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The Effect of Intermittent Preventive Treatment for Malaria with Dihydroartemisinin-Piperaquine on Vaccine-Specific Responses Among Schoolchildren in Rural Uganda: Results of the POPVAC B Randomised, Controlled Trial

29 Pages Posted: 21 Dec 2023

See all articles by Ludoviko Zirimenya

Ludoviko Zirimenya

Medical Research Council/Uganda Virus Research Institute & London School of Hygiene and Tropical Medicine (MRC/UVRI & LSHTM), Uganda Research Unit

Agnes Natukunda

Medical Research Council/Uganda Virus Research Institute & London School of Hygiene and Tropical Medicine (MRC/UVRI & LSHTM), Uganda Research Unit

Jacent Nassuuna

Medical Research Council/Uganda Virus Research Institute & London School of Hygiene and Tropical Medicine (MRC/UVRI & LSHTM), Uganda Research Unit

Gyaviira Nkurunungi

Medical Research Council/Uganda Virus Research Institute & London School of Hygiene and Tropical Medicine (MRC/UVRI & LSHTM), Uganda Research Unit; London School of Hygiene & Tropical Medicine

Christopher Zziwa

Medical Research Council/Uganda Virus Research Institute & London School of Hygiene and Tropical Medicine (MRC/UVRI & LSHTM), Uganda Research Unit

Caroline Ninsiima

Medical Research Council/Uganda Virus Research Institute & London School of Hygiene and Tropical Medicine (MRC/UVRI & LSHTM), Uganda Research Unit

Christine Kukundakwe

Medical Research Council/Uganda Virus Research Institute & London School of Hygiene and Tropical Medicine (MRC/UVRI & LSHTM), Uganda Research Unit

Christine Musoke Nankabirwa

Medical Research Council/Uganda Virus Research Institute & London School of Hygiene and Tropical Medicine (MRC/UVRI & LSHTM), Uganda Research Unit

Charity Katushabe

affiliation not provided to SSRN

Loyce Kisakye Namusobya

Medical Research Council/Uganda Virus Research Institute & London School of Hygiene and Tropical Medicine (MRC/UVRI & LSHTM), Uganda Research Unit

Gloria Oduru

Medical Research Council/Uganda Virus Research Institute & London School of Hygiene and Tropical Medicine (MRC/UVRI & LSHTM), Uganda Research Unit

Grace Kabami

Medical Research Council/Uganda Virus Research Institute & London School of Hygiene and Tropical Medicine (MRC/UVRI & LSHTM), Uganda Research Unit

Joel Kabali

Medical Research Council/Uganda Virus Research Institute & London School of Hygiene and Tropical Medicine (MRC/UVRI & LSHTM), Uganda Research Unit

John Kayiwa

Government of Uganda - Uganda Virus Research Institute (UVRI)

Joyce Kabagenyi

Medical Research Council/Uganda Virus Research Institute & London School of Hygiene and Tropical Medicine (MRC/UVRI & LSHTM), Uganda Research Unit

Govert J. van Dam

Leiden University - Leiden University Medical Center (LUMC)

Paul Corstjens

Leiden University - Leiden University Medical Center (LUMC)

Stephen Cose

Medical Research Council/Uganda Virus Research Institute & London School of Hygiene and Tropical Medicine (MRC/UVRI & LSHTM), Uganda Research Unit

Anne Wajja

Medical Research Council/Uganda Virus Research Institute & London School of Hygiene and Tropical Medicine (MRC/UVRI & LSHTM), Uganda Research Unit

Sarah Staedke

London School of Hygiene & Tropical Medicine - Department of Clinical Research

Pontiano Kaleebu

London School of Hygiene & Tropical Medicine - Uganda Research Unit

Alison Elliott

London School of Hygiene and Tropical Medicine - Department of Clinical Research

Emily Webb

London School of Hygiene & Tropical Medicine - MRC International Statistics and Epidemiology Group

More...

Abstract

Background: Several important vaccines differ in immunogenicity and efficacy between populations. We hypothesized that malaria suppresses responses to unrelated vaccines and that this effect can be reversed, at least partially, by monthly malaria intermittent preventive treatment (IPT) in high-transmission settings. 

Methods: We conducted an individually randomised, double-blind, placebo-controlled trial of the effect of malaria IPT with dihydroartemisinin-piperaquine (DP) on vaccine responses among schoolchildren (9-17 years) in Jinja district, Uganda (registration ISRCTN62041885). Participants were recruited from two schools and lacked exposure to vaccines of interest after five years of age (except HPV). Computer-generated 1:1 randomisation was implemented in REDCap. Three-day courses of DP (dosage by weight), or placebo were administered monthly, including twice before first vaccination. Participants received BCG [week zero], yellow fever, oral typhoid (Ty21a), HPV-prime [week 4], and HPV-boost, tetanus/diphtheria [week 28]. Primary outcomes were vaccine responses at week 8 and, for tetanus/diphtheria, week 52. Malaria parasite prevalence at enrolment and during follow up was determined retrospectively by PCR. 

Results: Between 25th May and 14th July 2021, we enrolled 341 participants, 44% male, and randomised 170 to DP, 171 to placebo; 145 (85%) and 140 (82%) participants were followed to week 52, respectively. At enrolment, 60% were malaria positive; this reduced to ≤6.2% at all follow-up visits in the DP arm. There was no effect of DP versus placebo on primary outcomes: BCG-specific IFN-γ GMR 0.99 (95%CI 0.77-1.28); yellow fever neutralising antibody 1.18 (0.91-1.54); IgG to Ty21a 1.04 (0.82-1.32), HPV-16 0.98 (0.58-1.64), HPV-18 0.93 (0.59-1.46), tetanus 1.12 (0.84-1.48), diphtheria 0.97 (0.83-1.12). There was some evidence that DP reduced waning of the yellow fever response. 

Interpretation: Intermittent preventive treatment with DP safely and effectively reduced malaria prevalence but did not improve peak vaccine responses. Possible longer-term effects on response waning should be further explored.

Trial Registration: This trial is registered with ISRCTN registry, ISRCTN62041885.

Funding: The POPVAC programme of work was supported primarily by the Medical Research Council (MRC) of the United Kingdom (grant # MR/R02118X/1 and MC_PC_21034). This award is jointly funded by the UK Medical Research Council (MRC) and the UK Foreign Commonwealth and Development Office (FCDO) under the MRC/FCDO Concordat agreement and is also part of the EDCTP2 programme supported by the European Union. SC and JN were also supported by the Makerere University – Uganda Virus Research Institute Centre of Excellence for Infection and Immunity Research and Training (MUII-plus), funded under the DELTAS Africa Initiative (grant # DEL-15-004). The DELTAS Africa Initiative was an independent funding scheme of the African Academy of Sciences, Alliance for Accelerating Excellence in Science in Africa and supported by the New Partnership for Africa’s Development Planning and Coordinating Agency with funding from the Wellcome Trust and the UK Government. AN, LZ, ELW and AME received additional support from the UK National Institute of Health and Care Research (NIHR; grant # NIHR134531) using UK aid from the UK Government to support global health research; GN received additional support from the EDCTP2 programme supported by the European Union (grant # TMA2019PF-2707) and from the Wellcome Trust (grant # 224263/Z/21/Z); ELW also received funding through the International Statistics and Epidemiology Group (ISEG) from the UK MRC grant # MR/R010161/1. The work was conducted at the MRC/UVRI and LSHTM Uganda Research Unit; both I-SEG and the MRC/UVRI and LSHTM Uganda Research Unit are jointly funded by the UK MRC part of UK Research and Innovation and the UK Foreign, Commonwealth and Development Office (FCDO) under the MRC/FCDO Concordat agreement and are also part of the EDCTP2 programme supported by the European Union.

Declaration of Interest: All authors declare no competing interests.

Ethical Approval: All participants and their parents or guardians gave written, informed assent and consent, espectively. Ethics approval was granted by the Uganda Virus Research Institute (reference: GC/127/18/09/681), the London School of Hygiene and Tropical Medicine (reference: 16033), the Uganda National Council for Science and Technology (reference: HS2487) and the Uganda National Drug Authority (reference: CTC 0117/2020). Independent trial steering and data safety monitoring committees oversaw the trial.

Keywords: Plasmodium falciparum, dihydroartemisinin-piperaquine, vaccine response, BCG, yellow fever, typhoid, HPV, tetanus, diphtheria, randomised controlled trial

Suggested Citation

Zirimenya, Ludoviko and Natukunda, Agnes and Nassuuna, Jacent and Nkurunungi, Gyaviira and Zziwa, Christopher and Ninsiima, Caroline and Kukundakwe, Christine and Nankabirwa, Christine Musoke and Katushabe, Charity and Namusobya, Loyce Kisakye and Oduru, Gloria and Kabami, Grace and Kabali, Joel and Kayiwa, John and Kabagenyi, Joyce and van Dam, Govert J. and Corstjens, Paul and Cose, Stephen and Wajja, Anne and Staedke, Sarah and Kaleebu, Pontiano and Elliott, Alison and Webb, Emily, The Effect of Intermittent Preventive Treatment for Malaria with Dihydroartemisinin-Piperaquine on Vaccine-Specific Responses Among Schoolchildren in Rural Uganda: Results of the POPVAC B Randomised, Controlled Trial. Available at SSRN: https://ssrn.com/abstract=4667621 or http://dx.doi.org/10.2139/ssrn.4667621

Ludoviko Zirimenya

Medical Research Council/Uganda Virus Research Institute & London School of Hygiene and Tropical Medicine (MRC/UVRI & LSHTM), Uganda Research Unit ( email )

Agnes Natukunda

Medical Research Council/Uganda Virus Research Institute & London School of Hygiene and Tropical Medicine (MRC/UVRI & LSHTM), Uganda Research Unit ( email )

Jacent Nassuuna

Medical Research Council/Uganda Virus Research Institute & London School of Hygiene and Tropical Medicine (MRC/UVRI & LSHTM), Uganda Research Unit ( email )

Gyaviira Nkurunungi (Contact Author)

Medical Research Council/Uganda Virus Research Institute & London School of Hygiene and Tropical Medicine (MRC/UVRI & LSHTM), Uganda Research Unit ( email )

Uganda

London School of Hygiene & Tropical Medicine ( email )

Keppel Street
London, WC1E 7HT
United Kingdom

Christopher Zziwa

Medical Research Council/Uganda Virus Research Institute & London School of Hygiene and Tropical Medicine (MRC/UVRI & LSHTM), Uganda Research Unit ( email )

Caroline Ninsiima

Medical Research Council/Uganda Virus Research Institute & London School of Hygiene and Tropical Medicine (MRC/UVRI & LSHTM), Uganda Research Unit ( email )

Christine Kukundakwe

Medical Research Council/Uganda Virus Research Institute & London School of Hygiene and Tropical Medicine (MRC/UVRI & LSHTM), Uganda Research Unit ( email )

Christine Musoke Nankabirwa

Medical Research Council/Uganda Virus Research Institute & London School of Hygiene and Tropical Medicine (MRC/UVRI & LSHTM), Uganda Research Unit ( email )

Charity Katushabe

affiliation not provided to SSRN ( email )

No Address Available

Loyce Kisakye Namusobya

Medical Research Council/Uganda Virus Research Institute & London School of Hygiene and Tropical Medicine (MRC/UVRI & LSHTM), Uganda Research Unit ( email )

Gloria Oduru

Medical Research Council/Uganda Virus Research Institute & London School of Hygiene and Tropical Medicine (MRC/UVRI & LSHTM), Uganda Research Unit ( email )

Grace Kabami

Medical Research Council/Uganda Virus Research Institute & London School of Hygiene and Tropical Medicine (MRC/UVRI & LSHTM), Uganda Research Unit ( email )

Joel Kabali

Medical Research Council/Uganda Virus Research Institute & London School of Hygiene and Tropical Medicine (MRC/UVRI & LSHTM), Uganda Research Unit ( email )

John Kayiwa

Government of Uganda - Uganda Virus Research Institute (UVRI) ( email )

Joyce Kabagenyi

Medical Research Council/Uganda Virus Research Institute & London School of Hygiene and Tropical Medicine (MRC/UVRI & LSHTM), Uganda Research Unit ( email )

Govert J. Van Dam

Leiden University - Leiden University Medical Center (LUMC) ( email )

Paul Corstjens

Leiden University - Leiden University Medical Center (LUMC) ( email )

Stephen Cose

Medical Research Council/Uganda Virus Research Institute & London School of Hygiene and Tropical Medicine (MRC/UVRI & LSHTM), Uganda Research Unit ( email )

Anne Wajja

Medical Research Council/Uganda Virus Research Institute & London School of Hygiene and Tropical Medicine (MRC/UVRI & LSHTM), Uganda Research Unit ( email )

Sarah Staedke

London School of Hygiene & Tropical Medicine - Department of Clinical Research ( email )

London
United Kingdom

Pontiano Kaleebu

London School of Hygiene & Tropical Medicine - Uganda Research Unit ( email )

Alison Elliott

London School of Hygiene and Tropical Medicine - Department of Clinical Research ( email )

Keppel Street
London, WC1E 7HT
United Kingdom

Emily Webb

London School of Hygiene & Tropical Medicine - MRC International Statistics and Epidemiology Group ( email )