Accelerating vaccine trials during an outbreak of Disease-X: the effect of pathogen super-spreading on ring-trial design

ABSTRACT The prospective design of vaccine efficacy trials for deployment in outbreaks requires advance consideration of plausible outbreak scenarios, anticipated vaccine characteristics, and logistical and ethical constraints. As part of CEPI’s 100 Days Mission to accelerate vaccine development against a novel Disease X, we evaluated trial designs for a hypothetical Nipah-X outbreak. We assumed Nipah-X would share key features with Nipah, including high case fatality rates and substantial super-spreading, but with sustained human-to-human transmission. Using simulations based on infection models, including an extended chain-binomial model incorporating super-spreading, we compared ring-trials using cluster-randomisation with individual-randomisation within rings. High levels of super-spreading markedly reduced the power of cluster-randomised designs due to strong intra-cluster correlations in case numbers, whereas individual-randomisation retained power. These findings highlight that understanding and accounting for super-spreading is critical when designing ring-trials, as cluster-randomised designs may fail unless vaccine efficacy is nearly complete.