A Study of the Efficacy and Safety of the LEISH-F2 + MPL-SE Vaccine for Treatment of Cutaneous Leishmaniasis

A phase 2, randomized, open-label, controlled study to evaluate the efficacy, safety, and immunogenicity of the vaccine administered three times (10 μg LEISH-F2 + 25 μg MPL-SE on Days 0, 28 and 56) in the treatment of adults and adolescents with CL compared to treatment with standard chemotherapy (20 mg/kg/day sodium stibogluconate for 20 days). The proportion cured in each group will be determined using clinical criteria.

• LEISH-F2 + MPL-SE (Biological), also known as There are no other names for the vaccine.: 10 μg LEISH-F2 + 25 μg MPL-SE on Days 0, 28 and 56
• Sodium stibogluconate (Drug), also known as Marfan SSG: 20 mg/kg/day IV daily for 20 days

Primary outcomes

• Date of Clinical Cure [Day 84]: Efficacy of immunotherapy with the LEISH-F2 + MPL-SE vaccine was compared to the efficacy of chemotherapy with sodium stibogluconate in the treatment of CL. Efficacy is measured by the date of clinical cure.
• Adverse Events of Grade 1 Severity or Higher Occurring in ≥ 3 Patients During Active Treatment Phase of the Study. [Day 0 through Day 84]: Safety of immunotherapy with the vaccine was compared to the safety of chemotherapy with sodium stibogluconate. All adverse events are listed regardless of relatedness.

Secondary outcomes

• IgG Antibodies and T-cell Cytokine Responses (IFN-g and IL-10) [Days 0, 56 or 84, and 168]: Immunogenicity of the vaccine was evaluated by measuring IgG antibody and T-cell responses to the LEISH-F2 protein and soluble Leishmania antigen (SLA). IgG antibodies were measured by ELISA and T-cell cytokine responses (IFN-g and IL-10) were measured by Luminex. Data is presented as median Post:Pre ratios comparing Days 56/84 or 168 to baseline at Day 0.

Sex: All, ages: 18 Years to 70 Years

Inclusion Criteria:

* Males and females ≥ 12 years and < 70 years of age. In the first stage of the study, only patients aged ≥ 18 years and < 70 years will be enrolled. In the second stage, enrollment will also include adolescent patients aged ≥ 12 - < 18 years.
* Must have a clinical diagnosis of cutaneous leishmaniasis confirmed by positive identification of Leishmania parasite and identification of L. peruviana by PCR.
* Lesions must be clear of any superinfection prior to enrollment.
* Female patients of childbearing age must have a negative serum pregnancy test at screening, a negative urine pregnancy test within 24 hours before the first vaccination or initiation of chemotherapy, must not be breast-feeding, and are required to use adequate contraception through Day 84 of the study. These precautions are necessary due to unknown effects that LEISH-F2 + MPL SE, sodium stibogluconate might have in a fetus or newborn infant.
* The following laboratory blood tests must have values within the normal ranges at screening: sodium, potassium, urea, total bilirubin, ALT, AST, glucose, creatinine, alkaline phosphatase, total WBC count and platelet count. Hemoglobin may exceed the ULN since patients reside in the Andes at very high altitude (up to 20 g/dL)
* The following serology tests must be negative at screening: HIV-1/2, hepatitis B surface antigen (HBsAg), and hepatitis C virus (HCV) antibody. All patients (or their parents) will receive HIV-related counseling prior to testing. Patients with positive HIV test results will be referred for counseling and treatment as appropriate.
* Potential study patients (or their guardians) must give written informed consent, be willing to be housed in Lima for a minimum of 20 days and up to 63 days, able to attend all required follow-up visits, have a permanent address, and be reachable by study site personnel.

Exclusion Criteria:

* Infection with species other than L.peruviana as confirmed by PCR.
* Presence of eleven or more active cutaneous leishmaniasis lesions.
* The diameter of the ulcerated area of any single lesion is >60 mm.
* Presence of lesions with superinfection at time of enrollment.
* History of mucocutaneous leishmaniasis or diagnosis of mucocutaneous leishmaniasis at screening.
* History of previous exposure to Leishmania vaccines.
* Known use of injected or oral corticosteroids within 6 weeks prior to the first vaccination or initiation of chemotherapy.
* Participation in another experimental protocol or receipt of any investigational products within 30 days prior to the first vaccination or initiation of chemotherapy.
* History of autoimmune disease or other causes of immunosuppressive states.
* History or evidence of any acute or chronic illness that, in the opinion of the study clinician, may interfere with the evaluation of the safety or the immunogenicity of the vaccine. (Patients presenting with concomitant illness will be referred for standard clinical care).
* History of use of any medication that, in the opinion of the study clinician, may interfere with the evaluation of the safety or the immunogenicity of the vaccine.
* History of significant psychiatric illness.
* Drug addiction including alcohol abuse.
* Patients with a history of previous anaphylaxis, severe allergic reaction to vaccines or unknown allergens, or allergic reaction to eggs.
* Patients who are unlikely to cooperate with the requirements of the study protocol.
* ECG with evidence of ventricular arrythmias ≥ 4 extra systoles per minute.
* Known allergy or contraindication to chemotherapy (e.g., known reaction to pentavalent antimonials, cardiopathy, myocarditis).

Participant flow

Outcome results

• Date of Clinical Cure (Primary), Number, participants: Immunotherapy v1.4/1.5 2; Immunotherapy v1.6 2; Chemotherapy 15
• Adverse Events of Grade 1 Severity or Higher Occurring in ≥ 3 Patients During Active Treatment Phase of the Study. (Primary), Number, participants: Immunotherapy v1.4/1.5 10; Immunotherapy v1.6 9; Chemotherapy 0
• IgG Antibodies and T-cell Cytokine Responses (IFN-g and IL-10) (Secondary), Median, Relative ELISA Units: Immunotherapy v1.4/1.5 NA (NA to NA); Immunotherapy v1.6 84.56 (40.99 to 409.8); Chemotherapy 2.004 (0.392 to 37.02)

Adverse events

Time frame: Day 0 through Day 336.

Serious adverse events by term

Other adverse events by term

Limitations and caveats: A total of 150 patients was planned, including age de-escalation to adolescents after the first 60 adults enrolled. Owing to slow recruitment and insufficient evidence of efficacy in the immunotherapy group, enrollment was closed early.

• Franco Piazza, MD, MPH, Study director, Access to Advanced Health Institute (AAHI)