| Study Abstract |
Abstract BACKGROUND: 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, the P. vivax parasite cannot be cultured long-term in vitro, meaning stocks of well-characterized parasites that are safe and suitable for use in modern CHMI models have been limiting. METHODS and FINDINGS: Two healthy malaria-naïve UK adults with universal donor blood group were safely infected with a clone of P. vivax from Thailand by mosquito-bite CHMI. Parasitemia, but minimal gametocytemia, developed in both volunteers and treatment successfully cleared the infection with no documented relapse. Prior to treatment, each volunteer donated blood to produce a cryopreserved stabilate of infected red blood cells. Following stringent safety screening, the parasite stabilate from one of these donors (which we called “PvW1”) was thawed and used to inoculate six healthy malaria-naïve UK adults by blood-stage CHMI. Three different dilutions of blood-stage inoculum were used (n=2 per dose). Parasitemia and gametocytemia developed in all six volunteers, who were then successfully drug treated. The adverse event profiles of mosquito-bite and blood-stage CHMI were comparable, with malaria symptoms resolving within a few days of treatment, however notable differences in gametocytemia and the blood-stage parasite multiplication rate were observed between the two human infection models. PvW1 parasite DNA was isolated and sequenced to produce a high quality genome assembly by using a hybrid assembly method which combined long PacBio reads with short Illumina reads. We analysed leading vaccine candidate antigens and multigene families, including the Vivax interspersed repeat (VIR) genes of which we identified 1145 in the PvW1 genome. CONCLUSIONS: We have demonstrated the safety and feasibility of mosquito-bite and blood-stage CHMI using the same PvW1 clone of P. vivax. Our genomic analysis will guide future assessment of candidate vaccines and drugs, as well as experimental medicine studies. The PvW1 parasite should prove to be an invaluable resource for the wider malaria community. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03377296 and NCT03797989. This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/ |
