1 Statistical and biological uncertainties associated with vaccine efficacy estimates and their implications for dengue vaccine impact projections T. Alex Perkins 1,2 *, Robert C. Reiner 2,3 , Quirine A. ten Bosch 1 , Guido España 1 , Amit Verma 4 , Kelly A. Liebman 5 , Valerie A. Paz-Soldan 6 , John P. Elder 7 , Amy C. Morrison 5 , Steven T. Stoddard 7 , Uriel Kitron 2,8 , Gonzalo M. Vazquez-Prokopec 2,8 , Thomas W. Scott 2,5 , David L. Smith 2,3 1 Department of Biological Sciences and Eck Institute for Global Health, University of Notre Dame, Notre Dame, IN 2 Fogarty International Center, National Institutes of Health, Bethesda, MD 3 Institute for Health Metrics and Evaluation, University of Washington, Seattle, WA 4 Center for Disease Dynamics, Economics, and Policy, Washington, DC 5 Department of Entomology and Nematology, University of California, Davis, CA 6 Department of Global Community Health and Behavioral Sciences, Tulane University School of Public Health and Tropical Medicine, New Orleans, LA 7 Institute for Behavioral and Community Health, Graduate School of Public Health, San Diego State University, San Diego, CA 8 Department of Environmental Sciences, Emory University, Atlanta, GA * Author for correspondence: taperkins@nd.edu ABSTRACT Given the limited effectiveness of strategies based solely on vector control to reduce dengue virus transmission, it is expected that an effective vaccine could play a pivotal role in reducing the global disease burden of dengue. Dengvaxia® from Sanofi Pasteur recently became the first dengue vaccine 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 the vaccine’s efficacy and mode of action complicate projections of its potential impact on public health. We used a new stochastic individual-based model for dengue transmission to perform simulations of the impact of Dengvaxia® in light of two key uncertainties: statistical uncertainty about the numerical value of the vaccine’s efficacy against disease, and biological uncertainty about the extent to which its efficacy against disease derives from the amelioration of symptoms, blocking of dengue infection, or some combination thereof. Our results suggest that projections of the vaccine’s public health impact may be far more sensitive to biological details of how the vaccine protects against disease than to statistical details of the extent to which it protects against disease. Under the full range of biological uncertainty that we considered, there was nearly three-fold variation in the population-wide number of disease episodes averted. These differences owe to variation in indirect effects of vaccination arising from uncertainty about the extent of onward transmission of dengue from vaccine recipients. These results demonstrate important 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 impact on public health. . CC-BY-NC-ND 4.0 International license peer-reviewed) is the author/funder. It is made available under a The copyright holder for this preprint (which was not . http://dx.doi.org/10.1101/082396 doi: bioRxiv preprint first posted online Oct. 24, 2016;