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

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

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.

Study Overview

• Status: Completed
• Conditions: Immunity to Oral Rotavirus Vaccine; Immunity to Oral Polio Vaccine; Shedding of Oral Rotavirus Vaccine
• Intervention / Treatment: Dietary supplement: Probiotic; Dietary supplement: Zinc; Biological: Rotavirus vaccine; Biological: Oral polio vaccine; Dietary supplement: Probiotic placebo; Dietary supplement: Zinc placebo

Detailed Description

Co- Primary objectives:

1. 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.
2. 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.

• Study Type: Interventional
• Enrollment (Actual): 620
• Phase: Phase 4

Contacts and Locations

Study Locations

• India
  • Tamil Nadu
    • Vellore, Tamil Nadu, India, 632 004
      • Christian Medical Center, Vellore

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 month to 3 months (Child)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Zinc and probiotic; Received daily zinc and probiotic supplements, in addition to rotavirus vaccine and trivalent oral polio vaccines.	Dietary supplement: Probiotic; 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.; Other Names: Culturelle; Dietary supplement: Zinc; Zinc sulphate syrup is zinc sulphate heptahydrate (concentration 1mg/ml). 5 ml of this suspension was given once daily orally.; Biological: Rotavirus vaccine; 1 ml Rotarix®, a lyophilized human rotavirus vaccine reconstituted with calcium carbonate buffer provided orally at 6 and 10 weeks.; Other Names: Rotarix®; Biological: Oral polio vaccine; A liquid trivalent polio vaccine provided orally at 6 and 10 weeks.; Other Names: Biopolio®
Active Comparator: Zinc alone; Received daily zinc and probiotic placebo supplement, in addition to rotavirus vaccine and trivalent oral polio vaccine.	Dietary supplement: Zinc; Zinc sulphate syrup is zinc sulphate heptahydrate (concentration 1mg/ml). 5 ml of this suspension was given once daily orally.; Biological: Rotavirus vaccine; 1 ml Rotarix®, a lyophilized human rotavirus vaccine reconstituted with calcium carbonate buffer provided orally at 6 and 10 weeks.; Other Names: Rotarix®; Biological: Oral polio vaccine; A liquid trivalent polio vaccine provided orally at 6 and 10 weeks.; Other Names: Biopolio®; Dietary supplement: Probiotic placebo; 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.
Active Comparator: Probiotic alone; Received daily zinc placebo and probiotic supplement, in addition to rotavirus vaccine and trivalent oral polio vaccine.	Dietary supplement: Probiotic; 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.; Other Names: Culturelle; Biological: Rotavirus vaccine; 1 ml Rotarix®, a lyophilized human rotavirus vaccine reconstituted with calcium carbonate buffer provided orally at 6 and 10 weeks.; Other Names: Rotarix®; Biological: Oral polio vaccine; A liquid trivalent polio vaccine provided orally at 6 and 10 weeks.; Other Names: Biopolio®; Dietary supplement: Zinc placebo; 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.
Placebo Comparator: Placebo; Received daily zinc placebo and probiotic placebo, in addition to rotavirus vaccine and trivalent oral polio vaccine.	Biological: Rotavirus vaccine; 1 ml Rotarix®, a lyophilized human rotavirus vaccine reconstituted with calcium carbonate buffer provided orally at 6 and 10 weeks.; Other Names: Rotarix®; Biological: Oral polio vaccine; A liquid trivalent polio vaccine provided orally at 6 and 10 weeks.; Other Names: Biopolio®; Dietary supplement: Probiotic placebo; 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.; Dietary supplement: Zinc placebo; 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: PATH
• Collaborators: Christian Medical College, Vellore, India; Ministry of Science and Technology, India
• Investigators: Principal Investigator: Gagandeep Kang, MD, PhD, Christian Medical Center, Vellore, India

Study record dates

Study Major Dates

• Study Start: July 1, 2012
• Primary Completion (Actual): July 1, 2013
• Study Completion (Actual): July 1, 2013

Study Registration Dates

• First Submitted: June 6, 2012
• First Submitted That Met QC Criteria: June 8, 2012
• First Posted (Estimate): June 12, 2012

Study Record Updates

• Last Update Posted (Actual): December 26, 2018
• Last Update Submitted That Met QC Criteria: December 3, 2018
• Last Verified: December 1, 2018

More Information

Terms related to this study

• Keywords: probiotic supplement; rotavirus; polio; zinc supplement; rotavirus vaccine shedding
• Additional Relevant MeSH Terms: Central Nervous System Diseases; Nervous System Diseases; RNA Virus Infections; Virus Diseases; Infections; Neuromuscular Diseases; Central Nervous System Infections; Enterovirus Infections; Picornaviridae Infections; Spinal Cord Diseases; Myelitis; Poliomyelitis; Physiological Effects of Drugs; Immunologic Factors; Trace Elements; Micronutrients; Vaccines; Zinc
• Other Study ID Numbers: CMC ZP 2012; PATH HS-658