Can giving adolescents preventive treatment for malaria, before vaccination, improve immune responses to these vaccines?

ISRCTN	ISRCTN62041885
DOI	https://doi.org/10.1186/ISRCTN62041885
ClinicalTrials.gov (NCT)	Nil known
Clinical Trials Information System (CTIS)	Nil known
Protocol serial number	1.0
Sponsor	London School of Hygiene and Tropical Medicine
Funder	Medical Research Council

Submission date: 11/07/2019
Registration date: 23/08/2019
Last edited: 21/10/2024

Recruitment status: No longer recruiting
Overall study status: Completed
Condition category: Other

Prospectively registered

Protocol

Statistical analysis plan

Results

Individual participant data

Plain English summary of protocol

Background and study aims
Infectious diseases remain very common in low-income countries (LICs). Vaccines protect people against infectious diseases, but several important vaccines do not work as well in LICs compared to high-income countries (HICs) and in rural, compared to urban, settings. One possible reason for this might be that people living in these settings are more likely to have malaria infections. Malaria infections impact on the immune system and may change an infected person’s response to a vaccine. This study aims to investigate whether giving adolescents presumptive treatment for malaria, before vaccination, will lead to a better immune response to these vaccines.

Who can participate?
Healthy volunteer children (aged 9-17 years, with no gender restriction) from selected schools located in Jinja district, Uganda. Malaria is very common in this area.

What does the study involve?
Children are randomly allocated to receive either monthly dihydroartemisinin-piperaquine (DP), a drug that has been shown to reduce the risk of getting malaria, or a monthly (inactive) placebo. They are then vaccinated against tuberculosis, yellow fever, human papilloma virus (which can cause cancer of the cervix [or opening] of the womb, and other cancers), typhoid and tetanus. Four weeks after vaccination, their immune responses to each vaccine are measured.

What are the possible benefits and risks of participating?
Participants will benefit from receiving the vaccines and treatments as they are expected to provide protection against infectious diseases. Participants and their families, schools and communities will benefit from improved understanding of malaria and vaccines. No major risks to the participants are anticipated since all the treatments and vaccines to be given are licensed and known to be safe. The main risk to participants will be time lost from school work, and the researchers will work with teachers and parents to minimise this. Very rarely, a vaccine may cause a severe allergic reaction, so individuals who have previously suffered a possible allergic reaction to drugs or vaccines or their components will not be included in the study.

Where is the study run from?
The host institution for the study will be the Medical Research Council/Uganda Virus Research Institute and London School of Hygiene and Tropical Medicine Uganda Research Unit (MRC/UVRI & LSHTM), Entebbe, Uganda.

When is the study starting and how long is it expected to run for?
May 2018 to April 2022

Who is funding the study?
Medical Research Council (UK)

Who is the main contact?
Prof. Alison Elliott
alison.elliott@lshtm.ac.uk

Contact information

Dr Emily Webb
Public

London School of Hygiene and Tropical Medicine
Keppel St
London
WC1E 7HT
United Kingdom

ORCID ID	0000-0002-4019-7456
Phone	+44 (0)207 9272012
Email	emily.webb@lshtm.ac.uk

Prof Alison Elliott
Scientific

MRC/UVRI and LSHTM Uganda Research Unit
UVRI P.O.Box 49 Entebbe
Entebbe
--
Uganda

ORCID ID	0000-0003-2818-9549
Phone	+44 (0)207 6368636
Email	alison.elliott@mrcuganda.org

Study information

Primary study design	Interventional
Study design	Single-centre individually randomized double-blind placebo-controlled two parallel-group trial
Secondary study design	Randomised controlled trial
Study type	Participant information sheet
Scientific title	The effect of intermittent preventive treatment for malaria with dihydroartemisinin-piperaquine on response to vaccines among rural Ugandan adolescents
Study acronym	POPVAC B
Study objectives	Malaria infection suppresses responses to unrelated vaccines, and this effect can be reversed, at least in part, by monthly preventive treatment of malaria in schools in high transmission settings
Ethics approval(s)	1. Approved 05/06/2019, London School of Hygiene and Tropical Medicine Ethics Committee (LSHTM, Keppel St, London WC1E 7HT; ethics@lshtm.ac.uk; +44 (0)207 6368636), ref: 16033. 2. Approved 06/09/2018, Uganda Virus Research Institute Research Ethics Committee (The REC secretariat, Uganda Virus Research Institute, P.O Box 49, Entebbe, Uganda; +245 (0)414321962; fayebazibwe@uvri.go.ug or directoruvri@uvri.go.ug), ref: GC/127/18/09/681. 3. Approved 07/05/2019, Uganda National Council for Science and Technology (Plot 6, Kimera Road, Ntinda, P.O. Box 6884, Kampala, Uganda; +256 (0)414 705500; info@uncst.go.ug), ref: HS 2487. 4. Uganda National Drug Authority (Secretariat office Kampala, Plot 19 Lumumba Avenue, P.O. Box 23096, Kampala, Uganda; +245 (0) 417 788 100; ndaug@nda.or.ug), ref: CTC0117/2020
Health condition(s) or problem(s) studied	Vaccine responses
Intervention	A randomisation code will be generated by the trial statistician using a randomly permuted block size. Participants will be allocated in a 1:1 ratio to receive either (DP) or placebo. Participants in the DP arm will receive two DP doses, one month apart, prior to immunisation followed by monthly DP doses for one year thereafter. Each dose will comprise treatment once a day for three consecutive days. DP will be dosed using weight-based guidelines targeting a total dose of 6.4 mg/kg dihydroartemisinin and 51.2 mg/kg piperaquine. Participants in the placebo arm will receive doses of placebo at the same time points as the DP arm receive DP, i.e. two doses of placebo, 1 month apart prior to immunisation followed by monthly placebo for one year thereafter. Both DP and placebo will be taken orally. As yet, routine preventive malaria treatment in schools is not Uganda Ministry of Health policy.
Intervention type	Drug
Phase	Not Applicable
Drug / device / biological / vaccine name(s)	Dihydroartemisinin-piperaquine
Primary outcome measure(s)	1. BCG: BCG-specific IFN-gamma ELIspot response 8 weeks post BCG immunisation 2. YF-17D: neutralising antibody titres (plaque-reduction neutralisation test) at 4 weeks post YF immunisation 3. Ty21a: Salmonella typhi lipopolysaccharide (LPS)-specific immunoglobulin(Ig)G concentration at 4 weeks post Ty21a immunisation 4. HPV: IgG specific for L1-proteins of HPV-16/18 at 4 weeks post HPV priming immunisation 5. Td: tetanus and diphtheria toxoid-specific IgG concentration at 4 weeks post Td immunisation
Key secondary outcome measure(s)	1. Protective immunity is measured using proportions with protective neutralising antibody (YF); protective IgG levels (TT); seroconversion rates (Ty21a) at 4 weeks post the corresponding immunisation 2. Response waning is measured using primary outcome measures (all vaccines) repeated at week 52, and area-under-the curve (AUC) analyses 3. Priming versus boosting is measured using effects on priming versus boosting will be examined for HPV only, comparing outcomes 4 weeks after the first, and 4 weeks after the second vaccine dose 4. Current malaria infection status and intensity is assessed retrospectively by PCR on stored samples collected on immunisation days and at week 52.
Completion date	30/04/2022

Eligibility

Participant type(s)	Healthy volunteer
Age group	Child
Lower age limit	9 Years
Upper age limit	17 Years
Sex	All
Target sample size at registration	640
Total final enrolment	341
Key inclusion criteria	1. Attending the selected school and planning to continue to attend the school for the duration of the study 2. Aged 9 to 17 years and enrolled in primary 1 to 6 3. Written informed assent by participant and consent by parent or guardian 4. Agree to avoid pregnancy for the duration of the trial (female only) 5. Willing to provide locator information and to be contacted during the course of the trial 6. Able and willing (in the investigator’s opinion) to comply with all the study requirements
Key exclusion criteria	1. Clinically significant history of immunodeficiency (including HIV), cancer, cardiovascular disease, gastrointestinal disease, liver disease, renal disease, endocrine disorder and neurological illnesses. 2. Moderate or severe acute illness characterised any of the following symptoms: fever, impaired consciousness, convulsions, difficulty in breathing, vomiting; or as determined by the attending project clinician. 3. Family history of sudden death attributable to a heart condition in a first-degree relative 4. Family history of long QT syndrome 5. Know congenital prolongation of the QTc interval 6. History of known heart disease or fainting 7. Known allergy or history of adverse reaction to DP or to artemether-lumefantrine 8. History of serious psychiatric condition or disorder 9. Previous immunisation with Yellow Fever (YF), oral typhoid or Human Papillomavirus (HPV) vaccine; previous immunisation with BCG or Tetanus and diphtheria vaccine (Td) at age >5 years 10. Concurrent oral or systemic steroid medication or the concurrent use of other immunosuppressive agents within 2 months prior to enrolment 11. Current use of medications known to prolong the QT interval (Table 2) 12. History of an allergic reaction to immunisation or any allergy likely to be exacerbated by any component of the study vaccines including egg or chicken proteins 13. Tendency to develop keloid scars 14. Haemoglobin less than 80g/L 15. Positive HIV serology 16. Positive pregnancy test 17. Female currently lactating, confirmed pregnancy or intention to become pregnant during the trial period 18. Use of an investigational medicinal product or non-registered drug, live vaccine, or medical device other than the study vaccines for 30 days prior to dosing with the study vaccine, or planned use during the study period 19. Administration of immunoglobulins and/or any blood products within the three months preceding the planned trial immunisation date.
Date of first enrolment	01/04/2021
Date of final enrolment	31/05/2021

Locations

Countries of recruitment

Uganda

Study participating centre

MRC/UVRI and LSHTM Uganda Research Unit

Plot 51-59 Nakiwogo Road
Entebbe - Uganda
--
Uganda

Results and Publications

Individual participant data (IPD) Intention to share	Yes
IPD sharing plan summary	Stored in non-publicly available repository
IPD sharing plan	The de-identified individual participant data that underlie the results reported in journal articles will be stored in a non-publically available repository (LSHTM Data Compass), together with a data dictionary. This will be done at the time of publication. Each dataset will be allocated a unique digital object identifier (DOI). Researchers who would like to access the data may submit a request through LSHTM Data Compass, detailing the data requested, the intended use for the data, and evidence of relevant experience and other information to support the request. The request will be reviewed by the Principal Investigator in consultation with the POPVAC Steering Committee, with oversight from the UVRI and LSHTM ethics committees. In line with the MRC policy on Data Sharing, there will have to be a good reason for turning down a request. Patient Information Sheets and consent forms specifically referenced making anonymised data available and this has been approved by the relevant ethics committees. Researchers given access to the data will sign data sharing agreements which will restrict the use to answering pre-specified research questions.

Study outputs

Output type	Details	Date created	Date added	Peer reviewed?	Patient-facing?
Results article		01/11/2024	21/10/2024	Yes	No
Protocol article		16/02/2021	16/08/2022	Yes	No
Protocol article		16/02/2021	03/05/2024	Yes	No
Participant information sheet	Participant information sheet	11/11/2025	11/11/2025	No	Yes
Statistical Analysis Plan	version 1.0	12/10/2022	25/10/2022	No	No

Additional files

ISRCTN62041885_SAP_V1.0_12Oct22.pdf: Statistical Analysis Plan

Editorial Notes

21/10/2024: Publication reference added.
03/05/2024: Publication reference added.
01/05/2024: The intention to publish date was changed from 31/12/2023 to 01/07/2024.
04/04/2023: The intention to publish date was changed from 30/04/2023 to 31/12/2023.
25/10/2022: Statistical analysis plan uploaded. Total final enrolment added.
16/08/2022: Uploaded protocol (not peer-reviewed) as an additional file.
02/02/2021: The following changes were made to the trial record:
1. The recruitment start date was changed from 01/02/2021 to 01/04/2021.
2. The recruitment end date was changed from 31/03/2021 to 31/05/2021.
11/09/2020: Internal review.
05/08/2020: The following changes were made to the trial record:
1. The recruitment start date has been changed from 01/06/2020 to 01/02/2021.
2. The recruitment end date has been changed from 01/07/2020 to 31/03/2021.
3. The reference number has been added for the ethics approval 4.
10/06/2020: The following changes were made to the trial record:
1. The publication and dissemination plan was updated and the IPD sharing statement was added.
2. The participant level data was changed from "To be made available at a later date" to "Stored in repository".
31/07/2019: Trial's existence confirmed by the Uganda Virus Research Institute Research Ethics Committee.