Plasmodium Falciparum
Conditions
Keywords
RTS,S/AS01E, hypo-immuno-responsiveness, open-label randomized study, Phase 2b, Kenyan adults, anti-malarials, fractional dose RTS,S/AS01E
Brief summary
The main goal of this study is to assess the efficacy of RTS,S/AS01E, a candidate vaccine against malaria caused by Plasmodium falciparum (P. falciparum), in adults positive for P. falciparum at the start of the study, but treated with anti-malarial medications to clear the parasite before receiving multiple doses of the vaccine. The goal is to overcome the reduced vaccine efficacy (hypo-responsiveness to the vaccine) reported in actively or chronically infected adults.
Detailed description
PATH and GlaxoSmithKline (GSK) are committed to developing a malaria vaccine to help reduce the burden of malaria disease in children and contribute to malaria elimination. GSK has developed a candidate vaccine against malaria caused by P. falciparum called RTS,S/AS01E. The vaccine has been shown to be safe in multiple trials and efficacy data in pediatric populations has led to a pilot implementation program in three African countries including Kenya. The RTS,S/AS01E vaccine mechanism of action is presumed to work on the initial sporozoite and liver stages of P. falciparum infection through neutralization of the circumsporozoite (CS) antigen on parasites invading after a mosquito bite in individuals immunized with the RTS,S/AS01E vaccine. In order to inform whether a vaccine such as RTS,S/AS01E may have a future role in malaria elimination, it will be important to establish vaccine efficacy in adults in Sub-Saharan Africa who are reservoirs of parasites and who contribute to ongoing malaria transmission. However, in previous trials, the vaccine has been less effective in adults who have had malaria before. There are probably multiple reasons for this, but one possible reason that is probably very important is that prior infection with malaria or an infection with malaria for long periods, even without symptoms of the disease, can prevent the vaccine from working properly. This study postulates that treatment of infection prior to immunization can reset the immune response leading to an improved vaccine efficacy. To evaluate this hypothesis, the study will recruit 5 groups. Groups 1 and 4 will have asymptomatic infection with P. falciparum as measured by a highly sensitive polymerase chain reaction (PCR) assay and will be treated with antimalarial medications prior to immunization with RTS,S/AS01E or the comparator rabies vaccine, respectively, with the primary objective of evaluating the vaccine efficacy of RTS,S/AS01E relative to the rabies vaccine in this context. Groups 2 and 5 will be negative for asymptomatic infection with P. falciparum as measured by a highly sensitive PCR assay and will be treated with antimalarial medications prior to immunization with RTS,S/AS01E or the comparator rabies vaccine, respectively, with the secondary objective of evaluating the vaccine efficacy of RTS,S/AS01 relative to the rabies vaccine in this context. Group 3 will have asymptomatic infection with P. falciparum as measured by a highly sensitive PCR assay but will not be treated with antimalarial medications prior to immunization with the RTS,S/AS01E vaccine; the immunological profile of this group and groups 1 and 2 will be evaluated as part of secondary and exploratory objectives. Other secondary objectives include safety assessments. The study will include an initial immunization period (vaccine given on 0, 1, and 7 month schedule with the final dose being 1/5 of the dose of the first two immunizations) followed by 6-12 months of follow-up (varying based on the number of events),
Interventions
BIOLOGICALMalaria Vaccine RTS,S/AS01E
RTS,S/AS01E vaccine 0.5 mL, containing 25 μg protein comprising circumsporozoite protein (CS) and hepatitis B surface antigen (RTS,S), 25 μg monophosphoryl lipid (AMPL), 25 μg Quillaja saponaria 21 (QS21) in a liposomal formulation) for the first two immunizations. One-fifth dose RTS,S/AS01E vaccine was used for the third immunization.
BIOLOGICALAbhayrab rabies vaccine
Abhayrab rabies vaccine, 0.5 mL, contains 2.5 IU rabies antigen.
DRUGDihydroartemisinin-piperaquine (DHA/Pip)
Dihydroartemisinin (120 mg or 160 mg based on weight) and piperaquine tetraphosphate (960 mg or 1280 mg based on weight) mg) administered once a day for 3 days. DHA/Pip is a long acting anti-malarial used to clear asexual stage and young gametocyte parasites.
Artemether (80 mg) and lumefantrine (480 mg) administered twice a day for 3 days. Coartem is a short-acting artemisinin combination therapy used to provide clearance of blood stage parasites in order to establish a clean baseline for determination of vaccine efficacy.
DRUGPrimaquine
One dose of 15 mg primaquine. Low dose primaquine (LD PQ) is used to clear mature gametocytes of P. falciparum.
Sponsors
Walter Reed Army Institute of Research (WRAIR)
GlaxoSmithKline
Kenya Medical Research Institute
FHI Clinical SA Proprietary Limited
DF/Net
PATH
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
NONE
Intervention model description
Three groups (Groups 1, 2, and 3) will be administered RTS,S/AS01E on a 0, 1, 7 month schedule with Dose 3 delivered as a 1/5th fractional dose. Two groups (Groups 4 and 5) will be administered a comparator vaccine on a 0, 1, 7 month schedule.
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
* Provision of signed or thumb printed and dated informed consent form * Stated willingness to comply with all study procedures and availability for the duration of the study * Male or female between 18 and 55 years of age, inclusive * In good general health as evidenced by medical history and clinical examination before entering the study * Ability to take oral medication and be willing to adhere to the medication regimen * For females, she must be of non-childbearing potential or use appropriate measures to prevent pregnancy for 30 days prior to vaccination through 2 months after completion of the vaccine series. Non-childbearing potential means she is surgically sterilized or at least one year post-menopausal. Appropriate measures to prevent pregnancy include abstinence or adequate contraceptive precautions (i.e. intrauterine contraceptive device; oral contraceptives; diaphragm or condom in combination with contraceptive jelly, cream or foam; Norplant or Depo-Provera). Clinical trial site staff will assist with provision of acceptable birth control for study entry and will discuss with volunteer at screening visit.
Exclusion criteria
* Planned administration/administration of a vaccine not foreseen by the study protocol from within 30 days before the first dose of study vaccine until 30 days after the last dose of study vaccine.† † In the context of the COVID-19 pandemic, the administration of the COVID-19 vaccine will be allowed as an exception to this
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Time to First PCR-detectable Malaria Infection During the Active Detection of Infection (ADI) Phase in Groups 1 and 4 | The active detection of infection phase began 2 weeks after the third vaccination (approximately week 30) for up to 35 weeks. Participants provided blood samples every 21 days during the ADI phase for PCR assays. | Participants were actively monitored for malarial infection starting 2 weeks after the third vaccination. Blood samples were assayed using a highly sensitive polymerase chain reaction (PCR) (Plasmodium falciparum/ Pan-Plasmodium 18S ribosomal ribonucleic acid (rRNA) laboratory developed test \[LDT\]) that can detect sub-clinical parasitemia at the US Army Medical Research Directorate-Africa (USAMRD-A) / Kenya Medical Research Institute (KEMRI) laboratories in Kisumu, Kenya. A positive PCR result from blood samples collected during the ADI was recorded as a positive event for the presence of P. falciparum blood stage infection. The time to first malaria infection is expressed in terms of rate of first malaria infection, that is, the number of malaria infection events reported over the time period elapsed until the event occurred (i.e. events per Persons Year at Risk \[PYAR\]) for each group. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Serious Adverse Events (SAEs) | From first dose to end of study, up to 65 weeks. | An adverse event is any untoward medical occurrence in a study participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product, or temporally associated with a study procedure. A serious adverse event is any adverse event that: * Resulted in death, * Was life-threatening, * Resulted in disability/incapacity, * Required hospitalization or prolongation of existing hospitalization, * Resulted in disability/incapacity. * Resulted in a congenital anomaly and / or birth defect. |
| Number of Participants With Solicited Local and Systemic Adverse Events (AEs) | Within 7 days after each vaccination. | Solicited AEs are pre-specified local and systemic AEs that occur relatively more frequently or are known to be associated with immunization, which are monitored actively as potential indicators of vaccine reactogenicity. Solicited local and general AEs were collected among RTS,S vaccinated groups in the first 50 participants enrolled in Groups 1 and 2 and all participants enrolled in Group 3 (Reactogenicity Cohort) for seven days (day of vaccination and six subsequent days) after each dose of vaccine. Local (injection site) adverse events are defined as: * Pain at injection site * Swelling at injection site Systemic adverse events are defined as: * Fever (temperature ≥ 37.5°C) * Headache * Gastrointestinal problems * Fatigue * Muscle ache |
| Number of Participants With Unsolicited Adverse Events | Within 28 days after each vaccination. | An adverse event is defined as any untoward medical occurrence in a study participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product, or temporally associated with a study procedure. Unsolicited AEs are any AEs reported spontaneously by the participant, observed by the study staff during study visits or those identified during review of medical records or source documents. Solicited AEs with an onset after the seven-day solicitation period were also considered unsolicited AEs. |
| Time to First PCR-detectable Malaria Infection During the Active Detection of Infection Phase in Groups 2 and 5 | The active detection of infection phase began 2 weeks after the third vaccination (approximately week 30) for up to 35 weeks. Participants provided blood samples every 21 days during the ADI phase for PCR assays. | Participants were actively monitored for malarial infection starting 2 weeks after the third vaccination. Blood samples were assayed using a highly sensitive PCR (Plasmodium falciparum/ Pan-Plasmodium 18S rRNA LDT) that can detect sub-clinical parasitemia. A positive PCR result from blood samples collected during the ADI phase was recorded as a positive event for the presence of P. falciparum blood stage infection. The time to first malaria infection is expressed in terms of rate of first malaria infection, that is, the number of malaria infection events reported over the time period elapsed until the event occurred (i.e. events per Persons Year at Risk \[PYAR\]) for each group. |
| Anti-Plasmodium Falciparum Circumsporozoite (CS) Antibody Avidity Index in Groups 1, 2, and 3 | Baseline, Day 29 (28 days after first vaccination), Day 57 (28 days after second vaccination), Day 197 (24 weeks after second vaccination), and Day 225 (28 days after third vaccination) | Antibody levels against P. falciparum circumsporozoite (CS) protein central repeat region (NANP) measured by standard enzyme-linked immunosorbent assays (ELISA) for participants in Groups 1, 2 and 3. To measure antibody-antigen avidity (strength of binding) ELISA was performed with and without urea (to dissociate the antigen-antibody complex). The avidity index is calculated by dividing the serum titer obtained in the presence of the urea by the serum titer without urea. |
| Geometric Mean Titer (GMT) of Anti-Hepatitis B Surface Antigen (HBsAg) Antibodies in Groups 1, 2, and 3 | Baseline, Day 29 (28 days after first vaccination) and Day 225 (28 days after third vaccination) | The RTS,S vaccine antigen consists of sequences of both the P. falciparum circumsporozoite protein and hepatitis B surface antigen, hence anti-HBsAg antibodies were also measured. Anti-hepatitis B surface antigen antibodies were assessed at the International AIDS Vaccine Initiative Human Immunology Laboratory (IAVI-HIL) at Imperial College, London, UK, using a commercially available ELISA kit. |
| Geometric Mean Titer of Anti-Plasmodium Falciparum Circumsporozoite (CS) Antibodies in Groups 1, 2, and 3 | Baseline, Day 29 (28 days after first vaccination), Day 57 (28 days after second vaccination), Day 197 (24 weeks after second vaccination), and Day 225 (28 days after third vaccination) | The RTS,S antigen consists of sequences of both the P. falciparum circumsporozoite protein and hepatitis B surface antigen. Antibody levels against P. falciparum circumsporozoite (CS) protein central repeat region (NANP) were measured from blood samples of participants in Groups 1, 2 and 3 using standard enzyme-linked immunosorbent assays (ELISA) at Walter Reed Army Institute of Research (WRAIR), in Silver Spring, MD, United States. |
Countries
Kenya
Participant flow
Recruitment details
Participants were recruited from the villages in the Kombewa Health and Demographics Surveillance System (HDSS) consisting of half of Kisumu West and all of Seme sub-counties of Kisumu County, Kenya. Prior to enrollment participants were tested for the presence or absence of asymptomatic infection with Plasmodium falciparum (P. falciparum, the parasite that causes malaria) measured using a highly sensitive polymerase chain reaction (PCR) assay.
Pre-assignment details
Participants were stratified by baseline P. falciparum parasitemia status and then block randomized. The first 105 participants who were positive for parasitemia at baseline were randomized in a 1:1:1 ratio with 35 participants assigned to each of Groups 1, 3 and 4. The next 258 participants with baseline parasitemia were randomized in a 1:1 ratio to Groups 1 and 4. Participants who were negative for parasitemia at baseline were randomized in a 1:1 ratio to Groups 2 and 5.
Participants by arm
| Arm | Count |
|---|---|
| Group 1: Positive Parasitemia; Anti-malarial Treatment + RTS,S/AS01E Vaccine Participants with detectable P. falciparum parasitemia at baseline received anti-malarial treatment with DHA/Pip plus LD PQ 4 weeks prior to the first vaccination and another course of DHA/Pip plus LD PQ two weeks before the second vaccination. One week before the third vaccination, a course of A/L plus LD PQ was administered.
Participants were randomized to receive 3 vaccinations with malarial vaccine RTS,S/AS01E by intramuscular injection given on a 0, 1, and 7 month schedule with the final dose being 1/5 of the dose of the first two immunizations. | 160 |
| Group 2: No Parasitemia; Anti-malarial Prophylaxis + RTS,S/AS01E Vaccine Participants with no detectable P. falciparum parasitemia at baseline received anti-malarial prophylaxis with DHA/Pip plus LD PQ 4 weeks prior to the first vaccination and a 2nd course of DHA/Pip plus LD PQ 2 weeks before the second vaccination. One week before the third vaccination, a course of A/L plus LD PQ was administered.
Participants were randomized to receive 3 vaccinations with malarial vaccine RTS,S/AS01E by intramuscular injection given on a 0, 1, and 7 month schedule with the final dose being 1/5 of the dose of the first two immunizations. | 124 |
| Group 3: Positive Parasitemia; RTS,S/AS01E Vaccine Participants with detectable P. falciparum parasitemia at baseline did not receive any anti-malarial medications to clear parasites.
Participants were randomized to receive 3 vaccinations with malarial vaccine RTS,S/AS01E by intramuscular injection given on a 0, 1, and 7 month schedule with the final dose being 1/5 of the dose of the first two immunizations.
This group is included only for immunological assessment and not for vaccine efficacy. | 35 |
| Group 4: Positive Parasitemia; Anti-malarial Treatment + Rabies Vaccine Participants with detectable P. falciparum parasitemia at baseline received anti-malarial treatment with DHA/Pip plus LD PQ 4 weeks prior to the first vaccination and another course of DHA/Pip plus LD PQ two weeks before the second vaccination. One week before the third vaccination, a three-day course of A/L plus LD PQ was administered.
Participants were randomized to receive 3 vaccinations of Abhayrab rabies vaccine on a 0, 1, 7 month schedule. | 159 |
| Group 5: No Parasitemia, Anti-malarial Prophylaxis + Rabies Vaccine Participants with no detectable P. falciparum parasitemia at baseline received anti-malarial prophylaxis with DHA/Pip plus LD PQ 4 weeks prior to the first vaccination and a 2nd course of DHA/Pip plus LD PQ 2 weeks before the second vaccination. One week before the third vaccination, a course of A/L plus LD PQ was administered.
Participants were randomized to receive 3 vaccinations of Abhayrab rabies vaccine on a 0, 1, 7 month schedule. | 127 |
| Total | 605 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 |
|---|---|---|---|---|---|---|
| Overall Study | Death | 1 | 0 | 0 | 0 | 0 |
| Overall Study | Lost to Follow-up | 19 | 10 | 2 | 7 | 11 |
| Overall Study | Other | 1 | 2 | 1 | 1 | 1 |
| Overall Study | Physician Decision | 2 | 0 | 0 | 1 | 0 |
| Overall Study | Randomized but Did Not Receive Study Product | 4 | 4 | 1 | 5 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 4 | 0 | 2 | 0 |
Baseline characteristics
| Characteristic | Group 1: Positive Parasitemia; Anti-malarial Treatment + RTS,S/AS01E Vaccine | Group 2: No Parasitemia; Anti-malarial Prophylaxis + RTS,S/AS01E Vaccine | Group 3: Positive Parasitemia; RTS,S/AS01E Vaccine | Group 4: Positive Parasitemia; Anti-malarial Treatment + Rabies Vaccine | Group 5: No Parasitemia, Anti-malarial Prophylaxis + Rabies Vaccine | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 31.94 years STANDARD_DEVIATION 8.04 | 34.02 years STANDARD_DEVIATION 7.63 | 34.57 years STANDARD_DEVIATION 8.93 | 31.76 years STANDARD_DEVIATION 8.49 | 34.04 years STANDARD_DEVIATION 8.04 | 32.91 years STANDARD_DEVIATION 8.19 |
| Race/Ethnicity, Customized Luhya | 2 Participants | 2 Participants | 0 Participants | 0 Participants | 2 Participants | 6 Participants |
| Race/Ethnicity, Customized Luo | 158 Participants | 122 Participants | 35 Participants | 159 Participants | 125 Participants | 599 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 160 Participants | 124 Participants | 35 Participants | 159 Participants | 127 Participants | 605 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Kenya | 160 participants | 124 participants | 35 participants | 159 participants | 127 participants | 605 participants |
| Sex: Female, Male Female | 72 Participants | 80 Participants | 21 Participants | 75 Participants | 75 Participants | 323 Participants |
| Sex: Female, Male Male | 88 Participants | 44 Participants | 14 Participants | 84 Participants | 52 Participants | 282 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 1 / 164 | 0 / 128 | 0 / 36 | 0 / 164 | 0 / 128 |
| other Total, other adverse events | 111 / 160 | 96 / 124 | 25 / 35 | 110 / 159 | 92 / 127 |
| serious Total, serious adverse events | 3 / 160 | 2 / 124 | 1 / 35 | 1 / 159 | 3 / 127 |
Outcome results
Primary
Time to First PCR-detectable Malaria Infection During the Active Detection of Infection (ADI) Phase in Groups 1 and 4
Participants were actively monitored for malarial infection starting 2 weeks after the third vaccination. Blood samples were assayed using a highly sensitive polymerase chain reaction (PCR) (Plasmodium falciparum/ Pan-Plasmodium 18S ribosomal ribonucleic acid (rRNA) laboratory developed test \[LDT\]) that can detect sub-clinical parasitemia at the US Army Medical Research Directorate-Africa (USAMRD-A) / Kenya Medical Research Institute (KEMRI) laboratories in Kisumu, Kenya. A positive PCR result from blood samples collected during the ADI was recorded as a positive event for the presence of P. falciparum blood stage infection. The time to first malaria infection is expressed in terms of rate of first malaria infection, that is, the number of malaria infection events reported over the time period elapsed until the event occurred (i.e. events per Persons Year at Risk \[PYAR\]) for each group.
Time frame: The active detection of infection phase began 2 weeks after the third vaccination (approximately week 30) for up to 35 weeks. Participants provided blood samples every 21 days during the ADI phase for PCR assays.
Population: The primary endpoint was pre-specified to be analyzed in Groups 1 and 4 only. The According to Protocol (ATP) cohort for efficacy includes all participants in the TVC with no major protocol deviations that could potentially interfere with the efficacy assessment of the study vaccine and who contributed to the time at risk starting 14 days after the third dose.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1: Positive Parasitemia; Anti-malarial Treatment + RTS,S/AS01E Vaccine | Time to First PCR-detectable Malaria Infection During the Active Detection of Infection (ADI) Phase in Groups 1 and 4 | 1.01 Events per person year at risk |
| Group 4: Positive Parasitemia; Anti-malarial Treatment + Rabies Vaccine | Time to First PCR-detectable Malaria Infection During the Active Detection of Infection (ADI) Phase in Groups 1 and 4 | 1.49 Events per person year at risk |
Comparison: Vaccine efficacy against the first PCR-positive P. falciparum infection among adults who were P. falciparum positive at baseline was assessed using Cox proportional hazards regression model with a covariate for group assignment to compare Groups 1 and 4. HIV status, Age (tertiles), and sleep under a bednet were included as covariates.p-value: 0.00995% CI: [10.3, 54.2]Wald test
Secondary
Anti-Plasmodium Falciparum Circumsporozoite (CS) Antibody Avidity Index in Groups 1, 2, and 3
Antibody levels against P. falciparum circumsporozoite (CS) protein central repeat region (NANP) measured by standard enzyme-linked immunosorbent assays (ELISA) for participants in Groups 1, 2 and 3. To measure antibody-antigen avidity (strength of binding) ELISA was performed with and without urea (to dissociate the antigen-antibody complex). The avidity index is calculated by dividing the serum titer obtained in the presence of the urea by the serum titer without urea.
Time frame: Baseline, Day 29 (28 days after first vaccination), Day 57 (28 days after second vaccination), Day 197 (24 weeks after second vaccination), and Day 225 (28 days after third vaccination)
Population: The according to protocol (ATP) cohort for immunogenicity; participants with available data at each time point.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Group 1: Positive Parasitemia; Anti-malarial Treatment + RTS,S/AS01E Vaccine | Anti-Plasmodium Falciparum Circumsporozoite (CS) Antibody Avidity Index in Groups 1, 2, and 3 | Baseline | 0.62 ratio |
| Group 1: Positive Parasitemia; Anti-malarial Treatment + RTS,S/AS01E Vaccine | Anti-Plasmodium Falciparum Circumsporozoite (CS) Antibody Avidity Index in Groups 1, 2, and 3 | Day 197 | 0.59 ratio |
| Group 1: Positive Parasitemia; Anti-malarial Treatment + RTS,S/AS01E Vaccine | Anti-Plasmodium Falciparum Circumsporozoite (CS) Antibody Avidity Index in Groups 1, 2, and 3 | Day 57 | 0.63 ratio |
| Group 1: Positive Parasitemia; Anti-malarial Treatment + RTS,S/AS01E Vaccine | Anti-Plasmodium Falciparum Circumsporozoite (CS) Antibody Avidity Index in Groups 1, 2, and 3 | Day 225 | 0.55 ratio |
| Group 1: Positive Parasitemia; Anti-malarial Treatment + RTS,S/AS01E Vaccine | Anti-Plasmodium Falciparum Circumsporozoite (CS) Antibody Avidity Index in Groups 1, 2, and 3 | Day 29 | 0.64 ratio |
| Group 4: Positive Parasitemia; Anti-malarial Treatment + Rabies Vaccine | Anti-Plasmodium Falciparum Circumsporozoite (CS) Antibody Avidity Index in Groups 1, 2, and 3 | Day 57 | 0.64 ratio |
| Group 4: Positive Parasitemia; Anti-malarial Treatment + Rabies Vaccine | Anti-Plasmodium Falciparum Circumsporozoite (CS) Antibody Avidity Index in Groups 1, 2, and 3 | Baseline | 0.64 ratio |
| Group 4: Positive Parasitemia; Anti-malarial Treatment + Rabies Vaccine | Anti-Plasmodium Falciparum Circumsporozoite (CS) Antibody Avidity Index in Groups 1, 2, and 3 | Day 29 | 0.67 ratio |
| Group 4: Positive Parasitemia; Anti-malarial Treatment + Rabies Vaccine | Anti-Plasmodium Falciparum Circumsporozoite (CS) Antibody Avidity Index in Groups 1, 2, and 3 | Day 197 | 0.63 ratio |
| Group 4: Positive Parasitemia; Anti-malarial Treatment + Rabies Vaccine | Anti-Plasmodium Falciparum Circumsporozoite (CS) Antibody Avidity Index in Groups 1, 2, and 3 | Day 225 | 0.65 ratio |
| Group 3: Positive Parasitemia; RTS,S/AS01E Vaccine | Anti-Plasmodium Falciparum Circumsporozoite (CS) Antibody Avidity Index in Groups 1, 2, and 3 | Day 225 | 0.66 ratio |
| Group 3: Positive Parasitemia; RTS,S/AS01E Vaccine | Anti-Plasmodium Falciparum Circumsporozoite (CS) Antibody Avidity Index in Groups 1, 2, and 3 | Day 197 | 0.66 ratio |
| Group 3: Positive Parasitemia; RTS,S/AS01E Vaccine | Anti-Plasmodium Falciparum Circumsporozoite (CS) Antibody Avidity Index in Groups 1, 2, and 3 | Baseline | 0.65 ratio |
| Group 3: Positive Parasitemia; RTS,S/AS01E Vaccine | Anti-Plasmodium Falciparum Circumsporozoite (CS) Antibody Avidity Index in Groups 1, 2, and 3 | Day 57 | 0.67 ratio |
| Group 3: Positive Parasitemia; RTS,S/AS01E Vaccine | Anti-Plasmodium Falciparum Circumsporozoite (CS) Antibody Avidity Index in Groups 1, 2, and 3 | Day 29 | 0.69 ratio |
Secondary
Geometric Mean Titer (GMT) of Anti-Hepatitis B Surface Antigen (HBsAg) Antibodies in Groups 1, 2, and 3
The RTS,S vaccine antigen consists of sequences of both the P. falciparum circumsporozoite protein and hepatitis B surface antigen, hence anti-HBsAg antibodies were also measured. Anti-hepatitis B surface antigen antibodies were assessed at the International AIDS Vaccine Initiative Human Immunology Laboratory (IAVI-HIL) at Imperial College, London, UK, using a commercially available ELISA kit.
Time frame: Baseline, Day 29 (28 days after first vaccination) and Day 225 (28 days after third vaccination)
Population: ATP Cohort for Immunogenicity with available data at each time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Group 1: Positive Parasitemia; Anti-malarial Treatment + RTS,S/AS01E Vaccine | Geometric Mean Titer (GMT) of Anti-Hepatitis B Surface Antigen (HBsAg) Antibodies in Groups 1, 2, and 3 | Day 29 | 61.27 titer |
| Group 1: Positive Parasitemia; Anti-malarial Treatment + RTS,S/AS01E Vaccine | Geometric Mean Titer (GMT) of Anti-Hepatitis B Surface Antigen (HBsAg) Antibodies in Groups 1, 2, and 3 | Baseline | 16.88 titer |
| Group 1: Positive Parasitemia; Anti-malarial Treatment + RTS,S/AS01E Vaccine | Geometric Mean Titer (GMT) of Anti-Hepatitis B Surface Antigen (HBsAg) Antibodies in Groups 1, 2, and 3 | Day 225 | 1500.56 titer |
| Group 4: Positive Parasitemia; Anti-malarial Treatment + Rabies Vaccine | Geometric Mean Titer (GMT) of Anti-Hepatitis B Surface Antigen (HBsAg) Antibodies in Groups 1, 2, and 3 | Day 29 | 60.16 titer |
| Group 4: Positive Parasitemia; Anti-malarial Treatment + Rabies Vaccine | Geometric Mean Titer (GMT) of Anti-Hepatitis B Surface Antigen (HBsAg) Antibodies in Groups 1, 2, and 3 | Baseline | 14.32 titer |
| Group 4: Positive Parasitemia; Anti-malarial Treatment + Rabies Vaccine | Geometric Mean Titer (GMT) of Anti-Hepatitis B Surface Antigen (HBsAg) Antibodies in Groups 1, 2, and 3 | Day 225 | 1789.89 titer |
| Group 3: Positive Parasitemia; RTS,S/AS01E Vaccine | Geometric Mean Titer (GMT) of Anti-Hepatitis B Surface Antigen (HBsAg) Antibodies in Groups 1, 2, and 3 | Baseline | 15.57 titer |
| Group 3: Positive Parasitemia; RTS,S/AS01E Vaccine | Geometric Mean Titer (GMT) of Anti-Hepatitis B Surface Antigen (HBsAg) Antibodies in Groups 1, 2, and 3 | Day 225 | 2321.30 titer |
| Group 3: Positive Parasitemia; RTS,S/AS01E Vaccine | Geometric Mean Titer (GMT) of Anti-Hepatitis B Surface Antigen (HBsAg) Antibodies in Groups 1, 2, and 3 | Day 29 | 87.89 titer |
Secondary
Geometric Mean Titer of Anti-Plasmodium Falciparum Circumsporozoite (CS) Antibodies in Groups 1, 2, and 3
The RTS,S antigen consists of sequences of both the P. falciparum circumsporozoite protein and hepatitis B surface antigen. Antibody levels against P. falciparum circumsporozoite (CS) protein central repeat region (NANP) were measured from blood samples of participants in Groups 1, 2 and 3 using standard enzyme-linked immunosorbent assays (ELISA) at Walter Reed Army Institute of Research (WRAIR), in Silver Spring, MD, United States.
Time frame: Baseline, Day 29 (28 days after first vaccination), Day 57 (28 days after second vaccination), Day 197 (24 weeks after second vaccination), and Day 225 (28 days after third vaccination)
Population: The ATP cohort for immunogenicity included all participants in the TVC who received all vaccinations according to protocol procedures and within the protocol specified intervals, performed blood samplings for immunogenicity according to protocol intervals, and did not use any medication or blood products forbidden by the protocol and did not have any reported underlying medical condition influencing immune responses. Participants with available data at each time point.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Group 1: Positive Parasitemia; Anti-malarial Treatment + RTS,S/AS01E Vaccine | Geometric Mean Titer of Anti-Plasmodium Falciparum Circumsporozoite (CS) Antibodies in Groups 1, 2, and 3 | Day 197 | 1627.01 titer |
| Group 1: Positive Parasitemia; Anti-malarial Treatment + RTS,S/AS01E Vaccine | Geometric Mean Titer of Anti-Plasmodium Falciparum Circumsporozoite (CS) Antibodies in Groups 1, 2, and 3 | Day 57 | 3391.18 titer |
| Group 1: Positive Parasitemia; Anti-malarial Treatment + RTS,S/AS01E Vaccine | Geometric Mean Titer of Anti-Plasmodium Falciparum Circumsporozoite (CS) Antibodies in Groups 1, 2, and 3 | Baseline | 171.89 titer |
| Group 1: Positive Parasitemia; Anti-malarial Treatment + RTS,S/AS01E Vaccine | Geometric Mean Titer of Anti-Plasmodium Falciparum Circumsporozoite (CS) Antibodies in Groups 1, 2, and 3 | Day 29 | 2328.78 titer |
| Group 1: Positive Parasitemia; Anti-malarial Treatment + RTS,S/AS01E Vaccine | Geometric Mean Titer of Anti-Plasmodium Falciparum Circumsporozoite (CS) Antibodies in Groups 1, 2, and 3 | Day 225 | 2121.04 titer |
| Group 4: Positive Parasitemia; Anti-malarial Treatment + Rabies Vaccine | Geometric Mean Titer of Anti-Plasmodium Falciparum Circumsporozoite (CS) Antibodies in Groups 1, 2, and 3 | Day 57 | 3530.57 titer |
| Group 4: Positive Parasitemia; Anti-malarial Treatment + Rabies Vaccine | Geometric Mean Titer of Anti-Plasmodium Falciparum Circumsporozoite (CS) Antibodies in Groups 1, 2, and 3 | Baseline | 139.80 titer |
| Group 4: Positive Parasitemia; Anti-malarial Treatment + Rabies Vaccine | Geometric Mean Titer of Anti-Plasmodium Falciparum Circumsporozoite (CS) Antibodies in Groups 1, 2, and 3 | Day 29 | 2538.76 titer |
| Group 4: Positive Parasitemia; Anti-malarial Treatment + Rabies Vaccine | Geometric Mean Titer of Anti-Plasmodium Falciparum Circumsporozoite (CS) Antibodies in Groups 1, 2, and 3 | Day 197 | 1584.13 titer |
| Group 4: Positive Parasitemia; Anti-malarial Treatment + Rabies Vaccine | Geometric Mean Titer of Anti-Plasmodium Falciparum Circumsporozoite (CS) Antibodies in Groups 1, 2, and 3 | Day 225 | 2519.28 titer |
| Group 3: Positive Parasitemia; RTS,S/AS01E Vaccine | Geometric Mean Titer of Anti-Plasmodium Falciparum Circumsporozoite (CS) Antibodies in Groups 1, 2, and 3 | Day 225 | 2586.04 titer |
| Group 3: Positive Parasitemia; RTS,S/AS01E Vaccine | Geometric Mean Titer of Anti-Plasmodium Falciparum Circumsporozoite (CS) Antibodies in Groups 1, 2, and 3 | Day 197 | 1751.77 titer |
| Group 3: Positive Parasitemia; RTS,S/AS01E Vaccine | Geometric Mean Titer of Anti-Plasmodium Falciparum Circumsporozoite (CS) Antibodies in Groups 1, 2, and 3 | Baseline | 231.64 titer |
| Group 3: Positive Parasitemia; RTS,S/AS01E Vaccine | Geometric Mean Titer of Anti-Plasmodium Falciparum Circumsporozoite (CS) Antibodies in Groups 1, 2, and 3 | Day 57 | 4708.33 titer |
| Group 3: Positive Parasitemia; RTS,S/AS01E Vaccine | Geometric Mean Titer of Anti-Plasmodium Falciparum Circumsporozoite (CS) Antibodies in Groups 1, 2, and 3 | Day 29 | 2744.34 titer |
Secondary
Number of Participants With Serious Adverse Events (SAEs)
An adverse event is any untoward medical occurrence in a study participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product, or temporally associated with a study procedure. A serious adverse event is any adverse event that: * Resulted in death, * Was life-threatening, * Resulted in disability/incapacity, * Required hospitalization or prolongation of existing hospitalization, * Resulted in disability/incapacity. * Resulted in a congenital anomaly and / or birth defect.
Time frame: From first dose to end of study, up to 65 weeks.
Population: The Safety analysis population includes all enrolled participants who received at least one vaccination and for whom any safety data were available.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group 1: Positive Parasitemia; Anti-malarial Treatment + RTS,S/AS01E Vaccine | Number of Participants With Serious Adverse Events (SAEs) | 3 Participants |
| Group 4: Positive Parasitemia; Anti-malarial Treatment + Rabies Vaccine | Number of Participants With Serious Adverse Events (SAEs) | 2 Participants |
| Group 3: Positive Parasitemia; RTS,S/AS01E Vaccine | Number of Participants With Serious Adverse Events (SAEs) | 1 Participants |
| Group 4: Positive Parasitemia; Anti-malarial Treatment + Rabies Vaccine | Number of Participants With Serious Adverse Events (SAEs) | 1 Participants |
| Group 5: No Parasitemia, Anti-malarial Prophylaxis + Rabies Vaccine | Number of Participants With Serious Adverse Events (SAEs) | 3 Participants |
Secondary
Number of Participants With Solicited Local and Systemic Adverse Events (AEs)
Solicited AEs are pre-specified local and systemic AEs that occur relatively more frequently or are known to be associated with immunization, which are monitored actively as potential indicators of vaccine reactogenicity. Solicited local and general AEs were collected among RTS,S vaccinated groups in the first 50 participants enrolled in Groups 1 and 2 and all participants enrolled in Group 3 (Reactogenicity Cohort) for seven days (day of vaccination and six subsequent days) after each dose of vaccine. Local (injection site) adverse events are defined as: * Pain at injection site * Swelling at injection site Systemic adverse events are defined as: * Fever (temperature ≥ 37.5°C) * Headache * Gastrointestinal problems * Fatigue * Muscle ache
Time frame: Within 7 days after each vaccination.
Population: The Reactogenicity Cohort (the first 50 participants in Groups 1 and 2 and all participants in Group 3) with available reactogenicity data.~Participants in Groups 4 and 5 did not have solicited AEs collected.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group 1: Positive Parasitemia; Anti-malarial Treatment + RTS,S/AS01E Vaccine | Number of Participants With Solicited Local and Systemic Adverse Events (AEs) | Local Solicited AEs | 24 Participants |
| Group 1: Positive Parasitemia; Anti-malarial Treatment + RTS,S/AS01E Vaccine | Number of Participants With Solicited Local and Systemic Adverse Events (AEs) | Systemic Solicited AEs | 20 Participants |
| Group 4: Positive Parasitemia; Anti-malarial Treatment + Rabies Vaccine | Number of Participants With Solicited Local and Systemic Adverse Events (AEs) | Local Solicited AEs | 26 Participants |
| Group 4: Positive Parasitemia; Anti-malarial Treatment + Rabies Vaccine | Number of Participants With Solicited Local and Systemic Adverse Events (AEs) | Systemic Solicited AEs | 16 Participants |
| Group 3: Positive Parasitemia; RTS,S/AS01E Vaccine | Number of Participants With Solicited Local and Systemic Adverse Events (AEs) | Local Solicited AEs | 14 Participants |
| Group 3: Positive Parasitemia; RTS,S/AS01E Vaccine | Number of Participants With Solicited Local and Systemic Adverse Events (AEs) | Systemic Solicited AEs | 14 Participants |
Secondary
Number of Participants With Unsolicited Adverse Events
An adverse event is defined as any untoward medical occurrence in a study participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product, or temporally associated with a study procedure. Unsolicited AEs are any AEs reported spontaneously by the participant, observed by the study staff during study visits or those identified during review of medical records or source documents. Solicited AEs with an onset after the seven-day solicitation period were also considered unsolicited AEs.
Time frame: Within 28 days after each vaccination.
Population: All enrolled participants who received at least one vaccination and for whom any safety data were available.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Group 1: Positive Parasitemia; Anti-malarial Treatment + RTS,S/AS01E Vaccine | Number of Participants With Unsolicited Adverse Events | 103 Participants |
| Group 4: Positive Parasitemia; Anti-malarial Treatment + Rabies Vaccine | Number of Participants With Unsolicited Adverse Events | 87 Participants |
| Group 3: Positive Parasitemia; RTS,S/AS01E Vaccine | Number of Participants With Unsolicited Adverse Events | 20 Participants |
| Group 4: Positive Parasitemia; Anti-malarial Treatment + Rabies Vaccine | Number of Participants With Unsolicited Adverse Events | 110 Participants |
| Group 5: No Parasitemia, Anti-malarial Prophylaxis + Rabies Vaccine | Number of Participants With Unsolicited Adverse Events | 92 Participants |
Secondary
Time to First PCR-detectable Malaria Infection During the Active Detection of Infection Phase in Groups 2 and 5
Participants were actively monitored for malarial infection starting 2 weeks after the third vaccination. Blood samples were assayed using a highly sensitive PCR (Plasmodium falciparum/ Pan-Plasmodium 18S rRNA LDT) that can detect sub-clinical parasitemia. A positive PCR result from blood samples collected during the ADI phase was recorded as a positive event for the presence of P. falciparum blood stage infection. The time to first malaria infection is expressed in terms of rate of first malaria infection, that is, the number of malaria infection events reported over the time period elapsed until the event occurred (i.e. events per Persons Year at Risk \[PYAR\]) for each group.
Time frame: The active detection of infection phase began 2 weeks after the third vaccination (approximately week 30) for up to 35 weeks. Participants provided blood samples every 21 days during the ADI phase for PCR assays.
Population: This endpoint was pre-specified to be analyzed in Groups 2 and 5 only. The ATP cohort for efficacy includes all participants in the TVC with no major protocol deviations that could potentially interfere with the efficacy assessment of the study vaccine and who contributed to the time at risk starting 14 days after the third dose.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Group 1: Positive Parasitemia; Anti-malarial Treatment + RTS,S/AS01E Vaccine | Time to First PCR-detectable Malaria Infection During the Active Detection of Infection Phase in Groups 2 and 5 | 0.77 Events per person year at risk |
| Group 4: Positive Parasitemia; Anti-malarial Treatment + Rabies Vaccine | Time to First PCR-detectable Malaria Infection During the Active Detection of Infection Phase in Groups 2 and 5 | 0.62 Events per person year at risk |
Comparison: Vaccine efficacy against the first PCR-positive P. falciparum infection among adults who were P. falciparum positive at baseline was assessed using Cox proportional hazards regression model with a covariate for group assignment to compare Groups 2 and 5. HIV status, Age (tertiles), and sleep under a bednet were included as covariates.p-value: 0.36995% CI: [-97, 22.2]Wald test