A Plasmodium vivax controlled human infection and transmission model to evaluate interventions across the life cycle

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Abstract Background Plasmodium vivax is an underappreciated cause of malaria disease burden. No reproducible and standardized full life-cycle controlled human malaria infection (CHMI) model to accelerate development of novel interventions is available. Methods This transmission-CHMI trial was conducted in Nijmegen, Netherlands. Healthy, malaria-naive adults were sequentially enrolled into three cohorts of four and inoculated with the asexual blood-stage isolate PvW1. Primary endpoint was proportion of oocyst-positive laboratory-reared Anopheles stephensi mosquitoes. The sequential design allowed for adaptations between cohorts. At parasitemia >10 parasites/µL or symptom onset, participants received oral gametocyte-sparing treatment (GST): mepacrine (Cohort 1 and 3; 100 mg at 0, 8 16 hours, then once daily for 3 days) or piperaquine (Cohort 3; 480 mg single-dose). Transmission was assessed by direct skin feeding (DSF) and membrane feeding assay (DMFA) with and without enrichment of gametocytes. End-of-study treatment was atovaquone-proguanil (1000/400 mg once daily for 3 days). The trial was registered: NL-OMON57011. Findings Participants were enrolled between September 17, 2024 and March 25, 2025, all (12/12) developed parasitemia and transmitted PvW1 to mosquitoes. No serious adverse events occurred. Most adverse reactions were related to malaria. Mepacrine and piperaquine reduced asexual parasitemia while preserving gametocytemia and transmission. Peak transmission occurred within 3 days after GST and depended on the parasite developmental cycle, with highest gametocyte-infectivity ∼48 h post ring-stage. In Cohort 3, mosquito infection reached 100% in all transmission assays. Median peak oocyst counts were 24 (IǪR: 14–31) for DSF, 17 (12–19) for DMFA, and 150 (116–199) for enriched DMFA. A two-fold increase in pre-GST maximal parasitemia was associated with 20 additional oocysts (95% CI 8·6–32) in enriched DMFA. Sporozoites were viable in primary human hepatocytes. Interpretation A PvW1 transmission-CHMI is reproducible and safe, enabling P. vivax sporozoite production, relapse models and evaluation of transmission-blocking interventions. Funding The OptiViVax project is supported by European Union Horizon Europe programme and UK Research and Innovation (UKRI); Swiss Government’s State Secretariat for Education, Research, and Innovation (SERI); National Institute for Health and Care Research Oxford Biomedical Research Centre (NIHR-BRC). Research in context Evidence before this study In its Malaria Vaccine Technology Roadmap, the World Health Organization prioritizes Plasmodium vivax research and vaccine development alongside Plasmodium falciparum . Controlled human malaria infections (CHMI) play an important role in the development of new interventions as they enable early evaluation of new drugs and vaccines in small groups of participants. Added value of this study To our knowledge this is the first study to achieve consistent transmission of a P. vivax clone to mosquitoes following blood-stage P. vivax CHMI. Reproducible high-level transmission was observed both in direct feeding assays and after gametocyte enrichment and parameters were identified that improve transmission success. It is also the first P. vivax CHMI trial that systematically assessed the use of piperaquine and mepacrine to attenuate asexual replication while preserving transmission-competent gametocytes. Implications of all the available evidence This study expands the repertoire of P. vivax CHMI models and builds on the success and knowledge of prior P. vivax and P. falciparum CHMIs. This optimised transmission model enables production of highly infected mosquitoes and sporozoites for downstream use with a genetically-defined clone, which is particularly important for P. vivax because it cannot be maintained in continuous culture. It also facilitates evaluation of transmission-blocking interventions.

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