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

• ClinicalTrials.gov Identifier: NCT02286895
• Recruitment Status: Completed
• First Posted: November 10, 2014
• Results First Posted: December 7, 2018
• Last Update Posted: January 2, 2019
• Sponsor: PATH
• Collaborators: Center for Vaccine Development - Mali; University of Maryland, College Park
• Information provided by (Responsible Party): PATH

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Diarrhea Rotavirus	Biological: pentavalent rotavirus vaccine (PRV); Biological: measles vaccine (MV); Biological: yellow fever vaccine (YFV); Biological: meningitis conjugate vaccine (PsA-TT-5μg)	Phase 4

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.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 600 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Study Start Date: October 2014
• Actual Primary Completion Date: March 2015
• Actual Study Completion Date: March 2015

Arms and Interventions

Arm	Intervention/treatment
Active Comparator: Group A (without rotavirus vaccine); Group A will receive measles vaccine (MV), yellow fever vaccine (YFV), and meningitis conjugate vaccine (PsA-TT-5μg).	Biological: measles 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.; Biological: yellow 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.; Biological: meningitis 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.; Other Name: PsA-TT
Experimental: 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).	Biological: pentavalent 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.; Other Name: RotaTeq; Biological: measles 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.; Biological: yellow 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.; Biological: meningitis 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.; Other Name: PsA-TT

Outcome Measures

Primary Outcome Measures :

1. Number/Percentage of Subjects With Seroconversion for Anti-measles Immunoglobulin G (IgG) Antibody [ Time Frame: 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
2. Number/Percentage of Subjects With Seroresponses for Yellow Fever Neutralizing Antibody [ Time Frame: 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 :

1. Number/Percentage of Subjects With Seroconversion for Anti-measles Immunoglobulin G (IgG) Antibody [ Time Frame: 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.
2. Serum Neutralization Geometric Mean Titers for Yellow Fever Vaccine [ Time Frame: 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.
3. Number/Percentage of Subjects With Seroresponses for Meningitis Conjugate Serum Bactericidal Antibody (SBA) [ Time Frame: 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).
4. Geometric Mean of Meningitis Serum Bactericidal Antibody Titer [ Time Frame: Baseline to Day 28 ]
   Measured using baby rabbit complement (rSBA).
5. Number/Percentage of Subjects With Anti-rotavirus Immunoglobulin A (IgA) Titer at Least 3 Times Baseline Value [ Time Frame: 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.
6. Number/Percentage of Subjects With Anti-rotavirus IgA Titer of ≥20 Units/mL [ Time Frame: 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.
7. Number/Percentage of Subjects With Anti-rotavirus IgA <20 Units/mL at Baseline Visit That Had >=20 Units/mL at Day 28 [ Time Frame: 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.
8. Number/Percentage of Subjects With Anti-rotavirus IgG Titer at Least 3 Times Baseline Value [ Time Frame: 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.
9. Number/Percentage of Subjects With Anti-rotavirus IgG Titer of ≥20 Units/mL [ Time Frame: 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.
10. Number/Percentage of Subjects With Anti-rotavirus IgG <20 Units/mL at Baseline Visit That Had >=20 Units/mL at Day 28 [ Time Frame: 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.
11. Geometric Mean of Anti-rotavirus IgA Concentration [ Time Frame: 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.
12. Geometric Mean of Anti-rotavirus IgG Concentration [ Time Frame: 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.
13. Geometric Mean of Anti-rotavirus IgA Among Subjects With <20 Units/mL Concentration at Baseline [ Time Frame: 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.
14. Geometric Mean of Anti-rotavirus IgG Among Subjects With <20 Units/mL Concentration at Baseline [ Time Frame: 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.
15. Number/Percentage of Participants Experiencing Immediate Reactions Post-vaccination [ Time Frame: Within 30 minutes post-vaccination ]
    With emphasis on allergic reactions, observed by study staff
16. Number of Solicited Adverse Reactions (AR) Experienced by Participants [ Time Frame: 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.
17. Number/Percentage of Participants Experiencing Serious Adverse Events (SAE) [ Time Frame: 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.

Eligibility Criteria

• Ages Eligible for Study: 9 Months to 11 Months (Child)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

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.

Contacts and Locations

Locations

Mali

CVD-Mali

Bamako, Mali

Sponsors and Collaborators

PATH

Center for Vaccine Development - Mali

University of Maryland, College Park

Investigators

• Principal Investigator: Samba O Sow, MD, Msc; Center for Vaccine Development - Mali

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Haidara FC, Tapia MD, Sow SO, Doumbia M, Coulibaly F, Diallo F, Traoré A, Kodio M, Kelly CL, Fitzpatrick M, Kotloff K, Victor JC, Neuzil K. Evaluation of a Booster Dose of Pentavalent Rotavirus Vaccine Coadministered With Measles, Yellow Fever, and Meningitis A Vaccines in 9-Month-Old Malian Infants. J Infect Dis. 2018 Jul 13;218(4):606-613. doi: 10.1093/infdis/jiy215. Erratum in: J Infect Dis. 2019 Jan 7;219(2):339.

• Responsible Party: PATH
• ClinicalTrials.gov Identifier: NCT02286895
• Other Study ID Numbers: PATH-RVI-PRV-01
• First Posted: November 10, 2014
• Results First Posted: December 7, 2018
• Last Update Posted: January 2, 2019
• Last Verified: December 2018

Keywords provided by PATH:

rotavirus; rotavirus vaccine; Mali; EPI vaccines

Additional relevant MeSH terms:

Diarrhea; Signs and Symptoms, Digestive; Vaccines; Immunologic Factors; Physiological Effects of Drugs