Modelling the Within-Host Dynamics of Plasmodium Vivax Hypnozoite Activation: an Analysis of the SPf66 Vaccine Trial

Plasmodium vivax parasites can lie dormant in the liver as hypnozoites, activating weeks to months after sporozoite inoculation to cause relapsing malarial illness. It is not known what biological processes govern hypnozoite activation. We use longitudinal data from the most detailed cohort study ever conducted in an area where both Plasmodium falciparum and P. vivax were endemic to fit a simple within-host mathematical model of P. vivax hypnozoite activation. 1344 children living on the Thailand-Myanmar border were followed each day for 21 months. There were 2504 vivax and 1164 falciparum malaria symptomatic episodes recorded over 1988 person-years. The model assumes that hypnozoites activate independently at a constant rate (‘exponential clock model’). When this model was embedded in a stochastic framework for repeated infectious mosquito bites, with seasonality inferred from the incidence of clinical falciparum malaria episodes, it explained the observed temporal patterns of multiple (up to 13) recurrent vivax malaria episodes. Under this model we estimate the mean dormancy period for a single hypnozoite to be 6 months (i.e. a half-life of 4 months). We use the calibrated within-host model to characterise population level overdispersion in the risk of relapse, and assess the potential utility of a serological test for radical cure in low transmission settings. We show that mefloquine treatment of falciparum malaria eliminates early vivax relapses; and that there are substantially more P. vivax recurrences than expected under the model following artesunate monotherapy treatment for falciparum malaria. These results suggest that hypnozoites can be activated by symptomatic malarial illness. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement NJW is a Principal Research Fellow funded by the Wellcome Trust (093956/Z/10/C). JAW is a Sir Henry Dale Fellow funded by the Wellcome Trust (223253/Z/21/Z). SM acknowledges funding from the Australian Research Council through Laureate Fellowship FL130100039. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This is a retrospective analysis of a historical study. The Oxford Tropical Research Ethics Committee provides a waiver of ethics review for existing de-identified data. The ethics statement from the original paper by Nosten et al (1996) (DOI:10.1016/s0140-6736(96)04465-0) reporting the results of the study is as follows: "The study was conducted under a clinical protocol that was approved by the ethics and scientific review committees of the Faculty of Tropical Medicine of Mahidol University and the Office of the Surgeon General of the US Army, and was also approved by the Karen Refugee Committee". I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data relevant to the study are openly available on a GitHub repository.