Immune Response to Rotavirus Vaccine After a Supplemental Dose Given at 9 Months of Age With Local EPI Vaccines in Mali

Study Overview
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Brief Summary
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This study is an evaluation of the immune response to pentavalent rotavirus vaccine (PRV) after an additional fourth dose is given at 9 months of age with local World Health Organization (WHO) Expanded Programme on Immunization (EPI) vaccines in Mali.

Detailed Description
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Vaccination is the best way to prevent severe rotavirus disease and the deadly, dehydrating diarrhea that it causes. However, given only moderate efficacy in the first year of life and a possible further decline in immunity, it is considered a top priority by public health experts to evaluate the possible value of a booster dose of rotavirus vaccine in low income countries to confer longer duration of protection into the second year of life when disease burden continues to be high. This study is an open-label, individual-randomized, parallel-group, comparative immunogenicity trial. Participating infants randomized to Group A will receive one dose each of measles vaccine (MV), yellow fever vaccine (YFV), and meningitis conjugate vaccine (PsA-TT-5μg) at 9 months of age, and infants randomized to Group B will receive one dose each of MV, YFV, PsA-TT-5μg, and PRV at 9 months of age. The study will simultaneously evaluate two primary objectives, one for noninferiority of the response to MV given with PRV (co-primary objective 1) and one for noninferiority of the response to YFV given with PRV (co-primary objective 2). Secondary objectives of the study were the following: To evaluate the non-inferiority of the immune response 3 months post-vaccination (as sero-conversion) to MV given with PRV (Group B) to that given without PRV (Group A). To compare the immune response (as geometric mean titers [GMTs]) to YFV given with PRV (Group B) to that given without PRV (Group A). To evaluate the non-inferiority of the immune response (as sero-response) to PsA-TT-5μg given with PRV (Group B) compared to that given without PRV (Group A). To compare the immune response (as GMTs) to PsA-TT-5μg given with PRV (Group B) to that given without PRV (Group A). To evaluate the superiority of the immune response (as sero-response and geometric mean concentrations [GMCs]) to a supplemental dose of PRV given at 9 months of age with local EPI vaccines (Group B) compared no supplemental dose (Group A). To describe the safety profile of study vaccination with PRV.

Official Title
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An Evaluation of the Immune Response to Pentavalent Rotavirus Vaccine After a Supplemental Dose Given at 9 Months of Age With Local EPI Vaccines in Mali

Conditions
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Diarrhea Rotavirus

Intervention / Treatment
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* Biological: pentavalent rotavirus vaccine (PRV)
* Biological: measles vaccine (MV)
* Biological: yellow fever vaccine (YFV)
* Biological: meningitis conjugate vaccine (PsA-TT-5μg)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: At least 9 months of age through 11 months of age (has not yet reached 1st birthday) at the time of administration of study vaccines. Residence in the study area. At least one parent or guardian who is at least 18 years of age and is willing to provide written informed consent. Generally healthy and free of obvious health problems as established by medical history including physical examination and clinical judgment of the investigator. A child who is fully vaccinated according to the local EPI schedule (exclusive of oral polio vaccine birth dose). A parent or guardian is willing to attend all planned study visits or allow home visits and mobile phone contacts, as required by the protocol. Exclusion Criteria: Previous receipt any measles-containing vaccine. Previous receipt of any yellow fever vaccine. Previous receipt of any meningitis vaccine. Receipt of rotavirus vaccine within the past 90 days. Administration of any other vaccine within 8 weeks prior to administration of study vaccines or planned vaccination during the 4 weeks after study vaccination. History of allergic disease or known hypersensitivity to any component of the study vaccines and/or following administration of vaccines included in the local program of immunization Use of any investigational or non-registered drug within 90 days prior to the administration of study vaccines. Administration of immunoglobulins and/or any blood products within 90 days prior to the administration of study vaccines or planned administration during the vaccine period. Chronic administration (defined as more than 14 days) of immunosuppressants or other immune-modifying agents since birth (including systemic corticosteroids, this means prednisone, or equivalent, ≥0.5 mg/kg/day; topical steroids including inhaled steroids are allowed). A family history of congenital or hereditary immunodeficiency. History of intussusception. Uncorrected congenital malformation of the gastrointestinal tract that would predispose for intussusception. Acute or chronic, clinically significant pulmonary, cardiovascular, hepatic, or renal functional abnormality, as determined by medical history or physical examination, which in the opinion of the investigator, might interfere with the study objectives. Acute illness at the time of enrollment (acute disease is defined as the presence of a moderate or severe illness with fever [axillary temperature ≥38°C] or without fever [severity determined at the discretion of the investigator]. Acute illness is a temporary exclusion. Any condition or criterion that in the opinion of the investigator might compromise the well-being of the subject or the compliance with study procedures or interfere with the outcome of the study.

Ages Eligible for Study
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Minimum Age: 9 Months
Maximum Age: 11 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: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Group A (without rotavirus vaccine)<br>Group A will receive measles vaccine (MV), yellow fever vaccine (YFV), and meningitis conjugate vaccine (PsA-TT-5μg). | Biological: measles vaccine (MV)<br>* A lyophilized vaccine in a pack containing one vial plus one ampoule of sterile water for injection. After reconstitution, each 0.5 ml/dose of MV contains active substances not less than 1000 units of 50% cell culture infectious doses (CCID50) of MV. Measles Vaccine Live Attenuated virus is propagated on Human Diploid Cells. This MV is currently part of the local EPI program in Mali. This vaccine was administered subcutaneously to the right deltoid.<br>Biological: yellow fever vaccine (YFV)<br>* A freeze-dried live attenuated yellow fever virus of the 17D strain for injection. After reconstitution, one dose (0.5 ml) contains active substances not less than 1000 units of 50% lethal doses (LD50) of yellow fever virus. This YFV is currently part of the local EPI program in Mali. This vaccine was administered intramuscularly to the left deltoid.<br>Biological: meningitis conjugate vaccine (PsA-TT-5μg)<br>* A meningococcal A vaccine, with meningococcal A polysaccharide (PsA) conjugated to the carrier protein, tetanus toxoid (TT). After reconstitution, one dose (0.5 ml) contains 5μg meningococcal A polysaccharide and 5-16 μg tetanus toxoid as a carrier protein. PsA-TT-5μg was considered experimental at the initiation of this study, but received approval from the WHO for infants on 30 December 2014. For all participants enrolled January 1st, 2015 or later, PsA-TT-5μg was not included in Group A or Group B, due to its December 2014 expiration date. This vaccine was administered intramuscularly to the right thigh.<br>* Other names: PsA-TT;|
| Experimental: Group B (with rotavirus vaccine)<br>Group A will receive measles vaccine (MV), yellow fever vaccine (YFV), and meningitis conjugate vaccine (PsA-TT-5μg) plus one oral dose of pentavalent rotavirus vaccine (PRV). | Biological: pentavalent rotavirus vaccine (PRV)<br>* Each two-ml dose contains 5 live human-bovine reassortant rotaviruses with a minimum of 2.0 - 2.8 x 106 infectious units (IU) per reassortant, depending on the serotype, and not greater than 116 x 106 IU per aggregate dose. Each vaccine dose contains sucrose, sodium citrate, sodium phosphate monobasic monohydrate, sodium hydroxide, polysorbate 80, cell culture media, and trace amounts of fetal bovine serum. RotaTeq contains no preservatives. RotaTeq is a pale yellow clear liquid that may have a pink tint. This vaccine was administered orally.<br>* Other names: RotaTeq;Biological: measles vaccine (MV)<br>* A lyophilized vaccine in a pack containing one vial plus one ampoule of sterile water for injection. After reconstitution, each 0.5 ml/dose of MV contains active substances not less than 1000 units of 50% cell culture infectious doses (CCID50) of MV. Measles Vaccine Live Attenuated virus is propagated on Human Diploid Cells. This MV is currently part of the local EPI program in Mali. This vaccine was administered subcutaneously to the right deltoid.<br>Biological: yellow fever vaccine (YFV)<br>* A freeze-dried live attenuated yellow fever virus of the 17D strain for injection. After reconstitution, one dose (0.5 ml) contains active substances not less than 1000 units of 50% lethal doses (LD50) of yellow fever virus. This YFV is currently part of the local EPI program in Mali. This vaccine was administered intramuscularly to the left deltoid.<br>Biological: meningitis conjugate vaccine (PsA-TT-5μg)<br>* A meningococcal A vaccine, with meningococcal A polysaccharide (PsA) conjugated to the carrier protein, tetanus toxoid (TT). After reconstitution, one dose (0.5 ml) contains 5μg meningococcal A polysaccharide and 5-16 μg tetanus toxoid as a carrier protein. PsA-TT-5μg was considered experimental at the initiation of this study, but received approval from the WHO for infants on 30 December 2014. For all participants enrolled January 1st, 2015 or later, PsA-TT-5μg was not included in Group A or Group B, due to its December 2014 expiration date. This vaccine was administered intramuscularly to the right thigh.<br>* Other names: PsA-TT;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number/Percentage of Subjects With Seroconversion for Anti-measles Immunoglobulin G (IgG) Antibody | Measured using a commercially-available Enzyme Linked Immunosorbent Assay (ELISA). Seroconversion was defined as a measurement ≥1.10 geometric mean titer (GMT) at Day 28 among subjects with measurement ≤0.90 at baseline | 28 days post-vaccination | 
| Number/Percentage of Subjects With Seroresponses for Yellow Fever Neutralizing Antibody | Measured by virus neutralization assay, determined using Robert Koch Institute's yellow fever standard of practice and relative to international scientific references for which the level of anti-YF neutralizing IgG protection was known. Seroresponse was defined as a geometric mean titer (GMT) of at least four times baseline value. | 28 days post-vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number/Percentage of Subjects With Seroconversion for Anti-measles Immunoglobulin G (IgG) Antibody | Measured using a commercially-available Enzyme Linked Immunosorbent Assay (ELISA). Seroconversion was defined as a measurement ≥1.10 geometric mean titer (GMT) at Day 28 among subjects with measurement ≤0.90 at baseline. | 3 months post-vaccination | 
| Serum Neutralization Geometric Mean Titers for Yellow Fever Vaccine | Measured by virus neutralization assay, determined using Robert Koch Institute's yellow fever standard of practice (SOP) and relative to international scientific references for which the level of anti-YF neutralizing IgG protection was known. | 28 days post-vaccination | 
| Number/Percentage of Subjects With Seroresponses for Meningitis Conjugate Serum Bactericidal Antibody (SBA) | Seroresponse was defined as a geometric mean titer (GMT) of at least four times baseline value. Measured using baby rabbit complement (rSBA). | 28 days post-vaccination | 
| Geometric Mean of Meningitis Serum Bactericidal Antibody Titer | Measured using baby rabbit complement (rSBA). | Baseline to Day 28 | 
| Number/Percentage of Subjects With Anti-rotavirus Immunoglobulin A (IgA) Titer at Least 3 Times Baseline Value | Conducted by validated Enzyme Linked Immunosorbent Assay (ELISA). The pre- and post-vaccination samples were to be evaluated in one run for consistency and each specimen was to be tested with a negative control for better specificity. | 28 days post-vaccination | 
| Number/Percentage of Subjects With Anti-rotavirus IgA Titer of ≥20 Units/mL | Conducted by validated Enzyme Linked Immunosorbent Assay (ELISA). The pre- and post-vaccination samples were to be evaluated in one run for consistency and each specimen was to be tested with a negative control for better specificity. | 28 days post-vaccination | 
| Number/Percentage of Subjects With Anti-rotavirus IgA <20 Units/mL at Baseline Visit That Had >=20 Units/mL at Day 28 | Conducted by validated Enzyme Linked Immunosorbent Assay (ELISA). The pre- and post-vaccination samples were to be evaluated in one run for consistency and each specimen was to be tested with a negative control for better specificity. | 28 days post-vaccination | 
| Number/Percentage of Subjects With Anti-rotavirus IgG Titer at Least 3 Times Baseline Value | Conducted by validated Enzyme Linked Immunosorbent Assay (ELISA). The pre- and post-vaccination samples were to be evaluated in one run for consistency and each specimen was to be tested with a negative control for better specificity. | 28 days post-vaccination | 
| Number/Percentage of Subjects With Anti-rotavirus IgG Titer of ≥20 Units/mL | Conducted by validated Enzyme Linked Immunosorbent Assay (ELISA). The pre- and post-vaccination samples were to be evaluated in one run for consistency and each specimen was to be tested with a negative control for better specificity. | 28 days post-vaccination | 
| Number/Percentage of Subjects With Anti-rotavirus IgG <20 Units/mL at Baseline Visit That Had >=20 Units/mL at Day 28 | Conducted by validated Enzyme Linked Immunosorbent Assay (ELISA). The pre- and post-vaccination samples were to be evaluated in one run for consistency and each specimen was to be tested with a negative control for better specificity. | 28 days post-vaccination | 
| Geometric Mean of Anti-rotavirus IgA Concentration | Conducted by validated Enzyme Linked Immunosorbent Assay (ELISA). The pre- and post-vaccination samples were to be evaluated in one run for consistency and each specimen was to be tested with a negative control for better specificity. | 28 days post-vaccination | 
| Geometric Mean of Anti-rotavirus IgG Concentration | Conducted by validated Enzyme Linked Immunosorbent Assay (ELISA). The pre- and post-vaccination samples were to be evaluated in one run for consistency and each specimen was to be tested with a negative control for better specificity. | 28 days post-vaccination | 
| Geometric Mean of Anti-rotavirus IgA Among Subjects With <20 Units/mL Concentration at Baseline | Conducted by validated Enzyme Linked Immunosorbent Assay (ELISA). The pre- and post-vaccination samples were to be evaluated in one run for consistency and each specimen was to be tested with a negative control for better specificity. | 28 days post-vaccination | 
| Geometric Mean of Anti-rotavirus IgG Among Subjects With <20 Units/mL Concentration at Baseline | Conducted by validated Enzyme Linked Immunosorbent Assay (ELISA). The pre- and post-vaccination samples were to be evaluated in one run for consistency and each specimen was to be tested with a negative control for better specificity. | 28 days post-vaccination | 
| Number/Percentage of Participants Experiencing Immediate Reactions Post-vaccination | With emphasis on allergic reactions, observed by study staff | Within 30 minutes post-vaccination | 
| Number of Solicited Adverse Reactions (AR) Experienced by Participants | identified or observed by study staff during home visits and/or reported by a parent at any time. Solicited adverse reactions were graded and sub-categorized as those deemed related to vaccination or not by the investigator. | 7 days post-vaccination | 
| Number/Percentage of Participants Experiencing Serious Adverse Events (SAE) | Occurring from vaccination through 3 months post-vaccination, identified or observed by study staff and/or reported by a parent at any time. Serious adverse events were graded for severity and sub-categorized as those deemed related to vaccination or not by the investigator. | 3 months post-vaccination | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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rotavirus vaccine, EPI vaccines, rotavirus, Mali