Can incorporating genotyping data into efficacy estimators improve efficiency of early phase malaria vaccine trials?

BACKGROUND: Early phase malaria vaccine field trials typically measure malaria infection by PCR or thick blood smear microscopy performed on serially sampled blood. Vaccine efficacy (VE) is the proportion reduction in an endpoint due to vaccination and is often calculated as [Formula: see text] – hazard ratio or [Formula: see text] – risk ratio. Genotyping information can distinguish different clones and distinguish multiple infections over time, potentially increasing statistical power. This paper investigates two alternative VE endpoints incorporating genotyping information: [Formula: see text] , the vaccine-induced proportion reduction in incidence of new clones acquired over time, and [Formula: see text] , the vaccine-induced proportion reduction in mean number of infecting clones per exposure. METHODS: We used simulations and analytic derivations to compare power of these methods to [Formula: see text] and [Formula: see text] and applied them to three data sets: a Phase 3 trial of RTS,S malaria vaccine in 6912 African infants, a Phase 2 trial of PfSPZ Vaccine in 80 Burkina Faso adults, and a trial comparing Plasmodium vivax incidence in 466 Papua New Guinean children after receiving chloroquine + artemether lumefantrine with or without primaquine (as these VE methods can also quantify effects of other prevention measures). By destroying hibernating liver-stage P. vivax, primaquine reduces subsequent reactivations after treatment completion. RESULTS: The RTS,S vaccine significantly reduced the number of clones at first infection, but PfSPZ vaccine and primaquine did not. Resampling smaller data sets from the large RTS,S trial to simulate phase 2 trials showed modest power gains from [Formula: see text] compared to [Formula: see text] for data like RTS,S, but [Formula: see text] is less powerful than [Formula: see text] for vaccines which do not reduce the number of clones at first infection. [Formula: see text] was most powerful in model-based simulations, but only the primaquine trial collected enough serial samples to precisely estimate [Formula: see text]. The primaquine [Formula: see text] estimate decreased after most control arm liver-stage infections reactivated (which mathematically resembles a waning vaccine), preventing [Formula: see text] from improving power. CONCLUSIONS: The power gain from the genotyping methods depends on the context. Because input parameters for early phase power calculations are often uncertain, we recommend against these estimators as primary endpoints for small trials unless supported by targeted data analysis. TRIAL REGISTRATIONS: NCT00866619, NCT02663700, NCT02143934