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Human Challenge With Live-attenuated Rotavirus to Assess Next-generation Rotavirus Vaccines in Africa

Primary Purpose

Diarrhea, Diarrhea Rotavirus

Status
Active
Phase
Phase 2
Locations
Zambia
Study Type
Interventional
Intervention
Rotarix
Trivalent P2-VP8
Sponsored by
Centre for Infectious Disease Research in Zambia
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional prevention trial for Diarrhea focused on measuring Human Infection Challenge

Eligibility Criteria

6 Weeks - 10 Weeks (Child)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

  • Healthy infants as established by medical history and physical examination.
  • Infants will be 6-10 weeks old at time of enrollment
  • parents plan to remain in the area for the duration of the study.
  • Parent/guardian understands the study procedures and willing to provide informed consent to participate in the study

Exclusion Criteria:

  • Acutely unwell
  • Infant or infant's mother has syndromic or documented evidence of being immunocompromised (independent of HIV status)
  • Known allergy to any vaccine component
  • Previously received rotavirus vaccine
  • Received immunosuppressive medication
  • Major congenital or genetic abnormality
  • Any condition in the parents/infant that, in the judgment of the investigator, would interfere with or serves as a contraindication to protocol adherence or a participant's parents' ability to give informed consent.
  • Participant's parents not available or willing to accept active follow-up by the study staff

Sites / Locations

  • Chawama first level hospital

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

No Intervention

Experimental

Experimental

Experimental

Arm Label

rotarix only

P2 VP8 only

Rotarix + 1 dose P2-VP8

Rotarix + 3 doses P2-VP8

Arm Description

Rotarix will be administered at 6 and 10 weeks of age following the national Expanded Program for Immunization (EPI) schedule. A challenge dose of Rotarix will be administered at 18 weeks of age and stool samples collected just before challenge and 5, 7 & 9 days later.

Parenteral P2-VP8 subunit vaccine will be administered at 6, 10 and 14 weeks of age. A challenge dose of Rotarix will be administered at 18 weeks of age and stool samples collected just before challenge and 5, 7 & 9 days later.

Rotarix will be administered at 6 and 10 weeks of age, followed by parenteral P2-VP8 subunit vaccine at 14 weeks of age. A challenge dose of Rotarix will be administered at 18 weeks of age and stool samples collected just before challenge and 5, 7 & 9 days later.

Rotarix and parenteral P2-VP8 subunit vaccine will be coadministered at 6 and 10 weeks of age, with an additional dose of P2-VP8 subunit vaccine administered at 14 weeks of age. A challenge dose of Rotarix will be administered at 18 weeks of age and stool samples collected just before challenge and 5, 7 & 9 days later.

Outcomes

Primary Outcome Measures

Vaccine Shedding
to detect a reduction in the proportion of children shedding vaccine rotavirus in stool at any timepoint 5 -9 days after challenge, among children immunized with P2-VP8 subunit vaccine alone or in combination with Rotarix, compared with infants receiving Rotarix alone. We estimate that approximately 50% (range 30-70%) of children previously vaccinated with 2 doses of Rotarix will shed Rotarix detected by Polymerase Chain Reaction (PCR) at any timepoint 5-9 days after challenge

Secondary Outcome Measures

Seroconversion following vaccination
Seroconversion After 2 doses of Rotarix in Zambia seroconversion was 60% (130/216) in an earlier study and 45% (10/22) in our Medical Research Council UK MRC-funded pilot of Rotarix challenge, based on IgA to whole virus cell culture lysate (largely anti -VP6 antibodies). Seroconversion based on anti-VP8 antibodies has not been studied after Rotarix administration but may be similar.
Immune boosting
i.) We will compare the number of gut-homing (alpha 4 beta 7+) IgA and IgG rotavirus VP8-specific ASCs 7 days after the third clinic visit in 50 infants from each study arm (i.e. after the first VP8 vaccine booster dose, after the third VP8 vaccine dose (alone or in combination with Rotarix), or after no vaccine (control) in the Rotarix only arm).

Full Information

First Posted
November 18, 2020
Last Updated
July 19, 2022
Sponsor
Centre for Infectious Disease Research in Zambia
Collaborators
Medical Research Council, PATH, University of Liverpool, Institut National de la Santé Et de la Recherche Médicale, France, Imperial College London
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1. Study Identification

Unique Protocol Identification Number
NCT04658914
Brief Title
Human Challenge With Live-attenuated Rotavirus to Assess Next-generation Rotavirus Vaccines in Africa
Official Title
Human Challenge With Live-attenuated Rotavirus to Assess Next-generation Rotavirus Vaccines in Africa
Study Type
Interventional

2. Study Status

Record Verification Date
July 2022
Overall Recruitment Status
Active, not recruiting
Study Start Date
April 15, 2021 (Actual)
Primary Completion Date
September 2022 (Anticipated)
Study Completion Date
October 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Centre for Infectious Disease Research in Zambia
Collaborators
Medical Research Council, PATH, University of Liverpool, Institut National de la Santé Et de la Recherche Médicale, France, Imperial College London

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Despite the widespread introduction of vaccines against Rotavirus, Rotavirus continues to be a cause of significant morbidity and mortality in the developing world. This study will assess protection against rotavirus infection and investigate immune correlates of protection following vaccination with a novel trivalent VP8 subunit rotavirus vaccine used alone or in combination with oral rotavirus vaccine.
Detailed Description
This is a randomized, open-label clinical trial of Rotarix and trivalent VP8 subunit vaccine given alone or in combined schedules to 720 infants in Zambia at 6, 10 and 14 weeks followed by challenge at 18 weeks used to assess mucosal immunity. Potential participants will be identified through antenatal and child health monitoring clinics in selected facilities in Lusaka Zambia. Interested parents will be invited to the clinical research site for informed consent procedures and assessment of eligibility. Children meeting the eligibility criteria with written informed consent for participation will be randomized to one of the four available study arms using simple randomization in block sizes of 8. Blood, stool, and saliva samples will be collected prior to completing vaccination according to randomization arm. All parents/guardians will be provided with post immunisation diary cards to document any reactions following vaccination. Trained study staff will contact parents and guardians of enrolled participants weekly to enquire on the child's health and assist with documentation of solicited reactions following vaccinations. Enrolled children will be followed up for at least five months following enrollment. Follow up vaccinations will be provided each month until all children have completed all assigned study vaccinations. Upon completion of study vaccination, participants will be challenged with oral rotavirus vaccine, Rotarix TM to assess mucosal immunity. Primary outcome: The primary objective of the study will be to detect a reduction in the proportion of children shedding vaccine rotavirus in stool at any timepoint 5-9 days after challenge, among children immunized with P2-VP8 subunit vaccine alone or in combination with Rotarix, compared with infants receiving Rotarix alone. The primary outcomes will be prevalence of rotavirus (Rotarix) shedding at any timepoint in samples collected 5,7 and 9 days after challenge. Secondary outcomes: i.) Seroconversion following vaccination: Detection of an increase in seroconversion in either of the combined vaccination arms compared with Rotarix alone. ii.) Immune boosting. We will compare the number of gut-homing (alpha 4 beta 7+) Immunoglobulin A (IgA) and Immunoglobulin G (IgG) rotavirus VP8-specific Antibody secreting cells (ASCs) 7 days after the third clinic visit in 50 infants from each study arm (i.e. after the first VP8 vaccine booster dose, after the third VP8 vaccine dose (alone or in combination with Rotarix), or after no vaccine (control) in the Rotarix only arm).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Diarrhea, Diarrhea Rotavirus
Keywords
Human Infection Challenge

7. Study Design

Primary Purpose
Prevention
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
single centre open label study, randomized, controlled trial
Masking
None (Open Label)
Allocation
Randomized
Enrollment
720 (Actual)

8. Arms, Groups, and Interventions

Arm Title
rotarix only
Arm Type
No Intervention
Arm Description
Rotarix will be administered at 6 and 10 weeks of age following the national Expanded Program for Immunization (EPI) schedule. A challenge dose of Rotarix will be administered at 18 weeks of age and stool samples collected just before challenge and 5, 7 & 9 days later.
Arm Title
P2 VP8 only
Arm Type
Experimental
Arm Description
Parenteral P2-VP8 subunit vaccine will be administered at 6, 10 and 14 weeks of age. A challenge dose of Rotarix will be administered at 18 weeks of age and stool samples collected just before challenge and 5, 7 & 9 days later.
Arm Title
Rotarix + 1 dose P2-VP8
Arm Type
Experimental
Arm Description
Rotarix will be administered at 6 and 10 weeks of age, followed by parenteral P2-VP8 subunit vaccine at 14 weeks of age. A challenge dose of Rotarix will be administered at 18 weeks of age and stool samples collected just before challenge and 5, 7 & 9 days later.
Arm Title
Rotarix + 3 doses P2-VP8
Arm Type
Experimental
Arm Description
Rotarix and parenteral P2-VP8 subunit vaccine will be coadministered at 6 and 10 weeks of age, with an additional dose of P2-VP8 subunit vaccine administered at 14 weeks of age. A challenge dose of Rotarix will be administered at 18 weeks of age and stool samples collected just before challenge and 5, 7 & 9 days later.
Intervention Type
Biological
Intervention Name(s)
Rotarix
Intervention Description
Live-attenuated oral human rotavirus vaccine (Rotarix) manufactured by GlaxoSmithKline containing at least 10^6 CCID50(median cell culture infective doses) of G1P[8] rotavirus, RIX4414 strain produced in Vero cells. This vaccine is an oral suspension with a single dose (1.5ml) administered using an oral applicator.
Intervention Type
Biological
Intervention Name(s)
Trivalent P2-VP8
Intervention Description
Trivalent P2-VP8 subunit vaccine manufactured by SK Chemicals containing 90ug of each VP8 antigen derived from P[4] (DS-1), P[6] (1076), and P[8] (Wa) rotavirus strains fused to the P2 epitope from tetanus toxoid and adsorbed to aluminium hydroxide. A single dose (0.5ml) of this vaccine is administered intramuscularly through injection.
Primary Outcome Measure Information:
Title
Vaccine Shedding
Description
to detect a reduction in the proportion of children shedding vaccine rotavirus in stool at any timepoint 5 -9 days after challenge, among children immunized with P2-VP8 subunit vaccine alone or in combination with Rotarix, compared with infants receiving Rotarix alone. We estimate that approximately 50% (range 30-70%) of children previously vaccinated with 2 doses of Rotarix will shed Rotarix detected by Polymerase Chain Reaction (PCR) at any timepoint 5-9 days after challenge
Time Frame
5-9 days after Challenge
Secondary Outcome Measure Information:
Title
Seroconversion following vaccination
Description
Seroconversion After 2 doses of Rotarix in Zambia seroconversion was 60% (130/216) in an earlier study and 45% (10/22) in our Medical Research Council UK MRC-funded pilot of Rotarix challenge, based on IgA to whole virus cell culture lysate (largely anti -VP6 antibodies). Seroconversion based on anti-VP8 antibodies has not been studied after Rotarix administration but may be similar.
Time Frame
14 and 18 weeks of age
Title
Immune boosting
Description
i.) We will compare the number of gut-homing (alpha 4 beta 7+) IgA and IgG rotavirus VP8-specific ASCs 7 days after the third clinic visit in 50 infants from each study arm (i.e. after the first VP8 vaccine booster dose, after the third VP8 vaccine dose (alone or in combination with Rotarix), or after no vaccine (control) in the Rotarix only arm).
Time Frame
7 days after 3rd clinic visit

10. Eligibility

Sex
All
Minimum Age & Unit of Time
6 Weeks
Maximum Age & Unit of Time
10 Weeks
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: Healthy infants as established by medical history and physical examination. Infants will be 6-10 weeks old at time of enrollment parents plan to remain in the area for the duration of the study. Parent/guardian understands the study procedures and willing to provide informed consent to participate in the study Exclusion Criteria: Acutely unwell Infant or infant's mother has syndromic or documented evidence of being immunocompromised (independent of HIV status) Known allergy to any vaccine component Previously received rotavirus vaccine Received immunosuppressive medication Major congenital or genetic abnormality Any condition in the parents/infant that, in the judgment of the investigator, would interfere with or serves as a contraindication to protocol adherence or a participant's parents' ability to give informed consent. Participant's parents not available or willing to accept active follow-up by the study staff
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Roma Chilengi, MD
Organizational Affiliation
Centre for Infectious Disease Research in Zambia
Official's Role
Principal Investigator
Facility Information:
Facility Name
Chawama first level hospital
City
Lusaka
ZIP/Postal Code
10101
Country
Zambia

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
Communicate with the participants results of the study and plans to share de-identified data. Disseminate to internal research meetings as well as the Ministry of Health Zambia. Submit manuscripts, publications, in peer review journal and also present at local and international scientific conferences
IPD Sharing Time Frame
after study completion

Learn more about this trial

Human Challenge With Live-attenuated Rotavirus to Assess Next-generation Rotavirus Vaccines in Africa

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