The bubonic plague.
In A.D. 1346 some 100 million people inhabited Europe, northern Africa and the Near East. Five years later 25 million were dead--victims of the Black Death. The plague kept reappearing, but the epidemics did not spread as widely: apparently a new and milder strain of Yersinia pestis evolved that made at least some people immune to the virulent strain.
McEvedy
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D000818:Animals; D001208:Asia; D004196:Disease Outbreaks / Q000266:history; D004197:Disease Reservoirs; D005060:Europe; D049668:History, 15th Century; D049669:History, 16th Century; D049670:History, 17th Century; D049671:History, 18th Century; D049672:History, 19th Century; D049673:History, 20th Century; D049691:History, Medieval; D006801:Humans; D010930:Plague / Q000266:history* / Q000635:transmission