Controlled human malaria infection with a clone of Plasmodium vivax with high-quality genome assembly
Angela M. Minassian, et al.
Angela M. Minassian, et al.
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Resource and Technical Advance Infectious disease

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

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.

Authors

Angela M. Minassian, Yrene Themistocleous, Sarah E. Silk, Jordan R. Barrett, Alison Kemp, Doris Quinkert, Carolyn M. Nielsen, Nick J. Edwards, Thomas A. Rawlinson, Fernando Ramos Lopez, Wanlapa Roobsoong, Katherine J.D. Ellis, Jee-Sun Cho, Eerik Aunin, Thomas D. Otto, Adam J. Reid, Florian A. Bach, Geneviève M.C. Labbé, Ian D. Poulton, Arianna Marini, Marija Zaric, Margaux Mulatier, Raquel Lopez Ramon, Megan Baker, Celia H. Mitton, Jason C. Sousa, Nattawan Rachaphaew, Chalermpon Kumpitak, Nongnuj Maneechai, Chayanut Suansomjit, Tianrat Piteekan, Mimi M. Hou, Baktash Khozoee, Kirsty McHugh, David J. Roberts, Alison M. Lawrie, Andrew M. Blagborough, Fay L. Nugent, Iona J. Taylor, Kimberly J. Johnson, Philip J. Spence, Jetsumon Sattabongkot, Sumi Biswas, Julian C. Rayner, Simon J. Draper

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Figure 1

Safety and parasite growth dynamics of P. vivax sporozoite CHMI.

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Safety and parasite growth dynamics of P. vivax sporozoite CHMI. (A) qPC...
(A) qPCR data for the VAC068 trial (n = 2). Parasitemia measured in genome copies/mL is shown over time for each volunteer. CHMI was initiated by mosquito bite on day 0. Cross symbols indicate the time point of blood donation followed by antimalarial treatment. Solid lines show qPCR readouts before treatment, and dotted lines after treatment. Solid black line indicates 20 gc/mL (the minimum level to meet positive reporting criteria); samples below this are shown for information only. (B) The solicited systemic adverse events (AEs) recorded during the CHMI period (from 1 day up until 45 days after challenge) are shown as the maximum severity reported by each volunteer and as a percentage of the volunteers reporting each individual AE (n = 2). Color-coding refers to AE grading: 0 = none; 1 = mild; 2 = moderate; 3 = severe. (C) Volunteer temperature (maximum self-recorded by volunteer or measured in clinic) at the indicated time points: baseline before CHMI; 9 and 11 days after CHMI (C+9, C+11); time of blood donation; and 1 and 2 days after treatment (T+1, T+2). AE grading cut-offs are indicated by the dotted lines (yellow = grade 1; orange = grade 2; red = grade 3). (D and E) Lymphocyte and platelet counts plotted as for C. (F) The PMR per 48 hours was modeled from the qPCR data up until the time point of blood donation/treatment; PMR ± 95% CI is shown for each volunteer. (G) Gametocytemia was assessed over time by qPCR for pvs25 transcripts; symbols and lines as per A.