Vaccines and Treatments

VACCINES:
Currently there are no drugs or vaccines for the prevention of Leishmaniasis. Leishmaniasis is an intracellular infection. Ideally a vaccine would illicit a strong Th1 response as a Th2 response has been implicated in chronic, non-healing disease. Live-attenuated candidates have been proven to create this kind of response, but the dangers associated with them have hindered their use. With the help of adjuvants and cytokines, whole-killed vaccines seem show great promise.

Whole-killed Leishmaniasis:
Currently, the most successful vaccine attempts in humans has been achieved with whole-killed leishmania promastigotes. Phase III clinical trials in the Middle East and South America with an autoclaved Leishmania and BCG have proven to be effective at reducing the incidence of cutaneous leishmaniasis. Reported efficacy rates range from 18% to 78% (Sharifi, 1998; Antunes, 1986). Evidence also suggests that the Leishmania major creates a certain degree of cross-protection to Leishmania donovani, the parasite implicated in the deadly visceral leishmaniasis (O'Daly JA, 1993).

The vaccine seems to boost IFN-gamma and T-cell production, inducing a strong Th1 response. This strong Th1 response may also explain cross-protection to another intracellular parasite Trypanosoma cruzi (Araujo, 1999) and it may account for its proven therapeutic qualities for individuals and mice infected with cutaneous Leismaniasis. It has been shown to have similar cure rates as standard antimonial regimens with fewer side effects (Convit, 1987).

Unfortunately, the autoclaved parasite shows decreasing efficacy with time. Studies of efficacy with thimerosal-preserved and nonautoclaved preparations have shown to keep better (De-Luca, 1999).

Live-attenuated:
Historically, protection from cutaneous leishmaniasis was achieved by taking the pus from a healing lesion and innoculating a naive recipient in an inconspicuous location. This crude version of a live-attenuated vaccine conferred protection upon the host, however serious disease was occasionally a complication. Both protection and disease stem from the parasites ability to get inside the cells and stimulate a cell-mediated T-cell response. Radioattenuated promasitigotes and biochemically altered Leishmanial parasites have proven to confer very good protection in mice and hamsters without adjuvant (Rivier, 1999). Unfortunately, live cultures of Leishmaniasis are hard to sustain and there is always the concern of reversion to a virulent strain.

Synthetic Peptide:
A single synthetic T-cell epitope from gp63 administered with Th1 stimulating poloxamer 407 conferred protection against Leishmania major in BALB/c mice (Spitzer, 1999).

Other:
Infection of mice with adenovirus expressing IL-12 skews the immune response in a Th1 direction preventing leishmaniasis in susceptible mice (Gabaglia, 1999).

Antibodies produced against Liposphoglycan (LPG) may prove to be effective in limiting the transmission of cutaneous leishmaniasis in its vector Phlebotomus dubosqi (Tonui, 1999).
 
 

TREATMENTS:
The drugs of choice today are the same compounds that were used in the early 1900s and their mechanisms of function are not completely understood. They are all extremely toxic, and the patient must be monitored closely during treatment.
 

Pentavalent Antimony Compounds:
Pentavalent antimony coumpounds, derived from the heavy metal antimony (Sb), are the drugs of choice for treating cutaneous and visceral Leishmaniasis. The recommended dosages follow:
 
 

Disease	Dose	Duration
cutaneous leishmaniasis	20 mg Sb/kg/day	20 days
mucocutaneous leishmaniasis	20 mg Sb/kg/day	28 days
visceral leishmaniasis	20 mg Sb/kg/day	28 days

Studies have shown that longer courses prove more effective in preventing relapse, however they also increase the risk of drug-related toxicity. Further complicating the issue is that parasite resistivity seems to be increasing and  relapse rates in some areas have been reported as high as 50%-70% with mucocutaneous leishmaniasis and 10% with visceral leishmaniasis.

Side effects include: Cardiotoxicity, reversible renal insufficience, pancreatitis, anemia, leukopenia, rash, headache, abdominal pain, nausea, vomiting, arthralgia, myalgia, thrombocytopenia, and transaminase elevation.

Amphotericin B:
Amphotericin B has been shown to be more effective than pentavalent antimony in vitro, but has not been used extensively in the past due to extreme toxicity. However, more recent developments have made Amphotericin B less toxic and more useful. It has also become useful in treating strains of visceral leishmaniasis causing organisms that are resistant to pentavalent anitmony. Amphotericin B cannot be used in the treatment of mucocutaneous leishmaniasis because very large doses are required.

Side effects include: fever nausea, vomiting malaise, anemia, phlebitis, hypokalemia, hypomagnesemia, and nephrotoxity.

Pentamidine Isoethionate:
Pentamidine isethionate is a general anti-parasitic drug that has demonstrated some success with the treatment of viceral leishmaniasis. Unfortunately the cure rate has declined from the early 1980s to the 1990s due to resistance of Leishmania to pentamide. Nonetheless, it can be used as a second-line agent in the event that the pentavalent antimony compounds fail.

Side effects include: nausea, vomiting, abdominal pain, and headache.

Other Agents:
The following drugs and therapeutic approaches seem promising and are currently being studied, but have not been approved for general use.

cytokine therapy: Cytokines such as interferon gamma and granulocyte macrophage colony-stimulating factors are being used in combination and with pentavalent antimony in attempts to enhance reponse.

miltefosine: An oral drug for visceral leishmaniasis is showing progress in studies. Apparently it is less toxic and exhibits higher cure rates than traditional drugs. Furthermore, a cheap, orally administered treatment would be extremely beneficial for the people most affected by leishmaniasis (WHO, 1999).
 

References:
Antunes CM, Mayrink W, Magalhaes PA, Costa CA, Melo MN, Dias M, Michalick MS, Williams P, Lima AO, Vieira JB, et al. Controlled field trials of a vaccine against New World cutaneous leishmaniasis. Int J Epidemiol. 1996 Dec;15(4):572-80.

Araujo Z, El Bouhdidi A, Heremans H, Van March E, Castes M, Carlier Y. Vaccination of mice with a combination of BCG and killed Leishmania promastigotes reduces acute Trypanosoma cruzi infection by promoting INF-gamma response. Vaccine. 1999 Feb 26;17(7-8):957-64.

Convit J, Castellanos PL, Rondon A, Pinardi ME, Ulrich M, Castes M, Bloom B, Garcia L. Immunotherapy versus chemotherapy in localized cutaneous leishmaniasis. Lancet. 1987 Feb 21;1(8530):401-5.

De-Luca PM, Mayrink W, Alves CR, Coutinho SG, Oliveira MP, Bertho AL, Toledo VP, Costa CA, Genaro O, Mendonsca SC. Evaluation of the stability and immunogenicity of autoclaved and nonautoclaved preparations of a vaccine against American tegumentary leishmaniasis. Vaccine. 1999 Mar 5;17(9-10):1179-85.

Gabaglia CR, Pederson B, Hitt M, Burdin N, Sercarz EE, Graham FL, Gauldie J, Braciak TA. A single intramuscular injection with adenovirus expressing IL-12 protects BALB/c mice against Leishmania major infection, while treatmentwith an IL-4 expressing vector increases disease susceptibility in B10.D2 mice. J Immunol. 1999 Jan 15;162(2):753-60.

Lee MB, Gilbert HM. Current Approaches to Leishmaniasis. Infect Med 1999;16(1):34,37-45. http://www.medscape.com/SCP/IIM/1999/v16.n01/m3148.lee/pnt-m3148.lee.html

Modabber F. Development of vaccines against leishmaniasis. Scand J Infect Dis Suppl. 1990;76:72-8.

O'Daly JA. A comparison of the molecular biology of trypanosomes and leishmaniae, and its impact on the development of methods for the diagnosis and vaccination of leishmaniasis and Chagas disease. Biol Res. 1993;26(1-2):219-24.

Rivier D, Bovay P, Shah R, Didisheim S, Mauel. Vaccination against Leishmania major in a CBA mouse model of infection: role of adjuvants and mechanism of protection. Parasite immunol. 1999 Sep;21(9):461-73.

Sharifi I, FeKri AR, Aflatonian MR, Khamesipour A, Nadim A, Mousavi MR, Momeni AZ, Dowlati Y, Godal T, Zicker F, Smith PG, Modabber F. Randomized vaccine trial of single dose of killed Leishmania major plus BCG against anthroponotic cutaneous leishmaniasis in Bam, Iran. Lancet. 1998 May 23;351(9115):1540-3.

The Special Programme for Research and Training in Tropical Diseases. Leishmaniasis. http://www.who.int/tdr/diseases/leish/default.htm

Spitzer N, Jardim A, Lippert D, Olafson RW. Long-term protection of mice against Leishmania major with a synthetic peptide vaccine. Vaccine. 1999 Mar 17;17(11-12):1298-300.

Tonui WK. Leishmania transmission-blocking vaccines: a review. East Afr Med J. 1999 Feb;76(2)93-6.

WHO. Leishmaniasis. Communicable Disease Surveillance and Response. http://www.who.int/emc/diseases/leish/leisgeo.html