The Effects of Increased Inoculum on Oral Rotavirus Vaccine Take and Immunogenicity

Study Overview
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Brief Summary
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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.

Official Title
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A Double-blind, Randomized Controlled Trial of the Effect of Vaccine Inoculum on Oral Rotavirus Vaccine (Rotarix, GlaxoSmithKline) Take and Immunogenicity in Dhaka, Bangladesh

Conditions
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Rotavirus Infection, Vaccine Response Impaired, Vaccine Virus Shedding

Intervention / Treatment
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* Biological: Rotarix, dose 1
* Biological: Rotarix, dose 2
* Drug: Placebo (for Rotarix dose 2)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Generally healthy infant (as determined by medical officers) Age 0-7 days at enrolment Mother willing and able to provide signed informed consent Mother willing to allow infant to be vaccinated according to study schedule Mother willing to allow biological specimens, including blood, stool, and saliva, to be collected from infant according to study protocol Mother willing and able to adhere to study schedule Exclusion Criteria: Obvious congenital malformation Birth weight (if known) or enrolment weight (if birth weight unknown) < 2000 gm Known immunocompromising condition in infant Enrolment in other vaccine research trials Other household member enrolled in this study

Ages Eligible for Study
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Maximum Age: 15 Weeks

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Rotarix, single dose<br>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 | Biological: Rotarix, dose 1<br>* Rotarix, dose 1<br>Drug: Placebo (for Rotarix dose 2)<br>* Sterile water to provide volume equivalent as a second dose of Rotarix<br>|
| Experimental: Rotarix, double dose<br>Rotarix 3 mL by mouth (two standard doses administered simultaneously) at both 6 and 10 weeks of life | Biological: Rotarix, dose 1<br>* Rotarix, dose 1<br>Biological: Rotarix, dose 2<br>* Rotarix, dose 2<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Measured through week 12 of life | 
| 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. | Measured at week 14 of life | 
| 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. | Measured at week 14 of life | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rotavirus, Oral vaccines, Vaccine underperformance, Vaccine shedding