After most of one family on a Montana camping trip are mysteriously stricken with fever and skin rashes, Dr. Connor and Dr. Durant soon make a startling discovery -- the victims suffer from smallpox, a deadly disease thought to be eradicated. The FBI moves to track a rogue scientist suspected of unleashing the virus. As the dragnet for the dangerous biochemist and his mobile RV lab continues, Dr. Connor's team finds a dead Native American who was infected as well as shot. At the hospital, Dr. Durant bonds with the family's otherwise healthy but frightened little girl (as Brooke, guest star Laura Marano).

Evidence of a strange plague is found near Baltimore as Dr. Connor, Dr. Durant and the response team arrive and discover a deadly link between infected police officers and a fugitive that adds a more chilling dimension to their investigation. When two children also display symptoms of the resistant contagion, Connor and Frank desperately work backwards to connect the dots and limit the contamination while curing those already sick.