaneous; SLA, soluble Leishmania antigen; TGF-β, transforming growth factor beta; Sb, sodium stibogluconate.

Figure 1 Roadmap for development of therapeutic vaccines against VL.

Abbreviations: PKDL, post kala azar dermal leishmaniasis; VL, visceral leishmaniasis.

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