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

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

doi:10.1172/jci.insight.152465

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.

Highlights

The majority of human malaria is caused by two species of parasite – Plasmodium falciparum and P.vivax
Patient blood samples that tested positive for P. vivax and negative for filarial disease were fed to Anopheles dirus mosquitoes via a direct membrane feeding system in Thailand
Our methodology elected to focus on a mosquito-bite Controlled human malaria infection (CHMI) protocol to provide the initial source of blood-stage parasites for the cryopreserved stabilate

Summary

Introduction

The majority of human malaria is caused by two species of parasite – Plasmodium falciparum and P. vivax. Asexual replication in the liver sees each infected cell produce thousands of merozoites. These rupture out into the blood and infect red blood cells (RBC), before undergoing exponential growth that leads to clinical symptoms and the associated morbidity and mortality. P. vivax is the predominant cause of malaria outside of Africa and is more geographically widespread than P. falciparum, with 2.5 billion people living at risk in Latin America, Oceania, Asia and the horn of Africa [1]. Recent data demonstrate a significant burden of morbidity and associated mortality in young children and pregnant women [2], challenging the long-held dogma that this parasite is “benign” [3]

Methods

Results

Conclusion