Exploration of Drug Science

Table 2. Types of leishmanial vaccines and their mechanism of action [87–98]

Name of vaccine	Essential component/antigen	Adjuvant and their mechanism of action
Leishvaccine	Whole-killed promastigotes of L. amazonensis	BCG (Bacillus Calmette Guerin); CD4+, CD8+, B cell activation
ALM^ϼ (autoclaved-killed L. major)	Autoclave-killed L. major	BCG; T cell activation
Leishmune	FML (fucose-mannose ligand)	Saponin; T cell activation
CaniLeish	LiESP (L. infantum excreted-secreted protein)	Saponin; induction of Th1 cell
GALM^α (gentamycin-attenuated L. major)	GALM	T and B cell activation
LEISH-F1	TSA + LmSTI1 + LeIF	MPL-SE (monophosphoryl lipid A-stable emulsion); T cell activation
LEISH-F2	LEISH-F2, designed from LEISH-F1	MPL-SE; T cell activation
LEISH-F3	NH + SMT (nucleoside hydrolase; sterol 24-c-methyltransferase)	GLA (glucopyranosyl lipid A)-SE; T cell activation
Leish-Tec	L. donovani A2 protein	Saponin; T cell activation
SMT^γ + NH^μ	NH + SMT	GLA-SE; T cell activation
ChAd63-KH	KMP-11 + HASPB (kinetoplastid membrane protein 11; hydrophilic acylated surface protein B)	Broad CD8+ T cell activation

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Declarations

Acknowledgments

I acknowledge the esteemed faculty and researchers at Bharati Vidyapeeth (Deemed to be University) Poona College of Pharmacy, Pune for their valuable contributions and support in the development of this review article. Their expertise and guidance have been instrumental in shaping the content and insights presented in this work. I extend my sincere gratitude to the institution for providing a conducive academic environment that fosters research excellence and innovation.

Author contributions

TM: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Software, Validation, Visualization, Writing—original draft, Writing—review & editing. DK and DB: Formal analysis, Project administration, Supervision, Visualization, Writing—review & editing.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

Not applicable.

Copyright

References

Roatt BM, de Oliveira Cardoso JM, De Brito RC, Coura-Vital W, de Oliveira Aguiar-Soares RD, Reis AB. Recent advances and new strategies on leishmaniasis treatment. Appl Microbiol Biotechnol. 2020;104:8965–77. [DOI] [PubMed]

Leishmaniasis [Internet]. Pan American Health Organization; [cited 2023 Oct 22]. Available from: https://www.paho.org/en/topics/leishmaniasis#:~:text=Cutaneous%20and%20visceral%20leishmaniasis%20are,645%20reported%20cases%20per%20year

Leishmaniasis [Internet]. WHO; c2024 [cited 2023 Oct 22]. Available from: https://www.who.int/news-room/fact-sheets/detail/leishmaniasis#:~:text=Leishmaniasis%20is%20caused%20by%20protozoan,and%20lack%20of%20financial%20resources

Choi HL, Jain S, Ruiz Postigo JA, Borisch B, Dagne DA. The global procurement landscape of leishmaniasis medicines. PLoS Negl Trop Dis. 2021;15:e0009181. [DOI] [PubMed] [PMC]

Olías-Molero AI, de la Fuente C, Cuquerella M, Torrado JJ, Alunda JM. Antileishmanial Drug Discovery and Development: Time to Reset the Model? Microorganisms. 2021;9:2500. [DOI] [PubMed] [PMC]

Scarpini S, Dondi A, Totaro C, Biagi C, Melchionda F, Zama D, et al. Visceral Leishmaniasis: Epidemiology, Diagnosis, and Treatment Regimens in Different Geographical Areas with a Focus on Pediatrics. Microorganisms. 2022;10:1887. [DOI] [PubMed] [PMC]

Malvolti S, Malhame M, Mantel CF, Le Rutte EA, Kaye PM. Human leishmaniasis vaccines: Use cases, target population and potential global demand. PLoS Negl Trop Dis. 2021;15:e0009742. [DOI] [PubMed] [PMC]

David CV, Craft N. Cutaneous and mucocutaneous leishmaniasis. Dermatol Ther. 2009;22:491–502. [DOI] [PubMed]

Ahluwalia S, Lawn SD, Kanagalingam J, Grant H, Lockwood DN. Mucocutaneous leishmaniasis: an imported infection among travellers to central and South America. BMJ. 2004;329:842–4. [DOI] [PubMed] [PMC]

10.

Bostanci A. Determination of Human Leishmaniasis Seroprevalence and Disease Causing Leishmania Species in Northern Cyprus [dissertation]. Nicosia: Near East University; 2016.

11.

ÖZÜMİT MİNTAŞ G. Diyareli vakalarda bağirsak parazitlerinin prevalansi ve direkt tani metotlarinin karşilaştirilmasi [dissertation]. Ankara: Ankara University; 2008.

12.

Özcel MA, Özbel Y, Ak M. Türkiye Parazitoloji Derneği Yayınları No: 22. İzmir: Met Basım; 2007.

13.

Sundar S, Sinha PR, Agrawal NK, Srivastava R, Rainey PM, Berman JD, et al. A cluster of cases of severe cardiotoxicity among kala-azar patients treated with a high-osmolarity lot of sodium antimony gluconate. Am J Trop Med Hyg. 1998;59:139–43. [DOI] [PubMed]

14.

Gasser RA Jr, Magill AJ, Oster CN, Franke ED, Grögl M, Berman JD. Pancreatitis induced by pentavalent antimonial agents during treatment of leishmaniasis. Clin Infect Dis. 1994;18:83–90. [DOI] [PubMed]

15.

Thakur CP, Sinha GP, Pandey AK, Kumar N, Kumar P, Hassan SM, et al. Do the diminishing efficacy and increasing toxicity of sodium stibogluconate in the treatment of visceral leishmaniasis in Bihar, India, justify its continued use as a first-line drug? An observational study of 80 cases. Ann Trop Med Parasitol. 1998;92:561–9. [DOI] [PubMed]

16.

Croft SL, Yardley V. Chemotherapy of leishmaniasis. Curr Pharm Des. 2002;8:319–42. [DOI] [PubMed]

17.

Sundar S, Jha TK, Thakur CP, Sinha PK, Bhattacharya SK. Injectable paromomycin for Visceral leishmaniasis in India. N Engl J Med. 2007;356:2571–81. [DOI] [PubMed]

18.

Sundar S, Rai M, Chakravarty J, Agarwal D, Agrawal N, Vaillant M, et al. New treatment approach in Indian visceral leishmaniasis: single-dose liposomal amphotericin B followed by short-course oral miltefosine. Clin Infect Dis. 2008;47:1000–6. [DOI] [PubMed]

19.

Omollo R, Alexander N, Edwards T, Khalil EA, Younis BM, Abuzaid AA, et al. Safety and efficacy of miltefosine alone and in combination with sodium stibogluconate and liposomal amphotericin B for the treatment of primary visceral leishmaniasis in East Africa: study protocol for a randomized controlled trial. Trials. 2011;12:166. [DOI] [PubMed] [PMC]

20.

Alvar J, Croft S, Olliaro P. Chemotherapy in the treatment and control of leishmaniasis. Adv Parasitol. 2006;61:223–74. [DOI] [PubMed]

21.

Baneth G, Shaw SE. Chemotherapy of canine leishmaniosis. Vet Parasitol. 2002;106:315–24. [DOI] [PubMed]

22.

Haldar AK, Sen P, Roy S. Use of antimony in the treatment of leishmaniasis: current status and future directions. Mol Biol Int. 2011;2011:571242. [DOI] [PubMed] [PMC]

23.

Roberts WL, Rainey PM. Antileishmanial activity of sodium stibogluconate fractions. Antimicrob Agents Chemother. 1993;37:1842–6. [DOI] [PubMed] [PMC]

24.

Shaked-Mishan P, Ulrich N, Ephros M, Zilberstein D. Novel Intracellular Sb^V reducing activity correlates with antimony susceptibility in Leishmania donovani. J Biol Chem. 2001;276:3971–6. [DOI] [PubMed]

25.

Wyllie S, Cunningham ML, Fairlamb AH. Dual action of antimonial drugs on thiol redox metabolism in the human pathogen Leishmania donovani. J Biol Chem. 2004;279:39925–32. [DOI] [PubMed]

26.

Frézard F, Monte-Neto R, Reis PG. Antimony transport mechanisms in resistant leishmania parasites. Biophys Rev. 2014;6:119–32. [DOI] [PubMed] [PMC]

27.

Brochu C, Wang J, Roy G, Messier N, Wang XY, Saravia NG, et al. Antimony uptake systems in the protozoan parasite Leishmania and accumulation differences in antimony-resistant parasites. Antimicrob Agents Chemother. 2003;47:3073–9. [DOI] [PubMed] [PMC]

28.

Alvar J, den Boer M, Dagne DA. Towards the elimination of visceral leishmaniasis as a public health problem in east Africa: reflections on an enhanced control strategy and a call for action. Lancet Glob Health. 2021;9:e1763–9. [DOI] [PubMed] [PMC]

29.

Mandal S, Maharjan M, Singh S, Chatterjee M, Madhubala R. Assessing aquaglyceroporin gene status and expression profile in antimony-susceptible and -resistant clinical isolates of Leishmania donovani from India. J Antimicrob Chemother. 2010;65:496–507. [DOI] [PubMed]

30.

Oliveira LF, Schubach AO, Martins MM, Passos SL, Oliveira RV, Marzochi MC, et al. Systematic review of the adverse effects of cutaneous leishmaniasis treatment in the New World. Acta Trop. 2011;118:87–96. [DOI] [PubMed]

31.

Wise ES, Armstrong MS, Watson J, Lockwood DN. Monitoring toxicity associated with parenteral sodium stibogluconate in the day-case management of returned travellers with New World cutaneous leishmaniasis [corrected]. PLoS Negl Trop Dis. 2012;6:e1688. [DOI] [PubMed] [PMC]

32.

Solomon M, Pavlotsky F, Leshem E, Ephros M, Trau H, Schwartz E. Liposomal amphotericin B treatment of cutaneous leishmaniasis due to Leishmania tropica. J Eur Acad Dermatol Venereol. 2011;25:973–7. [DOI] [PubMed]

33.

Hamill RJ. Amphotericin B formulations: a comparative review of efficacy and toxicity. Drugs. 2013;73:919–34. [DOI] [PubMed]

34.

Shirzadi MR. Lipsosomal amphotericin B: a review of its properties, function, and use for treatment of cutaneous leishmaniasis. Res Rep Trop Med. 2019;10:11–8. [DOI] [PubMed] [PMC]

35.

Romero GAS, Costa DL, Costa CHN, de Almeida RP, de Melo EV, de Carvalho SFG, et al.; Collaborative LVBrasil Group. Efficacy and safety of available treatments for visceral leishmaniasis in Brazil: A multicenter, randomized, open label trial. PLoS Negl Trop Dis. 2017;11:e0005706. [DOI] [PubMed] [PMC]

36.

Faustino C, Pinheiro L. Lipid Systems for the Delivery of Amphotericin B in Antifungal Therapy. Pharmaceutics. 2020;12:29. [DOI] [PubMed] [PMC]

37.

Dorlo TP, Balasegaram M, Beijnen JH, de Vries PJ. Miltefosine: a review of its pharmacology and therapeutic efficacy in the treatment of leishmaniasis. J Antimicrob Chemother. 2012;67:2576–97. [DOI] [PubMed]

38.

Coelho AC, Oliveira JC, Espada CR, Reimão JQ, Trinconi CT, Uliana SR. A Luciferase-Expressing Leishmania braziliensis Line That Leads to Sustained Skin Lesions in BALB/c Mice and Allows Monitoring of Miltefosine Treatment Outcome. PLoS Negl Trop Dis. 2016;10:e0004660. [DOI] [PubMed] [PMC]

39.

Chawla B, Jhingran A, Panigrahi A, Stuart KD, Madhubala R. Paromomycin Affects Translation and Vesicle-Mediated Trafficking as Revealed by Proteomics of Paromomycin –Susceptible –Resistant Leishmania donovani. PLoS One. 2011;6:e26660. [DOI] [PubMed] [PMC]

40.

Sinha PK, Jha TK, Thakur CP, Nath D, Mukherjee S, Aditya AK, et al. Phase 4 pharmacovigilance trial of paromomycin injection for the treatment of visceral leishmaniasis in India. J Trop Med. 2011;2011:645203. [DOI] [PubMed] [PMC]

41.

Harhay MO, Olliaro PL, Costa DL, Costa CH. Urban parasitology: visceral leishmaniasis in Brazil. Trends Parasitol. 2011;27:403–9. [DOI] [PubMed]

42.

Rai K, Cuypers B, Bhattarai NR, Uranw S, Berg M, Ostyn B, et al. Relapse after treatment with miltefosine for visceral leishmaniasis is associated with increased infectivity of the infecting Leishmania donovani strain. mBio. 2013;4:e00611-13. [DOI] [PubMed] [PMC]

43.

Adaui V, Lye LF, Akopyants NS, Zimic M, Llanos-Cuentas A, Garcia L, et al. Association of the Endobiont Double-Stranded RNA Virus LRV1 With Treatment Failure for Human Leishmaniasis Caused by Leishmania braziliensis in Peru and Bolivia. J Infect Dis. 2016;213:112–21. [DOI] [PubMed] [PMC]

44.

Bourreau E, Ginouves M, Prévot G, Hartley MA, Gangneux JP, Robert-Gangneux F, et al. Presence of Leishmania RNA Virus 1 in Leishmania guyanensis Increases the Risk of First-Line Treatment Failure and Symptomatic Relapse. J Infect Dis. 2016;213:105–11. [DOI] [PubMed]

45.

Jha MK, Sarode AY, Bodhale N, Mukherjee D, Pandey SP, Srivastava N, et al. Development and characterization of an avirulent Leishmania major strain. J Immunol. 2020;204:2734–53. [DOI] [PubMed]

46.

Bezemer JM, Meesters K, Naveda CL, Machado PRL, Calvopiña M, Leeflang MMG, et al. Clinical criteria for Mucosal Leishmaniasis diagnosis in rural South America: A systematic literature review. PLoS Negl Trop Dis. 2022;16:e0010621. [DOI] [PubMed] [PMC]

47.

Volpedo G, Pacheco-Fernandez T, Bhattacharya P, Oljuskin T, Dey R, Gannavaram S, et al. Determinants of Innate Immunity in Visceral Leishmaniasis and Their Implication in Vaccine Development. Front Immunol. 2021;12:748325. [DOI] [PubMed] [PMC]

48.

Mohebali M, Nadim A, Khamesipour A. An overview of leishmanization experience: A successful control measure and a tool to evaluate candidate vaccines. Acta Trop. 2019;200:105173. [DOI] [PubMed]

49.

Zhang WW, Karmakar S, Gannavaram S, Dey R, Lypaczewski P, Ismail N, et al. A second generation leishmanization vaccine with a markerless attenuated Leishmania major strain using CRISPR gene editing. Nat Commun. 2020;11:3461. [DOI] [PubMed] [PMC]

50.

Helou DG, Mauras A, Fasquelle F, Lanza JS, Loiseau PM, Betbeder D, et al. Intranasal vaccine from whole Leishmania donovani antigens provides protection and induces specific immune response against visceral leishmaniasis. PLoS Negl Trop Dis. 2021;15:e0009627. [DOI] [PubMed] [PMC]

51.

Miramin-Mohammadi A, Javadi A, Eskandari SE, Nateghi-Rostami M, Khamesipour A. Immune Responses in Cutaneous Leishmaniasis: In vitro Thelper1/Thelper2 Cytokine Profiles Using Live Versus Killed Leishmania major. J Arthropod Borne Dis. 2021;15:126–35. [DOI] [PubMed] [PMC]

52.

Wolf Nassif P, DE Mello TFP, Navasconi TR, Mota CA, Demarchi IG, Aristides SMA, et al. Safety and efficacy of current alternatives in the topical treatment of cutaneous leishmaniasis: a systematic review. Parasitology. 2017;144:995–1004. [DOI] [PubMed]

53.

Garza-Tovar TF, Sacriste-Hernández MI, Juárez-Durán ER, Arenas R. An overview of the treatment of cutaneous leishmaniasis. Fac Rev. 2020;9:28. [DOI] [PubMed] [PMC]

54.

Aronson NE, Wortmann GW, Byrne WR, Howard RS, Bernstein WB, Marovich MA, et al. A randomized controlled trial of local heat therapy versus intravenous sodium stibogluconate for the treatment of cutaneous Leishmania major infection. PLoS Negl Trop Dis. 2010;4:e628. [DOI] [PubMed] [PMC]

55.

Volpedo G, Huston RH, Holcomb EA, Pacheco-Fernandez T, Gannavaram S, Bhattacharya P, et al. From infection to vaccination: reviewing the global burden, history of vaccine development, and recurring challenges in global leishmaniasis protection. Expert Rev Vaccines. 2021;20:1431–46. [DOI] [PubMed]

56.

López-Carvajal L, Cardona-Arias JA, Zapata-Cardona MI, Sánchez-Giraldo V, Vélez ID. Efficacy of cryotherapy for the treatment of cutaneous leishmaniasis: meta-analyses of clinical trials. BMC Infect Dis. 2016;16:360. [DOI] [PubMed] [PMC]

57.

Berman JD, Neva FA. Effect of temperature on multiplication of Leishmania amastigotes within human monocyte-derived macrophages in vitro. Am J Trop Med Hyg. 1981;30:318–21. [DOI] [PubMed]

58.

Sacks DL, Barral A, Neva FA. Thermosensitivity patterns of Old vs. New World cutaneous strains of Leishmania growing within mouse peritoneal macrophages in vitro. Am J Trop Med Hyg. 1983;32:300–4. [DOI] [PubMed]

59.

Vega JC, Sanchez BF, Montero LM, Montaña R, Mahecha Mdel P, Dueñes B, et al. The efficacy of thermotherapy to treat cutaneous leishmaniasis in Colombia: a comparative observational study in an operational setting. Trans R Soc Trop Med Hyg. 2009;103:703–6. [DOI] [PubMed]

60.

López L, Robayo M, Vargas M, Vélez ID. Thermotherapy. An alternative for the treatment of American cutaneous leishmaniasis. Trials. 2012;13:58. [DOI] [PubMed] [PMC]

61.

Sadeghian G, Nilfroushzadeh MA, Iraji F. Efficacy of local heat therapy by radiofrequency in the treatment of cutaneous leishmaniasis, compared with intralesional injection of meglumine antimoniate. Clin Exp Dermatol. 2007;32:371–4. [DOI] [PubMed]

62.

Shaddel M, Sharifi I, Karvar M, Keyhani A, Baziar Z. Cryotherapy of cutaneous leishmaniasis caused by Leishmania major in BALB/c mice: A comparative experimental study. J Vector Borne Dis. 2018;55:42–6. [DOI] [PubMed]

63.

Gedda MR, Singh B, Kumar D, Singh AK, Madhukar P, Upadhyay S, et al. Post kala-azar dermal leishmaniasis: A threat to elimination program. PLoS Negl Trop Dis. 2020;14:e0008221. [DOI] [PubMed] [PMC]

64.

Mansueto P, Seidita A, Vitale G, Cascio A. Transfusion transmitted leishmaniasis. What to do with blood donors from endemic areas? Travel Med Infect Dis. 2014;12:617–27. [DOI] [PubMed]

65.

Antinori S, Cascio A, Parravicini C, Bianchi R, Corbellino M. Leishmaniasis among organ transplant recipients. Lancet Infect Dis. 2008;8:191–9. [DOI] [PubMed]

66.

Salmanpour R, Razmavar MR, Abtahi N. Comparison of intralesional meglumine antimoniate, cryotherapy and their combination in the treatment of cutaneous leishmaniasis. Int J Dermatol. 2006;45:1115–6. [DOI] [PubMed]

67.

el Darouti MA, al Rubaie SM. Cutaneous leishmaniasis. Treatment with combined cryotherapy and intralesional stibogluconate injection. Int J Dermatol. 1990;29:56–9. [DOI] [PubMed]

68.

Al-Mutairi N, Alshiltawy M, El Khalawany M, Joshi A, Eassa BI, Manchanda Y, et al. Tropical medicine rounds: Treatment of Old World cutaneous leishmaniasis with dapsone, itraconazole, cryotherapy, and imiquimod, alone and in combination. Int J Dermatol. 2009;48:862–9. [DOI] [PubMed]

69.

Liu R, Li X, Lam KS. Combinatorial chemistry in drug discovery. Curr Opin Chem Biol. 2017;38:117–26. [DOI] [PubMed] [PMC]

70.

Lavecchia A, Cerchia C. In silico methods to address polypharmacology: current status, applications and future perspectives. Drug Discov Today. 2016;21:288–98. [DOI] [PubMed]

71.

Cheng T, Li Q, Zhou Z, Wang Y, Bryant SH. Structure-based virtual screening for drug discovery: a problem-centric review. AAPS J. 2012;14:133–41. [DOI] [PubMed] [PMC]

72.

Wyllie S, Thomas M, Patterson S, Crouch S, De Rycker M, Lowe R, et al. Cyclin-dependent kinase 12 is a drug target for visceral leishmaniasis. Nature. 2018;560:192–7. [DOI] [PubMed] [PMC]

73.

Silva DKC, Teixeira JS, Moreira DRM, da Silva TF, Barreiro EJL, de Freitas HF, et al. In Vitro, In Vivo and In Silico Effectiveness of LASSBio-1386, an N-Acyl Hydrazone Derivative Phosphodiesterase-4 Inhibitor, Against Leishmania amazonensis. Front Pharmacol. 2020;11:590544. [DOI] [PubMed] [PMC]

74.

Kashif M, Hira SK, Upadhyaya A, Gupta U, Singh R, Paladhi A, et al. In silico studies and evaluation of antiparasitic role of a novel pyruvate phosphate dikinase inhibitor in Leishmania donovani infected macrophages. Int J Antimicrob Agents. 2019;53:508–14. [DOI] [PubMed]

75.

Kashif M, Paladhi A, Singh R, Bhattacharyya S, Hira SK, Manna PP. Leishmanicidal Activity of an In Silico-Screened Novel Inhibitor against Ascorbate Peroxidase of Leishmania donovani. Antimicrob Agents Chemother. 2020;64:e01766–19. [DOI] [PubMed] [PMC]

76.

Pandey RK, Kumbhar BV, Sundar S, Kunwar A, Prajapati VK. Structure-based virtual screening, molecular docking, ADMET and molecular simulations to develop benzoxaborole analogs as potential inhibitor against Leishmania donovani trypanothione reductase. J Recept Signal Transduct Res. 2017;37:60–70. [DOI] [PubMed]

77.

Ochoa R, Watowich SJ, Flórez A, Mesa CV, Robledo SM, Muskus C. Drug search for leishmaniasis: a virtual screening approach by grid computing. J Comput Aided Mol Des. 2016;30:541–52. [DOI] [PubMed]

78.

van Montfort RLM, Workman P. Structure-based drug design: aiming for a perfect fit. Essays Biochem. 2017;61:431–7. [DOI] [PubMed] [PMC]

79.

Ferreira LG, Dos Santos RN, Oliva G, Andricopulo AD. Molecular docking and structure-based drug design strategies. Molecules. 2015;20:13384–421. [DOI] [PubMed] [PMC]

80.

Stevanović S, Perdih A, Senćanski M, Glišić S, Duarte M, Tomás AM, et al. In Silico Discovery of a Substituted 6-Methoxy-quinalidine with Leishmanicidal Activity in Leishmania infantum. Molecules. 2018;23:772. [DOI] [PubMed] [PMC]

81.

Fiorillo A, Colotti G, Boffi A, Baiocco P, Ilari A. The crystal structures of the tryparedoxin-tryparedoxin peroxidase couple unveil the structural determinants of Leishmania detoxification pathway. PLoS Negl Trop Dis. 2012;6:e1781. [DOI] [PubMed] [PMC]

82.

Chen CY. A novel integrated framework and improved methodology of computer-aided drug design. Curr Top Med Chem. 2013;13:965–88. [DOI] [PubMed]

83.

Yousefinejad S, Hemmateenejad B. Chemometrics tools in QSAR/QSPR studies: A historical perspective. Chemometr Intell Lab Syst. 2015;149:177–204. [DOI]

84.

Khamesipour A. Therapeutic vaccines for leishmaniasis. Expert Opin Biol Ther. 2014;14:1641–9. [DOI] [PubMed]

85.

Berbert TRN, de Mello TFP, Wolf Nassif P, Mota CA, Silveira AV, Duarte GC, et al. Pentavalent Antimonials Combined with Other Therapeutic Alternatives for the Treatment of Cutaneous and Mucocutaneous Leishmaniasis: A Systematic Review. Dermatol Res Pract. 2018;2018:9014726. [DOI] [PubMed] [PMC]

86.

Machado-Pinto J, Pinto J, da Costa CA, Genaro O, Marques MJ, Modabber F, et al. Immunochemotherapy for cutaneous leishmaniasis: a controlled trial using killed Leishmania (Leishmania) amazonensis vaccine plus antimonial. Int J Dermatol. 2002;41:73–8. [DOI] [PubMed]

87.

Dinc R. Leishmania Vaccines: the Current Situation with Its Promising Aspect for the Future. Korean J Parasitol. 2022;60:379–91. [DOI] [PubMed] [PMC]

88.

Saljoughian N, Taheri T, Rafati S. Live vaccination tactics: possible approaches for controlling visceral leishmaniasis. Front Immunol. 2014;5:134. [DOI] [PubMed] [PMC]

89.

Moafi M, Rezvan H, Sherkat R, Taleban R. Leishmania Vaccines Entered in Clinical Trials: A Review of Literature. Int J Prev Med. 2019;10:95. [DOI] [PubMed] [PMC]

90.

Taheri T, Rafati S. Leishmaniasis: recombinant DNA vaccination and different approaches for vaccine development. Clin Invest. 2013;3:1023–44. [DOI]

91.

Convit J, Ulrich M, Polegre MA, Avila A, Rodríguez N, Mazzedo MI, et al. Therapy of Venezuelan patients with severe mucocutaneous or early lesions of diffuse cutaneous leishmaniasis with a vaccine containing pasteurized Leishmania promastigotes and bacillus Calmette-Guerin: preliminary report. Mem Inst Oswaldo Cruz. 2004;99:57–62. [DOI] [PubMed]

92.

Cecílio P, Pérez-Cabezas B, Fernández L, Moreno J, Carrillo E, Requena JM, et al. Pre-clinical antigenicity studies of an innovative multivalent vaccine for human visceral leishmaniasis. PLoS Negl Trop Dis. 2017;11:e0005951. [DOI] [PubMed] [PMC]

93.

Ikeogu NM, Akaluka GN, Edechi CA, Salako ES, Onyilagha C, Barazandeh AF, et al. Leishmania Immunity: Advancing Immunotherapy and Vaccine Development. Microorganisms. 2020;8:1201. [DOI] [PubMed] [PMC]

94.

Gillespie PM, Beaumier CM, Strych U, Hayward T, Hotez PJ, Bottazzi ME. Status of vaccine research and development of vaccines for leishmaniasis. Vaccine. 2016;34:2992–5. [DOI] [PubMed]

95.

Prasanna P, Kumar P, Kumar S, Rajana VK, Kant V, Prasad SR, et al. Current status of nanoscale drug delivery and the future of nano-vaccine development for leishmaniasis – A review. Biomed Pharmacother. 2021;141:111920. [DOI] [PubMed]

96.

Kaye P. A study to assess the safety, efficacy and immunogenicity of Leishmania vaccine ChAd63-KH in PKDL [Internet]. [cited 2024 Jun 20]. Available from: https://clinicaltrials.gov/ct2/show/NCT03969134

97.

Panasiuk M, Zimmer K, Czarnota A, Grzyb K, Narajczyk M, Peszyńska-Sularz G, et al. Immunization with Leishmania tarentolae-derived norovirus virus-like particles elicits high humoral response and stimulates the production of neutralizing antibodies. Microb Cell Fact. 2021;20:186. [DOI] [PubMed] [PMC]

98.

Osman M, Mistry A, Keding A, Gabe R, Cook E, Forrester S, et al. A third generation vaccine for human visceral leishmaniasis and post kala azar dermal leishmaniasis: First-in-human trial of ChAd63-KH. PLoS Negl Trop Dis. 2017;11:e0005527. [DOI] [PubMed] [PMC]

99.

Datta A, Podder I, Das A, Sil A, Das NK. Therapeutic Modalities in Post Kala-azar Dermal Leishmaniasis: A Systematic Review of the Effectiveness and Safety of the Treatment Options. Indian J Dermatol. 2021;66:34–43. [DOI] [PubMed] [PMC]

100.

Carregaro V, Costa DL, Brodskyn C, Barral AM, Barral-Netto M, Cunha FQ, et al. Dual effect of Lutzomyia longipalpis saliva on Leishmania braziliensis infection is mediated by distinct saliva-induced cellular recruitment into BALB/c mice ear. BMC Microbiol. 2013;13:102. [DOI] [PubMed] [PMC]

101.

Alvar J, Croft SL, Kaye P, Khamesipour A, Sundar S, Reed SG. Case study for a vaccine against leishmaniasis. Vaccine. 2013;31:B244–9. [DOI] [PubMed]

102.

Oliveira F, Rowton E, Aslan H, Gomes R, Castrovinci PA, Alvarenga PH, et al. A sand fly salivary protein vaccine shows efficacy against vector-transmitted cutaneous leishmaniasis in nonhuman primates. Sci Transl Med. 2015;7:290ra90. [DOI] [PubMed]

103.

Zahedifard F, Gholami E, Taheri T, Taslimi Y, Doustdari F, Seyed N, et al. Enhanced protective efficacy of nonpathogenic recombinant leishmania tarentolae expressing cysteine proteinases combined with a sand fly salivary antigen. PLoS Negl Trop Dis. 2014;8:e2751. [DOI] [PubMed] [PMC]

104.

Davarpanah E, Seyed N, Bahrami F, Rafati S, Safaralizadeh R, Taheri T. Lactococcus lactis expressing sand fly PpSP15 salivary protein confers long-term protection against Leishmania major in BALB/c mice. PLoS Negl Trop Dis. 2020;14:e0007939. [DOI] [PubMed] [PMC]

105.

Mitchell GF, Handman E, Spithill TW. Vaccination against cutaneous leishmaniasis in mice using nonpathogenic cloned promastigotes of Leishmania major and importance of route of injection. Aust J Exp Biol Med Sci. 1984;62 :145–53. [DOI] [PubMed]

106.

Gorczynski RM. Immunization of susceptible BALB/c mice against Leishmania braziliensis,: II. Use of temperature-sensitive avirulent clones of parasite for vaccination purposes. Cell Immunol. 1985;94:11–20. [DOI] [PubMed]

107.

Rivier D, Shah R, Bovay P, Mauel J. Vaccine development against cutaneous leishmaniasis. Subcutaneous administration of radioattenuated parasites protects CBA mice against virulent Leishmania major challenge. Parasite Immunol. 1993;15:75–84. [DOI] [PubMed]

108.

Kimsey PB, Theodos CM, Mitchen TK, Turco SJ, Titus RG. An avirulent lipophosphoglycan-deficient Leishmania major clone induces CD4+ T cells which protect susceptible BALB/c mice against infection with virulent L. major. Infect Immun. 1993;61:5205–13. [DOI] [PubMed] [PMC]

109.

Convit J, Ulrich M, Zerpa O, Borges R, Aranzazu N, Valera M, et al. Immunotherapy of American cutaneous leishmaniasis in Venezuela during the period 1990–1999. Trans R Soc Trop Med Hyg. 2003;97:469–72. [DOI] [PubMed]

110.

Kopelyanskiy D, Desponds C, Prevel F, Rossi M, Migliorini R, Snäkä T, et al. Leishmania guyanensis suppressed inducible nitric oxide synthase provoked by its viral endosymbiont. Front Cell Infect Microbiol. 2022;12:944819. [DOI] [PubMed] [PMC]

111.

Velez R, Gállego M. Commercially approved vaccines for canine leishmaniosis: a review of available data on their safety and efficacy. Trop Med Int Health. 2020;25:540–57. [DOI] [PubMed]

112.

Borja-Cabrera GP, Santos FN, Bauer FS, Parra LE, Menz I, Morgado AA, et al. Immunogenicity assay of the Leishmune vaccine against canine visceral leishmaniasis in Brazil. Vaccine. 2008;26:4991–7. [DOI] [PubMed] [PMC]

113.

Nagill R, Kaur S. Vaccine candidates for leishmaniasis: a review. Int Immunopharmacol. 2011;11:1464–88. [DOI] [PubMed]

114.

Olobo JO, Anjili CO, Gicheru MM, Mbati PA, Kariuki TM, Githure JI, et al. Vaccination of vervet monkeys against cutaneous leishmaniosis using recombinant Leishmania ‘major surface glycoprotein’ (gp63). Vet Parasitol. 1995;60:199–212. [DOI] [PubMed]

115.

Lage DP, Ribeiro PAF, Dias DS, Mendonça DVC, Ramos FF, Carvalho LM, et al. A candidate vaccine for human visceral leishmaniasis based on a specific T cell epitope-containing chimeric protein protects mice against Leishmania infantum infection. NPJ Vaccines. 2020;5:75. [DOI] [PubMed] [PMC]

116.

Dey R, Dagur PK, Selvapandiyan A, McCoy JP, Salotra P, Duncan R, et al. Live attenuated Leishmania donovani p27 gene knockout parasites are nonpathogenic and elicit long-term protective immunity in BALB/c mice. J Immunol. 2013;190:2138–49. [DOI] [PubMed] [PMC]

117.

Mutiso JM, Macharia JC, Kiio MN, Ichagichu JM, Rikoi H, Gicheru MM. Development of Leishmania vaccines: predicting the future from past and present experience. J Biomed Res. 2013;27:85–102. [DOI] [PubMed] [PMC]

118.

Aunguldee T, Gerdprasert O, Tangteerawatana P, Jariyapongskul A, Leelayoova S, Wongsatayanon BT. Immunogenicity and potential protection of DNA vaccine of Leishmania martiniquensis against Leishmania infection in mice. J Infect Dev Ctries. 2021;15:1328–38. [DOI] [PubMed]

119.

Pacheco-Fernandez T, Volpedo G, Gannavaram S, Bhattacharya P, Dey R, Satoskar A, et al. Revival of Leishmanization and Leishmanin. Front Cell Infect Microbiol. 2021;11:639801. [DOI] [PubMed] [PMC]

120.

Klatt S, Simpson L, Maslov DA, Konthur Z. Leishmania tarentolae: Taxonomic classification and its application as a promising biotechnological expression host. PLoS Negl Trop Dis. 2019;13:e0007424. [DOI] [PubMed] [PMC]

121.

Mendoza-Roldan JA, Latrofa MS, Iatta R, R S Manoj R, Panarese R, Annoscia G, et al. Detection of Leishmania tarentolae in lizards, sand flies and dogs in southern Italy, where Leishmania infantum is endemic: hindrances and opportunities. Parasit Vectors. 2021;14:461. [DOI] [PubMed] [PMC]

122.

Breton M, Tremblay MJ, Ouellette M, Papadopoulou B. Live nonpathogenic parasitic vector as a candidate vaccine against visceral leishmaniasis. Infect Immun. 2005;73:6372–82. [DOI] [PubMed] [PMC]

123.

De Beuckelaer A, Grooten J, De Koker S. Type I Interferons Modulate CD8⁺ T Cell Immunity to mRNA Vaccines. Trends Mol Med. 2017;23:216–26. [DOI] [PubMed]

124.

V Versteeg L, Almutairi MM, Hotez PJ, Pollet J. Enlisting the mRNA Vaccine Platform to Combat Parasitic Infections. Vaccines (Basel). 2019;7:122. [DOI] [PubMed] [PMC]

125.

Duthie MS, Van Hoeven N, MacMillen Z, Picone A, Mohamath R, Erasmus J, et al. Heterologous Immunization With Defined RNA and Subunit Vaccines Enhances T Cell Responses That Protect Against Leishmania donovani. Front Immunol. 2018;9:2420. [DOI] [PubMed] [PMC]

126.

Duthie MS, Machado BAS, Badaró R, Kaye PM, Reed SG. Leishmaniasis Vaccines: Applications of RNA Technology and Targeted Clinical Trial Designs. Pathogens. 2022;11:1259. [DOI] [PubMed] [PMC]

127.

Ponte-Sucre A, Gamarro F, Dujardin JC, Barrett MP, López-Vélez R, García-Hernández R, et al. Drug resistance and treatment failure in leishmaniasis: A 21st century challenge. PLoS Negl Trop Dis. 2017;11:e0006052. [DOI] [PubMed] [PMC]

128.

Stone V, Johnston H, Schins RPF. Development of in vitro systems for nanotoxicology: methodological considerations. Crit Rev Toxicol. 2009;39:613–26. [DOI] [PubMed]

129.

de Oliveira VVG, Aranda de Souza MA, Cavalcanti RRM, de Oliveira Cardoso MV, Leite ACL, da Silva Junior VA, et al. Study of in vitro biological activity of thiazoles on Leishmania (Leishmania) infantum. J Glob Antimicrob Resist. 2020;22:414–21. [DOI] [PubMed]

130.

Chauhan IS, Rao GS, Shankar J, Chauhan LKS, Kapadia GJ, Singh N. Chemoprevention of Leishmaniasis: In-vitro antiparasitic activity of dibenzalacetone, a synthetic curcumin analog leads to apoptotic cell death in Leishmania donovani. Parasitol Int. 2018;67:627–36. [DOI] [PubMed]

131.

Chaubey P, Mishra B, Mudavath SL, Patel RR, Chaurasia S, Sundar S, et al. Mannose-conjugated curcumin-chitosan nanoparticles: Efficacy and toxicity assessments against Leishmania donovani. Int J Biol Macromol. 2018;111:109–20. [DOI] [PubMed]

132.

Asthana S, Jaiswal AK, Gupta PK, Pawar VK, Dube A, Chourasia MK. Immunoadjuvant chemotherapy of visceral leishmaniasis in hamsters using amphotericin B-encapsulated nanoemulsion template-based chitosan nanocapsules. Antimicrob Agents Chemother. 2013;57:1714–22. [DOI] [PubMed] [PMC]

133.

Salah-Tazdaït R, Tazdaït D, Harrat Z, Eddaikra N, Moulti-Mati F, Abdi N, et al. Antileishmanial activity of low molecular weight chitin prepared from shrimp shell waste. In: Mendes-Vilas A, editor. Multidisciplinary Approaches for Studying and Combating Microbial Pathogens. Boca Raton: Formatex Research Center; 2015. pp. 39–43.

134.

El Hajj R. Efficacité d’un analogue d’Imiqualines, l’EAPB0503 : Un nouveau traitement prometteur contre la Leishmaniose Cutanée [dissertation]. Université Montpellier; 2018. French.

135.

Hoseini MH, Moradi M, Alimohammadian MH, Shahgoli VK, Darabi H, Rostami A. Immunotherapeutic effects of chitin in comparison with chitosan against Leishmania major infection. Parasitol Int. 2016;65:99–104. [DOI] [PubMed]

136.

Marques CSF, Barreto NS, Oliveira SSC, Santos ALS, Branquinha MH, Sousa DP, et al. β-Cyclodextrin/Isopentyl Caffeate Inclusion Complex: Synthesis, Characterization and Antileishmanial Activity. Molecules. 2020;25:4181. [DOI] [PubMed] [PMC]

137.

Oliveira SSC, Marques CSF, de Sousa DP, Andrade LN, Fricks AT, Jain S, et al. Analysis of the mechanisms of action of isopentenyl caffeate against Leishmania. Biochimie. 2021;189:158–67. [DOI] [PubMed]

138.

J B, M BM, Chanda K. An Overview on the Therapeutics of Neglected Infectious Diseases—Leishmaniasis and Chagas Diseases. Front Chem. 2021;9:622286. [DOI] [PubMed] [PMC]

139.

Freitas CS, Lage DP, Oliveira-da-Silva JA, Costa RR, Mendonça DVC, Martins VT, et al. In vitro and in vivo antileishmanial activity of β-acetyl-digitoxin, a cardenolide of Digitalis lanata potentially useful to treat visceral leishmaniasis. Parasite. 2021;28:38. [DOI] [PubMed] [PMC]

140.

Bilbao-Ramos P, Serrano DR, Ruiz Saldaña HK, Torrado JJ, Bolás-Fernández F, Dea-Ayuela MA. Evaluating the Potential of Ursolic Acid as Bioproduct for Cutaneous and Visceral Leishmaniasis. Molecules. 2020;25:1394. [DOI] [PubMed] [PMC]

141.

Huang W, Percie du Sert N, Vollert J, Rice ASC. General Principles of Preclinical Study Design. Handb Exp Pharmacol. 2020;257:55–69. [DOI] [PubMed] [PMC]

142.

Nascimento NRFD, Aguiar FLN, Santos CF, Costa AML, Hardoim DJ, Calabrese KDS, et al. In vitro and in vivo leishmanicidal activity of a ruthenium nitrosyl complex against Leishmania (Viannia) braziliensis. Acta Trop. 2019;192:61–5. [DOI] [PubMed]

143.

Horiuchi K, Shiota S, Hatano T, Yoshida T, Kuroda T, Tsuchiya T. Antimicrobial activity of oleanolic acid from Salvia officinalis and related compounds on vancomycin-resistant enterococci (VRE). Biol Pharm Bull. 2007;30:1147–9. [DOI] [PubMed]

144.

Bekhit AA, Hassan AM, Abd El Razik HA, El-Miligy MM, El-Agroudy EJ, Bekhit Ael-D. New heterocyclic hybrids of pyrazole and its bioisosteres: Design, synthesis and biological evaluation as dual acting antimalarial-antileishmanial agents. Eur J Med Chem. 2015;94:30–44. [DOI] [PubMed]

145.

Quintal S, Morais TS, Matos CP, Paula Robalo M, Piedade MFM, Villa de Brito MJ, et al. Synthesis, structural characterization and leishmanicidal activity evaluation of ferrocenyl N-heterocyclic compounds. J Organomet Chem. 2013;745-746:299–311. [DOI]

146.

Mandlik V, Patil S, Bopanna R, Basu S, Singh S. Biological Activity of Coumarin Derivatives as Anti-Leishmanial Agents. PLoS One. 2016;11:e0164585. [DOI] [PubMed] [PMC]

147.

Shaquiquzzaman M, Verma G, Marella A, Akhter M, Akhtar W, Khan MF, et al. Piperazine scaffold: A remarkable tool in generation of diverse pharmacological agents. Eur J Med Chem. 2015;102:487–529. [DOI] [PubMed]

148.

Al Nasr IS, Jentzsch J, Shaikh A, Singh Shuveksh P, Koko WS, Khan TA, et al. New Pyrano-4H-benzo[g]chromene-5,10-diones with Antiparasitic and Antioxidant Activities. Chem Biodivers. 2021;18:e2000839. [DOI] [PubMed]