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.
View: Text | PDF
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

×

Figure 3

Parasite growth dynamics of P. vivax PvW1 clone blood-stage CHMI.

Options: View larger image (or click on image) Download as PowerPoint
Parasite growth dynamics of P. vivax PvW1 clone blood-stage CHMI. (A) qP...
(A) qPCR data for the VAC069A trial (n = 6). Parasitemia measured in genome copies (gc)/mL is shown over time for each volunteer. CHMI was initiated by blood-stage inoculation on day 0. Cross symbols indicate the time point of diagnosis. Orange = neat inoculum dose; blue = 1:5; green = 1:20 dilution of the neat inoculum dose. Solid black line indicates 20 gc/mL (the minimum level to meet positive reporting criteria); samples below this are shown for information only. (B) Kaplan-Meier plot of time to diagnosis in days for the VAC069A study (n = 2/group). (C) Parasitemia measured in gc/mL at the time point of diagnosis. Individual data points and median are indicated for each dose group. Volunteers were diagnosed when they reached a threshold of 10,000 gc/mL OR if they had symptoms of malaria with a parasitemia > 5,000 gc/mL. (D) The PMR per 48 hours was modeled from the qPCR data up until the time point of diagnosis; PMR ± 95% CI is shown for each volunteer. (E) Individual and median PMR are shown with volunteers grouped according to their Duffy blood group antigen (Fy) serological phenotype. (F) Gametocytemia was assessed over time by qPCR for pvs25 transcripts; colored lines as per A. (G) Correlation of total parasitemia measured in gc/mL versus pvs25 transcripts/μL. Spearman’s rank correlation coefficient and P value are shown; n = 36.