Rotavirus Infection, Vaccine Response Impaired, Vaccine Virus Shedding
Conditions
Keywords
Rotavirus, Oral vaccines, Vaccine underperformance, Vaccine shedding
Brief summary
Rotavirus is the leading cause of diarrhea in children worldwide. Oral rotavirus vaccines work remarkably well in high-income countries, but for unclear reasons they underperform in low-income countries. A double-blind, randomized control trial will be performed to evaluate whether using a higher dose of a currently licensed vaccine (Rotarix, GlaxoSmithKline) can improve immune responses among infants in Dhaka, Bangladesh. Infants will be randomized 1:1 to receive either a standard or a double dose of Rotarix at 6 and 10 weeks of life. Infants will be assessed for fecal vaccine shedding and serum rotavirus-specific IgA responses to determine vaccine immunogenicity.
Interventions
BIOLOGICALRotarix, dose 1
Rotarix, dose 1
BIOLOGICALRotarix, dose 2
Rotarix, dose 2
DRUGPlacebo (for Rotarix dose 2)
Sterile water to provide volume equivalent as a second dose of Rotarix
Sponsors
International Centre for Diarrhoeal Disease Research, Bangladesh
Charles H. Hood Foundation
Thrasher Research Fund
University of Vermont
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
No minimum to 15 Weeks
Healthy volunteers
Yes
Inclusion criteria
1. Generally healthy infant (as determined by medical officers) 2. Age 0-7 days at enrolment 3. Mother willing and able to provide signed informed consent 4. Mother willing to allow infant to be vaccinated according to study schedule 5. Mother willing to allow biological specimens, including blood, stool, and saliva, to be collected from infant according to study protocol 6. Mother willing and able to adhere to study schedule
Exclusion criteria
1. Obvious congenital malformation 2. Birth weight (if known) or enrolment weight (if birth weight unknown) \< 2000 gm 3. Known immunocompromising condition in infant 4. Enrolment in other vaccine research trials 5. Other household member enrolled in this study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number (or Percentage) of Infants in Each Study Arm Who Test Positive for Fecal Rotavirus Vaccine-strain Virus Shedding Post-vaccination | Measured through week 12 of life | This will be an aggregate measure demonstrating a change from baseline. Infants will have stool collected immediately prior to Rotarix vaccination at weeks 6 and 10 of life, then 4, 7, and 14 days following each dose (i.e. last assessment at week 12 of life). Each specimen will be assessed for vaccine-strain virus (i.e. fecal vaccine shedding) at each time point by polymerase chain reaction. Any child who has a change in fecal vaccine shedding status, from negative at baseline (6 weeks) to positive at any subsequent time point, will be categorized as having met the outcome measure for positive fecal vaccine shedding. |
| Number (or Percentage) of Infants in Each Study Arm With Rotavirus-specific Plasma Immunoglobulin A (IgA) Seroconversion Post-vaccination | Measured at week 14 of life | This outcome will measure seroconversion, i.e. the change in plasma rotavirus-specific IgA concentration at week 14 of life compared to week 6 of life (baseline). Blood will be collected from infants prior to the first dose of Rotarix at week 6 of life and again at week 14 of life (4 weeks following the second dose) for measurement of plasma rotavirus-specific IgA by enzyme immunoassay. Infants will be assessed for seroconversion (IgA concentration \<=20 U/mL pre-vaccination and \>20 post-vaccination). Infants who demonstrate rotavirus-specific IgA seroconversion will be categorized as having met the outcome measure. |
| Number (or Percentage) of Infants in Each Study Arm With Successful Vaccine Take, Defined as Positive Fecal Vaccine Shedding Post-vaccination OR Rotavirus-specific Plasma IgA Seroconversion Post-vaccination | Measured at week 14 of life | Vaccine take is an aggregate, dichotomous immunogenicity measure (successful vaccine take vs no vaccine take). Infants positive for either fecal vaccine shedding OR plasma rotavirus-specific IgA seroconversion (as described in Outcomes 1 and 2, respectively) will be categorized as having met the outcome measure of successful vaccine take. Those who met neither outcome will be categorized as no vaccine take. |
Countries
Bangladesh
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Rotarix, Single Dose Rotarix 1.5 mL (standard single dose) and 1.5 mL of placebo by mouth (sterile, pharmacy-grade water) at both 6 and 10 weeks of life
Rotarix, dose 1: Rotarix, dose 1
Placebo (for Rotarix dose 2): Sterile water to provide volume equivalent as a second dose of Rotarix | 97 |
| Rotarix, Double Dose Rotarix 3 mL by mouth (two standard doses administered simultaneously) at both 6 and 10 weeks of life
Rotarix, dose 1: Rotarix, dose 1
Rotarix, dose 2: Rotarix, dose 2 | 92 |
| Total | 189 |
Baseline characteristics
| Characteristic | Rotarix, Single Dose | Total | Rotarix, Double Dose |
|---|---|---|---|
| Age, Categorical <=18 years | 97 Participants | 189 Participants | 92 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Continuous | 4.8 days STANDARD_DEVIATION 1.8 | 4.9 days STANDARD_DEVIATION 1.8 | 5.0 days STANDARD_DEVIATION 1.8 |
| Birth place Home birth | 19 Participants | 44 Participants | 25 Participants |
| Birth place Hospital/clinic birth | 78 Participants | 145 Participants | 67 Participants |
| Family demographics Any food deficit | 31 Participants | 68 Participants | 37 Participants |
| Family demographics Father's education <= secondary | 71 Participants | 143 Participants | 72 Participants |
| Family demographics Homeowner | 43 Participants | 75 Participants | 32 Participants |
| Family demographics Mother's education <= secondary | 81 Participants | 155 Participants | 74 Participants |
| Family demographics Municipal (piped) water source | 93 Participants | 173 Participants | 80 Participants |
| Head circumference | 34.1 cm STANDARD_DEVIATION 1.3 | 34.1 cm STANDARD_DEVIATION 1.3 | 34.2 cm STANDARD_DEVIATION 1.3 |
| Length | 48.9 cm STANDARD_DEVIATION 2.6 | 48.8 cm STANDARD_DEVIATION 2.2 | 48.7 cm STANDARD_DEVIATION 0.21 |
| Mode of delivery Caesarean section | 42 Participants | 84 Participants | 42 Participants |
| Mode of delivery Vaginal | 55 Participants | 105 Participants | 50 Participants |
| Monthly household income in Taka | 15000 Taka | 15000 Taka | 15000 Taka |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Region of Enrollment Bangladesh | 97 participants | 189 participants | 92 participants |
| Sex: Female, Male Female | 51 Participants | 92 Participants | 41 Participants |
| Sex: Female, Male Male | 46 Participants | 97 Participants | 51 Participants |
| Type of toilet Open drain beside home | 44 Participants | 99 Participants | 55 Participants |
| Type of toilet Pit latrine or open latrine | 4 Participants | 7 Participants | 3 Participants |
| Type of toilet Septic tank or toilet | 52 Participants | 97 Participants | 45 Participants |
| Type of toilet Water-sealed or slab latrine | 41 Participants | 85 Participants | 44 Participants |
| Water treatment Boil | 69 Participants | 130 Participants | 61 Participants |
| Water treatment None | 24 Participants | 53 Participants | 29 Participants |
| Water treatment Water filter | 4 Participants | 6 Participants | 2 Participants |
| Weight | 2.81 kg STANDARD_DEVIATION 0.44 | 2.83 kg STANDARD_DEVIATION 0.42 | 2.86 kg STANDARD_DEVIATION 0.38 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 110 | 0 / 110 |
| other Total, other adverse events | 28 / 107 | 31 / 106 |
| serious Total, serious adverse events | 2 / 110 | 4 / 110 |
Outcome results
Primary
Number (or Percentage) of Infants in Each Study Arm Who Test Positive for Fecal Rotavirus Vaccine-strain Virus Shedding Post-vaccination
This will be an aggregate measure demonstrating a change from baseline. Infants will have stool collected immediately prior to Rotarix vaccination at weeks 6 and 10 of life, then 4, 7, and 14 days following each dose (i.e. last assessment at week 12 of life). Each specimen will be assessed for vaccine-strain virus (i.e. fecal vaccine shedding) at each time point by polymerase chain reaction. Any child who has a change in fecal vaccine shedding status, from negative at baseline (6 weeks) to positive at any subsequent time point, will be categorized as having met the outcome measure for positive fecal vaccine shedding.
Time frame: Measured through week 12 of life
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rotarix, Single Dose | Number (or Percentage) of Infants in Each Study Arm Who Test Positive for Fecal Rotavirus Vaccine-strain Virus Shedding Post-vaccination | 63 Participants |
| Rotarix, Double Dose | Number (or Percentage) of Infants in Each Study Arm Who Test Positive for Fecal Rotavirus Vaccine-strain Virus Shedding Post-vaccination | 55 Participants |
Primary
Number (or Percentage) of Infants in Each Study Arm With Rotavirus-specific Plasma Immunoglobulin A (IgA) Seroconversion Post-vaccination
This outcome will measure seroconversion, i.e. the change in plasma rotavirus-specific IgA concentration at week 14 of life compared to week 6 of life (baseline). Blood will be collected from infants prior to the first dose of Rotarix at week 6 of life and again at week 14 of life (4 weeks following the second dose) for measurement of plasma rotavirus-specific IgA by enzyme immunoassay. Infants will be assessed for seroconversion (IgA concentration \<=20 U/mL pre-vaccination and \>20 post-vaccination). Infants who demonstrate rotavirus-specific IgA seroconversion will be categorized as having met the outcome measure.
Time frame: Measured at week 14 of life
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rotarix, Single Dose | Number (or Percentage) of Infants in Each Study Arm With Rotavirus-specific Plasma Immunoglobulin A (IgA) Seroconversion Post-vaccination | 41 Participants |
| Rotarix, Double Dose | Number (or Percentage) of Infants in Each Study Arm With Rotavirus-specific Plasma Immunoglobulin A (IgA) Seroconversion Post-vaccination | 42 Participants |
Primary
Number (or Percentage) of Infants in Each Study Arm With Successful Vaccine Take, Defined as Positive Fecal Vaccine Shedding Post-vaccination OR Rotavirus-specific Plasma IgA Seroconversion Post-vaccination
Vaccine take is an aggregate, dichotomous immunogenicity measure (successful vaccine take vs no vaccine take). Infants positive for either fecal vaccine shedding OR plasma rotavirus-specific IgA seroconversion (as described in Outcomes 1 and 2, respectively) will be categorized as having met the outcome measure of successful vaccine take. Those who met neither outcome will be categorized as no vaccine take.
Time frame: Measured at week 14 of life
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Rotarix, Single Dose | Number (or Percentage) of Infants in Each Study Arm With Successful Vaccine Take, Defined as Positive Fecal Vaccine Shedding Post-vaccination OR Rotavirus-specific Plasma IgA Seroconversion Post-vaccination | 69 Participants |
| Rotarix, Double Dose | Number (or Percentage) of Infants in Each Study Arm With Successful Vaccine Take, Defined as Positive Fecal Vaccine Shedding Post-vaccination OR Rotavirus-specific Plasma IgA Seroconversion Post-vaccination | 62 Participants |