Malaria
Conditions
Keywords
Plasmodium falciparum, malaria, merozoite surface protein-1
Brief summary
This study tested the safety of a new malaria vaccine in adults in Mali, West Africa, and measured the ability of the vaccine to stimulate antibodies directed against the malaria protein that the vaccine is based on. Forty adults were randomly assigned to get either the experimental malaria vaccine or a rabies vaccine, for comparison.
Detailed description
The study was a randomized, controlled trial in which participants and clinical investigators were blinded to vaccine group assignment. Forty adults were randomized in a 1:1 ratio to receive either FMP1/AS02A or the control rabies vaccine. The aims of the control group were to account for baseline morbidity and the impact of seasonal malaria transmission on the dynamics of anti-MSP-1 antibodies, and to minimize bias in assessment of adverse events. Vaccines were given on a 0-, 1- and 2-month schedule. The first immunization was given in early July just as malaria transmission began; the second dose at the end of July as transmission was increasing; and the third dose in late August near the peak of malaria transmission intensity. Study day 90 was in October, shortly after transmission crests and when severe and uncomplicated malaria disease episodes peak, study day 180 was at the end of the malaria season, and study day 272 was at the height of the dry season. The final study follow-up on day 364 coincided with the beginning of the 2004 malaria season. Interim safety analyses were reviewed by an independent Safety Monitoring Committee before the second and third immunizations.
Interventions
BIOLOGICALFMP1/AS02A
FMP1 antigen contained 62.5 ug of lyophilized protein with 3.1 percent lactose as cryoprotectant. It's reconstituted in approx. 600 uL AS02A adjuvant manufactured by GSK. AS02A contains 50 ug MPL and 50ug QS21, 250uL of SB62 (oil/water emulsion) in phosphate buffered saline (PBS) per volume of 0.5 mL. All AS02A vials contained 0.65 to 0.75 mL of liquid.
BIOLOGICALImovax Rabies Vaccine
Sterile, stable, freeze-dried suspension of rabies virus prepared from the strain PM-1503-3M, obtained from the Wistar Inst. in Philadelphia. Each 1 mL dose of vaccine contained 100 mg of human albumin, \<150g of neomycin sulfate, and \>2.5 IU of rabies antigen.
Sponsors
National Institute of Allergy and Infectious Diseases (NIAID)
Walter Reed Army Institute of Research (WRAIR)
GlaxoSmithKline
United States Agency for International Development (USAID)
U.S. Army Medical Research and Development Command
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* A male or non-pregnant female aged 18-55 years inclusive at the time of screening. * For women, willingness not to become pregnant until 1 month after the last dose of vaccine * Written informed screening and study consent obtained from the participant before study start. * Available and willing to participate in follow-up for the duration of study (12 months)
Exclusion criteria
* Previous vaccination with an investigational malaria vaccine or with any rabies vaccine. * Use of any investigational or non-registered drug or vaccine other than the study vaccine(s) within 30 days preceding the first dose of study vaccine, or planned use up to 30 days after the third dose. * Chronic administration (defined as more than 14 days) of immuno-suppressants or other immune-modifying drugs within six months prior to the first vaccine dose. This will include oral steroids and inhaled steroids, but not topical steroids. * Planned administration/administration of a vaccine not foreseen by the study protocol within 30 days before the first dose of study vaccine(s) with the exception of tetanus toxoid. * Previous vaccination with a vaccine containing MPL and/or QS-21 such as RTS,S. * Any confirmed or suspected immunosuppressive or immunodeficient condition, including human immunodeficiency virus (HIV) infection. * Any 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 or neomycin * History of splenectomy * Serum ALT \>=35 IU/L * Serum creatinine level \>133 micro moles per Liter (1.5 mg/dL) * Hb \<11 g/dL for males and \<10 g/dL for females * WBC \<3.0 x 103/mm3 or \>13.5 x 103/mm3 * Absolute lymphocyte count \<=1.0 x 103 per micro liter * Thrombocytopenia \< 100,000 per micro liter * More than trace protein, more than trace hemoglobin or positive glucose in urine * Administration of immunoglobulins and/or any blood products within the three months preceding the first dose of study vaccine or planned administration during the study period. * Suspected or known current alcohol or illicit drug abuse. * Pregnancy or positive urine beta-HCG on the day of or prior to immunization. * Breastfeeding * Simultaneous participation in any other interventional clinical trial. * Acute or chronic pulmonary, cardiovascular, hepatic, renal or neurologic condition, or any other findings that in the opinion of the PI may increase the risk to the participant from participating in the study. * Other condition that in the opinion of the investigator would jeopardize the safety or rights of a participant in the trial or would render the participant unable to comply with the protocol
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Solicited Adverse Events by Immunization and Type | Days 0, 1, 2, 3, 7, 30, 31, 32, 33, 37, 60, 61, 62, 63, 67 | Number of participants with solicited adverse events by immunization and type (local, general and any) during each of the three eight-day follow-up periods after each vaccination (day of vaccination and post-vaccination days 1, 2, 3, and 7). Subjects were immunized on days 0, 30+7, and 60+7. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Geometric Mean Titers for Anti-FMP1 Antibody | Days 0, 14, 30, 44, 60, 74, 90, 180, 272, and 364 | Immune response was measured by anti-FMP1 endpoint titers. Data were obtained on day 0, 14, 30, 44, 60, 74, 90, 180, 272, and 364. Samples collected on vaccination days (days 0, 30, and 60) were collected immediately prior to vaccination. |
Countries
Mali
Participant flow
Recruitment details
40 subjects were randomized at 1:1 ratio to receive either FMP1/AS02A or Imovax Rabies vaccine. All 40 subjects received all 3 immunizations and were followed for 12 months
Participants by arm
| Arm | Count |
|---|---|
| FMP1/AS02A Vaccine 500 uL of FMP1/AS02A is given to subject on days 0, 30+7, and 60+7 in the left deltoid muscle
FMP1/AS02A: FMP1 antigen contained 62.5 ug of lyophilized protein with 3.1 percent lactose as cryoprotectant. It's reconstituted in approx. 600 uL AS02A adjuvant manufactured by GSK. AS02A contains 50 ug MPL and 50ug QS21, 250uL of SB62 (oil/water emulsion) in phosphate buffered saline (PBS) per volume of 0.5 mL. All AS02A vials contained 0.65 to 0.75 mL of liquid. | 20 |
| Imovax Rabies Vaccine 1 mL of Imovax Rabies Vaccine is given to subject on days 0, 30+7, and 60+7 in the left deltoid muscle
Imovax Rabies Vaccine: Sterile, stable, freeze-dried suspension of rabies virus prepared from the strain PM-1503-3M, obtained from the Wistar Inst. in Philadelphia. Each 1 mL dose of vaccine contained 100 mg of human albumin, \<150g of neomycin sulfate, and \>2.5 IU of rabies antigen. | 20 |
| Total | 40 |
Baseline characteristics
| Characteristic | FMP1/AS02A Vaccine | Imovax Rabies Vaccine | Total |
|---|---|---|---|
| Age, Continuous | 40.3 years STANDARD_DEVIATION 8 | 38.5 years STANDARD_DEVIATION 10 | 39.4 years STANDARD_DEVIATION 9 |
| Region of Enrollment Mali | 20 Participants | 20 Participants | 40 Participants |
| Sex: Female, Male Female | 5 Participants | 2 Participants | 7 Participants |
| Sex: Female, Male Male | 15 Participants | 18 Participants | 33 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 20 | 0 / 20 |
| other Total, other adverse events | 20 / 20 | 20 / 20 |
| serious Total, serious adverse events | 0 / 20 | 2 / 20 |
Outcome results
Primary
Number of Participants With Solicited Adverse Events by Immunization and Type
Number of participants with solicited adverse events by immunization and type (local, general and any) during each of the three eight-day follow-up periods after each vaccination (day of vaccination and post-vaccination days 1, 2, 3, and 7). Subjects were immunized on days 0, 30+7, and 60+7.
Time frame: Days 0, 1, 2, 3, 7, 30, 31, 32, 33, 37, 60, 61, 62, 63, 67
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Imovax Rabies Vaccine | Number of Participants With Solicited Adverse Events by Immunization and Type | Immunization 1: Local Symptom | 4 Participants |
| Imovax Rabies Vaccine | Number of Participants With Solicited Adverse Events by Immunization and Type | Immunization 2: General Symptom | 8 Participants |
| Imovax Rabies Vaccine | Number of Participants With Solicited Adverse Events by Immunization and Type | Immunization 2: Any Symptom | 12 Participants |
| Imovax Rabies Vaccine | Number of Participants With Solicited Adverse Events by Immunization and Type | Immunization 3: Any Symptom | 11 Participants |
| Imovax Rabies Vaccine | Number of Participants With Solicited Adverse Events by Immunization and Type | Immunization 1: General Symptom | 4 Participants |
| Imovax Rabies Vaccine | Number of Participants With Solicited Adverse Events by Immunization and Type | Immunization 3: Local Symptom | 9 Participants |
| Imovax Rabies Vaccine | Number of Participants With Solicited Adverse Events by Immunization and Type | Immunization 2: Local Symptom | 7 Participants |
| Imovax Rabies Vaccine | Number of Participants With Solicited Adverse Events by Immunization and Type | Immunization 3: General Symptom | 5 Participants |
| Imovax Rabies Vaccine | Number of Participants With Solicited Adverse Events by Immunization and Type | Immunization 1: Any Symptom | 8 Participants |
| FMP1/AS02A Vaccine | Number of Participants With Solicited Adverse Events by Immunization and Type | Immunization 3: General Symptom | 8 Participants |
| FMP1/AS02A Vaccine | Number of Participants With Solicited Adverse Events by Immunization and Type | Immunization 1: Any Symptom | 18 Participants |
| FMP1/AS02A Vaccine | Number of Participants With Solicited Adverse Events by Immunization and Type | Immunization 1: Local Symptom | 13 Participants |
| FMP1/AS02A Vaccine | Number of Participants With Solicited Adverse Events by Immunization and Type | Immunization 1: General Symptom | 14 Participants |
| FMP1/AS02A Vaccine | Number of Participants With Solicited Adverse Events by Immunization and Type | Immunization 2: Any Symptom | 13 Participants |
| FMP1/AS02A Vaccine | Number of Participants With Solicited Adverse Events by Immunization and Type | Immunization 2: Local Symptom | 10 Participants |
| FMP1/AS02A Vaccine | Number of Participants With Solicited Adverse Events by Immunization and Type | Immunization 2: General Symptom | 12 Participants |
| FMP1/AS02A Vaccine | Number of Participants With Solicited Adverse Events by Immunization and Type | Immunization 3: Any Symptom | 11 Participants |
| FMP1/AS02A Vaccine | Number of Participants With Solicited Adverse Events by Immunization and Type | Immunization 3: Local Symptom | 8 Participants |
Secondary
Geometric Mean Titers for Anti-FMP1 Antibody
Immune response was measured by anti-FMP1 endpoint titers. Data were obtained on day 0, 14, 30, 44, 60, 74, 90, 180, 272, and 364. Samples collected on vaccination days (days 0, 30, and 60) were collected immediately prior to vaccination.
Time frame: Days 0, 14, 30, 44, 60, 74, 90, 180, 272, and 364
Population: Immune response was measured by anti-FMP1 endpoint titers. Data were obtained on day 0, 14, 30, 44, 60, 74, 90, 180, 272, and 364. Samples collected on vaccination days (days 0, 30, and 60) were collected immediately prior to vaccination.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Imovax Rabies Vaccine | Geometric Mean Titers for Anti-FMP1 Antibody | FMP1/AS02A: Day 272 | 19518 geometric mean titers |
| Imovax Rabies Vaccine | Geometric Mean Titers for Anti-FMP1 Antibody | FMP1/AS02A: Day 364 | 14693 geometric mean titers |
| Imovax Rabies Vaccine | Geometric Mean Titers for Anti-FMP1 Antibody | Imovax: Pre-Imm 1 | 3282 geometric mean titers |
| Imovax Rabies Vaccine | Geometric Mean Titers for Anti-FMP1 Antibody | Imovax: Imm 1+14 days | 3089 geometric mean titers |
| Imovax Rabies Vaccine | Geometric Mean Titers for Anti-FMP1 Antibody | Imovax: Pre-Imm 2 | 3485 geometric mean titers |
| Imovax Rabies Vaccine | Geometric Mean Titers for Anti-FMP1 Antibody | Imovax: Imm 2+14 days | 4036 geometric mean titers |
| Imovax Rabies Vaccine | Geometric Mean Titers for Anti-FMP1 Antibody | Imovax: Pre-Imm 3 | 6915 geometric mean titers |
| Imovax Rabies Vaccine | Geometric Mean Titers for Anti-FMP1 Antibody | Imovax: Imm 3+14 days | 7051 geometric mean titers |
| Imovax Rabies Vaccine | Geometric Mean Titers for Anti-FMP1 Antibody | Imovax: Imm 3+30 days | 6892 geometric mean titers |
| Imovax Rabies Vaccine | Geometric Mean Titers for Anti-FMP1 Antibody | Imovax: Day 180 | 9089 geometric mean titers |
| Imovax Rabies Vaccine | Geometric Mean Titers for Anti-FMP1 Antibody | Imovax: Day 272 | 6367 geometric mean titers |
| Imovax Rabies Vaccine | Geometric Mean Titers for Anti-FMP1 Antibody | Imovax: Day 364 | 5015 geometric mean titers |
| Imovax Rabies Vaccine | Geometric Mean Titers for Anti-FMP1 Antibody | FMP1/AS02A: Pre-Imm 1 | 5858 geometric mean titers |
| Imovax Rabies Vaccine | Geometric Mean Titers for Anti-FMP1 Antibody | FMP1/AS02A: Imm 1+14 days | 7627 geometric mean titers |
| Imovax Rabies Vaccine | Geometric Mean Titers for Anti-FMP1 Antibody | FMP1/AS02A: Pre-Imm 2 | 8007 geometric mean titers |
| Imovax Rabies Vaccine | Geometric Mean Titers for Anti-FMP1 Antibody | FMP1/AS02A: Imm 2+14 days | 20044 geometric mean titers |
| Imovax Rabies Vaccine | Geometric Mean Titers for Anti-FMP1 Antibody | FMP1/AS02A: Pre-Imm 3 | 26321 geometric mean titers |
| Imovax Rabies Vaccine | Geometric Mean Titers for Anti-FMP1 Antibody | FMP1/AS02A: Imm 3+14 days | 35194 geometric mean titers |
| Imovax Rabies Vaccine | Geometric Mean Titers for Anti-FMP1 Antibody | FMP1/AS02A: Imm 3+30 days | 37923 geometric mean titers |
| Imovax Rabies Vaccine | Geometric Mean Titers for Anti-FMP1 Antibody | FMP1/AS02A: Day 180 | 29150 geometric mean titers |