History’s greatest killers are small, invisible and deceptive microbes. All together killed many more than history’s greatest criminal. They include Mycobacterium tuberculosis (Mtb), variola virus, human immunodeficiency virus (HIV), Plasmidium falciparum, Yesinia pestis, influenza, Vibrio cholerae, and recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), among others [1-3].

Going back in time... Plague, caused by Yersinia pestis, bacterium transmitted from rodents (usually rats or squirrels) by flea bites, is infamous for killing millions of people in Europe during the Middle Ages. It is considered the likely cause of the Black Death that swept through Asia, Europe and Africa, killing an estimated 75-200 million people in the 14th century, including one third of the European population (!) [1, 2].

The other example, smallpox, caused by the variola virus, haunted humanity for millennia, easily spreading through sneezing or shared contact. In 30% of cases, smallpox was lethal, while the survivors often exhibited complications such as blindness, arthritis, secondary infections and scars from the lesions. It is estimated that smallpox killed around 500 million people in the last 100 years of its existence. In 1980, following mass-vaccination campaigns, smallpox became the first and only human infectious disease declared eradicated by the World Health Organisation  (WHO) [4]. Of note, today smallpox only exists frozen in research laboratories. Interestingly, there are two WHO-designated sites where stocks of variola virus are stored and used for research: Centers for Disease Control and Prevention, Atlanta, Georgia, United States, and the Russian State Centre for Research on Virology and Biotechnology, Koltsovo, Novosibirsk Region, Russian Federation [5].

Flu, a very well known virus to  a modern human. Seasonal influenza outbreaks occur annually and affect around 4 million people with about 250 000 deaths worldwide. Typically, people with weakened immune system, such as elderly and people with pre-existing conditions such as heart failure are at increased risk. The most notable influenza pandemic was the Spanish flu pandemic of 1918 that killed more than 40 million people. Smaller outbreaks have also occurred with bird and swine flu's emerging. A threat of a new outbreak exists due to large scale farming of chickens and pigs, flu's natural reservoirs, and close proximity of humans to those animals [1, 2].

New outbreaks continuously emerge in human populations, an obvious reminder of this being a recent pandemic of SARS-CoV-2, but also previous outbreaks of avian influenza, Ebola, SARS, Middle East respiratory syndrome coronavirus (MERS-CoV) and Zika virus. Factors such as population growth, urbanization, increase in global connectivity and variety of human activities contributing to antimicrobial resistance, climate change, disturbance of ecological balances, biodiversity loss, all promote a fertile environment for the emergence of new infectious diseases [6]. Nevertheless, it is important to say, the vast majority of the viruses that infect humans have little or no impact on our health and well-being. We eat and breathe billions of virions regularly and we carry viral genomes as part of our own.


4. WHO. Smallpox.  [cited 2023; Available from:

5. CDC. History of smallpox.  [cited 2023; Available from:

6.  Heiman F. L. Wertheim, P.H., John P. Woodall,, Atlas of Human Infectious Diseases. 2012: Wiley-Blackwell.