Clinical trial NCT00460525: Phase II AMA-1 Malaria Vaccine FMP2.1/AS02A Trial in Mali
Official title: Randomized, Controlled Phase II Clinical Trial to Evaluate the Safety, Immunogenicity and Efficacy of the AMA-1 Malaria Vaccine FMP2.1/AS02A Versus Rabies Vaccine in 1-6 Year Old Children in Bandiagara, Mali
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Plasmodium Falciparum Malaria
Keywords: malaria, Mali, children, Plasmodium falciparum, vaccine
Lead sponsor: U.S. Army Medical Research and Development Command
Sponsor class: FED
Collaborators: name: National Institute of Allergy and Infectious Diseases (NIAID)
name: Walter Reed Army Institute of Research (WRAIR)
name: GlaxoSmithKline
name: University of Maryland
First posted: 2007-04-16
Enrollment: 400
Sex: ALL
Minimum age (years): 1
Maximum age (years): 6
Standard ages: CHILD
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: PREVENTION

Brief summary: Malaria is a disease that affects many people in Africa. Malaria is caused by germs spread by mosquito bites. The purpose of this study is to compare the number of children who get malaria after receiving an experimental malaria vaccine (FMP2.1/AS02A) to the number of children who get malaria after receiving a vaccine for rabies (an approved vaccine that does not prevent malaria). The children will be assigned to one of the vaccine groups by chance. Participants and doctors will not know which vaccine was given. Study participants will include 400 children, ages 1-6 years, living in Bandiagara, Mali. Children will receive 3 vaccine doses, by injection, to their upper arm. Study procedures will include physical exams and several blood samples. Participants will be involved in the study for 26 months.

Detailed description: This is a randomized, controlled, phase II clinical trial to evaluate the efficacy, safety and immunogenicity of the apical membrane antigen-1 of Plasmodium (P.) falciparum (AMA-1) malaria vaccine FMP2.1/AS02A using rabies vaccine as a control in healthy children 1-6 years old in Bandiagara, Mali. This study is linked to DMID protocol 05-0146, which is a phase I dose escalation trial at the same site in the same population. In this study, 400 subjects will be randomized in a 1:1 ratio to receive either 50 micrograms of FMP2.1 in 0.5 mL AS02A or rabies vaccine. Immunizations will be given on days 0, 30 and 60. Solicited adverse events will be recorded on the days of immunization and at 1, 2, 3 and 7 days after each immunization. Unsolicited adverse events will be recorded for 30 days after each immunization. Passive case detection will be used to capture clinical malaria episodes and adverse events including serious adverse events, and will occur by continuous availability of clinical care in a population with high utilization of this care. Active surveillance will be used to capture malaria infections and adverse events including serious adverse events. For active case detection, following the third dose, participants will be followed monthly for 6 months and then at 12, 18 and 24 months after randomization, for clinical assessment, malaria smear and hemoglobin. Routine monthly malaria smears will not be read immediately unless symptoms are present. Children will be followed for 2 years after the first immunization. Sera will be collected for anti-FMP2.1 antibody titers on the days of immunization and 1, 3, 6, 8, 12, 18 and 24 months after the first immunization. Peripheral blood mononuclear cells (PBMCs) will be collected on the days of immunization, 30 days after the third immunization and 8, 12, 18 and 24 months after the first immunization. The study Final Report will be based on data collected up to 6 months after the assigned date of the third immunization. A supplemental report will include data from the entire 24-month observation period. Primary study objectives are to: determine the efficacy of FMP2.1/AS02A in children aged 1-6 years against first clinical malaria episodes (axillary temperature of greater than or equal to 37.5 degrees Celsius and parasitemia of greater than or equal to 2500/mm\^3) occurring between randomization and 6 months after the assigned date of the third immunization; and assess the safety of the vaccine in children aged 1-6 years. Secondary study objectives are to: describe the dynamics of anti-AMA-1 antibody responses in recipients of the malaria vaccine compared to natural responses in the control group; determine whether serum anti-AMA-1 IgG titer by enzyme linked immunosorbent assay (ELISA) 1 month after the third immunization correlates with protection against clinical malaria episode; measure allele-specific efficacy against parasites with AMA-1 genotypes homologous to and heterologous to the 3D7 clone of P. falciparum; determine vaccine efficacy against clinical malaria episodes occurring between randomization and 6 months after the assigned date of the third immunization; and if efficacy is observed based on the primary endpoint, to determine vaccine efficacy against first clinical malaria episode and all clinical episodes (using increasing parasitemia thresholds) occurring during 2 years after randomization.

Eligibility criteria: Inclusion Criteria:

* Age 1-6 years inclusive at the time of screening
* Residing in Bandiagara town
* Appear to be in generally good health based on clinical and laboratory investigation
* Separate written informed consent obtained from the parent/guardian before screening and study start, respectively
* Available to participate in follow-up for the duration of study (26 months)

Exclusion Criteria:

* Previous vaccination with an investigational vaccine or a rabies vaccine
* Use of an investigational or non-registered drug or vaccine other than the study vaccine(s) within 30 days preceding the first study immunization, or planned use up to 30 days after the third immunization
* Chronic administration (defined as more than 14 days) of immunosuppressants or other immune-modifying drugs within six months prior to the first immunization. This exclusion includes any dose level of oral steroids or inhaled steroids, but not topical steroids.
* Confirmed or suspected immunosuppressive or immunodeficient condition, including human immunodeficiency virus (HIV) infection
* Confirmed or suspected autoimmune disease
* History of allergic reactions or anaphylaxis to immunizations or to any vaccine component
* History of serious allergic reactions to any substance, requiring hospitalization or emergent medical care
* History of allergy to tetracycline, doxycycline, nickel, Imidazole, eggs, neomycin, chlortetracycline or amphotericin B
* History of splenectomy
* Laboratory evidence of liver disease (alanine aminotransferase \[ALT\] greater than the upper limit of normal of the testing laboratory = 49.6 U/L)
* Laboratory evidence of renal disease (serum or plasma creatinine greater than 62 micro mol/L), or more than trace protein or blood on urine dipstick testing)
* Laboratory evidence of hematologic disease (absolute leukocyte count \<5,300/mm\^3 or \>15,300/mm\^3, absolute lymphocyte count \<2,300 mm\^3, platelet count \<133,000/mm\^3, or hemoglobin \<9.0 g/dL)
* Hepatitis B surface antigen positive
* Chronic skin condition that could interfere with vaccine site reactogenicity assessment
* Administration of immunoglobulins and/or any blood products within the three months preceding the first study immunization or planned administration during the study period
* Simultaneous participation in any other interventional clinical trial
* Acute or chronic pulmonary, cardiovascular, hepatic (including hepatomegaly), renal or neurological condition, severe malnutrition, or any other clinical findings that in the opinion of the PI may increase the risk of participating in the study
* Other condition that in the opinion of the Principal Investigator (PI) would jeopardize the safety or rights of a participant in the trial or would render the participant unable to comply with the protocol

Primary outcomes:
measure: Number of Subjects Reporting Solicited Adverse Events During the 7-day Surveillance Period After the First Vaccination
timeFrame: 0-7 days after first vaccination
measure: Number of Subjects Reporting Solicited Adverse Events During the 7-day Surveillance Period After the Second Vaccination.
timeFrame: 0-7 days after the second vaccination
measure: Number of Subjects Reporting Solicited Adverse Events During the 7-day Surveillance Period After the Third Vaccination.
timeFrame: 0-7 days after the third vaccination
measure: Number of Unsolicited Non-serious Adverse Events Reported During the 30-day Surveillance Period After the First Vaccination
timeFrame: Day 0-29 after first vaccination
measure: Number of Unsolicited Non-serious Adverse Events Reported During the 30-day Surveillance Period After the Second Vaccination
timeFrame: Day 0-29 after second vaccination
measure: Number of Unsolicited Non-serious Adverse Events Reported During the 30-day Surveillance Period After the Third Vaccination
timeFrame: Day 0-29 after third vaccination
measure: Time to First Clinical Malaria Episode With Significant Parasitemia (2500/mm^3) and Temperature of Greater Than or Equal to 37.5 Degrees C.
timeFrame: Occurring between randomization and 6 months after the assigned date of the 3rd immunization.
measure: Number of Subjects Reporting Serious Adverse Events
timeFrame: 24 months after initial vaccination
Secondary outcomes:
measure: Incidence Density of Clinical Malaria Episode
timeFrame: Between randomization and 6 months after 3rd immunization.
measure: Geometric Mean Titers of Anti-FMP2.1 Antibody Measured by Enzyme Linked ImmunoSorbent Assay (ELISA) at Day 0
timeFrame: Day 0
measure: Geometric Mean Titers of Anti-FMP2.1 Antibody Measured by ELISA at Day 30.
timeFrame: Day 30 after initial vaccination
measure: Geometric Mean Titers of Anti-FMP2.1 Antibody Measured by ELISA at Day 60.
timeFrame: Day 60 after initial vaccination
measure: Geometric Mean Titers of Anti-FMP2.1 Antibody Measured by ELISA at Day 90.
timeFrame: Day 90 after initial vaccination
measure: Geometric Mean Titers of Anti-FMP2.1 Antibody Measured by ELISA at Day 150.
timeFrame: Day 150 after initial vaccination
measure: Geometric Mean Titers of Anti-FMP2.1 Antibody Measured by ELISA at Day 240.
timeFrame: Day 240 after initial vaccination
measure: Geometric Mean Titers of Anti-FMP2.1 Antibody Measured by ELISA at Day 364
timeFrame: Day 364 after initial vaccination
measure: Geometric Mean Titers of Anti-FMP2.1 Antibody Measured by ELISA at Day 547
timeFrame: Day 547 after initial vaccination
measure: Geometric Mean Titers of Anti-FMP2.1 Antibody Measured by ELISA at Day 730
timeFrame: Day 730 after initial vaccination
Other outcomes:
Locations:
city: Bamako
country: Mali
facility: University of Bamako, Malaria Research and Training Center
Study officials:
affiliation: University of Bamako
name: Mahamadou A Thera, MD, MPH
role: PRINCIPAL_INVESTIGATOR
References:
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citation: Graves SF, Kouriba B, Diarra I, Daou M, Niangaly A, Coulibaly D, Keita Y, Laurens MB, Berry AA, Vekemans J, Ripley Ballou W, Lanar DE, Dutta S, Gray Heppner D, Soisson L, Diggs CL, Thera MA, Doumbo OK, Plowe CV, Sztein MB, Lyke KE. Strain-specific Plasmodium falciparum multifunctional CD4(+) T cell cytokine expression in Malian children immunized with the FMP2.1/AS02A vaccine candidate. Vaccine. 2016 May 17;34(23):2546-55. doi: 10.1016/j.vaccine.2016.04.019. Epub 2016 Apr 15.
citation: Laurens MB, Thera MA, Coulibaly D, Ouattara A, Kone AK, Guindo AB, Traore K, Traore I, Kouriba B, Diallo DA, Diarra I, Daou M, Dolo A, Tolo Y, Sissoko MS, Niangaly A, Sissoko M, Takala-Harrison S, Lyke KE, Wu Y, Blackwelder WC, Godeaux O, Vekemans J, Dubois MC, Ballou WR, Cohen J, Dube T, Soisson L, Diggs CL, House B, Bennett JW, Lanar DE, Dutta S, Heppner DG, Plowe CV, Doumbo OK. Extended safety, immunogenicity and efficacy of a blood-stage malaria vaccine in malian children: 24-month follow-up of a randomized, double-blinded phase 2 trial. PLoS One. 2013 Nov 18;8(11):e79323. doi: 10.1371/journal.pone.0079323. eCollection 2013.
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