Rotavirus Gastroenteritis
Conditions
Brief summary
The purpose of this study is to determine whether giving the Human Rotavirus Vaccine on alternate dosing schedules will enhance the immune response to the vaccine in a low-resource, high-burden country in Africa. Alternate dosing schedules studied include giving the 2-dose vaccine schedule at a slightly older age and giving an additional dose of the vaccine.
Interventions
BIOLOGICALHuman Rotavirus Vaccine
Rotavirus vaccine will be administered concomitantly with other routine Expanded Programme on Immunization (EPI) vaccinations at 6 & 10 weeks of age, 10 & 14 weeks of age, or 6, 10, & 14 weeks of age, depending on study arm assignment.
Sponsors
Noguchi Memorial Institute for Medical Research
Navrongo Health Research Center
Centers for Disease Control and Prevention
PATH
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
42 Days to 55 Days
Healthy volunteers
Yes
Inclusion criteria
* Between 42 and 55 days of age at the time of enrollment. * Healthy infant free of chronic or serious medical condition as determined by history and physical examination at the time of study enrollment. * Parents/guardians of each subject are able to understand and follow study procedures and agree to participate in the study by providing parental/guardian permission.
Exclusion criteria
* If child has previously had intussusception or abdominal surgery. * Use of any immunosuppressive drugs or immunoglobulin and/or blood product use since birth or anticipated during study period. * Current enrollment in any other intervention trial or use of any investigational drug or vaccine throughout the study period. * Birthweight less than 2000 grams or gestation \< 36 weeks, if this information is available. * Any subject who reports plan to leave the study area before the completion of the study (i.e., relocation, migration, etc.). * Another child living in the same compound is already enrolled in the trial (i.e., only one participant can be enrolled per compound). * After the rotavirus vaccine is introduced into the routine EPI system in Navrongo: Another child in the compound is less than 16 weeks of age. * The child has received rotavirus vaccine outside of this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Immunoglobulin A (IgA) Seroconversion: 6 & 10 Week vs. 6, 10, & 14 Week Vaccination Schedules | 4-weeks post-vaccination (All Groups) and 8 weeks post-vaccination (6 & 10 week Group) | Anti-rotavirus IgA seroconversion will be defined as the detection of anti-rotavirus IgA antibodies at a concentration ≥20 U/mL post-vaccination in infants seronegative for anti-rotavirus IgA pre-vaccination as measured by Enzyme Immunoassay (EIA). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| IgA Geometric Mean Titers (GMTs): 6 & 10 Week vs. 6, 10, & 14 Week Vaccination Schedules | 4-weeks post-vaccination (All Groups) and 8 weeks post-vaccination (6 & 10 week Group) | IgA GMTs measured by EIA will be compared post-vaccination between participants receiving Rotarix at 6 and 10 weeks of age and those receiving Rotarix at 6, 10, and 14 weeks of age. For participants in Group 1, where post-vaccination response was measured at both 14 and 18 weeks of age, the highest response between these two visits was used as the final response for comparison. |
| IgA GMTs: 6 & 10 Week vs. 10 & 14 Week Vaccination Schedule | 4-weeks post-vaccination (All Groups) and 8 weeks post-vaccination (6 & 10 week Group) | IgA GMTs measured by EIA will be compared post-vaccination between participants receiving Rotarix at 6 and 10 weeks of age and those receiving Rotarix at 10 and 14 weeks of age. For participants in Group 1, where post-vaccination response was measured at both 14 and 18 weeks of age, the highest response between these two visits was used as the final response for comparison. |
| IgA Seroconversion: 6 & 10 Week vs. 10 & 14 Week Vaccination Schedules | 4-weeks post-vaccination (All Groups) and 8 weeks post-vaccination (6 & 10 week Group) | Anti-rotavirus IgA seroconversion will be defined as the detection of anti-rotavirus IgA antibodies at a concentration ≥20 U/mL post-vaccination in infants seronegative for anti-rotavirus IgA pre- vaccination as measured by EIA. |
| Vaccine-type Rotavirus Shedding in Stool | Days 4 and 7 post each study vaccination | Vaccine-type rotavirus shedding in the stool at 4 (±1 day) and 7 days (±1 day) following each Rotarix vaccination will be identified using EIA for rotavirus antigens and compared to baseline levels obtained just prior to each study vaccination. If shedding in stool is detected at either time point (per manufacturer's specifications) following each Rotarix vaccination, this will be considered evidence of vaccine take. |
| SAE Assessment | Throughout study period; Group 1: from enrollment through approximately 8 weeks of study participation, Groups 2 & 3: from enrollment through approximately 12 weeks of study participation | Serious adverse events (SAEs) occurring at anytime during the study will be measured as observed by study staff and/or reported by parent at any time. SAEs will be subcategorized according to treatment group as those deemed related to vaccination or not by an independent study monitor. |
| Baseline Immunoglobulin G (IgG) Levels: Impact on IgA Seroconversion Post-vaccination | Baseline, 4-weeks post-vaccination (All Groups) and 8 weeks post-vaccination (6 & 10 week Group) | The number and percentage of participants demonstrating IgA seroconversion post-vaccination as defined above in infants seronegative for anti-rotavirus IgA pre- vaccination using the EIA assay) by EIA pre- and post-vaccination will be compared between participants in each group who had low as compared to high rotavirus immunoglobulin G (IgG) antibody levels pre-vaccination (i.e., at 6 weeks in Groups 1 and 3 and at 10 weeks in Group 2) as measured by Enzyme linked immunosorbent assay (ELISA). Low and high IgG categories will be determined based on the IgG antibody level distribution. |
Countries
Ghana
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Rotavirus Vaccine at Age 6 & 10 Weeks Human rotavirus vaccine was administered concomitantly with other routine EPI vaccinations at 6 & 10 weeks of age. | 150 |
| Rotavirus Vaccine at Age 10 & 14 Weeks Human rotavirus vaccine was administered concomitantly with other routine EPI vaccinations at 10 & 14 weeks of age. | 149 |
| Rotavirus Vaccine at Age 6,10,&14 Weeks Human rotavirus vaccine was administered concomitantly with other routine EPI vaccinations at 6, 10, & 14 weeks of age. | 151 |
| Total | 450 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 1 | 0 |
| Overall Study | Migration out of study area | 1 | 5 | 4 |
| Overall Study | Protocol Violation | 2 | 1 | 1 |
| Overall Study | SAE | 0 | 1 | 0 |
| Overall Study | Withdrawal by Subject | 0 | 1 | 1 |
Baseline characteristics
| Characteristic | Rotavirus Vaccine at Age 6 & 10 Weeks | Rotavirus Vaccine at Age 10 & 14 Weeks | Rotavirus Vaccine at Age 6,10,&14 Weeks | Total |
|---|---|---|---|---|
| Age, Continuous | 6.2 weeks STANDARD_DEVIATION 0.2 | 6.2 weeks STANDARD_DEVIATION 0.2 | 6.2 weeks STANDARD_DEVIATION 0.2 | 6.2 weeks STANDARD_DEVIATION 0.2 |
| Region of Enrollment Ghana | 150 participants | 149 participants | 151 participants | 450 participants |
| Sex: Female, Male Female | 68 Participants | 79 Participants | 72 Participants | 219 Participants |
| Sex: Female, Male Male | 82 Participants | 70 Participants | 79 Participants | 231 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 78 / 152 | 76 / 152 | 71 / 151 |
| serious Total, serious adverse events | 1 / 152 | 4 / 152 | 3 / 151 |
Outcome results
Primary
Immunoglobulin A (IgA) Seroconversion: 6 & 10 Week vs. 6, 10, & 14 Week Vaccination Schedules
Anti-rotavirus IgA seroconversion will be defined as the detection of anti-rotavirus IgA antibodies at a concentration ≥20 U/mL post-vaccination in infants seronegative for anti-rotavirus IgA pre-vaccination as measured by Enzyme Immunoassay (EIA).
Time frame: 4-weeks post-vaccination (All Groups) and 8 weeks post-vaccination (6 & 10 week Group)
Population: Per-protocol analysis population--participants who (1) meet inclusion/exclusion criteria; (2) seronegative pre- vaccination; (3) concomitant administration of HRV and oral polio vaccine (OPV) according to Group schedule, (4) study visits in window periods (vaccination visits 4 weeks + 2 weeks), and (5) valid serology results.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rotavirus Vaccine at Age 6 & 10 Weeks | Immunoglobulin A (IgA) Seroconversion: 6 & 10 Week vs. 6, 10, & 14 Week Vaccination Schedules | 28.9 percentage of participants |
| Rotavirus Vaccine at Age 6,10,&14 Weeks | Immunoglobulin A (IgA) Seroconversion: 6 & 10 Week vs. 6, 10, & 14 Week Vaccination Schedules | 43.4 percentage of participants |
p-value: 0.014Fisher Exact
Secondary
Baseline Immunoglobulin G (IgG) Levels: Impact on IgA Seroconversion Post-vaccination
The number and percentage of participants demonstrating IgA seroconversion post-vaccination as defined above in infants seronegative for anti-rotavirus IgA pre- vaccination using the EIA assay) by EIA pre- and post-vaccination will be compared between participants in each group who had low as compared to high rotavirus immunoglobulin G (IgG) antibody levels pre-vaccination (i.e., at 6 weeks in Groups 1 and 3 and at 10 weeks in Group 2) as measured by Enzyme linked immunosorbent assay (ELISA). Low and high IgG categories will be determined based on the IgG antibody level distribution.
Time frame: Baseline, 4-weeks post-vaccination (All Groups) and 8 weeks post-vaccination (6 & 10 week Group)
Secondary
IgA Geometric Mean Titers (GMTs): 6 & 10 Week vs. 6, 10, & 14 Week Vaccination Schedules
IgA GMTs measured by EIA will be compared post-vaccination between participants receiving Rotarix at 6 and 10 weeks of age and those receiving Rotarix at 6, 10, and 14 weeks of age. For participants in Group 1, where post-vaccination response was measured at both 14 and 18 weeks of age, the highest response between these two visits was used as the final response for comparison.
Time frame: 4-weeks post-vaccination (All Groups) and 8 weeks post-vaccination (6 & 10 week Group)
Population: Per-protocol analysis population--participants who (1) meet inclusion/exclusion criteria; (2) seronegative pre- vaccination; (3) concomitant administration of HRV and OPV according to Group schedule, (4) study visits in window periods (vaccination visits 4 weeks + 2 weeks), and (5) valid serology results.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Rotavirus Vaccine at Age 6 & 10 Weeks | IgA Geometric Mean Titers (GMTs): 6 & 10 Week vs. 6, 10, & 14 Week Vaccination Schedules | 22.5 titers |
| Rotavirus Vaccine at Age 6,10,&14 Weeks | IgA Geometric Mean Titers (GMTs): 6 & 10 Week vs. 6, 10, & 14 Week Vaccination Schedules | 32.6 titers |
p-value: 0.038t-test, 2 sided
Secondary
IgA GMTs: 6 & 10 Week vs. 10 & 14 Week Vaccination Schedule
IgA GMTs measured by EIA will be compared post-vaccination between participants receiving Rotarix at 6 and 10 weeks of age and those receiving Rotarix at 10 and 14 weeks of age. For participants in Group 1, where post-vaccination response was measured at both 14 and 18 weeks of age, the highest response between these two visits was used as the final response for comparison.
Time frame: 4-weeks post-vaccination (All Groups) and 8 weeks post-vaccination (6 & 10 week Group)
Population: Per-protocol analysis population--participants who (1) meet inclusion/exclusion criteria; (2) seronegative pre- vaccination; (3) concomitant administration of HRV and OPV according to Group schedule, (4) study visits in window periods (vaccination visits 4 weeks + 2 weeks), and (5) valid serology results.
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Rotavirus Vaccine at Age 6 & 10 Weeks | IgA GMTs: 6 & 10 Week vs. 10 & 14 Week Vaccination Schedule | 22.1 titers |
| Rotavirus Vaccine at Age 6,10,&14 Weeks | IgA GMTs: 6 & 10 Week vs. 10 & 14 Week Vaccination Schedule | 26.5 titers |
p-value: 0.3t-test, 2 sided
Secondary
IgA Seroconversion: 6 & 10 Week vs. 10 & 14 Week Vaccination Schedules
Anti-rotavirus IgA seroconversion will be defined as the detection of anti-rotavirus IgA antibodies at a concentration ≥20 U/mL post-vaccination in infants seronegative for anti-rotavirus IgA pre- vaccination as measured by EIA.
Time frame: 4-weeks post-vaccination (All Groups) and 8 weeks post-vaccination (6 & 10 week Group)
Population: Per-protocol analysis population--participants who (1) meet inclusion/exclusion criteria; (2) seronegative pre- vaccination; (3) concomitant administration of HRV and OPV according to Group schedule, (4) study visits in window periods (vaccination visits 4 weeks + 2 weeks), and (5) valid serology results.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Rotavirus Vaccine at Age 6 & 10 Weeks | IgA Seroconversion: 6 & 10 Week vs. 10 & 14 Week Vaccination Schedules | 28.9 percentage of participants |
| Rotavirus Vaccine at Age 6,10,&14 Weeks | IgA Seroconversion: 6 & 10 Week vs. 10 & 14 Week Vaccination Schedules | 37.4 percentage of participants |
p-value: 0.16Fisher Exact
Secondary
SAE Assessment
Serious adverse events (SAEs) occurring at anytime during the study will be measured as observed by study staff and/or reported by parent at any time. SAEs will be subcategorized according to treatment group as those deemed related to vaccination or not by an independent study monitor.
Time frame: Throughout study period; Group 1: from enrollment through approximately 8 weeks of study participation, Groups 2 & 3: from enrollment through approximately 12 weeks of study participation
Secondary
Vaccine-type Rotavirus Shedding in Stool
Vaccine-type rotavirus shedding in the stool at 4 (±1 day) and 7 days (±1 day) following each Rotarix vaccination will be identified using EIA for rotavirus antigens and compared to baseline levels obtained just prior to each study vaccination. If shedding in stool is detected at either time point (per manufacturer's specifications) following each Rotarix vaccination, this will be considered evidence of vaccine take.
Time frame: Days 4 and 7 post each study vaccination