HighlightsCandidate RSV vaccines are under development.Early infant RSV illness is associated with subsequent wheeze-associated disorders.We estimated sample sizes needed for vaccine trials to prevent these outcomes.RSV vaccine trials will likely not be large enough to detect reductions in wheeze.Alternative study designs to demonstrate RSV vaccine impact on wheeze are needed.

Background: Over half the world's population is at risk for viruses transmitted by Aedes mosquitoes, such as, dengue and Zika. The primary vector, Aedes aegypti, thrives in urban environments. Despite decades of effort, cases and the geographic range of Aedes-borne viruses (ABV) continue to expand. To date, there are no rigorously proven vector control interventions that prevent ABV diseases. Spatial repellents, a new option, are designed to decrease human exposure to ABV by releasing active ingredients into the air that disrupt mosquito-human contact. Methods: A parallel, cluster-randomized controlled trial was conducted in Iquitos, Peru to quantify the impact of a transfluthrin-based spatial repellent on ABV infection. From 2,907 households across 26 clusters (13 per arm), 1,578 participants were assessed for seroconversion (primary endpoint) by survival analysis. Incidence of acute disease was calculated among 16,683 participants (secondary endpoint). Bi-monthly adult mosquito collections were conducted to compare Ae. aegypti abundance, blood-fed capture rate and parity status through mixed effect difference-in-difference analyses. Results: The spatial repellent significantly reduced ABV infection by 34.1% (95% CI 6.9%, ∞); p = 0.0236, z=1.98). Aedes aegypti abundance and blood-fed capture rates were significantly reduced by 28.6% (95% CI 24.1%, ∞); z=-9.11) and 12.4% (95% CI 4.2%, ∞); z=-2.43), respectively. Conclusions: Our trial provides the first conclusive evidence of significant protective efficacy by any chemical vector control intervention, in this case a spatial repellent, to reduce the risk of ABV transmission. Results support vector control as a beneficial component to ABV disease prevention. Trial registration number:NCT03553277 (clinicaltrials.gov)

Given the limited effectiveness of strategies based solely on vector control to reduce dengue virus (DENV) transmission, it is expected that an effective vaccine could play a pivotal role in reducing the global disease burden of dengue. Of several dengue vaccines under development, Dengvaxia® from Sanofi Pasteur recently became the first to become licensed in select countries and to achieve WHO recommendation for use in certain settings, despite the fact that a number of uncertainties about its profile complicate projections of its public health impact. We used a stochastic, agent-based model for DENV transmission to perform simulations of the public health impact of dengue vaccines in light of two key uncertainties: (1) "statistical uncertainty" about the numerical value of the vaccine's efficacy against disease, and (2) "biological uncertainty" about the extent to which its efficacy against disease derives from the amelioration of symptoms, blocking of DENV infection, or some combination thereof. Simulations of a generic dengue vaccine showed that the proportion of disease episodes averted following 20 years of routine vaccination of nine-year olds at 80% coverage was sensitive to both the numerical value of vaccine efficacy and to the extent to which efficacy derives from blocking of DENV infection. Simulations of a vaccine resembling Dengvaxia® took into account that vaccine trial results substantially reduced statistical uncertainty but did not address biological uncertainty, resulting in the proportion of disease episodes averted being more sensitive to biological uncertainty than to statistical uncertainty. Taken together, our results indicate limitations associated with the use of symptomatic disease as the primary endpoint of dengue vaccine trials and highlight the importance of considering multiple forms of uncertainty in projections of a vaccine's public health impact.