Diarrhea Rotavirus
Conditions
Keywords
rotavirus, rotavirus vaccine, Mali, EPI vaccines
Brief summary
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
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: 1. 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). 2. To compare the immune response (as geometric mean titers \[GMTs\]) to YFV given with PRV (Group B) to that given without PRV (Group A). 3. 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). 4. To compare the immune response (as GMTs) to PsA-TT-5μg given with PRV (Group B) to that given without PRV (Group A). 5. 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). 6. To describe the safety profile of study vaccination with PRV.
Interventions
BIOLOGICALpentavalent rotavirus vaccine (PRV)
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.
BIOLOGICALmeasles vaccine (MV)
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.
BIOLOGICALyellow fever vaccine (YFV)
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.
BIOLOGICALmeningitis conjugate vaccine (PsA-TT-5μg)
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.
Sponsors
Center for Vaccine Development - Mali
University of Maryland
PATH
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
9 Months to 11 Months
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number/Percentage of Subjects With Seroresponses for Yellow Fever Neutralizing Antibody | 28 days post-vaccination | 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. |
| Number/Percentage of Subjects With Seroconversion for Anti-measles Immunoglobulin G (IgG) Antibody | 28 days post-vaccination | 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 |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number/Percentage of Subjects With Seroresponses for Meningitis Conjugate Serum Bactericidal Antibody (SBA) | 28 days post-vaccination | Seroresponse was defined as a geometric mean titer (GMT) of at least four times baseline value. Measured using baby rabbit complement (rSBA). |
| Geometric Mean of Meningitis Serum Bactericidal Antibody Titer | Baseline to Day 28 | Measured using baby rabbit complement (rSBA). |
| Number/Percentage of Subjects With Anti-rotavirus Immunoglobulin A (IgA) Titer at Least 3 Times Baseline Value | 28 days post-vaccination | 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. |
| Number/Percentage of Subjects With Anti-rotavirus IgA Titer of ≥20 Units/mL | 28 days post-vaccination | 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. |
| Number/Percentage of Subjects With Anti-rotavirus IgA <20 Units/mL at Baseline Visit That Had >=20 Units/mL at Day 28 | 28 days post-vaccination | 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. |
| Number/Percentage of Subjects With Anti-rotavirus IgG Titer at Least 3 Times Baseline Value | 28 days post-vaccination | 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. |
| Number/Percentage of Subjects With Anti-rotavirus IgG Titer of ≥20 Units/mL | 28 days post-vaccination | 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. |
| Number/Percentage of Subjects With Seroconversion for Anti-measles Immunoglobulin G (IgG) Antibody | 3 months post-vaccination | 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. |
| Geometric Mean of Anti-rotavirus IgA Concentration | 28 days post-vaccination | 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. |
| Geometric Mean of Anti-rotavirus IgG Concentration | 28 days post-vaccination | 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. |
| Geometric Mean of Anti-rotavirus IgA Among Subjects With <20 Units/mL Concentration at Baseline | 28 days post-vaccination | 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. |
| Geometric Mean of Anti-rotavirus IgG Among Subjects With <20 Units/mL Concentration at Baseline | 28 days post-vaccination | 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. |
| Number/Percentage of Participants Experiencing Immediate Reactions Post-vaccination | Within 30 minutes post-vaccination | With emphasis on allergic reactions, observed by study staff |
| Number of Solicited Adverse Reactions (AR) Experienced by Participants | 7 days post-vaccination | 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. |
| Number/Percentage of Participants Experiencing Serious Adverse Events (SAE) | 3 months post-vaccination | 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. |
| Number/Percentage of Subjects With Anti-rotavirus IgG <20 Units/mL at Baseline Visit That Had >=20 Units/mL at Day 28 | 28 days post-vaccination | 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. |
| Serum Neutralization Geometric Mean Titers for Yellow Fever Vaccine | 28 days post-vaccination | 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. |
Countries
Mali
Participant flow
Recruitment details
Recruited up to 750 healthy male and female infant subjects of 9-11 months of age from the local communities and community health centers in Bamako, Mali. The duration of planned study participation for each subject was to be approximately 3 months and the estimated duration of the recruitment period was to be 3 months.
Participants by arm
| Arm | Count |
|---|---|
| Group A (Without Rotavirus Vaccine) Group A will receive measles vaccine (MV), yellow fever vaccine (YFV), and meningitis conjugate vaccine (PsA-TT-5μg).
measles vaccine (MV): At enrollment, all infants will receive one dose of 0.5ml subcutaneously
yellow fever vaccine (YFV): At enrollment, all infants will receive one dose of 0.5ml intramuscularly
meningitis conjugate vaccine (PsA-TT-5μg): At enrollment, all infants will receive one dose of 0.5ml intramuscularly | 300 |
| Group B (With Rotavirus Vaccine) 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).
pentavalent rotavirus vaccine (PRV): At enrollment, infants in this group receive one dose of 2.0ml orally
measles vaccine (MV): At enrollment, all infants will receive one dose of 0.5ml subcutaneously
yellow fever vaccine (YFV): At enrollment, all infants will receive one dose of 0.5ml intramuscularly
meningitis conjugate vaccine (PsA-TT-5μg): At enrollment, all infants will receive one dose of 0.5ml intramuscularly | 300 |
| Total | 600 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Assessed for Measles Seroconversion | Baseline measure non-negative | 41 | 32 |
| Assessed for Measles Seroconversion | Missing measurement | 6 | 3 |
| Assessed for Measles Seroconversion | Protocol Violation | 1 | 4 |
Baseline characteristics
| Characteristic | Group A (Without Rotavirus Vaccine) | Group B (With Rotavirus Vaccine) | Total |
|---|---|---|---|
| Age, Continuous | 9.7 months STANDARD_DEVIATION 0.7 | 9.7 months STANDARD_DEVIATION 0.7 | 9.7 months STANDARD_DEVIATION 0.7 |
| Age, Customized 10 months | 53 Participants | 51 Participants | 104 Participants |
| Age, Customized 11 months | 24 Participants | 25 Participants | 49 Participants |
| Age, Customized 9 months | 223 Participants | 224 Participants | 447 Participants |
| Ethnicity Bambara | 101 Participants | 120 Participants | 221 Participants |
| Ethnicity Fula/Peulh | 49 Participants | 34 Participants | 83 Participants |
| Ethnicity Mandika/Malinke | 41 Participants | 37 Participants | 78 Participants |
| Ethnicity Other | 74 Participants | 72 Participants | 146 Participants |
| Ethnicity Sarahule/Sarakole | 35 Participants | 37 Participants | 72 Participants |
| Region of Enrollment Mali | 300 participants | 300 participants | 600 participants |
| Sex: Female, Male Female | 133 Participants | 151 Participants | 284 Participants |
| Sex: Female, Male Male | 167 Participants | 149 Participants | 316 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 300 | 0 / 300 |
| other Total, other adverse events | 125 / 300 | 103 / 300 |
| serious Total, serious adverse events | 8 / 300 | 7 / 300 |
Outcome results
Primary
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
Time frame: 28 days post-vaccination
Population: Number of subjects with valid measurements and measurement ≤0.90 at baseline (per protocol)
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group A (Without Rotavirus Vaccine) | Number/Percentage of Subjects With Seroconversion for Anti-measles Immunoglobulin G (IgG) Antibody | Seroconversion | 246 Participants |
| Group A (Without Rotavirus Vaccine) | Number/Percentage of Subjects With Seroconversion for Anti-measles Immunoglobulin G (IgG) Antibody | No seroconversion (≤0.90) | 2 Participants |
| Group A (Without Rotavirus Vaccine) | Number/Percentage of Subjects With Seroconversion for Anti-measles Immunoglobulin G (IgG) Antibody | Equivocal measurements (≥0.91 and ≤1.09) | 4 Participants |
| Group B (With Rotavirus Vaccine) | Number/Percentage of Subjects With Seroconversion for Anti-measles Immunoglobulin G (IgG) Antibody | Seroconversion | 255 Participants |
| Group B (With Rotavirus Vaccine) | Number/Percentage of Subjects With Seroconversion for Anti-measles Immunoglobulin G (IgG) Antibody | No seroconversion (≤0.90) | 3 Participants |
| Group B (With Rotavirus Vaccine) | Number/Percentage of Subjects With Seroconversion for Anti-measles Immunoglobulin G (IgG) Antibody | Equivocal measurements (≥0.91 and ≤1.09) | 3 Participants |
Comparison: Based on results from a prior study, the sponsor assumed 90% sero-conversion rates in each Arms A and B for each antigen in the two co-primary objectives. To rule out a non-inferiority margin of no more than 10% with 95% power (95% power was chosen to give an overall power of at least 90%) and a one-sided type-one error rate of no more than 2.5%, 237 evaluable subjects were required in each group to explore the co-primary objectives.95% CI: [-4, 4.2]
Primary
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.
Time frame: 28 days post-vaccination
Population: Number of subjects with valid measurements and negative result at baseline (per protocol)
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group A (Without Rotavirus Vaccine) | Number/Percentage of Subjects With Seroresponses for Yellow Fever Neutralizing Antibody | Seroresponse | 153 Participants |
| Group A (Without Rotavirus Vaccine) | Number/Percentage of Subjects With Seroresponses for Yellow Fever Neutralizing Antibody | No seroresponse | 137 Participants |
| Group B (With Rotavirus Vaccine) | Number/Percentage of Subjects With Seroresponses for Yellow Fever Neutralizing Antibody | Seroresponse | 141 Participants |
| Group B (With Rotavirus Vaccine) | Number/Percentage of Subjects With Seroresponses for Yellow Fever Neutralizing Antibody | No seroresponse | 146 Participants |
Comparison: Based on results from a prior study completed by PATH and CVD-Mali, the sponsor assumed 90% sero-conversion rates in each Arms A and B for each antigen in the two co-primary objectives. To rule out a non-inferiority margin of no more than 10% with 95% power (95% power was chosen to give an overall power of at least 90%) and a one-sided type-one error rate of no more than 2.5%, 237 evaluable subjects were required in each group to explore the co-primary objectives.95% CI: [-12.2, 4]
Secondary
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.
Time frame: 28 days post-vaccination
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Group A (Without Rotavirus Vaccine) | Geometric Mean of Anti-rotavirus IgA Among Subjects With <20 Units/mL Concentration at Baseline | 28 days post-vaccination | 22.2 titer |
| Group A (Without Rotavirus Vaccine) | Geometric Mean of Anti-rotavirus IgA Among Subjects With <20 Units/mL Concentration at Baseline | Baseline | 5.1 titer |
| Group B (With Rotavirus Vaccine) | Geometric Mean of Anti-rotavirus IgA Among Subjects With <20 Units/mL Concentration at Baseline | 28 days post-vaccination | 41.5 titer |
| Group B (With Rotavirus Vaccine) | Geometric Mean of Anti-rotavirus IgA Among Subjects With <20 Units/mL Concentration at Baseline | Baseline | 4.8 titer |
Comparison: Null hypothesis: geometric mean titer (GMT) in group receiving rotavirus vaccine/GMT in group not receiving rotavirus vaccine ≤ 195% CI: [1.2, 3.3]
Secondary
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.
Time frame: 28 days post-vaccination
Population: Number of subjects with valid measurements (per protocol)
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Group A (Without Rotavirus Vaccine) | Geometric Mean of Anti-rotavirus IgA Concentration | Baseline | 23.7 titer |
| Group A (Without Rotavirus Vaccine) | Geometric Mean of Anti-rotavirus IgA Concentration | 28 days post-vaccination | 67.9 titer |
| Group B (With Rotavirus Vaccine) | Geometric Mean of Anti-rotavirus IgA Concentration | Baseline | 25.3 titer |
| Group B (With Rotavirus Vaccine) | Geometric Mean of Anti-rotavirus IgA Concentration | 28 days post-vaccination | 118.4 titer |
Comparison: Null hypothesis: geometric mean titer (GMT) in group receiving rotavirus vaccine/GMT in group not receiving rotavirus vaccine ≤ 195% CI: [1.2, 2.4]
Secondary
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.
Time frame: 28 days post-vaccination
Population: Participants with valid measures of anti-rotavirus IgG \<20 units/mL at baseline
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Group A (Without Rotavirus Vaccine) | Geometric Mean of Anti-rotavirus IgG Among Subjects With <20 Units/mL Concentration at Baseline | Baseline | 7.8 titer |
| Group A (Without Rotavirus Vaccine) | Geometric Mean of Anti-rotavirus IgG Among Subjects With <20 Units/mL Concentration at Baseline | 28 days post-vaccination | 28.3 titer |
| Group B (With Rotavirus Vaccine) | Geometric Mean of Anti-rotavirus IgG Among Subjects With <20 Units/mL Concentration at Baseline | Baseline | 7.4 titer |
| Group B (With Rotavirus Vaccine) | Geometric Mean of Anti-rotavirus IgG Among Subjects With <20 Units/mL Concentration at Baseline | 28 days post-vaccination | 123.7 titer |
Comparison: Null hypothesis: geometric mean titer (GMT) in group receiving rotavirus vaccine/GMT in group not receiving rotavirus vaccine ≤ 195% CI: [2.4, 8.9]
Secondary
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.
Time frame: 28 days post-vaccination
Population: Number of subjects with valid measurements (per protocol)
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Group A (Without Rotavirus Vaccine) | Geometric Mean of Anti-rotavirus IgG Concentration | Baseline | 58.9 titer |
| Group A (Without Rotavirus Vaccine) | Geometric Mean of Anti-rotavirus IgG Concentration | 28 days post-vaccination | 153.3 titer |
| Group B (With Rotavirus Vaccine) | Geometric Mean of Anti-rotavirus IgG Concentration | Baseline | 62.5 titer |
| Group B (With Rotavirus Vaccine) | Geometric Mean of Anti-rotavirus IgG Concentration | 28 days post-vaccination | 363.6 titer |
Comparison: Null hypothesis: 28 days post-vaccination, geometric mean titer (GMT) in group receiving rotavirus vaccine/GMT in group not receiving rotavirus vaccine ≤ 195% CI: [1.7, 3.1]
Secondary
Geometric Mean of Meningitis Serum Bactericidal Antibody Titer
Measured using baby rabbit complement (rSBA).
Time frame: Baseline to Day 28
Population: Number of subjects with valid measurements (per protocol)
| Arm | Measure | Value (GEOMETRIC_MEAN) |
|---|---|---|
| Group A (Without Rotavirus Vaccine) | Geometric Mean of Meningitis Serum Bactericidal Antibody Titer | 2.8 titer |
| Group B (With Rotavirus Vaccine) | Geometric Mean of Meningitis Serum Bactericidal Antibody Titer | 3.2 titer |
95% CI: [0.7, 1.3]
Secondary
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.
Time frame: 7 days post-vaccination
| Arm | Measure | Category | Value (COUNT_OF_UNITS) |
|---|---|---|---|
| Group A (Without Rotavirus Vaccine) | Number of Solicited Adverse Reactions (AR) Experienced by Participants | Diarrhea | 24 systemic reaction |
| Group A (Without Rotavirus Vaccine) | Number of Solicited Adverse Reactions (AR) Experienced by Participants | Vomiting | 8 systemic reaction |
| Group A (Without Rotavirus Vaccine) | Number of Solicited Adverse Reactions (AR) Experienced by Participants | Pyrexia | 5 systemic reaction |
| Group A (Without Rotavirus Vaccine) | Number of Solicited Adverse Reactions (AR) Experienced by Participants | Irritability | 1 systemic reaction |
| Group A (Without Rotavirus Vaccine) | Number of Solicited Adverse Reactions (AR) Experienced by Participants | Lethargy | 2 systemic reaction |
| Group A (Without Rotavirus Vaccine) | Number of Solicited Adverse Reactions (AR) Experienced by Participants | Rash | 1 systemic reaction |
| Group B (With Rotavirus Vaccine) | Number of Solicited Adverse Reactions (AR) Experienced by Participants | Lethargy | 0 systemic reaction |
| Group B (With Rotavirus Vaccine) | Number of Solicited Adverse Reactions (AR) Experienced by Participants | Diarrhea | 21 systemic reaction |
| Group B (With Rotavirus Vaccine) | Number of Solicited Adverse Reactions (AR) Experienced by Participants | Irritability | 2 systemic reaction |
| Group B (With Rotavirus Vaccine) | Number of Solicited Adverse Reactions (AR) Experienced by Participants | Vomiting | 7 systemic reaction |
| Group B (With Rotavirus Vaccine) | Number of Solicited Adverse Reactions (AR) Experienced by Participants | Rash | 0 systemic reaction |
| Group B (With Rotavirus Vaccine) | Number of Solicited Adverse Reactions (AR) Experienced by Participants | Pyrexia | 8 systemic reaction |
Secondary
Number/Percentage of Participants Experiencing Immediate Reactions Post-vaccination
With emphasis on allergic reactions, observed by study staff
Time frame: Within 30 minutes post-vaccination
Population: Among all subjects enrolled (intent-to-treat population)
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group A (Without Rotavirus Vaccine) | Number/Percentage of Participants Experiencing Immediate Reactions Post-vaccination | Any immediate reaction | 0 Participants |
| Group A (Without Rotavirus Vaccine) | Number/Percentage of Participants Experiencing Immediate Reactions Post-vaccination | No immediate reaction | 300 Participants |
| Group B (With Rotavirus Vaccine) | Number/Percentage of Participants Experiencing Immediate Reactions Post-vaccination | Any immediate reaction | 0 Participants |
| Group B (With Rotavirus Vaccine) | Number/Percentage of Participants Experiencing Immediate Reactions Post-vaccination | No immediate reaction | 300 Participants |
Secondary
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.
Time frame: 3 months post-vaccination
Population: Among all subjects enrolled (intent-to-treat population)
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group A (Without Rotavirus Vaccine) | Number/Percentage of Participants Experiencing Serious Adverse Events (SAE) | At least 1 SAE not related to vaccination | 6 Participants |
| Group A (Without Rotavirus Vaccine) | Number/Percentage of Participants Experiencing Serious Adverse Events (SAE) | No SAE | 292 Participants |
| Group A (Without Rotavirus Vaccine) | Number/Percentage of Participants Experiencing Serious Adverse Events (SAE) | 1 SAE unlikely to be related to vaccination | 1 Participants |
| Group A (Without Rotavirus Vaccine) | Number/Percentage of Participants Experiencing Serious Adverse Events (SAE) | At least 1 SAE probably related to vaccination | 1 Participants |
| Group B (With Rotavirus Vaccine) | Number/Percentage of Participants Experiencing Serious Adverse Events (SAE) | At least 1 SAE probably related to vaccination | 0 Participants |
| Group B (With Rotavirus Vaccine) | Number/Percentage of Participants Experiencing Serious Adverse Events (SAE) | At least 1 SAE not related to vaccination | 7 Participants |
| Group B (With Rotavirus Vaccine) | Number/Percentage of Participants Experiencing Serious Adverse Events (SAE) | 1 SAE unlikely to be related to vaccination | 0 Participants |
| Group B (With Rotavirus Vaccine) | Number/Percentage of Participants Experiencing Serious Adverse Events (SAE) | No SAE | 293 Participants |
Secondary
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.
Time frame: 28 days post-vaccination
Population: Participants with valid measures of anti-rotavirus IgA \<20 units/mL at baseline
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group A (Without Rotavirus Vaccine) | Number/Percentage of Subjects With Anti-rotavirus IgA <20 Units/mL at Baseline Visit That Had >=20 Units/mL at Day 28 | Seroresponse | 52 Participants |
| Group A (Without Rotavirus Vaccine) | Number/Percentage of Subjects With Anti-rotavirus IgA <20 Units/mL at Baseline Visit That Had >=20 Units/mL at Day 28 | No seroresponse | 113 Participants |
| Group B (With Rotavirus Vaccine) | Number/Percentage of Subjects With Anti-rotavirus IgA <20 Units/mL at Baseline Visit That Had >=20 Units/mL at Day 28 | Seroresponse | 91 Participants |
| Group B (With Rotavirus Vaccine) | Number/Percentage of Subjects With Anti-rotavirus IgA <20 Units/mL at Baseline Visit That Had >=20 Units/mL at Day 28 | No seroresponse | 69 Participants |
Comparison: Null hypothesis: percentage of the seroresponse to rotavirus in the group that received rotavirus vaccine minus the percentage of the seroresponse to rotavirus in the group that did not receive rotavirus vaccine is less than or equal to 0.95% CI: [14.6, 36.2]
Secondary
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.
Time frame: 28 days post-vaccination
Population: Number of subjects with valid measurements (per protocol)
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group A (Without Rotavirus Vaccine) | Number/Percentage of Subjects With Anti-rotavirus IgA Titer of ≥20 Units/mL | ≥20 Units/mL | 172 Participants |
| Group A (Without Rotavirus Vaccine) | Number/Percentage of Subjects With Anti-rotavirus IgA Titer of ≥20 Units/mL | <20 Units/mL | 120 Participants |
| Group B (With Rotavirus Vaccine) | Number/Percentage of Subjects With Anti-rotavirus IgA Titer of ≥20 Units/mL | ≥20 Units/mL | 218 Participants |
| Group B (With Rotavirus Vaccine) | Number/Percentage of Subjects With Anti-rotavirus IgA Titer of ≥20 Units/mL | <20 Units/mL | 74 Participants |
Comparison: Null hypothesis: percentage of the seroresponse to rotavirus in the group that received rotavirus vaccine minus the percentage of the seroresponse to rotavirus in the group that did not receive rotavirus vaccine is less than or equal to 0.95% CI: [8.1, 23.4]
Secondary
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.
Time frame: 28 days post-vaccination
Population: Participants with valid measures of anti-rotavirus IgA \<20 units/mL at baseline
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group A (Without Rotavirus Vaccine) | Number/Percentage of Subjects With Anti-rotavirus IgG <20 Units/mL at Baseline Visit That Had >=20 Units/mL at Day 28 | Seroresponse | 29 Participants |
| Group A (Without Rotavirus Vaccine) | Number/Percentage of Subjects With Anti-rotavirus IgG <20 Units/mL at Baseline Visit That Had >=20 Units/mL at Day 28 | No seroresponse | 63 Participants |
| Group B (With Rotavirus Vaccine) | Number/Percentage of Subjects With Anti-rotavirus IgG <20 Units/mL at Baseline Visit That Had >=20 Units/mL at Day 28 | Seroresponse | 76 Participants |
| Group B (With Rotavirus Vaccine) | Number/Percentage of Subjects With Anti-rotavirus IgG <20 Units/mL at Baseline Visit That Had >=20 Units/mL at Day 28 | No seroresponse | 15 Participants |
Comparison: Null hypothesis: percentage of the seroresponse to rotavirus in the group that received rotavirus vaccine minus the percentage of the seroresponse to rotavirus in the group that did not receive rotavirus vaccine is less than or equal to 0.95% CI: [37.7, 66.3]
Secondary
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.
Time frame: 28 days post-vaccination
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group A (Without Rotavirus Vaccine) | Number/Percentage of Subjects With Anti-rotavirus IgG Titer at Least 3 Times Baseline Value | Seroresponse | 77 Participants |
| Group A (Without Rotavirus Vaccine) | Number/Percentage of Subjects With Anti-rotavirus IgG Titer at Least 3 Times Baseline Value | No seroresponse | 216 Participants |
| Group B (With Rotavirus Vaccine) | Number/Percentage of Subjects With Anti-rotavirus IgG Titer at Least 3 Times Baseline Value | Seroresponse | 168 Participants |
| Group B (With Rotavirus Vaccine) | Number/Percentage of Subjects With Anti-rotavirus IgG Titer at Least 3 Times Baseline Value | No seroresponse | 125 Participants |
Comparison: Null hypothesis: percentage of the seroresponse to rotavirus in the group that received rotavirus vaccine minus the percentage of the seroresponse to rotavirus in the group that did not receive rotavirus vaccine is less than or equal to 0.95% CI: [23.1, 39]
Secondary
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.
Time frame: 28 days post-vaccination
Population: Number of subjects with valid measurements (per protocol)
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group A (Without Rotavirus Vaccine) | Number/Percentage of Subjects With Anti-rotavirus IgG Titer of ≥20 Units/mL | ≥20 Units/mL | 223 Participants |
| Group A (Without Rotavirus Vaccine) | Number/Percentage of Subjects With Anti-rotavirus IgG Titer of ≥20 Units/mL | <20 Units/mL | 70 Participants |
| Group B (With Rotavirus Vaccine) | Number/Percentage of Subjects With Anti-rotavirus IgG Titer of ≥20 Units/mL | ≥20 Units/mL | 275 Participants |
| Group B (With Rotavirus Vaccine) | Number/Percentage of Subjects With Anti-rotavirus IgG Titer of ≥20 Units/mL | <20 Units/mL | 18 Participants |
Comparison: Null hypothesis: percentage of the seroresponse to rotavirus in the group that received rotavirus vaccine minus the percentage of the seroresponse to rotavirus in the group that did not receive rotavirus vaccine is less than or equal to 0.95% CI: [12, 23.5]
Secondary
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.
Time frame: 28 days post-vaccination
Population: Number of subjects with valid measurements (per protocol)
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group A (Without Rotavirus Vaccine) | Number/Percentage of Subjects With Anti-rotavirus Immunoglobulin A (IgA) Titer at Least 3 Times Baseline Value | At least 3 times baseline value | 80 Participants |
| Group A (Without Rotavirus Vaccine) | Number/Percentage of Subjects With Anti-rotavirus Immunoglobulin A (IgA) Titer at Least 3 Times Baseline Value | Not at least 3 times baseline value | 212 Participants |
| Group B (With Rotavirus Vaccine) | Number/Percentage of Subjects With Anti-rotavirus Immunoglobulin A (IgA) Titer at Least 3 Times Baseline Value | At least 3 times baseline value | 131 Participants |
| Group B (With Rotavirus Vaccine) | Number/Percentage of Subjects With Anti-rotavirus Immunoglobulin A (IgA) Titer at Least 3 Times Baseline Value | Not at least 3 times baseline value | 161 Participants |
Comparison: Null hypothesis: percentage of the seroresponse to rotavirus in the group that received rotavirus vaccine minus the percentage of the seroresponse to rotavirus in the group that did not receive rotavirus vaccine is less than or equal to 0.95% CI: [9.7, 25.3]
Secondary
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.
Time frame: 3 months post-vaccination
Population: Subjects with valid measurements and measurement ≤0.90 at baseline (per protocol)
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group A (Without Rotavirus Vaccine) | Number/Percentage of Subjects With Seroconversion for Anti-measles Immunoglobulin G (IgG) Antibody | Seroconversion | 206 Participants |
| Group A (Without Rotavirus Vaccine) | Number/Percentage of Subjects With Seroconversion for Anti-measles Immunoglobulin G (IgG) Antibody | No seroconversion (≤0.90) | 4 Participants |
| Group A (Without Rotavirus Vaccine) | Number/Percentage of Subjects With Seroconversion for Anti-measles Immunoglobulin G (IgG) Antibody | Equivocal measurements (≥0.91 and ≤1.09) | 8 Participants |
| Group B (With Rotavirus Vaccine) | Number/Percentage of Subjects With Seroconversion for Anti-measles Immunoglobulin G (IgG) Antibody | Seroconversion | 210 Participants |
| Group B (With Rotavirus Vaccine) | Number/Percentage of Subjects With Seroconversion for Anti-measles Immunoglobulin G (IgG) Antibody | No seroconversion (≤0.90) | 5 Participants |
| Group B (With Rotavirus Vaccine) | Number/Percentage of Subjects With Seroconversion for Anti-measles Immunoglobulin G (IgG) Antibody | Equivocal measurements (≥0.91 and ≤1.09) | 13 Participants |
Comparison: Based on results from a prior study completed by PATH and CVD-Mali, the sponsor assumed 90% sero-conversion rates in each Arms A and B for each antigen in the two co-primary objectives. To rule out a non-inferiority margin of no more than 10% with 95% power (95% power was chosen to give an overall power of at least 90%) and a one-sided type-one error rate of no more than 2.5%, 237 evaluable subjects were required in each group to explore the co-primary objectives.95% CI: [-7.5, 2.7]
Secondary
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).
Time frame: 28 days post-vaccination
Population: Number of subjects with valid measurements (per protocol)
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Group A (Without Rotavirus Vaccine) | Number/Percentage of Subjects With Seroresponses for Meningitis Conjugate Serum Bactericidal Antibody (SBA) | Seroresponse | 276 Participants |
| Group A (Without Rotavirus Vaccine) | Number/Percentage of Subjects With Seroresponses for Meningitis Conjugate Serum Bactericidal Antibody (SBA) | No seroresponse | 17 Participants |
| Group B (With Rotavirus Vaccine) | Number/Percentage of Subjects With Seroresponses for Meningitis Conjugate Serum Bactericidal Antibody (SBA) | Seroresponse | 273 Participants |
| Group B (With Rotavirus Vaccine) | Number/Percentage of Subjects With Seroresponses for Meningitis Conjugate Serum Bactericidal Antibody (SBA) | No seroresponse | 19 Participants |
95% CI: [-5.2, 3.8]
Secondary
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.
Time frame: 28 days post-vaccination
Population: Number of subjects with valid measurements (per protocol)
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) |
|---|---|---|---|
| Group A (Without Rotavirus Vaccine) | Serum Neutralization Geometric Mean Titers for Yellow Fever Vaccine | Baseline | 2.4 titer |
| Group A (Without Rotavirus Vaccine) | Serum Neutralization Geometric Mean Titers for Yellow Fever Vaccine | 28 days post-vaccination | 16.8 titer |
| Group B (With Rotavirus Vaccine) | Serum Neutralization Geometric Mean Titers for Yellow Fever Vaccine | Baseline | 2.5 titer |
| Group B (With Rotavirus Vaccine) | Serum Neutralization Geometric Mean Titers for Yellow Fever Vaccine | 28 days post-vaccination | 15 titer |
95% CI: [0.8, 1.1]