A Controlled Human Malaria Infection model for relapsing Plasmodium vivax
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Background
Plasmodium vivax malaria relapses are a major source of morbidity and onward transmission of infection. The underlying mechanisms are poorly understood and current therapies sub-optimal. We examined the safety and feasibility of a controlled human malaria infection (CHMI) model for relapsing P. vivax .
Methods
We conducted an open-label, proof-of-concept, CHMI study of relapsing P. vivax . Healthy, malaria-naïve, Duffy-positive adults aged 18–45 years with extensive CYP2D6 metaboliser phenotype and normal blood glucose-6-phosphate dehydrogenase (G6PD) levels were recruited in Oxford, UK. Mosquito-bite CHMI was performed in Nijmegen, The Netherlands, using Anopheles stephensi mosquitoes infected with PvW1, a clonal isolate of P. vivax from Thailand. All follow-up visits were conducted in Oxford, UK. Primary P. vivax infections (qPCR > 500 genome copies/mL) were treated with artemether-lumefantrine (80mg/480mg at 8, 24, 36, 48 and 60 hours). From Day 28 following CHMI, participants attended a fortnightly clinic for clinical review and qPCR blood sampling, with additional assessments performed for any reported symptoms. P. vivax relapse infections (qPCR > 500 genome copies/mL) were treated with artemether-lumefantrine as per primary infection. Definitive anti-malarial treatment with atovaquone-proguanil (1000mg/400mg once daily for three days) and primaquine (0·5 mg/kg/day for 14 days) was administered six months following CHMI, regardless of parasitaemia or symptoms. The primary objective was to assess the safety, feasibility and frequency of relapsing P. vivax after CHMI. Remote follow-up (5 years) is ongoing. The study is registered with ISRCTN registry ( ISRCTN48625883 ).
Findings
20 participants were screened for eligibility from 21 January 2025. Five participants (median age 22 years) underwent CHMI (five infected mosquitoes per participant) on 15 April 2025. All participants developed primary P. vivax infection and experienced at least one relapse infection. Two participants experienced a second relapse. Overall incidence rate was 3·6 relapse infections per person-year. Solicited adverse events were mild or moderate and there were no serious adverse events. Definitive anti-malarial treatment was administered to all participants. One participant experienced primaquine-induced methaemoglobinaemia, resolving with early discontinuation of treatment (total dose 5·3 mg/kg). To date, more than six months after primaquine treatment, no further relapses have been recorded.
Interpretation
CHMI of relapsing P. vivax is safe and feasible, allowing exploration of the mechanisms underlying relapse infections and providing a platform for future anti-relapse efficacy studies.
Funding
European Union Horizon Europe programme and UK Research and Innovation (UKRI) via OptiViVax consortium; UK National Institute for Health and Care Research Biomedical Research Centre: Oxford; and UK Medical Research Council.
Research in Context
Evidence before this study
Relapse infections account for the majority of cases of Plasmodium vivax malaria. There are no licensed vaccines for P. vivax and current anti-relapse hypnozoiticidal therapies (primaquine and tafenoquine) have restrictive contraindications, side effects and variable efficacy. A controlled human malaria infection (CHMI) model for relapsing P. vivax , using a well-characterised clonal isolate of P. vivax administered by mosquito bite, would present an opportunity to improve understanding of hypnozoite immuno-biology and provide a platform for efficacy studies of novel anti-relapse interventions. We searched PubMed on 23 April 2026 for research articles using the terms (“P. vivax” OR “Plasmodium vivax” OR “vivax”) AND (“malaria challenge” OR “Controlled Human Malaria Infection” OR “CHMI” OR “sporozoite challenge”). No date or language filters were applied. The search identified seven published CHMI studies in which P. vivax was administered by mosquito bite. All these studies utilised mosquitoes infected from a source patient(s) with naturally-acquired infection, thereby limiting interstudy comparison and creating logistical challenges for reproducibility. Only one study reported relapse infections which occurred following primaquine treatment in two participants with poor and intermediate CYP2D6 metaboliser phenotype respectively. In addition to this PubMed search, historical records were identified which described the deliberate infection of humans with P. vivax i) in experiments conducted in the early 20 th Century, and ii) as part of malariotherapy for the treatment of “general paralysis of the insane” (neurosyphilis). Although some of these records used well-characterised strains of P. vivax (e.g. Madagascar strain) and included relapse infections, these pre-dated modern molecular and serological laboratory techniques. Having previously generated a cryopreserved inoculum of P. vivax -infected red blood cells (PvW1) with high-quality genome assembly, we set out to administer this clonal isolate in a CHMI study by mosquito bite, and characterise P. vivax relapse infections over a six-month period prior to the administration of primaquine treatment.
Added value of this study
This study reports the administration of PvW1 by mosquito bite to five healthy adult participants in the UK. All participants developed primary P. vivax infection and experienced at least one relapse infection in a six-month follow-up period. Two participants experienced a second relapse infection prior to the administration of definitive anti-malarial treatment with atovaquone-proguanil and primaquine. Solicited adverse events (foreseeable symptoms of malaria) were mild or moderate. Long-term remote follow-up is ongoing. However, to date, more than six months after primaquine treatment, no further relapse infections have been recorded. To our knowledge, this is the first CHMI study in the modern era to administer a well-characterised clonal isolate of P. vivax by mosquito bite. We demonstrate that a CHMI model for relapsing P. vivax is safe and feasible.
Implications of all the available evidence
The World Health Organisation (WHO) Technical Brief on the Control and Elimination of Plasmodium vivax Malaria calls for better understanding of the biology and epidemiology of P. vivax, and the development of new interventions and strategies. Specifically, it highlights a need for improved knowledge of the underlying mechanisms of P. vivax relapse infections; a single-dose hypnozoiticidal treatment that can be used for all population groups without significant side effects; and development of P. vivax vaccines. CHMI studies allow the study of host-pathogen interactions in detail and accelerate the development of vaccines and therapeutic drugs by providing evidence of efficacy early in clinical development. This proof-of-concept study presents an opportunity to explore the mechanisms behind hypnozoite formation and activation in humans, and provides a novel clinical platform for future drug and vaccine efficacy studies.
