Controlled human malaria infection with a clone of <i>Plasmodium vivax</i> with high-quality genome assembly

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Abstract

Controlled human malaria infection (CHMI) provides a highly informative means to investigate host-pathogen interactions and enable in vivo proof-of-concept efficacy testing of new drugs and vaccines. However, unlike Plasmodium falciparum, well-characterized P. vivax parasites that are safe and suitable for use in modern CHMI models are limited. Here, 2 healthy malaria-naive United Kingdom adults with universal donor blood group were safely infected with a clone of P. vivax from Thailand by mosquito-bite CHMI. Parasitemia developed in both volunteers, and prior to treatment, each volunteer donated blood to produce a cryopreserved stabilate of infected RBCs. Following stringent safety screening, the parasite stabilate from one of these donors (PvW1) was thawed and used to inoculate 6 healthy malaria-naive United Kingdom adults by blood-stage CHMI, at 3 different dilutions. Parasitemia developed in all volunteers, who were then successfully drug treated. PvW1 parasite DNA was isolated and sequenced to produce a high-quality genome assembly by using a hybrid assembly method. We analyzed leading vaccine candidate antigens and multigene families, including the vivax interspersed repeat (VIR) genes, of which we identified 1145 in the PvW1 genome. Our genomic analysis will guide future assessment of candidate vaccines and drugs, as well as experimental medicine studies.

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Most cited references 64

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Comparative genomics of the neglected human malaria parasite Plasmodium vivax.

Jane M-R Carlton, John H. Adams, Joana C. Silva … (2008)

The human malaria parasite Plasmodium vivax is responsible for 25-40% of the approximately 515 million annual cases of malaria worldwide. Although seldom fatal, the parasite elicits severe and incapacitating clinical symptoms and often causes relapses months after a primary infection has cleared. Despite its importance as a major human pathogen, P. vivax is little studied because it cannot be propagated continuously in the laboratory except in non-human primates. We sequenced the genome of P. vivax to shed light on its distinctive biological features, and as a means to drive development of new drugs and vaccines. Here we describe the synteny and isochore structure of P. vivax chromosomes, and show that the parasite resembles other malaria parasites in gene content and metabolic potential, but possesses novel gene families and potential alternative invasion pathways not recognized previously. Completion of the P. vivax genome provides the scientific community with a valuable resource that can be used to advance investigation into this neglected species.

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Key gaps in the knowledge of Plasmodium vivax, a neglected human malaria parasite.

Ivo Mueller, Mary Galinski, J. Baird … (2009)

Plasmodium vivax is geographically the most widely distributed cause of malaria in people, with up to 2.5 billion people at risk and an estimated 80 million to 300 million clinical cases every year--including severe disease and death. Despite this large burden of disease, P vivax is overlooked and left in the shadow of the enormous problem caused by Plasmodium falciparum in sub-Saharan Africa. The technological advances enabling the sequencing of the P vivax genome and a recent call for worldwide malaria eradication have together placed new emphasis on the importance of addressing P vivax as a major public health problem. However, because of this parasite's biology, it is especially difficult to interrupt the transmission of P vivax, and experts agree that the available methods for preventing and treating infections with P vivax are inadequate. It is thus imperative that the development of new methods and strategies become a priority. Advancing the development of such methods needs renewed emphasis on understanding the biology, pathogenesis, and epidemiology of P vivax. This Review critically examines what is known about P vivax, focusing on identifying the crucial gaps that create obstacles to the elimination of this parasite in human populations.

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Determinants of relapse periodicity in Plasmodium vivax malaria

Nicholas J. White (2011)

Plasmodium vivax is a major cause of febrile illness in endemic areas of Asia, Central and South America, and the horn of Africa. Plasmodium vivax infections are characterized by relapses of malaria arising from persistent liver stages of the parasite (hypnozoites) which can be prevented only by 8-aminoquinoline anti-malarials. Tropical P. vivax relapses at three week intervals if rapidly eliminated anti-malarials are given for treatment, whereas in temperate regions and parts of the sub-tropics P. vivax infections are characterized either by a long incubation or a long-latency period between illness and relapse - in both cases approximating 8-10 months. The epidemiology of the different relapse phenotypes has not been defined adequately despite obvious relevance to malaria control and elimination. The number of sporozoites inoculated by the anopheline mosquito is an important determinant of both the timing and the number of relapses. The intervals between relapses display a remarkable periodicity which has not been explained. Evidence is presented that the proportion of patients who have successive relapses is relatively constant and that the factor which activates hypnozoites and leads to regular interval relapse in vivax malaria is the systemic febrile illness itself. It is proposed that in endemic areas a large proportion of the population harbours latent hypnozoites which can be activated by a systemic illness such as vivax or falciparum malaria. This explains the high rates of vivax following falciparum malaria, the high proportion of heterologous genotypes in relapses, the higher rates of relapse in people living in endemic areas compared with artificial infection studies, and, by facilitating recombination between different genotypes, contributes to P. vivax genetic diversity particularly in low transmission settings. Long-latency P. vivax phenotypes may be more widespread and more prevalent than currently thought. These observations have important implications for the assessment of radical treatment efficacy and for malaria control and elimination.

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Author and article information

Contributors

Angela M. Minassian:

ORCID: http://orcid.org/0000-0001-7832-9824

Yrene Themistocleous

Sarah E. Silk:

ORCID: http://orcid.org/0000-0003-0563-4814

Jordan R. Barrett:

ORCID: http://orcid.org/0000-0003-0746-1945

Alison Kemp

Doris Quinkert:

ORCID: http://orcid.org/0000-0003-4135-6452

Carolyn M. Nielsen:

ORCID: http://orcid.org/0000-0002-9033-1318

Nick J. Edwards:

ORCID: http://orcid.org/0000-0002-7030-7839

Thomas A. Rawlinson

Wanlapa Roobsoong:

ORCID: http://orcid.org/0000-0002-1789-0439

Katherine J.D. Ellis

Jee-Sun Cho

Eerik Aunin:

ORCID: http://orcid.org/0000-0001-8385-2636

Thomas D. Otto:

ORCID: http://orcid.org/0000-0002-1246-7404

Adam J. Reid:

ORCID: http://orcid.org/0000-0002-5926-7768

Florian A. Bach:

ORCID: http://orcid.org/0000-0002-0126-5516

Geneviève M.C. Labbé:

ORCID: http://orcid.org/0000-0002-1015-8579

Ian D. Poulton:

ORCID: http://orcid.org/0000-0002-6603-8461

Arianna Marini:

ORCID: http://orcid.org/0000-0003-3416-7362

Marija Zaric:

ORCID: http://orcid.org/0000-0002-0569-6049

Margaux Mulatier:

ORCID: http://orcid.org/0000-0001-9604-8479

Megan Baker

Celia H. Mitton

Jason C. Sousa

Nattawan Rachaphaew:

ORCID: http://orcid.org/0000-0002-8366-7585

Chalermpon Kumpitak

Nongnuj Maneechai

Chayanut Suansomjit

Tianrat Piteekan

Mimi M. Hou:

ORCID: http://orcid.org/0000-0002-8517-9147

Baktash Khozoee:

ORCID: http://orcid.org/0000-0002-2470-3283

Kirsty McHugh

David J. Roberts:

ORCID: http://orcid.org/0000-0003-0648-6585

Alison M. Lawrie

Andrew M. Blagborough

Fay L. Nugent:

ORCID: http://orcid.org/0000-0001-6312-7293

Iona J. Taylor:

ORCID: http://orcid.org/0000-0002-2287-9488

Kimberly J. Johnson:

ORCID: http://orcid.org/0000-0002-6365-906X

Philip J. Spence

Jetsumon Sattabongkot

Sumi Biswas

Julian C. Rayner:

ORCID: http://orcid.org/0000-0002-9835-1014

Simon J. Draper:

ORCID: http://orcid.org/0000-0002-9415-1357

Journal

Journal ID (nlm-ta): JCI Insight

Journal ID (iso-abbrev): JCI Insight

Journal ID (publisher-id): JCI Insight

Title: JCI Insight

Publisher: American Society for Clinical Investigation

ISSN (Electronic): 2379-3708

Publication date (Electronic, pub): 8 December 2021

Publication date (Electronic, collection): 8 December 2021

Publication date PMC-release: 8 December 2021

Volume: 6

Issue: 23

Electronic Location Identifier: e152465

Affiliations

[1 ]The Jenner Institute and

[2 ]Department of Biochemistry, University of Oxford, Oxford, United Kingdom.

[3 ]Wellcome Sanger Institute, Wellcome Genome Campus, Cambridge, United Kingdom.

[4 ]Cambridge Institute for Medical Research, University of Cambridge, Cambridge, United Kingdom.

[5 ]Mahidol Vivax Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.

[6 ]Institute of Immunology and Infection Research, University of Edinburgh, Edinburgh, United Kingdom.

[7 ]Walter Reed Army Institute of Research, Silver Spring, Maryland, USA.

[8 ]Mahidol-Oxford Tropical Medicine Research Unit, Faculty of Tropical Medicine, Mahidol University, Bangkok, Thailand.

[9 ]Nuffield Division of Clinical Laboratory Sciences, Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom.

[10 ]Department of Pathology, University of Cambridge, Cambridge, United Kingdom.

Author notes

Address correspondence to: Angela M. Minassian, Centre for Clinical Vaccinology and Tropical Medicine, University of Oxford, Churchill Hospital, Oxford OX3 7LA, United Kingdom. Phone: 44.7973.684040; Email: angela.minassian@ 123456ndm.ox.ac.uk . Or to: Simon J. Draper, Department of Biochemistry, South Parks Road, Oxford OX1 3QU, United Kingdom. Phone: 44.1865.285438; Email: simon.draper@ 123456bioch.ox.ac.uk .

Authorship note: AMM and YT contributed equally to this work.

Author information

Angela M. Minassian http://orcid.org/0000-0001-7832-9824

Sarah E. Silk http://orcid.org/0000-0003-0563-4814

Jordan R. Barrett http://orcid.org/0000-0003-0746-1945

Doris Quinkert http://orcid.org/0000-0003-4135-6452

Carolyn M. Nielsen http://orcid.org/0000-0002-9033-1318

Nick J. Edwards http://orcid.org/0000-0002-7030-7839

Wanlapa Roobsoong http://orcid.org/0000-0002-1789-0439

Eerik Aunin http://orcid.org/0000-0001-8385-2636

Thomas D. Otto http://orcid.org/0000-0002-1246-7404

Adam J. Reid http://orcid.org/0000-0002-5926-7768

Florian A. Bach http://orcid.org/0000-0002-0126-5516

Geneviève M.C. Labbé http://orcid.org/0000-0002-1015-8579

Ian D. Poulton http://orcid.org/0000-0002-6603-8461

Arianna Marini http://orcid.org/0000-0003-3416-7362

Marija Zaric http://orcid.org/0000-0002-0569-6049

Margaux Mulatier http://orcid.org/0000-0001-9604-8479

Nattawan Rachaphaew http://orcid.org/0000-0002-8366-7585

Mimi M. Hou http://orcid.org/0000-0002-8517-9147

Baktash Khozoee http://orcid.org/0000-0002-2470-3283

David J. Roberts http://orcid.org/0000-0003-0648-6585

Fay L. Nugent http://orcid.org/0000-0001-6312-7293

Iona J. Taylor http://orcid.org/0000-0002-2287-9488

Kimberly J. Johnson http://orcid.org/0000-0002-6365-906X

Julian C. Rayner http://orcid.org/0000-0002-9835-1014

Simon J. Draper http://orcid.org/0000-0002-9415-1357

Article

Publisher ID: 152465

DOI: 10.1172/jci.insight.152465

PMC ID: 8675201

PubMed ID: 34609964

SO-VID: ae90f019-e017-410b-b75d-9f06add21900

License:

This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

History

Funding

Funded by: European Union’s Horizon 2020 research and innovation programme

Award ID: grant agreement 733073 for MultiViVax

Funded by: UK Medical Research Council (MRC) Confidence in Concept Scheme, University of Oxford

Award ID: MC_PC_16056

Funded by: National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC)

Controlled human malaria infection with a clone of Plasmodium vivax with high-quality genome assembly

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SDG 3: Good Health and Well-Being

Most cited references 64

Comparative genomics of the neglected human malaria parasite Plasmodium vivax.

Key gaps in the knowledge of Plasmodium vivax, a neglected human malaria parasite.

Determinants of relapse periodicity in Plasmodium vivax malaria

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