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

Phase 4

Completed

Conditions: Diarrhea Rotavirus

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

Registration Number: NCT02286895

Lead Sponsor: PATH

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 600

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Group A (without rotavirus vaccine)	meningitis conjugate vaccine (PsA-TT-5μg)	Group A will receive measles vaccine (MV), yellow fever vaccine (YFV), and meningitis conjugate vaccine (PsA-TT-5μg).
Group B (with rotavirus vaccine)	meningitis conjugate vaccine (PsA-TT-5μg)	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).
Group A (without rotavirus vaccine)	measles vaccine (MV)	Group A will receive measles vaccine (MV), yellow fever vaccine (YFV), and meningitis conjugate vaccine (PsA-TT-5μg).
Group A (without rotavirus vaccine)	yellow fever vaccine (YFV)	Group A will receive measles vaccine (MV), yellow fever vaccine (YFV), and meningitis conjugate vaccine (PsA-TT-5μg).
Group B (with rotavirus vaccine)	yellow fever vaccine (YFV)	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).
Group B (with rotavirus vaccine)	pentavalent rotavirus vaccine (PRV)	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).
Group B (with rotavirus vaccine)	measles vaccine (MV)	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).

Primary Outcome Measures

Name	Time	Method
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
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.

Secondary Outcome Measures

Name	Time	Method
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.
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.
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 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.
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.