Abstract

Zoonotic spillover, the transmission of viral pathogens from animal reservoirs to human hosts, has caused the majority of emerging infectious disease events in the past century, including
HIV, Ebola, Zika, SARS, MERS, and SARS-CoV-2. Understanding the mechanisms that
drive spillover is essential for pandemic prevention and preparedness. This comprehensive
review synthesizes evidence from 150 studies (2000–2025) examining the ecological, virological, host, and behavioral determinants of viral spillover. We analyze the multi-step
process: viral circulation in reservoir hosts (bats, rodents, non-human primates, birds, livestock), mechanisms of cross-species transmission (receptor binding, host restriction
factors, viral polymerase fidelity), bridging factors that bring reservoir and human populations
into contact (land use change, deforestation, wildlife trade, livestock intensification, bushmeat
hunting), and within-human transmission potential (R₀, antigenic novelty, pre-existing
immunity). Spillover is not a random event but a predictable consequence of anthropogenic
environmental change and viral evolution. Key findings: bats are the reservoirs for
coronaviruses, filoviruses, henipaviruses, and lyssaviruses; rodents for hantaviruses and
arenaviruses. Land use change is the dominant driver, increasing human-wildlife contact. We
recommend One Health surveillance at human-animal interfaces, targeted viral discovery in
high-risk reservoirs, land use policy reforms, wildlife trade regulation, and early warning
systems for spillover hotspots.