Environmental distribution of certain modified live-virus vaccines with a high safety profile presents a low-risk, high-reward to control zoonotic diseases.

Oral vaccines aid immunization of hard to reach animal populations but often contain live-attenuated viruses that pose risks of reversion to virulence or residual pathogenicity. Human risk assessment is crucial prior to vaccine field distribution but there is currently no standardized approach. We mapped exposure pathways by which distribution of oral vaccines may result in inoculation into people and applied a Markov chain to estimate the number of severe adverse events. We simulated three 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. The risk of SAD-B19-associated human deaths was predicted to be low (0.18 per 10 million baits, 95% CI: 0.08, 0.36) when distributed to foxes, but, consistent with international concern, 19 times greater (3.35 per 10 million baits, 95% CI: 2.83, 3.98) when distributed to dogs. We simulated no deaths from SPBN GAS-GAS. Human deaths during dog campaigns were particularly sensitive to dog bite rate, and during wildlife campaigns to animal consumption rate and human contact rate with unconsumed baits. This model highlights the safety of third generation rabies vaccines and serves as a platform for standardized approaches to inform risk assessments.