Phase II AMA-1 Malaria Vaccine FMP2.1/AS02A Trial in Mali

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

National Institute of Allergy and Infectious Diseases (NIAID), Walter Reed Army Institute of Research (WRAIR), GlaxoSmithKline, University of Maryland

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.

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.

3 doses administered a month apart: 50 µg recombinant subunit protein FMP2.1 (Plasmodium falciparum Apical Membrane Antigen-1 from strain 3D7 expressed in and purified from Escherichia coli), adjuvanted with 0.5 mL of AS02A (proprietary oil-in-water emulsion and phosphate buffered saline with the immunostimulants monophosphoral lipid A and QS21).

White, freeze-dried vaccine for reconstitution with the diluent prior to use; dosage 1.0 mL of rabies vaccine.

Number of Subjects Reporting Solicited Adverse Events During the 7-day Surveillance Period After the First Vaccination

Solicited symptoms were recorded by study staff at clinic visits on Days 0, 1, 2 and 7 after each vaccination. "Reported Limitation of Arm Motion" refers to the parents' report of the symptom while "Limitation of Arm Motion" refers to the clinicians' assessment of the symptom, collected separately.

Number of Subjects Reporting Solicited Adverse Events During the 7-day Surveillance Period After the Second Vaccination.

Solicited symptoms were recorded by study staff at clinic visits on Days 0, 1, 2 and 7 after vaccination. "Reported Limitation of Arm Motion" refers to the parents' report of the symptom while "Limitation of Arm Motion" refers to the clinicians' assessment of the symptom, collected separately.

Number of Subjects Reporting Solicited Adverse Events During the 7-day Surveillance Period After the Third Vaccination.

Solicited symptoms were recorded by study staff at clinic visits on Days 0, 1, 2 and 7 after vaccination. "Reported Limitation of Arm Motion" refers to the parents' report of the symptom while "Limitation of Arm Motion" refers to the clinicians' assessment of the symptom, collected separately.

Number of Unsolicited Non-serious Adverse Events Reported During the 30-day Surveillance Period After the First Vaccination

Unsolicited non-serious adverse events reported are those occurring within 30 days after vaccination. The categories are the MedDRA System Organ Classes for which at least one adverse event was reported. All non-serious adverse events are included, regardless of severity or relationship to vaccination.

Number of Unsolicited Non-serious Adverse Events Reported During the 30-day Surveillance Period After the Second Vaccination

Unsolicited non-serious adverse events reported are those occurring within 30 days after vaccination. The categories are the MedDRA System Organ Classes for which at least one adverse event was reported. All non-serious adverse events are included, regardless of severity or relationship to vaccination.

Number of Unsolicited Non-serious Adverse Events Reported During the 30-day Surveillance Period After the Third Vaccination

Unsolicited non-serious adverse events reported are those occurring within 30 days after vaccination. The categories are the MedDRA System Organ Classes for which at least one adverse event was reported. All non-serious adverse events are included, regardless of severity or relationship to vaccination.

Time to First Clinical Malaria Episode With Significant Parasitemia (2500/mm^3) and Temperature of Greater Than or Equal to 37.5 Degrees C.

Time to first clinical malaria episode is displayed in a life table format to display the number of subjects at risk, the number with first clinical episode and the number censored at each time point.

A serious adverse event was defined as any untoward medical occurrence that results in death, is life threatening, results in persistent or significant disability/incapacity, requires in-patient hospitalization or prolongation of existing hospitalization or is a congenital anomaly/birth defect in the offspring of a study subject. In addition, important medical events that may jeopardize the participant or may require intervention to prevent one of the other outcomes listed above was considered serious.

Clinical malaria episode was defined by significant parasitemia (2500/mm^3) and temperature of greater than or equal to 37.5 degrees C. Event rate was determined by dividing the number of episodes (150 for the Rabies group and 121 for the FMP2.1/ASO2A group) by the number of Person Years at Risk (PYAR) (126.341 for Rabies group and 127.411 for the FMP2.1/ASO2A group).

Geometric Mean Titers of Anti-FMP2.1 Antibody Measured by Enzyme Linked ImmunoSorbent Assay (ELISA) at Day 0

Titers of Anti-FMP2.1 antibody were determined by ELISA from sera collected at Day 0 prior to the first vaccination.

Titers of Anti-FMP2.1 antibody were determined by ELISA from sera collected at Day 30, prior to the second vaccination.

Titers of Anti-FMP2.1 antibody were determined by ELISA from sera collected at Day 60, prior to the third vaccination.

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

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