What's the Harm? A Risk Model to Quantify Human and Animal Adverse Events From Environmentally Distributed Modified Live-Vaccine Viruses : [Preprint]

Background: While oral vaccines aid immunization of hard to reach animal populations, the use of live-attenuated viruses in many oral vaccines, including first generation oral rabies vaccines, pose risks of reversion to virulence or residual pathogenicity. While a detailed human risk assessment is crucial prior to field distribution of live-attenuated vaccines, there is currently no standardized approach. Methods: We mapped exposure pathways by which distribution of oral vaccines targeting wildlife or free-roaming dogs may result in mucosal, transdermal, or severe inoculation into people. We applied a continuous-time Markov chain to estimate the number of severe adverse events. We tested the model using three scenarios of oral rabies vaccination (ORV) campaigns: 1) first generation ORV (SAD-B19) in foxes, 2) SAD-B19 in dogs, and 3) third generation ORV (SPBN GASGAS) in dogs. Findings: A low risk of 0·18 (95% CI: 0·08, 0·36) vaccine-associated human deaths per 10 million baits was simulated for campaigns where SAD-B19 was distributed to foxes. However, consistent with international concern, our model predicts that SAD-B19 distributed to dogs could result in 3·35 (95% CI: 2·83, 3·98) vaccine-associated human deaths per 10 million baits. The model simulated no deaths for SPBN GASGAS. Human deaths during dog campaigns was particularly sensitive to dog bite rate, and human deaths during wildlife campaigns was particularly sensitive to animal uptake rate and human contact rate with unconsumed baits. Interpretation: This model highlights the safety of newer live-attenuated rabies vaccines and serves as a platform for standardized approaches to inform risk assessments. Funding Statement: Time for this study was funded through a co-agreement between the Pubic Health Institute and the Centers for Disease Prevention and Control. The funding source had no role in the study design, analysis, preparation of the manuscript, or decision to publish the manuscript. Declaration of Interests: AV is a full time employee of a pharmaceutical company, IDT Biologika GmbH, which manufactures oral rabies vaccine baits. TM from the FriedrichLoeffler-Institute received funding from IDT Biologika GmbH in the frame of a research cooperation for research into mechanisms of oral rabies vaccination and resulting immunity