LEISHMANIASIS IN HUMANS

DRUG OR VACCINE THERAPY

OBJECTIVES:
• INTRODUCTION ON LEISHMANIASIS.
• INFORMATION ON SANDFLIES.
• HISTORY OF LEISHAMNIA.
• LIFE CYCLE OF LEISHMANIA PARASITE.
• DRUGS CURRENTLY USED FOR LEISHMANIASIS.
• VACCINE METHODS CURRENTLY USED FOR LEISHMANIASIS.
• ROLE OF IMMUNITY TO RESIST THE DISEASE.
• PREVENTION AND CONTROL OF LEISHMANIASIS
• RECENT ADVANCES IN LEISHMANIASIS TREATMENT
LEISHMANIASIS:

• LEISHMANIASIS IS CAUSED BY AN INTRACELLULAR PROTOZOAN PARASITE

TRANSMITTED TO HUMANS BY THE BITE OF A SAND FLY.
• IT’S AN ENDEMIC DISEASE USUALLY SPREAD IN ASIA, AFRICA, THE
AMERICAS AND THE MEDITERRANEAN REGION.
• WORLDWIDE, 1.5 TO 2 MILLION NEW CASES OCCUR EACH YEAR, 350
MILLION ARE AT RISK OF ACQUIRING THE DISEASE, AND LEISHMANIASIS
CAUSES 70,000 DEATHS PER YEAR.
 CLINICAL PICTURE:
-THE CLINICAL SPECTRUM OF LEISHMANIASIS RANGES FROM A SELF-
RESOLVING CUTANEOUS ULCER TO A MUTILATING MUCOCUTANEOUS
DISEASE AND EVEN TO A LETHAL SYSTEMIC ILLNESS.
-FOR THOSE WHO LACK IMMUNE RESPONSE TO PARASITE
ANTIGENS MIGHT SUFFER WITH THE DISSEMINATION OF THE
PARASITE THROUGH TISSUE, LYMPH, AND BLOOD PATHWAYS,
DEVELOPING LESIONS IN MOST OF THE SKIN.

Early self-resolving cutaneous

ulcer
HOSTS OF THE LEISHMANIA PARASITE:

AS IT’S KNOWN EACH PARASITE HAS DIFFERENT TYPES OF HOSTS AND FOR
THE LEISHMANIA PARASITE IT HAS 3 DIFFERENT TYPES OF HOSTS:
• DEFINITIVE HOST: MAN
• VECTOR: SANDFLIES
• RESERVOIR HOST: RODENTS, DOGS, CATS AND FOXES
SANDFLIES:
• IT’S A VERY SMALL INSECT WHOSE SIZE DOES NOT EXCEED A THIRD OF
THE SIZE OF THE REGULAR MOSQUITO.
• IT’S YELLOW IN COLOR AND TRANSMITS BY LEAPING, DOES NOT MAKE
SOUND SO IT MAY STING THE PERSON WITHOUT FEELING IT.
• IT IS PRESENT IN ALL SEASONS OF THE YEAR EXCEPT WINTER AND IT IS
ACTIVE AT NIGHT.
• HOWEVER, DURING THE DAY IT SETTLES IN THE INTERNAL CRACKS OF
THE WALLS OF HOUSES AND IN THE ANIMAL BURROWS SUCH AS
RODENTS AND FOXES AND IN THE TRUNKS OF TREES FOR REST, WHICH
MAKE THEM SO HARD TO FIND DURING THE DAY AND GIVE THEM THE
ADVANTAGE TO INFECT MAN.
• SANDFLIES ONLY CARRY THE LEISHMANIA PARASITE WHEN THEY SUCK
BLOOD FROM AN INFECTED MAN OR ANIMAL.
• THEY ARE CONSIDERED THE VECTOR OF LEISHMANIA PARASITE WHERE
BIOLOGICAL CHANGES OR MULTIPLICATION OF PARASITE TAKES PLACE
INSIDE THE ARTHROPOD.
HISTORY OF LEISHMANIA

• IN DUM DUM, A TOWN NEAR CALCUTTA IN INDIA, LEISHMAN DISCOVERED

OVOID BODIES IN THE SPLEEN OF A BRITISH SOLDIER WHO WAS
EXPERIENCING BOUTS OF FEVER, ANEMIA, MUSCULAR ATROPHY AND
SWELLING OF THE SPLEEN. LEISHMAN DESCRIBED THIS ILLNESS AS “DUM
DUM FEVER” AND PUBLISHED HIS FINDINGS IN 1903.

The soldier named Donovan and Leishman

 SPECIES OF LEISHMANIA
• AS MENTIONED BEFORE THERE ARE MANY SPECIES FOR THE LEISHMANIA
PARASITE, HOWEVER THERE ARE TWO MAIN SPECIES L.DONOVANI AND
L.BRAZILIENSIS.

L. donovani Asia – Africa Visceral, muco-

(middle east) cutaneous,
cutaneous,
dermal
L. braziliens Central and Cutaneous, Dermal
South America muco-
cutaneous

Cutaneous
LIFE CYCLE OF LIESHMANIA PARASITE

Amastigote

Promastigote
SOME DRUGS WHICH USED FOR
TREATMENT OF LEISHMANIASIS
SODIUM STIBOGLUCONATE

• SODIUM STIBOGLUCONATE, SOLD UNDER THE BRAND

NAME PENTOSAM AMONG OTHERS IS A MEDICATION

USED TO TREAT LEISHMANIASIS. THIS INCLUDES

LEISHMANIASIS OF THE CUTANEOUS, VISCERAL AND

MUCO-CUTANEOUS.
PAROMOMYCIN
• THERE ARE SOME DEVELOPED CREAMS WHICH CONTAIN
PAROMOMYCIN.

• IT’S USED AS A TOPICAL CREAM ON THE AFFECTED AREA TWICE A

DAY FOR 10 DAYS.
THE EFFECT OF THE
CREAM ON ONE OF
LEISHMANIASIS CASES
VACCINE METHODS
THAT HAVE BEEN
APPLIED FOR
LEISHMANIASIS
 There is no perfect vaccine or suitable drug to
eradicate leishmaniasis completely.

 So far, no vaccine or drug has been provided to

induce long-term protection and ensure
effective immunity against leishmaniasis.

 However, vaccination can provide long-term

protection against disease and also works on
infectious reservoirs to reduce transmission of
infection.
Therefore, extensive vaccination programs are
required to reduce the incidence of leishmaniasis,
the perfect vaccine is yet to be produced.
 MANY STUDIES HAVE SHOWN THAT SAND FLY HAS IMMUNOGENIC
PROTEINS IN SALIVA, WHICH COULD INDUCE IMMUNE RESPONSES AS AN
ADJUVANT. IN RODENT MODELS OF INFECTION, SALIVARY MOLECULES
COULD INDUCE IMMUNITY TO PROTECT AGAINST BOTH CL AND VL.
 IN FACT, WE FOUND THAT VACCINE PREPARATION NEEDS TO ADOPT AN
OPTIMUM ADJUVANT FOR ENHANCING IMMUNOGENICITY. FORMULATING
VACCINE WITH AN ADJUVANT WILL DETERMINE WHAT KIND OF IMMUNITY IS
GENERATED. THE BEST ADJUVANT STIMULATES BOTH HUMORAL AND
CELLULAR IMMUNE RESPONSES.
 IN A CLINICAL TRIAL, L. MAJOR (ALM) AUTOCLAVED AS A VACCINE IN A
DOUBLE-RANDOMIZED TRIAL. THEY SHOWED THAT ALM DOES NOT HAVE
ANY SIGNIFICANT PROTECTIVE IMMUNITY. HOWEVER, ADOPTION OF
SUITABLE ADJUVANT WOULD BE HELPFUL TO INDUCE THE MAXIMUM
PROTECTIVE IMMUNITY WITH THE MINIMUM SIDE EFFECT .
 IN ANOTHER STUDY, RECOMBINING LEISHMANIA POLY-PROTEIN LEISH-F1
ANTIGEN PLUS MZPL-SE AS AN ADJUVANT IN THE CLINICAL TRIAL. THEY
SHOWED THAT THE VACCINE WAS SAFE AND CAN INDUCE T-CELL
PRODUCTION OF IFN-Γ. RESULTS OF THE CLINICAL TRIAL SHOWED THAT
THIS VACCINE IS IMMUNOGENIC AND SAFE IN HEALTHY INDIVIDUALS WITH
AND WITHOUT PREVIOUS HISTORY OF INFECTION.
 SIDE EFFECTS OF AN ADJUVANT, SUCH AS TOXICITY, SHOULD BE NOTED
FOR THE FORMULATION OF THE VACCINE. STUDIES HAVE SHOWN THAT
ADJUVANTS ADOPTED FOR VACCINE FORMULATION ARE CONSIDERABLY
IMPORTANT BECAUSE SOME ADJUVANTS COULD SHIFT IMMUNE
RESPONSES TO DIFFERENT PATHWAYS.
FIRST-GENERATION VACCINES:
1)VACCINES MADE OF WHOLE KILLED PARASITES.
2)CAN BE PRODUCED WITH LOW COST IN DEVELOPING COUNTRIES.
3)THREE FORMS OF VACCINES CONSISTING OF L. MAJOR, LEISHMANIA AMAZONENSIS, AND
L. MEXICANA WERE EVALUATED BY FIRST-GENERATION VACCINES OF HUMAN CLINICAL TRIALS.
TWO MAIN VACCINES WERE APPRAISED IN THE WORLD. ONE OF THEM WAS PENTAVALENT
PREPARATION IN BRAZIL.
PARASITE INACTIVATION WAS PERFORMED USING MERTHIOLATE AND THE VACCINE, KNOWN AS
LEISHVACCINE, WAS WITHOUT ANY ADJUVANT. THE OTHER WAS A PREPARATION OF
AUTOCLAVED SIMILAR VACCINE, WHICH GAVE THE SAME RESULTS OF IMMUNOGENICITY AS
WELL. L. MEXICANA MIXED WITH BACILLUS CALMETTE–GUÉRIN (BCG) ADJUVANT WAS
PRODUCED IN VENEZUELA AND UTILIZED AS AN IMMUNOTHERAPY APPROACH IN PATIENTS
WITH CL.

SECOND-GENERATION VACCINE:
1)THIS CLASSIFICATION INCLUDES GENETICALLY MODIFIED VACCINES IN WHICH ESSENTIAL
GENES SUCH AS THYMIDYLATE SYNTHASE, DIHYDROFOLATE REDUCTASE, CYSTEINE
PROTEINASE, AND BIOPTERIN TRANSPORTER WERE KNOCKED OUT. IT IS THOUGHT THAT THE
MAIN AIM OF THE SECOND-GENERATION VACCINE WAS TO INVOLVE PURIFIED LEISHMANIA TO
THEIR EXTRACTS.
2)THE FIRST DESIGNED VACCINE FOR CANINE VL, WHICH CONSISTED OF PURIFIED L.
DONOVANI, IS CALLED LEISHMUNE. FRUCTOSE MAN-NOSE LIGAND (FML) AND SAPONINS AS AN
ADJUVANT WERE UTILIZED FOR THE GENERATION OF THIS VACCINE.
3)USE OF RECOMBINANT PROTEINS IS THE LAST STRATEGY IN THE SECOND-GENERATION
THIRD-GENERATION VACCINE:
 STUDIES HAVE SHOWN THAT DNA VACCINES ARE MUCH MORE STABLE
THAN RECOMBINANT PROTEIN VACCINES AND THEY ALSO HAVE A LOWER
COST OF PRODUCTION COMPARED WITH OTHER VACCINES , MODE OF
ACTION IN DNA VACCINES IS PERFORMED BY GENERATION OF IMMUNE
RESPONSES THROUGH ACTIVATION OF INNATE IMMUNITY, WHICH, IN
SEQUENCES OF NONMETHYLATED CPG OF BACTERIA, ARE ENGAGED AND
HIGH REPLICATION WITHIN THE HOST COULD LEAD TO EXPRESSION OF
THE RECOMBINANT PROTEINS FOR A LONGER PERIOD AND WITH NATIVE
CONFORMATION.
AS A RESULT, THE SECOND GENERATION WITH NATIVE ANTIGENS
COULD INCREASE AVERAGE VACCINE EFFICACY VALUE REMARKABLY.
THEREFORE, MORE STUDIES AND CLINICAL TRIAL IN PHASE III WILL
BE CONDUCTED IN NEAR FUTURE.
ROLE OF IMMUNITY TO RESIST THE
DISEASE
• LET’S NOT FORGET THAT OUR HUMAN BODY WOULD ALSO HAVE ITS OWN
DEFENSE AGAINST LEISHMANIASIS WHICH IS THE IMMUNE SYSTEM.
• THE IMMUNE SYSTEM INCLUDE TWO ELEMENTS: -THE INNATE SYSTEM -THE
ADAPTIVE SYSTEM.

THE COMPLEMENT SYSTEM:

• SUSCEPTIBILITY OF LEISHMANIA PARASITES TO COMPLEMENT-MEDIATED
LYSIS IN VITRO IS DIRECTLY RELATED TO THE CONCENTRATION OF SERUM.
• ALTHOUGH THE CLASSICAL PATHWAY OF THE COMPLEMENT SYSTEM IS
ACTIVATED BY LEISHMANIA, COMPLEMENT-MEDIATED DESTRUCTION OF
PARASITES IS GENERALLY AMPLIFIED BY THE ALTERNATE PATHWAY.
• SOME LEISHMANIA SPECIES MIGHT ACTIVELY RESIST THIS PROCESS.
CELLS OF INNATE IMMUNITY:
• NEUTROPHILS ARE THE FIRST HOST CELLS TO REACH THE SITE OF
LEISHMANIA INFECTION WITHIN A FEW HOURS OF INOCULATION BY A
SANDFLY BITE LIKE PREVIOUSLY MENTIONED.

• THEY ACTIVELY ENGULF THE PROMASTIGOTES AND PRODUCE SOME

MICROBICIDAL FACTORS AGAINST LEISHMANIA SUCH AS NITRIC OXIDE.
• EARLY DURING THE INFECTION, NK CELLS CAN MEDIATE DIRECT
PARASITE LYSIS THROUGH ITS CYTOTOXIC ACTIVITY.
CELLS OF ADAPTIVE IMMUNITY:
• LYMPHOCYTES ARE INVOLVED IN ADAPTIVE IMMUNE RESPONSES TO LEISHMANIA
INFECTION, PRIMARILY THROUGH THE ELABORATION OF CYTOKINES THAT
ACTIVATE OR DAMPEN THE ANTIPARASITIC ACTIVITY OF MACROPHAGES.
• T-CELLS PLAY A MAJOR ROLE IN IMMUNITY TO THE VARIOUS FORMS OF
LEISHMANIA BY DIFFERENTIATING TO -HELPER T-CELLS -CYTOTOXIC T-CELLS.
 CYTOKINES AND CHEMOKINES:
CYTOKINES ARE PRODUCED BY IMMUNE OR INFECTED CELLS AND EXERT THEIR
FUNCTION BY ACTIVATING OTHER CALLS TO RELEASE MOLECULES THAT INHIBIT OR
FAVOR THE GROWTH OF LEISHMANIA.
CHEMOKINES AND CHEMOKINE RECEPTORS ARE INVOLVED IN TRAFFICKING OF
IMMUNE CELLS TO INFLAMMATORY SITES.
 PREVENTION & CONTROL

AS PREVIOUSLY MENTIONED, NO EFFECTIVE VACCINES

OR DRUGS ARE YET PRESENT TO PREVENT INFECTION
OF LEISHMANIASIS. THE BEST WAY FOR TRAVELERS TO
PREVENT INFECTION IS TO PROTECT THEMSELVES FROM
SAND FLY BITES. TO DECREASE THE RISK OF BEING
BITTEN, FOLLOW THESE PREVENTIVE MEASURES:
WHEN OUTDOORS:
• AVOID OUTDOOR ACTIVITIES, ESPECIALLY FROM DUSK TO DAWN,
WHEN SAND FLIES GENERALLY ARE THE MOST ACTIVE.
• MINIMIZE THE AMOUNT OF EXPOSED (UNCOVERED) SKIN. WEAR
LONG-SLEEVED SHIRTS, LONG PANTS, AND SOCKS.
• APPLY INSECT REPELLENT TO EXPOSED SKIN AND UNDER THE ENDS
OF SLEEVES AND PANT LEGS. THE MOST EFFECTIVE REPELLENTS
GENERALLY ARE THOSE THAT CONTAIN THE CHEMICAL DEET (N,N-
DIETHYLMETATOLUAMIDE).
 WHEN INDOORS:

• STAY IN WELL-SCREENED OR AIR-CONDITIONED AREAS.

• SPRAY ALL AREAS WITH AN INSECTICIDE TO KILL INSECTS.
• KEEP IN MIND THAT SAND FLIES ARE MUCH SMALLER THAN MOSQUITOES
AND THEREFORE CAN GET THROUGH SMALLER HOLES.
• IF YOU ARE NOT SLEEPING IN A WELL-SCREENED OR AIR-CONDITIONED AREA,
USE A BED NET AND TUCK IT UNDER YOUR MATTRESS.
 RECENT ADVANCES IN
LEISHMANIASIS TREATMENT
 CURRENT TREATMENT AND RECENT ADVANCES

• CHEMOTHERAPY STILL RELIES ON

THE USE OF PENTAVALENT
ANTIMONIALS, AMPHOTERICIN B,
PAROMOMYCIN, MILTEFOSIN AND
LIPOSOMAL AMPHOTERICIN B.
HOWEVER, THE APPLICATION OF
THESE DRUGS IS LIMITED DUE TO
LOW EFFICACY, LIFE-THREATENING
SIDE EFFECTS, HIGH TOXICITY,
INDUCTION OF PARASITE
RESISTANCE, LENGTH OF
TREATMENT AND HIGH COST.
 OTHER TREATMENT APPROACHES

• COMBINATION THERAPY OF ANTI-LEISHMANIAL DRUGS IS CURRENTLY CONSIDERED AS ONE

OF THE MOST RATIONAL AND PROMISING APPROACHES THAT HAS ADVANTAGES SUCH AS
REDUCED TOXICITY, SYNERGIC EFFECTS, LIMITED DRUG RESISTANCE DEVELOPMENT, LOW
TREATMENT FAILURE RATE, AND SHORTER TREATMENT REGIMENS.
• ALSO A METHOD FOR IMPROVING A DRUG’S ANTI-LEISHMANIAL EFFICACY IS NANONIZATION.
THIS APPROACH IS IDENTIFIED AS FOREIGN BODIES/NANOPARTICLES PHAGOCYTOZED BY THE
MACROPHAGES ALLOWING TARGETED DRUG DELIVERY.
• ANOTHER SIMPLE AND COST-EFFECTIVE MODALITY FOR IMPROVING THE TREATMENT WITH
ANTIMONY COMPOUNDS IS THERMOTHERAPY. THE POTENTIAL MECHANISM OF ACTION OF
THIS METHOD IS PROBABLY DIRECT DESTRUCTION OF PARASITES BY HEAT.
  PLANTS AS MEDICINE FOR LEISHMANIASIS
• ESSENTIAL OILS DERIVED FROM THYMUS CAPITELLATUS HAVE ANTI-LEISHMANIAL ACTIVITY WITHOUT
SIGNIFICANT CYTOTOXICITY AGAINST MACROPHAGES. IN ADDITION TO THE ANTI-LEISHMANIAL ACTIVITY
OF THESE ESSENTIAL OILS, THEY HAVE ALSO SHOWN INSECTICIDAL ACTIVITY, WHICH IS EXTREMELY
IMPORTANT IN THE CONTROL OF SANDFLIES AND LEISHMANIASIS
• ESSENTIAL OILS DERIVED FROM PLANTS SUCH AS CROTON CAJUCARA (RED SACACA) HAVE
IMMUNOMODULATORY EFFECTS AND THIS MAKES THEM USEFUL IN THE TREATMENT OF LEISHMANIASIS.

Thymus capitellatus Croton cajucara