- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT01953510
Trial of Pneumococcal Vaccine Schedules in Ho Chi Minh City, Vietnam
Evaluation of Different Infant Vaccination Schedules Incorporating Pneumococcal Vaccination
Pneumococcus is a group of bacteria that can cause pneumonia, meningitis and other diseases. These bacteria normally live in the nose of humans and are spread from person to person by touching or sneezing. There are vaccines available to protect against infection with these bacteria, and pneumococcus is currently the leading vaccine-preventable cause of death in young children. In countries where pneumococcal vaccine (PCV) has been introduced, there has been a big impact on the amount of disease caused by these bacteria. However, many countries, especially developing countries, are yet to introduce PCV as part of their routine immunizations. Currently a total of four doses of PCV is recommended, and the main barrier to vaccine introduction is cost. This study aims to identify a vaccination schedule to make PCV more effective and affordable for Vietnam and other developing countries.
This study has two distinct purposes: 1) to compare different dosage schedules of PCV and 2) to compare different PCV vaccines.
- Schedules of Synflorix (PCV10) involving a three, two or one dose PCV primary series and two booster options will be compared. Comparisons will be made firstly in terms of measures of immunity to the vaccine, and secondly in terms of the effect of vaccination on the carriage of bacteria in the nose.
- The responses to PCV10 and Prevenar-13 (PCV13) will be compared, in the schedule most likely to be considered for global use. Again, comparisons will be made in terms of measures of immunity and effect on carriage in the nose.
Infants aged two months will be randomly assigned to one of six study groups and will provide up to four blood samples for analysis of the measures of immunity and five nose swabs for analysis of carriage of bacteria. Infants will be followed up 8-9 times until the age of 24 months. An additional control group will be recruited at 18 months of age and also followed up until 24 months of age.
The results of this study will be used to facilitate decision making, at global and national levels, regarding introduction of PCV.
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
Introduction
The overall purpose of this study is to investigate simplified childhood vaccination schedules that are more appropriate for developing country use. This study is specifically designed to address two independent questions within a single study:
- What is the optimal schedule for provision of EPI vaccines with the incorporation of PCV10? Schedules involving a three, two or one dose PCV10 primary series will be evaluated, timed around options for simplification of the Expanded Programme of Immunization (EPI) schedule for developing countries. A simplified schedule with the pneumococcal booster dose brought forward closer to the peak incidence of disease is likely both to increase compliance and vaccine effectiveness. A booster at nine months of age coincides with the usual time for administration of measles vaccine, whereas a booster at six months of age would provide earlier protection and may enable a further abbreviated 1+1 pneumococcal vaccination schedule.
- How do the responses to PCV vaccination with PCV10 or PCV13 compare? PCV10 and PCV13 are the two PCVs available through the Advanced Market Commitment (AMC) mechanism, a mechanism that provides funds for vaccine introduction into developing countries. However, there have been no studies to date directly comparing these two vaccines. Directly comparing these two vaccines will provide useful information to countries considering introduction of PCV. There are important differences between these vaccines. PCV10 includes ten pneumococcal serotypes and PCV13 includes thirteen. PCV10 uses a non-typeable Haemophilus influenzae (NTHi) Protein D carrier, which may confer protection against H. influenzae, and PCV13 uses a CRM197 carrier. It is of interest to know whether these vaccines differ either in their immunogenicity or their impact on nasopharyngeal (NP) carriage.
Design
Infants will be randomized to one of six study arms (A-F). All infant participants receive four doses of Infanrix-hexa (DTaP-Hib-HBV-IPV) and at least two doses of PCV. The PCV schedules to be evaluated are: a 3+1 PCV10 schedule at 2, 3, 4 and 9 months of age (Arm A); a 3+0 PCV10 schedule at 2, 3 and 4 months of age (Arm B); a 2+1 PCV10 schedule at 2, 4 and 9 months of age (Arm C); a 1+1 PCV10 schedule at 2 and 6 months of age (Arm D); a 2+1 PCV13 schedule at 2, 4 and 9 months of age (Arm E). Arm F, the control group, receives two doses of PCV10 at 18 and 24 months of age. An additional control group (Arm G) will be recruited at 18 months of age and will receive Infanrix-hexa at 18 months of age and a single dose of PCV10 at 24 months of age. Reactogenicity will be assessed following all vaccination visits through the use of diary cards.
Participants from arms A-E will provide six NP swabs for analysis of the NP carriage outcomes, at 2, 6, 9, 12, 18 and 24 months of age; and will provide four blood samples over the course of the trial for analysis of vaccine responses. Blood 1 will be taken four weeks post-primary series; Blood 2 will be taken pre-booster (arms A, C, D and E) or at 9 months of age (subset of arm B); and Blood 3 will be taken four weeks post-booster (arms A, C, D and E) or at 10 months of age (arm B). An additional blood sample will be taken at: 18 months of age for a subset of arms A, B, C, D and E; 2 months of age for a subset of arm A; 6 months of age for a subset of arms B and C; 9 months of age for a subset of arm D; or 3 months of age for a subset of arm E. Participants from the control arms will provide NP swabs at 2, 6, 9, 12, 18 and 24 months of age (arm F) or at 18 and 24 months of age (arm G), and will provide blood samples at 18 (Blood 4), 19 (Blood X) and 24 (Blood Y) months of age.
Objectives
- What is the optimal schedule for provision of EPI vaccines with the incorporation of PCV10? The primary objective is to compare a 2+1 schedule at 2, 4 and 9 months of age with a 3+1 schedule at 2, 3, 4 and 9 months of age, with a primary outcome of the immunogenicity of PCV10, four weeks post-primary series (Arm C vs. Arm A+B). Secondary objectives are to investigate an experimental 1+1 schedule at 2 and 6 months of age (Arm D vs. Arm A+B and Arm D vs. Arm C), and to assess the impact of a booster dose on carriage (Arm A vs. Arm F and Arm A vs. Arm B).
- How do the responses to PCV vaccination with PCV10 or PCV13 compare? The primary objective is to compare a PCV13 schedule at 2, 4 and 9 months of age with a PCV10 schedule at 2, 3, 4 and 9 months of age, with a primary outcome of the immunogenicity of PCV, four weeks post-primary series (Arm E vs. Arm A+B). Secondary objectives are to compare a PCV13 schedule at 2, 4 and 9 months of age with a PCV10 schedule at 2, 4 and 9 months of age (Arm E vs. Arm C), and to compare the responses to a single dose of PCV13 or PCV10 (Arm E vs. Arm D).
Other objectives are: to examine the decline in pneumococcal antibody levels over time (Arm B); to describe the serotype profile of transferred maternal pneumococcal antibodies (Arm A); and to describe the early rates of carriage (Arms A-F); to evaluate a single dose of PCV10 at 18 months of age (Arm F); and to evaluate the immunogenicity of Infanrix-hexa at 18 months of age in children who have received three doses of Infanrix-hexa or three doses of Quinvaxem (DTwP-Hib-HBV) in infancy.
Sample Size
The proposed infant sample size is 1200 with an allocation ratio of 3:3:5:4:5:4, resulting in arm sizes of: A=150, B=150, C=250, D=200, E=250, F=200. Sample size calculations were based on the primary outcomes for each of the two study questions: the post-primary series immunogenicity comparing 1) a two dose (Arm C) and three dose (Arm A+B) PCV10 primary series and 2) a two dose PCV13 (Arm E) and three dose PCV10 (Arm A+B) primary series. A non-inferiority margin of 10% difference in absolute risk (Arm A+B minus Arm C or Arm E), as used by regulatory authorities, is deemed clinically significant. The Farrington-Manning (1990) method was used for the sample size/power estimation, assuming one-sided 5% type I error. If the alternative hypotheses of non-inferiority are accepted for at least 7 out of 10 serotypes, overall non-inferiority will be declared. The power for testing individual serotype hypotheses was calculated using PASS Software 2002. The power for rejecting the overall null hypothesis was estimated by simulation, using a tailor-made simulation program written for implementation in Stata with 10,000 replications. A sample size of 1200 results in >99% power for rejecting the overall null hypothesis for each of the two study questions, allowing for 5% loss to follow-up at four weeks post-primary series. An additional 200 participants aged 18 months (Arm G) will be recruited at the same time as participants from Arms A-F reach 18 months of age, bringing the total sample size of the trial to 1400 participants.
Study Type
Enrollment (Actual)
Phase
- Phase 2
- Phase 3
Contacts and Locations
Study Locations
-
-
-
Ho Chi Minh City, Vietnam
- Pasteur Institute of Ho Chi Minh City
-
-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Aged between 2 months and 2 months plus 2 weeks (Arms A-F) or aged between 18 months and 18 months plus 2 weeks (Arm G)
- No significant maternal or perinatal history
- Born at or after 36 weeks gestation
- Written and signed informed consent from parent/legal guardian
- Lives within approximately 30 minutes of the commune health centre
- Family anticipates living in the study area for the next 22 months (Arms A-F) or 6 months (Arm G)
- Has received three doses of either Infanrix-hexa or Quinvaxem in infancy (Arm G)
Exclusion Criteria:
- Known allergy to any component of the vaccine
- Allergic reaction or anaphylactic reaction to any previous vaccine
- Known immunodeficiency disorder
- Known HIV-infected mother
- Known thrombocytopenia or coagulation disorder
- On immunosuppressive medication
- Administration or planned administration of any immunoglobulin or blood product since birth
- Severe birth defect requiring ongoing medical care
- Chronic or progressive disease
- Seizure disorder
- History of invasive pneumococcal, meningococcal or Haemophilus influenzae type b diseases, or tetanus, measles, pertussis or diphtheria infections
- Receipt of any 2 month vaccines through the EPI program (Arms A-F) or receipt of PCV (Arm G)
- Family plans on giving the infant Quinvaxem or oral polio vaccine (Arms A-F)
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Prevention
- Allocation: Randomized
- Interventional Model: Parallel Assignment
- Masking: Single
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Active Comparator: A: 3+1 PCV10
PCV10 administered at 2, 3, 4 and 9 months of age
|
PCV10 includes serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F and protein D is the main carrier protein
Other Names:
|
Experimental: B: 3+0 PCV10
PCV10 administered at 2, 3 and 4 months of age
|
PCV10 includes serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F and protein D is the main carrier protein
Other Names:
|
Experimental: C: 2+1 PCV10
PCV10 administered at 2, 4 and 9 months of age
|
PCV10 includes serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F and protein D is the main carrier protein
Other Names:
|
Experimental: D: 1+1 PCV10
PCV10 administered at 2 and 6 months of age
|
PCV10 includes serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F and 23F and protein D is the main carrier protein
Other Names:
|
Experimental: E: 2+1 PCV13
PCV13 administered at 2, 4 and 9 months of age
|
PCV13 includes serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F, individually linked to non-toxic diphtheria CRM197 carrier protein
Other Names:
|
No Intervention: F: control
No infant PCV vaccination.
PCV10 administered at 18 and 24 months of age
|
|
No Intervention: G: control
Recruited at 18 months of age (non-randomised).
PCV10 administered at 24 months of age
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
proportion of children with antibody concentration ≥0.35µg/mL for individual pneumococcal serotypes
Time Frame: 4 weeks post-primary series
|
The immunogenicity of PCV will be measured by ELISA in terms of serotype-specific IgG antibody concentrations.
Primary comparisons between arms will be made in terms of the proportion of children with antibody concentration ≥0.35µg/mL for the ten serotypes included in both PCVs.
An overall conclusion for between arm comparisons will be based on the rejection of at least seven out of the ten individual serotype null hypotheses.
|
4 weeks post-primary series
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
geometric mean concentration (GMC) of pneumococcal serotype-specific IgG
Time Frame: four weeks post-primary series
|
measured by ELISA
|
four weeks post-primary series
|
proportion of children with pneumococcal serotype-specific opsonisation index (OI) ≥8
Time Frame: four weeks post-primary series
|
OIs for selected pneumococcal serotypes will be measured by opsonophagocytic assay (OPA)
|
four weeks post-primary series
|
proportion of children with four-fold rise in pneumococcal serotype-specific IgG
Time Frame: change from pre-booster to four weeks post-booster
|
measured by ELISA
|
change from pre-booster to four weeks post-booster
|
proportion of children with pneumococcal serotype-specific OI ≥8
Time Frame: four weeks post-booster
|
measured by OPA
|
four weeks post-booster
|
median number of pneumococcal polysaccharide (PS)-specific memory B cells
Time Frame: four weeks post-booster
|
The number of PS-specific memory B cells will be measured by ELISPOT assays.
|
four weeks post-booster
|
median proportion of pneumococcal PS-specific memory B cells
Time Frame: four weeks post-booster
|
The proportion of PS-specific memory B cells will be measured in relation to the total number of memory B cells.
|
four weeks post-booster
|
median number of pneumococcal PS-specific memory B cells
Time Frame: 18 months of age
|
measured by ELISPOT
|
18 months of age
|
median proportion of pneumococcal PS-specific memory B cells
Time Frame: 18 months of age
|
measured by ELISPOT
|
18 months of age
|
NP carriage rate of NTHi
Time Frame: 12 months of age
|
12 months of age
|
|
NP carriage rate of vaccine-type (VT) Streptococcus pneumoniae (S. pneumoniae)
Time Frame: 12 months of age
|
12 months of age
|
|
NP carriage rate of non-VT S. pneumoniae
Time Frame: 12 months of age
|
12 months of age
|
|
NP carriage rate of H. influenzae
Time Frame: 12 months of age
|
12 months of age
|
|
Density of NP carriage of S. pneumoniae
Time Frame: 12 months of age
|
measured by quantitative real-time PCR (qPCR)
|
12 months of age
|
Density of NP carriage of H. influenzae
Time Frame: 12 months of age
|
measured by qPCR
|
12 months of age
|
NP carriage rate of NTHi
Time Frame: 18 months of age
|
18 months of age
|
|
NP carriage rate of VT S. pneumoniae
Time Frame: 18 months of age
|
18 months of age
|
|
NP carriage rate of non-VT S. pneumoniae
Time Frame: 18 months of age
|
18 months of age
|
|
NP carriage rate of H. influenzae
Time Frame: 18 months of age
|
18 months of age
|
|
NP carriage rate of VT S. pneumoniae
Time Frame: 24 months of age
|
assessed primarily by qPCR and microarray
|
24 months of age
|
Other Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
proportion of children with a measles IgG antibody titre >150mIU/mL
Time Frame: four weeks post-booster
|
measured by ELISA
|
four weeks post-booster
|
proportion of children achieving protective antibody levels to the components of Infanrix-hexa
Time Frame: four weeks post-primary series
|
Protective antibody levels are defined as: >0.1 IU/mL diphtheria IgG, >0.15 IU/mL tetanus IgG, >0.15 µg/mL Hib PRP antigen IgG, and >10 mIU/mL hepatitis B surface antigen IgG.
|
four weeks post-primary series
|
proportion of children achieving the expected booster-response antibody levels to the components of Infanrix-hexa
Time Frame: four weeks post-booster
|
The expected booster-response antibody levels are : >1.0 IU/mL diphtheria IgG, >1.0 IU/mL tetanus IgG, >1.0 µg/mL Hib PRP antigen IgG, and >1000 IU/mL hepatitis B surface antigen IgG.
|
four weeks post-booster
|
NP carriage rate of VT S. pneumoniae
Time Frame: 2 months of age
|
2 months of age
|
|
NP carriage rate of non-VT S. pneumoniae
Time Frame: 2 months of age
|
2 months of age
|
|
NP carriage rate of H. influenzae
Time Frame: 2 months of age
|
2 months of age
|
|
NP carriage rate of NTHi
Time Frame: 2 months of age
|
2 months of age
|
Collaborators and Investigators
Collaborators
Investigators
- Principal Investigator: Edward K Mulholland, MBBS, FRACP, Murdoch Childrens Research Institute
Publications and helpful links
General Publications
- Licciardi PV, Temple B, Dai VTT, Toan NT, Uyen D, Nguyen CD, Phan TV, Bright K, Marimla RA, Balloch A, Huu TN, Mulholland K. Immunogenicity of alternative ten-valent pneumococcal conjugate vaccine schedules in infants in Ho Chi Minh City, Vietnam: results from a single-blind, parallel-group, open-label, randomised, controlled trial. Lancet Infect Dis. 2021 Oct;21(10):1415-1428. doi: 10.1016/S1473-3099(20)30775-1. Epub 2021 Jun 23.
- Temple B, Nation ML, Dai VTT, Beissbarth J, Bright K, Dunne EM, Hinds J, Hoan PT, Lai J, Nguyen CD, Ortika BD, Phan TV, Thuy HNL, Toan NT, Uyen DY, Satzke C, Smith-Vaughan H, Huu TN, Mulholland K. Effect of a 2+1 schedule of ten-valent versus 13-valent pneumococcal conjugate vaccine on pneumococcal carriage: Results from a randomised controlled trial in Vietnam. Vaccine. 2021 Apr 15;39(16):2303-2310. doi: 10.1016/j.vaccine.2021.02.043. Epub 2021 Mar 19.
- Temple B, Toan NT, Dai VTT, Bright K, Licciardi PV, Marimla RA, Nguyen CD, Uyen DY, Balloch A, Huu TN, Mulholland EK. Immunogenicity and reactogenicity of ten-valent versus 13-valent pneumococcal conjugate vaccines among infants in Ho Chi Minh City, Vietnam: a randomised controlled trial. Lancet Infect Dis. 2019 May;19(5):497-509. doi: 10.1016/S1473-3099(18)30734-5. Epub 2019 Apr 8.
- Temple B, Toan NT, Uyen DY, Balloch A, Bright K, Cheung YB, Licciardi P, Nguyen CD, Phuong NTM, Satzke C, Smith-Vaughan H, Vu TQH, Huu TN, Mulholland EK. Evaluation of different infant vaccination schedules incorporating pneumococcal vaccination (The Vietnam Pneumococcal Project): protocol of a randomised controlled trial. BMJ Open. 2018 Jun 8;8(6):e019795. doi: 10.1136/bmjopen-2017-019795.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
Other Study ID Numbers
- 09/19
- 566792 (Other Grant/Funding Number: NHMRC Project Grant)
- 10PN-PD-DIT-079 (Other Identifier: GlaxoSmithKline Biologicals)
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
Clinical Trials on Pneumococcal Vaccines
-
Wyeth is now a wholly owned subsidiary of PfizerCompletedVaccines, Pneumococcal | Vaccines, Pneumococcal Conjugate Vaccine
-
Vaxcyte, Inc.CompletedPneumococcal VaccinesUnited States
-
Wyeth is now a wholly owned subsidiary of PfizerCompletedVaccines, PneumococcalGermany
-
Wyeth is now a wholly owned subsidiary of PfizerCompletedPneumococcal VaccinesUnited States
-
PfizerCompletedPneumococcal Vaccines | Pneumococcal Conjugate VaccineJapan
-
VA Sierra Nevada Health Care SystemMerck Sharp & Dohme LLCNot yet recruitingImmunosuppression | Pneumococcal Vaccines
-
Maria de Lourdes de Sousa Maia, MDNot yet recruiting
-
Vaxcyte, Inc.CompletedPneumococcal VaccinesUnited States
-
Vaxcyte, Inc.Active, not recruitingPneumococcal VaccinesUnited States
-
Inventprise Inc.PATH; Canadian Center for Vaccinology; Vaccine Evaluation Center, CanadaActive, not recruitingPneumococcal VaccinesCanada
Clinical Trials on PCV10
-
KEMRI-Wellcome Trust Collaborative Research ProgramUniversity of Colorado, Denver; GlaxoSmithKline; University of Oxford; Kenya Ministry...Unknown
-
EpicentreKenya Medical Research Institute; LSHTM; Universite Abdou Moumouni de Niamey UAMActive, not recruitingPneumococcal CarriageNiger
-
Sheba Medical CenterUnited States Agency for International Development (USAID); Maccabi Healthcare... and other collaboratorsUnknownStreptococcus PneumoniaeIsrael
-
University of Witwatersrand, South AfricaUniversity College, LondonCompleted
-
University of Witwatersrand, South AfricaUnknownPneumonia | MeningitisSouth Africa
-
Public Health EnglandImperial College London; Institute of Child HealthWithdrawnVaccination | ImmunizationUnited Kingdom
-
Papua New Guinea Institute of Medical ResearchThe University of Western AustraliaUnknownPneumonia | Sepsis | Meningitis | Otitis Media | BacteraemiaPapua New Guinea
-
Finnish Institute for Health and WelfareTurku University Hospital; GlaxoSmithKlineCompletedPneumococcal InfectionsFinland
-
London School of Hygiene and Tropical MedicineUniversity College, London; Bill and Melinda Gates Foundation; Wellcome Trust; KEMRI-Wellcome... and other collaboratorsActive, not recruitingPneumococcal Infection | Streptococcus Pneumoniae Infection | Invasive Pneumococcal Disease, Protection AgainstKenya
-
PATHCompletedPneumonia, PneumococcalKenya