Future threats: Animal orthoflaviviruses that currently infect fewer than 100 people per year.

After long periods of evolution, several orthoflaviviruses, including dengue, Japanese encephalitis, tick-borne encephalitis, West Nile, yellow fever, and Zika viruses, have emerged from nature to infect humans in high numbers. It should be worrisome that there are other orthoflaviviruses now undergoing the same emergence steps, with potential for the same type of outcome as the viruses above. In this review, we document 25 orthoflaviviruses currently infecting fewer than 100 people per year and another 12 for which serological data suggest human exposure, though infection has not been confirmed. The viruses highlighted here have a non-trivial chance of causing human epidemics or pandemics. However, very little is known about the biology of these neglected viruses, and medical countermeasures are lacking for most. Now, before these viruses spill over into the human population, is the time to study the biology of these viruses and to develop or improve PCR- and serology-based diagnostics to enable better monitoring.