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

• Sponsor: U.S. Army Medical Research and Development Command (U.S. Fed)
• Overall Status: Completed
• CT.gov ID: NCT00460525
• Collaborator: National Institute of Allergy and Infectious Diseases (NIAID) (NIH), Walter Reed Army Institute of Research (WRAIR) (U.S. Fed), GlaxoSmithKline (Industry), University of Maryland (Other)
• Enrollment: 400
• Location: 1
• Arms: 2
• Duration (Months): 26
• Patients Per Site Per Month: 15.4

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Plasmodium Falciparum Malaria	Biological: FMP2.1/AS02A; Biological: Rabies Vaccine	Phase 2

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 400 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Care Provider, Investigator)
• Primary Purpose: Prevention
• 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 Start Date: May 1, 2007
• Actual Primary Completion Date: Jul 1, 2009
• Actual Study Completion Date: Jul 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Rabies Vaccine Rabies vaccine administered on Days 0, 30, and 60.	Biological: Rabies Vaccine; White, freeze-dried vaccine for reconstitution with the diluent prior to use; dosage 1.0 mL of rabies vaccine.
Experimental: FMP2.1/AS02A 50 mcg of FMP2.1 in 0.5 mL AS02A administered on Days 0, 30, and 60.	Biological: FMP2.1/AS02A; 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).

Outcome Measures

Primary Outcome Measures

1. Number of Subjects Reporting Solicited Adverse Events During the 7-day Surveillance Period After the First Vaccination [0-7 days after 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.

2. Number of Subjects Reporting Solicited Adverse Events During the 7-day Surveillance Period After the Second Vaccination. [0-7 days 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.

3. Number of Subjects Reporting Solicited Adverse Events During the 7-day Surveillance Period After the Third Vaccination. [0-7 days 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.

4. Number of Unsolicited Non-serious Adverse Events Reported During the 30-day Surveillance Period After the First Vaccination [Day 0-29 after 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.

5. Number of Unsolicited Non-serious Adverse Events Reported During the 30-day Surveillance Period After the Second Vaccination [Day 0-29 after 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.

6. Number of Unsolicited Non-serious Adverse Events Reported During the 30-day Surveillance Period After the Third Vaccination [Day 0-29 after 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.

7. Time to First Clinical Malaria Episode With Significant Parasitemia (2500/mm^3) and Temperature of Greater Than or Equal to 37.5 Degrees C. [Occurring between randomization and 6 months after the assigned date of the 3rd immunization.]

   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.

8. Number of Subjects Reporting Serious Adverse Events [24 months after initial vaccination]

   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.

Secondary Outcome Measures

1. Incidence Density of Clinical Malaria Episode [Between randomization and 6 months after 3rd immunization.]

   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).

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

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

3. Geometric Mean Titers of Anti-FMP2.1 Antibody Measured by ELISA at Day 30. [Day 30 after initial vaccination]

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

4. Geometric Mean Titers of Anti-FMP2.1 Antibody Measured by ELISA at Day 60. [Day 60 after initial vaccination]

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

5. Geometric Mean Titers of Anti-FMP2.1 Antibody Measured by ELISA at Day 90. [Day 90 after initial vaccination]

   Titers of Anti-FMP2.1 antibody were determined by ELISA from sera collected at Day 90.

6. Geometric Mean Titers of Anti-FMP2.1 Antibody Measured by ELISA at Day 150. [Day 150 after initial vaccination]

   Titers of Anti-FMP2.1 antibody were determined by ELISA from sera collected at Day 150.

7. Geometric Mean Titers of Anti-FMP2.1 Antibody Measured by ELISA at Day 240. [Day 240 after initial vaccination]

   Titers of Anti-FMP2.1 antibody were determined by ELISA from sera collected at Day 240.

8. Geometric Mean Titers of Anti-FMP2.1 Antibody Measured by ELISA at Day 364 [Day 364 after initial vaccination]

   Titers of Anti-FMP2.1 antibody were determined by ELISA from sera collected at Day 364.

9. Geometric Mean Titers of Anti-FMP2.1 Antibody Measured by ELISA at Day 547 [Day 547 after initial vaccination]

   Titers of Anti-FMP2.1 antibody were determined by ELISA from sera collected at Day 547.

10. Geometric Mean Titers of Anti-FMP2.1 Antibody Measured by ELISA at Day 730 [Day 730 after initial vaccination]

    Titers of Anti-FMP2.1 antibody were determined by ELISA from sera collected at Day 730.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 1 Year to 6 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Bamako, Malaria Research and Training Center	Bamako		Mali

Sponsors and Collaborators

• U.S. Army Medical Research and Development Command
• National Institute of Allergy and Infectious Diseases (NIAID)
• Walter Reed Army Institute of Research (WRAIR)
• GlaxoSmithKline
• University of Maryland

Investigators

• Principal Investigator: Mahamadou A Thera, MD, MPH, University of Bamako

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: U.S. Army Medical Research and Development Command
• ClinicalTrials.gov Identifier: NCT00460525
• Other Study ID Numbers: 07-0003; U01AI065683; 2U01AI065683-06; Malaria-056 (110060); HSRRB # A-14262
• First Posted: Apr 16, 2007
• Last Update Posted: Nov 9, 2018
• Last Verified: Oct 1, 2018

• Keywords provided by U.S. Army Medical Research and Development Command: malaria, Mali, children, Plasmodium falciparum, vaccine
• Additional relevant MeSH terms: Malaria; Malaria, Falciparum

Study Results

Participant Flow

Recruitment Details	Subjects were recruited from the population of healthy children aged 1-6 years residing in the town of Bandiagara.

Arm/Group Title	Rabies Vaccine	FMP2.1/AS02A
Arm/Group Description	Rabies vaccine administered on Days 0, 30, and 60.	50 mcg of FMP2.1 in 0.5 mL AS02A administered on Days 0, 30, and 60.
Period Title: Overall Study
STARTED	201	199
COMPLETED	190	194
NOT COMPLETED	11	5

Baseline Characteristics

Arm/Group Title	Rabies Vaccine	FMP2.1/AS02A	Total
Arm/Group Description	Rabies vaccine administered on Days 0, 30, and 60.	50 mcg of FMP2.1 in 0.5 mL AS02A administered on Days 0, 30, and 60.	Total of all reporting groups
Overall Participants	201	199	400
Age (Count of Participants)
<=18 years	201 100%	199 100%	400 100%
Between 18 and 65 years	0 0%	0 0%	0 0%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	3.4 (1.5)	3.4 (1.6)	3.4 (1.5)
Sex: Female, Male (Count of Participants)
Female	112 55.7%	103 51.8%	215 53.8%
Male	89 44.3%	96 48.2%	185 46.3%
Region of Enrollment (participants) [Number]
Mali	201 100%	199 100%	400 100%

Outcome Measures

1. Primary Outcome

Title	Number of Subjects Reporting Solicited Adverse Events During the 7-day Surveillance Period After the First Vaccination
Description	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.
Time Frame	0-7 days after first vaccination

Outcome Measure Data

Analysis Population Description

All subjects receiving the vaccination are included.

Arm/Group Title	Rabies Vaccine	FMP2.1/AS02A
Arm/Group Description	Rabies vaccine administered on Days 0, 30, and 60.	50 mcg of FMP2.1 in 0.5 mL AS02A administered on Days 0, 30, and 60.
Measure Participants	201	199
Drowsiness	0 0%	5 2.5%
Irritability/Fussiness	0 0%	12 6%
Loss of Appetite	3 1.5%	25 12.6%
Vomiting	1 0.5%	4 2%
Fever	30 14.9%	61 30.7%
Site Pain	55 27.4%	157 78.9%
Swelling	34 16.9%	153 76.9%
Erythema	0 0%	12 6%
Reported Limitation of Arm Motion	4 2%	55 27.6%
Limitation of Arm Motion	2 1%	54 27.1%

2. Primary Outcome

Title	Number of Subjects Reporting Solicited Adverse Events During the 7-day Surveillance Period After the Second Vaccination.
Description	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.
Time Frame	0-7 days after the second vaccination

Outcome Measure Data

Analysis Population Description

All subjects receiving the vaccination are included.

Arm/Group Title	Rabies Vaccine	FMP2.1/AS02A
Arm/Group Description	Rabies vaccine administered on Days 0, 30, and 60.	50 mcg of FMP2.1 in 0.5 mL AS02A administered on Days 0, 30, and 60.
Measure Participants	193	193
Drowsiness	0 0%	0 0%
Irritability/Fussiness	1 0.5%	5 2.5%
Loss of Appetite	1 0.5%	10 5%
Vomiting	3 1.5%	3 1.5%
Fever	13 6.5%	64 32.2%
Site Pain	57 28.4%	132 66.3%
Swelling	69 34.3%	151 75.9%
Erythema	0 0%	1 0.5%
Reported Limitation of Arm Motion	0 0%	31 15.6%
Limitation of Arm Motion	2 1%	37 18.6%

3. Primary Outcome

Title	Number of Subjects Reporting Solicited Adverse Events During the 7-day Surveillance Period After the Third Vaccination.
Description	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.
Time Frame	0-7 days after the third vaccination

Outcome Measure Data

Analysis Population Description

All subjects receiving the vaccination are included.

Arm/Group Title	Rabies Vaccine	FMP2.1/AS02A
Arm/Group Description	Rabies vaccine administered on Days 0, 30, and 60.	50 mcg of FMP2.1 in 0.5 mL AS02A administered on Days 0, 30, and 60.
Measure Participants	187	184
Drowsiness	1 0.5%	0 0%
Irritability/Fussiness	2 1%	6 3%
Loss of Appetite Post	0 0%	3 1.5%
Vomiting	2 1%	2 1%
Fever	18 9%	64 32.2%
Site Pain	48 23.9%	134 67.3%
Swelling	90 44.8%	159 79.9%
Erythema	0 0%	3 1.5%
Reported Limitation of Arm Motion	4 2%	26 13.1%
Limitation of Arm Motion	2 1%	28 14.1%

4. Primary Outcome

Title	Number of Unsolicited Non-serious Adverse Events Reported During the 30-day Surveillance Period After the First Vaccination
Description	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 Frame	Day 0-29 after first vaccination

Outcome Measure Data

Analysis Population Description

All subjects receiving the vaccination are included.

Arm/Group Title	Rabies Vaccine	FMP2.1/AS02A
Arm/Group Description	Rabies vaccine administered on Days 0, 30, and 60.	50 mcg of FMP2.1 in 0.5 mL AS02A administered on Days 0, 30, and 60.
Measure Participants	201	199
Blood and lymphatic system disorders	7	4
Ear and labyrinth disorders	0	0
Eye disorders	5	5
Gastrointestinal disorders	17	11
General disorders, administrative site conditions	16	44
Hepatobiliary disorders	2	0
Infections and infestations	56	53
Injury, poisoning, and procedural complications	5	4
Investigations	45	42
Metabolism and nutrition disorders	0	0
Musculoskeletal and connective tissue disorders	0	0
Nervous system disorders	3	2
Psychiatric disorders	0	4
Renal and urinary disorders	1	1
Reproductive system and breast disorders	1	2
Respiratory, thoracic and mediastinal disorders	23	28
Skin and subcutaneous tissue disorders	5	6
Vascular disorders	0	0

5. Primary Outcome

Title	Number of Unsolicited Non-serious Adverse Events Reported During the 30-day Surveillance Period After the Second Vaccination
Description	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 Frame	Day 0-29 after second vaccination

Outcome Measure Data

Analysis Population Description

All subjects receiving the vaccination are included.

Arm/Group Title	Rabies Vaccine	FMP2.1/AS02A
Arm/Group Description	Rabies vaccine administered on Days 0, 30, and 60.	50 mcg of FMP2.1 in 0.5 mL AS02A administered on Days 0, 30, and 60.
Measure Participants	193	193
Blood and lymphatic system disorders	1	2
Ear and labyrinth disorders	0	1
Eye disorders	1	1
Gastrointestinal disorders	19	11
General disorders, administrative site conditions	9	26
Hepatobiliary disorders	0	0
Infections and infestations	67	68
Injury, poisoning, and procedural complications	6	3
Investigations	71	74
Metabolism and nutrition disorders	0	1
Musculoskeletal and connective tissue disorders	0	1
Nervous system disorders	0	1
Psychiatric disorders	1	1
Renal and urinary disorders	0	1
Reproductive system and breast disorders	0	1
Respiratory, thoracic and mediastinal disorders	17	16
Skin and subcutaneous tissue disorders	4	5
Vascular disorders	0	0

6. Primary Outcome

Title	Number of Unsolicited Non-serious Adverse Events Reported During the 30-day Surveillance Period After the Third Vaccination
Description	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 Frame	Day 0-29 after third vaccination

Outcome Measure Data

Analysis Population Description

All subjects receiving the vaccination are included.

Arm/Group Title	Rabies Vaccine	FMP2.1/AS02A
Arm/Group Description	Rabies vaccine administered on Days 0, 30, and 60.	50 mcg of FMP2.1 in 0.5 mL AS02A administered on Days 0, 30, and 60.
Measure Participants	187	184
Blood and lymphatic system disorders	7	1
Ear and labyrinth disorders	0	0
Eye disorders	8	7
Gastrointestinal disorders	13	16
General disorders, administrative site conditions	14	29
Hepatobiliary disorders	0	0
Infections and infestations	84	73
Injury, poisoning, and procedural complications	6	5
Investigations	110	109
Metabolism and nutrition disorders	2	0
Musculoskeletal and connective tissue disorders	0	0
Nervous system disorders	5	1
Psychiatric disorders	1	1
Renal and urinary disorders	0	0
Reproductive system and breast disorders	0	0
Respiratory, thoracic and mediastinal disorders	32	36
Skin and subcutaneous tissue disorders	7	9
Vascular disorders	0	1

7. Primary Outcome

Title	Time to First Clinical Malaria Episode With Significant Parasitemia (2500/mm^3) and Temperature of Greater Than or Equal to 37.5 Degrees C.
Description	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.
Time Frame	Occurring between randomization and 6 months after the assigned date of the 3rd immunization.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Rabies Vaccine	FMP2.1/AS02A
Arm/Group Description	Rabies vaccine administered on Days 0, 30, and 60.	50 mcg of FMP2.1 in 0.5 mL AS02A administered on Days 0, 30, and 60.
Measure Participants	201	199
Days 0 - 30, Number at Risk	201 100%	199 100%
Days 0 - 30, Number with First Episode	1 0.5%	0 0%
Days 0 -30, Number Censored	4 2%	1 0.5%
Days 31 - 60, Number at Risk	196 97.5%	198 99.5%
Days 31 - 60, Number with First Episode	9 4.5%	10 5%
Days 31 - 60, Number Censored	1 0.5%	0 0%
Days 61 - 90 Number at Risk	186 92.5%	188 94.5%
Days 61 - 90, Number with First Episode	40 19.9%	25 12.6%
Days 61 - 90, Number Censored	0 0%	1 0.5%
Days 91 - 120, Number at Risk	146 72.6%	162 81.4%
Days 91 - 120, Number with First Episode	28 13.9%	33 16.6%
Days 91 - 120, Number Censored	0 0%	0 0%
Days 121 - 150, Number at Risk	118 58.7%	129 64.8%
Days 121 - 150, Number with First Episode	16 8%	10 5%
Days 121 - 150, Number Censored	1 0.5%	1 0.5%
Days 151 - 180, Number at Risk	101 50.2%	118 59.3%
Days 151 - 180, Number with First Episode	5 2.5%	9 4.5%
Days 151 - 180, Number Censored	2 1%	1 0.5%
Days 181 - 210, Number at Risk	94 46.8%	108 54.3%
Days 181 - 210, Number with First Episode	5 2.5%	5 2.5%
Days 181 - 210, Number Censored	0 0%	0 0%
Days 211 - 240, Number at Risk	89 44.3%	103 51.8%
Days 211 - 240, Number with First Episode	2 1%	3 1.5%
Days 211 - 240, Number Censored	87 43.3%	100 50.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rabies Vaccine, FMP2.1/AS02A
	Comments	Time to first clinical malaria episode with significant parasitemia (2500/mm^3) and temperature of greater than or equal to 37.5 degrees C was analyzed by fitting a Cox Proportional Hazards model. The null hypothesis of no vaccine efficacy was tested by the stratified log-rank test (score test). The point and interval estimates for vaccine efficacy were obtained by transforming those for treatment effect in the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.175
	Comments	The a priori threshold for statistical significance was set at 0.05.
	Method	Regression, Cox
	Comments	No adjustments were made.
Method of Estimation	Estimation Parameter	Vaccine Efficacy, VE=1-RR=1-exp(ß)
	Estimated Value	0.17
	Confidence Interval	() 95%; -0.09 to 0.37
	Parameter Dispersion	Type: Value:
	Estimation Comments	Vaccine efficacy (VE) was defined as one minus the relative risk (RR), which was estimated by exponentiating the treatment parameter (ß) from the Cox model fit.

8. Primary Outcome

Title	Number of Subjects Reporting Serious Adverse Events
Description	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.
Time Frame	24 months after initial vaccination

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Rabies Vaccine	FMP2.1/AS02A
Arm/Group Description	Rabies vaccine administered on Days 0, 30, and 60.	50 mcg of FMP2.1 in 0.5 mL AS02A administered on Days 0, 30, and 60.
Measure Participants	201	199
Number [Participants]	2 1%	8 4%

9. Secondary Outcome

Title	Incidence Density of Clinical Malaria Episode
Description	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).
Time Frame	Between randomization and 6 months after 3rd immunization.

Outcome Measure Data

Analysis Population Description

Analyses are ITT.

Arm/Group Title	Rabies Vaccine	FMP2.1/AS02A
Arm/Group Description	Rabies vaccine administered on Days 0, 30, and 60.	50 mcg of FMP2.1 in 0.5 mL AS02A administered on Days 0, 30, and 60.
Measure Participants	201	199
Number [Events Per PYAR]	1.187263	0.949683

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Rabies Vaccine, FMP2.1/AS02A
	Comments	Incidence density, defined as number of clinical malaria episodes per PYAR, was compared using Poisson regression. The null hypothesis of no vaccine efficacy was tested. The point and interval estimates for vaccine efficacy were obtained by transforming those for treatment effect in the model.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	0.068
	Comments	The a priori threshold for statistical significance was set at 0.05.
	Method	Poisson regression
	Comments	No adjustments
Method of Estimation	Estimation Parameter	Vaccine Efficacy, VE=1-RR=1-exp(ß)
	Estimated Value	0.20
	Confidence Interval	() 95%; -0.02 to 0.37
	Parameter Dispersion	Type: Value:
	Estimation Comments	Vaccine efficacy (VE) was defined as one minus the relative risk (RR), which was estimated by exponentiating the treatment parameter (ß) from the Poisson model fit.

10. Secondary Outcome

Title	Geometric Mean Titers of Anti-FMP2.1 Antibody Measured by Enzyme Linked ImmunoSorbent Assay (ELISA) at Day 0
Description	Titers of Anti-FMP2.1 antibody were determined by ELISA from sera collected at Day 0 prior to the first vaccination.
Time Frame	Day 0

Outcome Measure Data

Analysis Population Description

Analyses are ITT. No imputation techniques were used.

Arm/Group Title	Rabies Vaccine	FMP2.1/AS02A
Arm/Group Description	Rabies vaccine administered on Days 0, 30, and 60.	50 mcg of FMP2.1 in 0.5 mL AS02A administered on Days 0, 30, and 60.
Measure Participants	201	199
Geometric Mean (95% Confidence Interval) [Titer]	430.4	393.1

11. Secondary Outcome

Title	Geometric Mean Titers of Anti-FMP2.1 Antibody Measured by ELISA at Day 30.
Description	Titers of Anti-FMP2.1 antibody were determined by ELISA from sera collected at Day 30, prior to the second vaccination.
Time Frame	Day 30 after initial vaccination

Outcome Measure Data

Analysis Population Description

Analyses are ITT. No imputation techniques were used.

Arm/Group Title	Rabies Vaccine	FMP2.1/AS02A
Arm/Group Description	Rabies vaccine administered on Days 0, 30, and 60.	50 mcg of FMP2.1 in 0.5 mL AS02A administered on Days 0, 30, and 60.
Measure Participants	195	194
Geometric Mean (95% Confidence Interval) [Titer]	403.7	21248.7

12. Secondary Outcome

Title	Geometric Mean Titers of Anti-FMP2.1 Antibody Measured by ELISA at Day 60.
Description	Titers of Anti-FMP2.1 antibody were determined by ELISA from sera collected at Day 60, prior to the third vaccination.
Time Frame	Day 60 after initial vaccination

Outcome Measure Data

Analysis Population Description

Analyses are ITT. No imputation techniques were used.

Arm/Group Title	Rabies Vaccine	FMP2.1/AS02A
Arm/Group Description	Rabies vaccine administered on Days 0, 30, and 60.	50 mcg of FMP2.1 in 0.5 mL AS02A administered on Days 0, 30, and 60.
Measure Participants	194	195
Geometric Mean (95% Confidence Interval) [Titer]	512.2	98199.0

13. Secondary Outcome

Title	Geometric Mean Titers of Anti-FMP2.1 Antibody Measured by ELISA at Day 90.
Description	Titers of Anti-FMP2.1 antibody were determined by ELISA from sera collected at Day 90.
Time Frame	Day 90 after initial vaccination

Outcome Measure Data

Analysis Population Description

Analyses are ITT. No imputation techniques were used.

Arm/Group Title	Rabies Vaccine	FMP2.1/AS02A
Arm/Group Description	Rabies vaccine administered on Days 0, 30, and 60.	50 mcg of FMP2.1 in 0.5 mL AS02A administered on Days 0, 30, and 60.
Measure Participants	191	194
Geometric Mean (95% Confidence Interval) [Titer]	781.8	188449.1

14. Secondary Outcome

Title	Geometric Mean Titers of Anti-FMP2.1 Antibody Measured by ELISA at Day 150.
Description	Titers of Anti-FMP2.1 antibody were determined by ELISA from sera collected at Day 150.
Time Frame	Day 150 after initial vaccination

Outcome Measure Data

Analysis Population Description

Analyses are ITT. No imputation techniques were used.

Arm/Group Title	Rabies Vaccine	FMP2.1/AS02A
Arm/Group Description	Rabies vaccine administered on Days 0, 30, and 60.	50 mcg of FMP2.1 in 0.5 mL AS02A administered on Days 0, 30, and 60.
Measure Participants	188	194
Geometric Mean (95% Confidence Interval) [Titer]	1202.9	100746.5

15. Secondary Outcome

Title	Geometric Mean Titers of Anti-FMP2.1 Antibody Measured by ELISA at Day 240.
Description	Titers of Anti-FMP2.1 antibody were determined by ELISA from sera collected at Day 240.
Time Frame	Day 240 after initial vaccination

Outcome Measure Data

Analysis Population Description

Analyses are ITT. No imputation techniques were used.

Arm/Group Title	Rabies Vaccine	FMP2.1/AS02A
Arm/Group Description	Rabies vaccine administered on Days 0, 30, and 60.	50 mcg of FMP2.1 in 0.5 mL AS02A administered on Days 0, 30, and 60.
Measure Participants	189	193
Geometric Mean (95% Confidence Interval) [Titer]	774.6	65031.7

16. Secondary Outcome

Title	Geometric Mean Titers of Anti-FMP2.1 Antibody Measured by ELISA at Day 364
Description	Titers of Anti-FMP2.1 antibody were determined by ELISA from sera collected at Day 364.
Time Frame	Day 364 after initial vaccination

Outcome Measure Data

Analysis Population Description

Analyses are ITT. No imputation techniques were used.

Arm/Group Title	Rabies Vaccine	FMP2.1/AS02A
Arm/Group Description	Rabies vaccine administered on Days 0, 30, and 60.	50 mcg of FMP2.1 in 0.5 mL AS02A administered on Days 0, 30, and 60.
Measure Participants	185	192
Geometric Mean (95% Confidence Interval) [Titer]	505.0	42596.8

17. Secondary Outcome

Title	Geometric Mean Titers of Anti-FMP2.1 Antibody Measured by ELISA at Day 547
Description	Titers of Anti-FMP2.1 antibody were determined by ELISA from sera collected at Day 547.
Time Frame	Day 547 after initial vaccination

Outcome Measure Data

Analysis Population Description

Analyses are ITT. No imputation techniques were used.

Arm/Group Title	Rabies Vaccine	FMP2.1/AS02A
Arm/Group Description	Rabies vaccine administered on Days 0, 30, and 60.	50 mcg of FMP2.1 in 0.5 mL AS02A administered on Days 0, 30, and 60.
Measure Participants	183	183
Geometric Mean (95% Confidence Interval) [Titer]	1589.3	81205.1

18. Secondary Outcome

Title	Geometric Mean Titers of Anti-FMP2.1 Antibody Measured by ELISA at Day 730
Description	Titers of Anti-FMP2.1 antibody were determined by ELISA from sera collected at Day 730.
Time Frame	Day 730 after initial vaccination

Outcome Measure Data

Analysis Population Description

Analyses are ITT. No imputation techniques were used.

Arm/Group Title	Rabies Vaccine	FMP2.1/AS02A
Arm/Group Description	Rabies vaccine administered on Days 0, 30, and 60.	50 mcg of FMP2.1 in 0.5 mL AS02A administered on Days 0, 30, and 60.
Measure Participants	168	179
Geometric Mean (95% Confidence Interval) [Titer]	636.5	40605.3

Adverse Events

Time Frame	Solicited adverse events were collected for 7 days after each immunization. Serious adverse events and unsolicited non-serious adverse events were collected for 24 months after initial vaccination.
Arm/Group Title	Rabies Vaccine		FMP2.1/AS02A
Arm/Group Description	Rabies vaccine administered on Days 0, 30, and 60.		50 mcg of FMP2.1 in 0.5 mL AS02A administered on Days 0, 30, and 60.
All Cause Mortality
	Rabies Vaccine		FMP2.1/AS02A
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Rabies Vaccine		FMP2.1/AS02A
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/201 (1%)		8/199 (4%)
Gastrointestinal disorders
Ileus paralytic	0/201 (0%)	0	1/199 (0.5%)	1
General disorders
Pyrexia	0/201 (0%)	0	1/199 (0.5%)	1
Infections and infestations
Malaria	0/201 (0%)	0	2/199 (1%)	2
Cerebral malaria	0/201 (0%)	0	1/199 (0.5%)	1
Metabolism and nutrition disorders
Dehydration	0/201 (0%)	0	1/199 (0.5%)	1
Nervous system disorders
Febrile Convulsion	0/201 (0%)	0	1/199 (0.5%)	1
Status epilepticus	1/201 (0.5%)	1	0/199 (0%)	0
Febrile convulsion	1/201 (0.5%)	1	0/199 (0%)	0
Respiratory, thoracic and mediastinal disorders
Respiratory distress	0/201 (0%)	0	1/199 (0.5%)	1
Other (Not Including Serious) Adverse Events
	Rabies Vaccine		FMP2.1/AS02A
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	198/201 (98.5%)		199/199 (100%)
Eye disorders
Conjunctivitis	55/201 (27.4%)	71	49/199 (24.6%)	61
Gastrointestinal disorders
Abdominal Pain	39/201 (19.4%)	57	45/199 (22.6%)	74
Diarrhoea	64/201 (31.8%)	96	48/199 (24.1%)	81
Vomiting	17/201 (8.5%)	20	24/199 (12.1%)	30
General disorders
Pyrexia	50/201 (24.9%)	65	89/199 (44.7%)	120
Injection site erythema	0/201 (0%)	0	13/199 (6.5%)	13
Injection site pain	92/201 (45.8%)	114	180/199 (90.5%)	324
Injection site swelling	129/201 (64.2%)	167	192/199 (96.5%)	438
Irritability	1/201 (0.5%)	1	17/199 (8.5%)	19
Pyrexia	46/201 (22.9%)	52	104/199 (52.3%)	133
Infections and infestations
Bronchitis	126/201 (62.7%)	273	121/199 (60.8%)	259
Ear infection	47/201 (23.4%)	65	46/199 (23.1%)	55
Fungal skin infection	27/201 (13.4%)	31	24/199 (12.1%)	27
Furuncle	18/201 (9%)	18	17/199 (8.5%)	20
Mumps	19/201 (9.5%)	19	12/199 (6%)	12
Nasopharyngitis	43/201 (21.4%)	59	41/199 (20.6%)	54
Pharyngitis	31/201 (15.4%)	32	33/199 (16.6%)	40
Pneumonia	31/201 (15.4%)	37	33/199 (16.6%)	42
Pyoderma	54/201 (26.9%)	71	60/199 (30.2%)	89
Rhinitis	127/201 (63.2%)	244	123/199 (61.8%)	251
Salmonellosis	11/201 (5.5%)	13	5/199 (2.5%)	5
Staphylococcal infection	12/201 (6%)	12	11/199 (5.5%)	11
Tinea capitis	30/201 (14.9%)	36	26/199 (13.1%)	27
Tonsillitis	19/201 (9.5%)	22	18/199 (9%)	22
Trichomoniasis intestinal	12/201 (6%)	13	19/199 (9.5%)	21
Varicella	57/201 (28.4%)	57	49/199 (24.6%)	50
Injury, poisoning and procedural complications
Wound	39/201 (19.4%)	51	41/199 (20.6%)	49
Investigations
Alanine aminotransferase increased	12/201 (6%)	13	10/199 (5%)	11
Granulocyte count increased	36/201 (17.9%)	37	24/199 (12.1%)	24
Haemoglobin increased	94/201 (46.8%)	145	92/199 (46.2%)	143
Lymphocyte count decreased	12/201 (6%)	12	13/199 (6.5%)	14
Lymphocyte count increased	10/201 (5%)	12	16/199 (8%)	16
Platelet count increased	47/201 (23.4%)	60	59/199 (29.6%)	80
Red blood cell count increased	15/201 (7.5%)	16	4/199 (2%)	5
White blood cell count decreased	18/201 (9%)	21	17/199 (8.5%)	19
White blood cell count increased	17/201 (8.5%)	19	18/199 (9%)	19
Metabolism and nutrition disorders
Anorexia	11/201 (5.5%)	11	4/199 (2%)	4
Anorexia	4/201 (2%)	4	32/199 (16.1%)	35
Nervous system disorders
Headache	25/201 (12.4%)	34	30/199 (15.1%)	36
Respiratory, thoracic and mediastinal disorders
Cough	109/201 (54.2%)	166	104/199 (52.3%)	190
Rhinorrhoea	39/201 (19.4%)	46	28/199 (14.1%)	30
Skin and subcutaneous tissue disorders
Rash papular	7/201 (3.5%)	8	11/199 (5.5%)	13
Skin lesion	6/201 (3%)	8	11/199 (5.5%)	11

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.