Zinc and/or Probiotic Supplementation of Rotavirus and Oral Polio Virus Vaccines

Study Overview
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Brief Summary
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Background: Strategies are needed to improve oral rotavirus vaccine (RV), which provides suboptimal protection in developing countries. Probiotics and zinc supplementation could improve RV immunogenicity by altering the intestinal microbiota and immune function. This study enrolled infants 5 weeks old living in urban Vellore, India to assess the effects of daily zinc (5 mg), probiotic (1010 Lactobacillus rhamnosus GG) or placebo on the immunogenicity of two doses of RV (Rotarix,GlaxoSmithKline Biologicals) given at 6 and 10 weeks of age. Probiotics and zinc (or placebo) were provided for six weeks. A single dose of test product was administered daily one week prior to first study dose of rotavirus and polio vaccines through 1 week following second study dose of rotavirus and polio vaccines.

Detailed Description
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Co- Primary objectives: To evaluate the serologic immune response to rotavirus vaccine (sero-conversion or four-fold rise in rotavirus immunoglobulin A (IgA) antibodies) among Indian infants receiving zinc supplementation given daily for a week prior to the administration of the first dose through a week following the second dose of oral rotavirus vaccine compared to those receiving a zinc placebo. To evaluate the serologic immune response to rotavirus vaccine (sero-conversion or four-fold rise in rotavirus IgA antibodies) among Indian infants receiving probiotic supplementation given daily for a week prior to the administration of the first dose through a week following the second dose of oral rotavirus vaccine compared to those receiving a probiotic placebo.

Official Title
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Supplementation With Zinc and/or Probiotics to Enhance the Immune Response of Oral Rotavirus and Polio Vaccines in Indian Infants

Conditions
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Immunity to Oral Rotavirus Vaccine, Immunity to Oral Polio Vaccine, Shedding of Oral Rotavirus Vaccine

Intervention / Treatment
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* Dietary Supplement: Probiotic
* Dietary Supplement: Zinc
* Dietary Supplement: Probiotic placebo
* Dietary Supplement: Zinc placebo
* Biological: Rotavirus vaccine
* Biological: Oral polio vaccine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Infants 35-41 days old Live in area under surveillance Current weight ≥3.2 kg No syndromic evidence of immunocompromise as determined by medical doctor No prior illness requiring hospitalization No current medical condition as determined by medical doctor which precludes study involvement Available for follow up for duration of study (through approximately 14 weeks of age) Parents/guardians of infant are able to understand and follow study procedures and agree to participate in the study by providing signed informed consent Exclusion Criteria: Child has history of atopic symptoms Child has a known digestive system defect Child has history of chronic diarrhea Child has major congenital anomalies Child has received a prior dose of rotavirus vaccine Child has received a prior dose of polio vaccine (beyond the birth dose)

Ages Eligible for Study
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Minimum Age: 5 Weeks
Maximum Age: 16 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: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Zinc and probiotic<br>Received daily zinc and probiotic supplements, in addition to rotavirus vaccine and trivalent oral polio vaccines. | Dietary Supplement: Probiotic<br>* A capsule that contains at least 1 x 10^9 Lactobacillus rhamnosus GG organisms per capsule. The contents of this capsule were given once daily orally.<br>* Other names: Culturelle;Dietary Supplement: Zinc<br>* Zinc sulphate syrup is zinc sulphate heptahydrate (concentration 1mg/ml). 5 ml of this suspension was given once daily orally.<br>Biological: Rotavirus vaccine<br>* 1 ml Rotarix®, a lyophilized human rotavirus vaccine reconstituted with calcium carbonate buffer provided orally at 6 and 10 weeks.<br>* Other names: Rotarix®;Biological: Oral polio vaccine<br>* A liquid trivalent polio vaccine provided orally at 6 and 10 weeks.<br>* Other names: Biopolio®;|
| Active Comparator: Zinc alone<br>Received daily zinc and probiotic placebo supplement, in addition to rotavirus vaccine and trivalent oral polio vaccine. | Dietary Supplement: Zinc<br>* Zinc sulphate syrup is zinc sulphate heptahydrate (concentration 1mg/ml). 5 ml of this suspension was given once daily orally.<br>Dietary Supplement: Probiotic placebo<br>* The probiotic placebo was manufactured by the same company that manufactured the probiotic and contained inulin powder but no Lactobacillus rhamnosus GG. The contents of the capsule were given once daily orally.<br>Biological: Rotavirus vaccine<br>* 1 ml Rotarix®, a lyophilized human rotavirus vaccine reconstituted with calcium carbonate buffer provided orally at 6 and 10 weeks.<br>* Other names: Rotarix®;Biological: Oral polio vaccine<br>* A liquid trivalent polio vaccine provided orally at 6 and 10 weeks.<br>* Other names: Biopolio®;|
| Active Comparator: Probiotic alone<br>Received daily zinc placebo and probiotic supplement, in addition to rotavirus vaccine and trivalent oral polio vaccine. | Dietary Supplement: Probiotic<br>* A capsule that contains at least 1 x 10^9 Lactobacillus rhamnosus GG organisms per capsule. The contents of this capsule were given once daily orally.<br>* Other names: Culturelle;Dietary Supplement: Zinc placebo<br>* The zinc placebo excluded the zinc sulphate but contained lactose and was diluted to match the taste. 5 ml of this suspension was given orally once daily.<br>Biological: Rotavirus vaccine<br>* 1 ml Rotarix®, a lyophilized human rotavirus vaccine reconstituted with calcium carbonate buffer provided orally at 6 and 10 weeks.<br>* Other names: Rotarix®;Biological: Oral polio vaccine<br>* A liquid trivalent polio vaccine provided orally at 6 and 10 weeks.<br>* Other names: Biopolio®;|
| Placebo Comparator: Placebo<br>Received daily zinc placebo and probiotic placebo, in addition to rotavirus vaccine and trivalent oral polio vaccine. | Dietary Supplement: Probiotic placebo<br>* The probiotic placebo was manufactured by the same company that manufactured the probiotic and contained inulin powder but no Lactobacillus rhamnosus GG. The contents of the capsule were given once daily orally.<br>Dietary Supplement: Zinc placebo<br>* The zinc placebo excluded the zinc sulphate but contained lactose and was diluted to match the taste. 5 ml of this suspension was given orally once daily.<br>Biological: Rotavirus vaccine<br>* 1 ml Rotarix®, a lyophilized human rotavirus vaccine reconstituted with calcium carbonate buffer provided orally at 6 and 10 weeks.<br>* Other names: Rotarix®;Biological: Oral polio vaccine<br>* A liquid trivalent polio vaccine provided orally at 6 and 10 weeks.<br>* Other names: Biopolio®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number/Percentage of Subjects With Immune Response to Rotavirus Vaccine | Defined as an increase in serum anti-rotavirus (RV) VP6 IgA antibodies consistent with seroconversion (detection of serum anti-RV VP6 immunoglobulin A (IgA) antibodies at a concentration ≥20 U/ml in a previously seronegative individual) or a fourfold rise in anti-RV VP6 IgA antibodies between baseline and 14 weeks of age. Pre-vaccination blood samples were taken when the subject received the first dose of rotavirus vaccine (when the subject was 6 weeks of age); post-vaccination blood samples were taken 4 weeks after the second dose of rotavirus vaccine was administered (14 weeks of age). | from first dose of rotavirus vaccine to 4 weeks after last dose of vaccine | 
| Geometric Mean Concentration of Rotavirus-specific IgA | Pre-vaccination blood samples were taken when the subject received the first dose of rotavirus vaccine (when the subject was 6 weeks of age); post-vaccination blood samples were taken 4 weeks after the second dose of rotavirus was administered (14 weeks of age). Pre-vaccination blood samples were taken when the subject received the first dose of rotavirus vaccine (when the subject was 6 weeks of age); post-vaccination blood samples were taken 4 weeks after the second dose of rotavirus vaccine was administered (14 weeks of age). | from first dose of rotavirus vaccine to 4 weeks after last dose of vaccine | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number/Percentage of Subjects With Immune Response to Trivalent Oral Poliovirus Vaccine (OPV) | A serologic immune response to OPV is defined as a neutralizing antibody titer to polio virus subtype 3 greater than or equal to 1:8 at 14 weeks of age. This antigen will be used as a conservative estimate because it gives the lowest immune response of all three polio antigens. Pre-vaccination blood samples were taken when the subject received the first dose of OPV vaccine (when the subject was 6 weeks of age); post-vaccination blood samples were taken 4 weeks after the second dose of OPV was administered (14 weeks of age). | from first dose of OPV to 4 weeks after last dose of OPV | 
| Number/Percentage of Subjects Exhibiting Rotavirus Shedding in Stool After Dose 1 | Shedding of rotavirus following vaccination through detection of rotavirus antigen by ELISA and confirmed as vaccine type by Real-time polymerase chain reaction (RT-PCR). Stool samples were collected on Day 0 (i.e., day of vaccination or -1), Day 4 (±1) and Day 7 (-1 to +2) post vaccination. | 0, 4 and/or 7 day post dose 1 of rotavirus vaccine | 
| Number/Percentage of Subjects Exhibiting Rotavirus Shedding in Stool After Dose 2 | Shedding of rotavirus following vaccination through detection of rotavirus antigen by ELISA and confirmed as vaccine type by RT-PCR. Stool samples were collected on Day 0 (i.e., day of vaccination or -1), Day 4 (±1) and Day 7 (-1 to +2) post vaccination. | 0, 4 and/or 7 day post dose 2 of rotavirus vaccine | 
| Serious Adverse Events (SAEs) | Field workers documented information on SAEs through the duration of the study during home visits (twice weekly between study clinic visits) or SAEs were documented by study clinicians at the study clinic or hospital. All SAEs occurring at any time during the study were recorded on a SAE Form and were reviewed and evaluated by a study clinician and the local IRB. The relationship of the SAE to study vaccine was evaluated and recorded and reported to the local institutional review board (IRB). All SAEs were followed until satisfactory resolution. | from first day of study to 4 weeks after last dose | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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rotavirus, polio, zinc supplement, probiotic supplement, rotavirus vaccine shedding