The Antonine Plague 165 - 180 AD A suspected smallpox outbreak, it may have killed as many as five million. 5,000 a day were dying in Rome.
The Asiatic (Russian) Flu 1889 - 1890 First reported in Russia in May of 1889, it hit North America in December. By February 1890, it had travelled to South America. Later, it hit India and Australia. The flu had a very high mortality rate, killing at least 250,000 in Western Europe.
Smallpox Epidemics Among Native Americans 1492 - 1900 Although no one knows for sure, various sources estimate that the pre Columbian population of the Americas was around 75 million, with as many as 12 million living in North America. A US census count in 1900 put the Native American population at 237,000. That is, by any standard, a precipitous drop in population.
While there are dozens of things to blame for this decline, the spreading of European diseases—especially the highly virulent smallpox—throughout the Native American populations was a major factor. The smallpox (and other disease) outbreaks among Native Americans, therefore, must rank as one of the worst outbreaks of disease of all time.
We know we were inoculated against small pox by the scar on our arm or leg. In 1980, when Ryen was the age to get the incolated, it had been decided their was more risk from the vaccine than from not having it.