title: Considerations for Comprehensive Analyses of Sporozoite-Based Controlled Human Malaria Infection Studies.
abstract: There has been renewed interest in the use of sporozoite-based approaches for controlled human malaria infections (CHMIs), and several sets of human challenge studies have recently completed. A study undertaken in Tanzania and published in 2014 found dose dependence between 10,000 and 25,000 sporozoite doses, as well as divergent times-to-parasitemia relative to earlier studies in European volunteers, with important implications for planning future studies. Analysis of time-to-event data has had extensive development in recent years, but these methods have had limited exposure outside biostatistics. Expansion of the published analyses to include recent methodological approaches optimized for the types of data used could provide a richer analysis of these studies and may result in alternative findings. Specifically, in a re-analysis of these data using survival analysis techniques, the differences recorded in prepatent periods between the two dosing regimens do not reach statistical significance, and there is no evidence for statistically significant differences in prepatent periods between the Dutch and Tanzanian study sites. Although these findings do not impact the reported safety and tolerability of challange with cryopreserved Plasmodium falciparum sporozoites (PfSPZ), or invalidate the authors' hypotheses regarding naturally acquired immunity and its effect on parasite growth rates and prepatent periods, they highlight important opportunities to more fully use datasets from these trials and related CHMI experiments in the planning of future challenge studies.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Lover
mesh_terms: D003627:Data Interpretation, Statistical; D006801:Humans; D053208:Kaplan-Meier Estimate; D008288:Malaria / Q000469:parasitology / Q000517:prevention & control*; D015999:Multivariate Analysis; D016016:Proportional Hazards Models; D034101:Sporozoites / Q000276:immunology / Q000469:parasitology; D016019:Survival Analysis; D016896:Treatment Outcome