The first outbreaks of Nipah virus were discovered in Bangladesh in 2001 (25), and after years of One Health investigations of spillovers, an understanding of the source began to form in 2005 (26). Epidemiologic studies identified date palm sap consumption as a key risk factor for Nipah virus infection, and social scientists studied how the sap was harvested and sold (26–29). Date palm sap is collected from trees and drunk fresh during the cool, winter months; it is a cultural delicacy (29). Wildlife investigations identified that bats shed virus in their urine and saliva (30), ecologic investigations revealed that bats drink and contaminate date palm sap as it drips into the pots (31), and virologic studies showed that Nipah virus is stable in date palm sap (32). Further studies then demonstrated that simple covers of the pots and sap stream on the tree, which were already being used by some sap collectors, would protect the sap from contact with bats

The investigation typically begins with medical experts who understand the clinical manifestations of the disease and natural history of infection because the spillover is detected when a sick person seeks care. Spillovers sometimes also occur first in other species, which become bridging hosts to humans. Laboratory analysis of the genetic sequence of the pathogen can provide more information about its origins and potential reservoir hosts. Concurrently, epidemiologic investigations can determine the exposures that led to infection and assess if transmission is ongoing through extensive contact tracing efforts. Next, veterinary and ecologic investigations of animals in the affected communities can identify potential reservoir species and bridging hosts. Social scientists contribute in-depth understanding of how local practices might have enabled exposure and transmission, including human–animal interactions and their drivers. Finally, environmental and ecologic investigations elucidate how changes in the reservoir host condition or distribution might have enabled spillover.

Spillovers do provide actionable data. Once an emerging pathogen infects a human, a public health threat is actualized. Those events garner our attention and concern much more than hypothetical risk warnings. Particularly alarming is evidence of transmission of the pathogen from human to human, because this capability is necessary to cause a pandemic.

One approach is to model geographic areas at high risk for spillovers, correlating putative drivers with locations of past spillovers and overlap of humans and reservoir species (4–6). Those efforts aim to focus surveillance and resources on areas or species of high risk. Substantial investments have led to the discovery of new viruses infecting rodents, bats, and primates, including viruses that were phylogenetically related to outbreak causing pathogens, suggesting a potential risk for spillover (7–19). Although such efforts have produced findings of interest, they have not produced actionable public health data. Those approaches do not inform which pathogens are spilling over and the mechanisms driving these events.

A spillover occurs when a pathogen infects a new host species (2,3). The vast majority of spillovers will not lead to an outbreak or pandemic. However, for pathogens with pandemic potential, each spillover into a human is an opportunity to launch a pandemic.