Phase I/II Descending Age Study of P2VP8 Subunit Parenteral Rotavirus Vaccine in Healthy Toddlers and Infants

Study Overview
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Brief Summary
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This is is a study of a parenteral rotavirus vaccine (P2-VP8 subunit rotavirus vaccine). The study will examine the safety and immunogenicity of this vaccine first in healthy South African toddlers. If the safety profile is deemed appropriate, the study will continue to explore the safety and immunogenicity of the vaccine in healthy South African infants. The primary safety hypothesis is that the P2-VP8 subunit rotavirus vaccine is safe and well-tolerated in healthy toddlers and infants. The primary immunogenicity hypothesis is that the P2-VP8 subunit rotavirus vaccine is immunogenic in infant participants and will induce an immune response in at least 80% of participants in at least one of the study groups.

Official Title
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Phase I/II Descending Age Double-blinded Randomized Placebo-controlled Dose Escalation Study to Examine the Safety Reactogenicity Tolerability & Immunogenicity of the P2-VP8 Subunit Parenteral Rotavirus Vaccine in Healthy Toddlers & Infants

Conditions
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Evaluation of a Rotavirus Vaccine

Intervention / Treatment
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* Biological: P2-VP8 Subunit Vaccine 10mcg
* Biological: P2-VP8 Subunit Vaccine 30 mcg
* Biological: P2-VP8 Subunit Vaccine 60mcg
* Other: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: healthy infants/toddlers as established by medical history and clinical examination before entering study age: toddler cohort: > or = 2 and <3 years old at the time of enrollment infant cohort: > or = 6 and <8 weeks at the time of enrollment parental ability and willingness to provide informed consent parental intention to remain in the area with the child during the study period. Exclusion Criteria: Presence of fever on the day of enrollment Acute disease at the time of enrollment Concurrent participation in another clinical trial throughout the entire timeframe for this study Presence of malnutrition or any systemic disorder (cardiovascular, pulmonary, hepatic, renal, gastrointestinal, hematological, endocrine, immunological, dermatological, neurological, cancer or autoimmune disease) as determined by medical history and/or physical examination that would compromise the participant's health or is likely to result in nonconformance to the protocol For infant cohort, history of premature birth (<37 weeks gestation) History of congenital abdominal disorders, intussusception, or abdominal surgery Known or suspected impairment of immunological function based on medical history and physical examination For infant cohort only, prior receipt of rotavirus vaccine A known sensitivity or allergy to any components of the study vaccine History of anaphylactic reaction Major congenital or genetic defect Participant's parents not able, available or willing to accept active weekly follow-up by the study staff Has received any immunoglobulin therapy and/or blood products since birth or planned administration during the study period History of chronic administration (defined as more than 14 days) of immunosuppressant medications, including corticosteroids. Infants on inhaled or topical steroids may be permitted to participate in the study Any medical 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 HIV infection For toddlers, to be assessed by HIV ELISA For infants, to be assessed by PCR, if mother is not known to be negative (negative test result between 24 weeks gestation and screening)

Ages Eligible for Study
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Minimum Age: 6 Weeks
Maximum Age: 35 Months

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 |
| --- | --- |
| Experimental: Cohort A P2-VP8 30 mcg<br>Cohort A toddlers (24-35 mo) receiving P2-VP8 Subunit Vaccine (30 mcg) | Biological: P2-VP8 Subunit Vaccine 30 mcg<br>* 30 mcg<br>|
| Placebo Comparator: Cohort A Placebo<br>Cohort A toddlers (24-35 mo) | Other: Placebo<br> <br> |
| Experimental: Cohort A P2-VP8 60 mcg<br>Cohort A toddlers (24-35 mo) receiving high dose P2-VP8 Subunit Vaccine (60mcg) | Biological: P2-VP8 Subunit Vaccine 60mcg<br>* 60 mcg<br>|
| Experimental: Cohort B P2-VP8 10mcg<br>Cohort B infants receiving P2-VP8 Subunit Vaccine (10mcg) | Biological: P2-VP8 Subunit Vaccine 10mcg<br>* 10 mcg<br>|
| Placebo Comparator: Cohort B placebo<br>Cohort B infants aged 6 to < 8 weeks receiving placebo | Other: Placebo<br> <br> |
| Experimental: Cohort B P2-VP8 30mcg<br>Cohort B infants aged 6 to < 8 weeks receiving P2-VP8 Subunit Vaccine (30mcg) | Biological: P2-VP8 Subunit Vaccine 30 mcg<br>* 30 mcg<br>|
| Experimental: Cohort B1 P2-VP8 60mcg<br>Cohort B1 Infants aged 6 to < 8 weeks receiving P2-VP8 Subunit Vaccine (60mcg) | Biological: P2-VP8 Subunit Vaccine 60mcg<br>* 60 mcg<br>|
| Experimental: Cohort A P2-VP8 10mcg<br>Cohort A toddlers (24-35 mo) receiving P2VP8 Subunit Vaccine (10mcg) | Biological: P2-VP8 Subunit Vaccine 10mcg<br>* 10 mcg<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Vaccine Induced Reactions | Maximum severity of all local reactions or systemic reactogenicity after any vaccination | 7 days following each dose | 
| Number of Participants With Serious Adverse Events | Number of participants experiencing a Serious Adverse Event within 28 days of a vaccination and at any time during the study | within 28 days of a study dose and at any time | 
| Number of Participants Reporting Any Non-Serious Adverse Event | all adverse events will be recorded over the duration of the 6 month follow up period. | 6 mo following first vaccination | 
| Number/Percentage of Infant Participants With Anti-P2-VP8 IgA to P[8] Seroresponse. | Seroresponse is defined as 4 fold rise in Geometric Mean Titer (GMT) between pre-(baseline) and post vaccination (4 weeks after third vaccination). Confidence intervals are displayed as percentages. | Baseline to day 84 | 
| Number/Percentage of Infants With Anti-P2-VP8 IgG to P[8] Seroresponses | Seroresponse is defined as 4 fold rise in Geometric Mean Titer (GMT) between pre-(baseline) and post vaccination (4 weeks after third injection).An unadjusted serioresponse was defined as an increase of 4 times or more in titers between baseline and 4 weeks after the 3rd injection. Adjusted IgG and neutralizing antibody post injection titres accounted for the decay in maternal antibodies using the half-life calculated from participants in the placebo group with detectable baseline titers higher than those at the post injection visit. | Baseline to day 84 | 
| Number/Percentage of Infants With Neutralizing Antibody Response to WA Strain (G1[P8]) | Seroresponse is defined as 4 fold rise in Geometric Mean Titer (GMT) between pre-(baseline) and post vaccination (4 weeks after third injection).An unadjusted serioresponse was defined as an increase of 4 times or more in titers between baseline and 4 weeks after the 3rd injection. Adjusted IgG and neutralizing antibody post injection titres accounted for the decay in maternal antibodies using the half-life calculated from participants in the placebo group with detectable baseline titers higher than those at the post injection visit. | Baseline to Day 84 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Rotavirus Shedding After Administration of Rotarix in Infants Receiving 3 Doses of Vaccine or Placebo. | Percent of infants who shed rotavirus at any timepoint after receiving 3 doses of study vaccine and one dose of Rotarix. Infants received Rotarix vaccination beginning on Day 84. Stool specimens were collected from these infants on the 5th, 7th and 9th day following first administration of Rotarix. This test was performed as a novel functional assessment of the ability to suppress local gut multiplication of the vaccine strain contained in Rotarix. | Rotarix vaccination on Day 84 to day 91 |