Measures of clinical malaria in field trials of interventions against Plasmodium falciparum

BACKGROUND: Standard methods for defining clinical malaria in intervention trials in endemic areas do not guarantee that efficacy estimates will be unbiased, and do not indicate whether the intervention has its effect by modifying the force of infection, the parasite density, or the risk of pathology at given parasite density. METHODS: Three different sets, each of 500 Phase IIb or III malaria vaccine trials were simulated corresponding to each of a pre-erythrocytic, blood stage, and anti-disease vaccine, each in a population with 80% prevalence of patent malaria infection. Simulations considered only the primary effects of vaccination in a homogeneous trial population. The relationships between morbidity and parasite density and the performance of different case definitions for clinical malaria were analysed using conventional likelihood ratio tests to compare incidence of episodes defined using parasite density cut-offs. Bayesian latent class models were used to compare the overall frequencies of clinical malaria episodes in analyses that did not use diagnostic cut-offs. RESULTS: The different simulated interventions led to different relationships between clinical symptoms and parasite densities. Consequently, the operating characteristics of parasitaemia cut-offs in general differ between vaccine and placebo arms of the simulated trials, leading to different patterns of bias in efficacy estimates depending on the type of intervention effect. Efficacy was underestimated when low parasitaemia cut-offs were used but the efficacy of an asexual blood stage vaccine was overestimated when a high parasitaemia cut-off was used. The power of a trial may be maximal using case definitions that are associated with substantial bias in efficacy. CONCLUSION: Secondary analyses of the data of malaria intervention trials should consider the relationship between clinical symptoms and parasite density, and attempt to estimate overall numbers of clinical episodes and the degree of bias of the primary efficacy measure. Such analyses would help to clarify whether the effect of an intervention corresponds to that anticipated on the basis of the parasite stage that is targeted, and would highlight whether the primary measure of efficacy results from unexpected behaviour in the parasitological and clinical data used to estimate it.