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 hostpathogen 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, 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 developed in both volunteers and, 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 ("PvW1") was thawed and used to inoculate six healthy malaria-naïve UK adults by blood-stage CHMI, at three 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 analysed 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.

Impact of a blood-stage vaccine on Plasmodium vivax malaria

“…Vaccinees underwent CHMI 2-4 weeks following their final vaccination and in parallel with unvaccinated infectivity controls in the VAC069 study. Blood-stage CHMI was initiated by intravenous injection of blood infected with the PvW1 clone of P. vivax , which originated from Thailand 8 . PvW1 possesses a single copy of the PvDBP gene and its PvDBPII sequence is heterologous to SalI 8 ( Table S1 ).…”

“…Blood-stage CHMI was initiated by intravenous injection of blood infected with the PvW1 clone of P. vivax , which originated from Thailand 8 . PvW1 possesses a single copy of the PvDBP gene and its PvDBPII sequence is heterologous to SalI 8 ( Table S1 ). On the day of CHMI, aliquots of 0.5mL cryopreserved PvW1 infected blood were thawed and each participant was challenged with a 1:10 dilution of one aliquot by intravenous injection into the forearm 8 .…”

“…From day 6 or 7 post-CHMI, participants were reviewed in clinic once to twice daily for symptoms of malaria and blood parasitemia was measured in real time by qPCR of the 18S ribosomal RNA gene 8 . Volunteers were commenced on antimalarial treatment if they had significant malaria symptoms and parasitemia ≥5,000 genome copies (gc)/mL; or if parasitemia reached ≥10,000 gc/mL irrespective of symptoms.…”

“…Here we report results from two Phase I/IIa clinical trials in healthy malaria-naïve adults using either the same viral-vectored vaccine or the PvDBPII protein vaccine reformulated in Matrix-M™ adjuvant. Both vaccines were tested for efficacy for the first time by blood-stage CHMI using the heterologous PvW1 clone of P. vivax 8 .…”

Systems biology of malaria explored with nonhuman primates

“…Thus, it may be possible in the future to perform such investigations routinely. At any rate, CHMI studies initiated with iRBCs are also now a viable option for investigations of P. falciparum [ 71 – 74 ], P. vivax [ 53 , 55 , 74 – 76 ] and P. malariae [ 77 , 78 ]. Such CHMI studies involve low-dose blood-stage inoculations, with very clear ethical guidelines in place to ensure the safety of volunteers.…”