Assessing optimal timing for childhood vaccines in Nepal
| ISRCTN | ISRCTN12240140 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN12240140 |
| Secondary identifying numbers | OxTREC 12-20 |
- Submission date
- 07/12/2020
- Registration date
- 07/01/2021
- Last edited
- 28/06/2024
- Recruitment status
- No longer recruiting
- Overall study status
- Completed
- Condition category
- Infections and Infestations
Plain English summary of protocol
Background and study aims
Vaccines help protect our bodies against diseases. When a child comes into contact with a disease against which they have been vaccinated, their body will be able to recognise and fight the disease. Without vaccines, children are at increased risk of catching many serious diseases.
The World Health Organization (WHO) recommends that all children receive a number of different vaccines at specific ages. One of the vaccines recommended protects against 5 diseases called diphtheria, tetanus, whooping cough, hepatitis B and Haemophilus influenzae type b (Hib) infection, which can cause pneumonia and meningitis. This vaccine is sometimes called a DTP-containing vaccine. Many countries around the world gives this vaccine at different time points and it is not known which schedule is best.
Who can participate?
Children aged 42 - 50 days
What does the study involve?
Participants will be randomly allocated to receive one of five different immunisation schedules containing the vaccine containing DTP. The timing of doses and whether a child receives two or three doses (both have been shown to be effective) will vary between trial arms. Children will then have blood tests taken to see whether they have antibodies for DTP before their booster doses.
What are the possible benefits and risks of participating?
The benefit include the opportunity to receive vaccines for Typhoid and Varicella which are not currently included as part of the Expanded Programme on Immunisation. The risks are those associated with phlebotomy (blood-drawing), and include pain and discomfort.
Where is the study run from?
The trial is run at two sites in Kathmandu, Patan Hospital and Tribhuvan University Teaching Hospital (Nepal).
When is the study starting and how long is it expected to run for?
September 2019 to January 2025
Who is funding the study?
Bill and Melinda Gates Foundation (USA).
Who is the main contact?
1. Professor Andrew Pollard (scientific), andrew.pollard@paediatrics.ox.ac.uk
2. Sarah Kelly (public), sarah.kelly@paediatrics.ox.ac.uk
3. Ella Morley (scientific), ella.morey@paediatrics.ox.ac.uk
Contact information
Scientific
Oxford Vaccine Group
Churchill Hospital
Centre for Vaccinology and Tropical Medicine
Oxford
OX3 7LE
United Kingdom
 ORCID ID |
0000-0001-7361-719X |
|---|---|
| andrew.pollard@paediatrics.ox.ac.uk |
Public
Oxford Vaccine Group
Churchill Hospital
Centre for Vaccinology and Tropical Medicine
Oxford
OX3 7LE
United Kingdom
| sarah.kelly@paediatrics.ox.ac.uk |
Scientific
Oxford Vaccine Group
Churchill Hospital
Centre for Vaccinology and Tropical Medicine
Oxford
OX3 7LE
United Kingdom
| Phone | +44 1865 611400 |
|---|---|
| ella.morey@paediatrics.ox.ac.uk |
Study information
| Study design | Multi-site randomized 5-arm non-inferiority clinical trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Randomised controlled trial |
| Study setting(s) | Hospital |
| Study type | Other |
| Participant information sheet | 39138 OptImms_PIS_V2.0_17Nov2020.pdf |
| Scientific title | Optimising diptheria, tetanus toxoids and pertussis (DTP)-containing vaccine infant immunisation schedules in Nepal |
| Study acronym | OptImms-Nepal |
| Study objectives | The aim of this project is to identify an optimal immunisation schedule for infants by comparing the immunogenicity of 5 different immunisation schedules including the current WHO recommended “accelerated” schedule, investigating the effect of number, spacing and timing of doses of routine infant vaccines in the different schedules. Each schedule has been selected based on positive immunogenicity data from previous research. We will use the WHO recommended EPI schedule as the reference schedule. |
| Ethics approval(s) | 1. Approved 20/09/2020, Nepal Health Research Council ethics committee (Ethical Review M&E Section, Ramshah Path, Kathmandu, Nepal; +977-1-4254220; approval@nhrc.gov.np), ref: 95/2020 P 2. Approved 28/02/2020, Patan Institutional Review Committee (Patan Academy of Health Sciences IRC, Patan Academy of Health Sciences, Lagankhel, Lalitpur, Nepal; +977-1-5545112; irc-pahs@pahs.edu.np), ref: none provided 3. Approved 17/12/2020, OxTREC (Research Services, University Of Oxford, University Offices, Oxford, OX1 2JD, UK; +44 (0)1865 282585; oxtrec@admin.ox.ac.uk), ref: 12-20 |
| Health condition(s) or problem(s) studied | Optimising diphtheria, tetanus toxoids and pertussis (DTP) immunity through infant immunisation schedules in Nepal |
| Intervention | Participants will be recruited across 2 sites; at Patan Hospital and the Tribhuvan University Teaching Hospital (TUTH), both in Kathmandu. Recruitment and randomisation will take place at the time of attendance for the child’s 6-week immunisations. Participants will be enrolled at immunisation clinics linked to both health facilities. The study will be open-label for participants and clinical trial staff but blinded for laboratory staff. The study will assess the immunogenicity of the current DTP-Hib-HBV-containing vaccine administered in 5 different immunisation schedules Following informed parent/legal guardian consent, enrolled infants will be randomly allocated to one of 5 main vaccination groups, and one of four booster dose schedule. The first two schedules (Groups 1 and 2) are two 'Early Pertussis' schedules and correspond to the WHO standard, and a modified, EPI schedules (two rather than 3 early doses). Group 3 will be vaccinated according to the OptImms-proposed schedule (which is also the E-CDC recommended schedule). Groups 4 and 5 correspond to the programs currently in use in the UK and Americas. Blood tests will be performed at standard time points considered necessary for evaluation of vaccine responses. The primary outcome Pertussis IgG immune response will be measured at the pre-booster dose time point, i.e. at 9 or 12 months of age. Children will receive varicella and typhoid vaccination as a benefit of participation in the study. Vaccinations will occur over a 15-month time period, with a 24-month follow-up period for all study arms. Randomisation will occur electronically via a plugin on RedCAP. |
| Intervention type | Biological/Vaccine |
| Pharmaceutical study type(s) | |
| Phase | Not Applicable |
| Drug / device / biological / vaccine name(s) | DTwP-HBV-Hib vaccine (Serum Institute of India), Oral Polio Vaccine – Bi-valent, Injectable Polio Vaccine, Pneumococcal conjugate vaccine (Synflorix), Measles Rubella vaccine, Typhoid conjugate vaccine (Typbar-TCV®, Bharat-Biotech.), Japanese encephalitis vaccine (JE), Varicella vaccine - TBC, Rotavirus vaccine (Rotarix) |
| Primary outcome measure | Pertussis IgG immune response measured in Multiplexed Immune Assay (MIA)-5 plex at the pre-booster dose time point, i.e. at age 9 or 12 months |
| Secondary outcome measures | Current secondary outcome measures as of 28/06/2024: 1. Pertussis IgG immune response measured in an MIA 4-plex at the post-prime dose time point, (i.e. at age 10, 12, 14 or 16 weeks), 1-month post-primary series (i.e. age 18, 20, or 28 weeks), pre-booster timepoint (i.e. at age 9 or 12 months), post-booster timepoint (i.e. at age 10 or 13 months) and at age 24 months. 2. Diphtheria IgG immune response measured on an MIA 5-plex using in-house reference sera calibrated against the WHO standard, at age 14 or 16 weeks, 1-month post-primary series (i.e. age 18, 20, or 28 weeks), pre-booster timepoint (i.e. at age 9 or 12 months), post-booster timepoint (i.e. at age 10 or 13 months) and at age 24 months. The MIA 5-plex uses in-house reference sera as standard, which are calibrated against the WHO standard (van Gageldonk et al.,2008; van Gageldonk et al., 2011) 3. Tetanus IgG immune response measured on an MIA 5-plex using in-house reference sera calibrated against the WHO standard, at age 14 or 16 weeks, 1-month post-primary series (i.e. age 18, 20, or 28 weeks), pre-booster timepoint (i.e. at age 9 or 12 months), post-booster timepoint (i.e. at age 10 or 13 months) and at age 24 months 4. Hep B virus S antigen, mIU/ml measured using an assay currently under development at the Dutch Institute of Public Health, at age 14 or 16 weeks, 1-month post-primary series (i.e. age 18, 20, or 28 weeks), pre-booster timepoint (i.e. at age 9 or 12 months), post-booster timepoint (i.e. at age 10 or 13 months) and at age 24 months 5. PRP (Hib) IgG immune response measured using a multiplexed immune assay, at age 14 or 16 weeks, 1-month post-primary series (i.e. age 18, 20, or 28 weeks), pre-booster timepoint (i.e. at age 9 or 12 months), post-booster timepoint (i.e. at age 10 or 13 months) and at age 24 months. 6. Serotype specific anti-pneumococcal IgG measured in an MIA x-plex in 1a, 2, 3 and 4 blood samples in all arms and booster groups. IVIG that has been calibrated against the 89-S serum is used as reference serum (Elberse et al., 2010). 7. Polio type I-III IgG immune response measured using a 3-plex inhibition assay, at the pre-booster timepoint (i.e. at age 9 or 12 months) and at age 24 months (Schepp et al., 2017) 8. Typhoid vi-IgG will be measured using an assay currently under development at the Dutch Institute of Public Health, in blood 2 in Arm 5 at 28 weeks, in blood 3 & 4 in booster groups 2, 3, and 4 (12 and 24 months). 9. Serum volumes permitting JE response will be measured using plaque reduction neutralization titre (PRNT) assays, by ELISA and/or indirect fluorescent antibody test (IFA) at age 13 and 24 months. Exploratory outcome measures: 10. Measles IgG antibody concentrations are measured in an MIA 4-plex at all time points up to the first measles and rubella vaccine dose, if possible given blood sample volumes 11. For measles only, serum volumes permitting, serum will also be analysed using plaque reduction neutralization titre (PRNT) assay at the same timepoints 12. Rubella IgG response measured in an MIA 4-plex at all time points up to the first measles and rubella vaccine dose, if possible given blood sample volume As standard, the international rubella standard (RUBI-1-94) is used, which has been calibrated against the international reference serum for measles (Smits et al.,2012) Measle and rubella titres will only be measured prior to administration of the first MR vaccine 13. Rotavirus IgG will be measured using MIA 4-plex in all blood samples of all arms and booster groups. 14. SARS-COV2 IgG and RAV IgG will be measured using MIA 4-plex in all blood samples of all arms and booster groups. Safety outcome measures: 15. Descriptive summary of self-reported local and systemic vaccine reactions occurring within 7 days post-vaccination collected verbally at each point of contact, using Brighton Collaboration case definitions. _____ Previous secondary outcome measures: 1. Pertussis IgG immune response measured in an MIA 4-plex at the post-prime dose time point, (i.e. at age 10, 12, 14 or 16 weeks), 1-month post-primary series (i.e. age 18, 20, or 28 weeks), pre-booster timepoint (i.e. at age 9 or 12 months), post-booster timepoint (i.e. at age 10 or 13 months) and at age 24 months. 2. Diphtheria IgG immune response measured on an MIA 5-plex using in-house reference sera calibrated against the WHO standard, at age 14 or 16 weeks, 1-month post-primary series (i.e. age 18, 20, or 28 weeks), pre-booster timepoint (i.e. at age 9 or 12 months), post-booster timepoint (i.e. at age 10 or 13 months) and at age 24 months. The MIA 5-plex uses in-house reference sera as standard, which are calibrated against the WHO standard (van Gageldonk et al.,2008; van Gageldonk et al., 2011) 3. Tetanus IgG immune response measured on an MIA 5-plex using in-house reference sera calibrated against the WHO standard, at age 14 or 16 weeks, 1-month post-primary series (i.e. age 18, 20, or 28 weeks), pre-booster timepoint (i.e. at age 9 or 12 months), post-booster timepoint (i.e. at age 10 or 13 months) and at age 24 months 4. Hep B virus S antigen, mIU/ml measured using an assay currently under development at the Dutch Institute of Public Health, at age 14 or 16 weeks, 1-month post-primary series (i.e. age 18, 20, or 28 weeks), pre-booster timepoint (i.e. at age 9 or 12 months), post-booster timepoint (i.e. at age 10 or 13 months) and at age 24 months 5. PRP (Hib) IgG immune response measured using a multiplexed immune assay, at age 14 or 16 weeks, 1-month post-primary series (i.e. age 18, 20, or 28 weeks), pre-booster timepoint (i.e. at age 9 or 12 months), post-booster timepoint (i.e. at age 10 or 13 months) and at age 24 months. 6. Serotype specific anti-pneumococcal IgG measured in an MIA x-plex, at the pre-booster timepoint (i.e. at age 9 months), post-booster timepoint (i.e. at age 10 months) and at age 24 months. IVIG that has been calibrated against the 89-S serum is used as reference serum (Elberse et al., 2010) 7. Polio type I-III IgG immune response measured using a 3-plex inhibition assay, at the pre-booster timepoint (i.e. at age 9 or 12 months) and at age 24 months (Schepp et al., 2017) 8. Typhoid vi-IgG will be measured using an assay currently under development at the Dutch Institute of Public Health, at age 13 and 24 months 9. Serum volumes permitting JE response will be measured using plaque reduction neutralization titre (PRNT) assays, by ELISA and/or indirect fluorescent antibody test (IFA) at age 13 and 24 months. Exploratory outcome measures: 10. Measles IgG antibody concentrations are measured in an MIA 4-plex at all time points up to the first measles and rubella vaccine dose, if possible given blood sample volumes 11. For measles only, serum volumes permitting, serum will also be analysed using plaque reduction neutralization titre (PRNT) assay at the same timepoints 12. Rubella IgG response measured in an MIA 4-plex at all time points up to the first measles and rubella vaccine dose, if possible given blood sample volume As standard, the international rubella standard (RUBI-1-94) is used, which has been calibrated against the international reference serum for measles (Smits et al.,2012) Measle and rubella titres will only be measured prior to administration of the first MR vaccine Safety outcome measures: 13. Descriptive summary of self-reported local and systemic vaccine reactions occurring within 7 days post-vaccination collected verbally at each point of contact, using Brighton Collaboration case definitions. |
| Overall study start date | 01/09/2019 |
| Completion date | 31/07/2025 |
Eligibility
| Participant type(s) | Healthy volunteer |
|---|---|
| Age group | Child |
| Lower age limit | 42 Days |
| Upper age limit | 50 Days |
| Sex | Both |
| Target number of participants | 956 |
| Total final enrolment | 956 |
| Key inclusion criteria | 1. Age of 42 - 50 days old at time of first visit 2. Generally healthy as determined by a medical history and examination 3. Resident in the Kathmandu Valley, Nepal study area and planning to remain in the study area for the 2 years of the study |
| Key exclusion criteria | 1. Born at less than 36 weeks gestation 2. Birth weight <2.5 kg, or a current weight of <3 kg at 6 weeks of age, as determined by a medical professional 3. Prior receipt of any vaccination except Polio, Hepatitis B, or BCG 4. Planned administration of vaccines other than the study vaccines (with the exception of vaccines against rotavirus, hepatitis A & B, inactivated influenza and varicella, which can be administered 14 days before or after study vaccines; polio and measles/rubella vaccines as part of national campaigns; and BCG vaccines which will be administered when indicated by national programme) 5. Parents who plan to move out of the geographical study area 6. Concurrently participating in another clinical study, which includes blood draws or IMPs, at any time during the study period, in which the participant has been or will be exposed to an investigational or a non-investigational product (pharmaceutical product or device) 7. Any major congenital defects, serious chronic illness, significant disease, disorder, family history or diagnosis of immunosuppressive condition, or medical treatments which, in the opinion of the Investigator, may either put the participants at risk because of participation in the study, or may influence the result of the study, or the participant’s ability to participate in the study 8. Use of any investigational or non-registered product (drug or vaccine) within 30 days preceding the vaccination, or planned use during the study period; Known allergy to any vaccine components |
| Date of first enrolment | 05/12/2021 |
| Date of final enrolment | 27/02/2023 |
Locations
Countries of recruitment
- Nepal
Study participating centres
Kathmandu
44700
Nepal
Dept of Child Health
Maharajgunj Road
Kathmandu
44600
Nepal
Sponsor information
University/education
Churchill Centre for Vaccinology and Tropical Medicine
Oxford
OX3 7LE
England
United Kingdom
| Phone | +44 (0)1865 611400 |
|---|---|
| info@ovg.ox.ac.uk | |
| Website | https://www.ox.ac.uk |
"ROR" |
https://ror.org/052gg0110 |
Funders
Funder type
Charity
Government organisation / Trusts, charities, foundations (both public and private)
- Alternative name(s)
- Bill & Melinda Gates Foundation, Gates Foundation, BMGF, B&MGF, GF
- Location
- United States of America
Results and Publications
| Intention to publish date | 31/07/2025 |
|---|---|
| Individual participant data (IPD) Intention to share | No |
| IPD sharing plan summary | Not expected to be made available |
| Publication and dissemination plan | Planned publication in a high-impact peer-reviewed journal. End of study report intended to be available for the funder 30/5/2024. |
| IPD sharing plan | The datasets generated during and/or analysed during the current study are not expected to be made available due to their size, but analyses will be published with summary data. |
Study outputs
| Output type | Details | Date created | Date added | Peer reviewed? | Patient-facing? |
|---|---|---|---|---|---|
| Participant information sheet | version 2.0 | 17/11/2020 | 11/02/2022 | No | Yes |
| Protocol article | 21/07/2023 | 24/07/2023 | Yes | No |
Additional files
Editorial Notes
28/06/2024: The following changes were made to the trial record:
1. The overall end date was changed from 31/01/2025 to 31/07/2025.
2. The vaccine name "Rotavirus vaccine (Rotarix)" was added to the Drug/device/biological/vaccine name(s)
3. The secondary outcome measures were changed.
15/03/2024: The following changes were made:
1. The intention to publish date was changed from 01/01/2025 to 31/07/2025.
2. The overall study end date was changed from 13/03/2024 to 31/01/2025.
24/07/2023: Publication reference added.
17/03/2023: The recruitment end date was changed from 31/03/2023 to 27/02/2023.
15/02/2023: The recruitment end date was changed from 28/02/2023 to 31/03/2023.
14/12/2022: The following changes were made to the trial record:
1. The recruitment end date was changed from 31/12/2022 to 28/02/2023.
2. A scientific contact was added.
11/02/2022: The following changes were made to the trial record:
1. The recruitment end date was changed from 10/02/2022 to 31/12/2022.
2. The participant information sheet was uploaded as an additional file.
07/12/2021: The recruitment start date was changed from 01/12/2021 to 05/12/2021.
01/10/2021: The recruitment start date was changed from 15/09/2021 to 01/12/2021.
19/07/2021: The recruitment start date was changed from 16/06/2021 to 15/09/2021.
14/06/2021: The following changes were made to the trial record:
1. The overall start date was changed from 24/06/2019 to 01/09/2019.
2. The overall end date was changed from 13/02/2024 to 13/03/2024.
3. The plain English summary was updated to reflect these changes.
19/04/2021: The recruitment start date was changed from 16/04/2021 to 16/06/2021.
15/03/2021: The following changes were made to the trial record:
1. The ethics approval (3) was added.
2. The recruitment start date was changed from 16/03/2021 to 16/04/2021.
21/12/2020: Trial's existence confirmed by the Nepal Health Research Council.
