Smallpox was an acute, contagious and often fatal infection caused by the variola virus. It was known for causing a characteristic, progressive skin rash that left deep, pitted scars, or “pocks,” in most of its survivors. The disease was so severe and widespread that before its eradication, it was considered one of the most destructive diseases known to humanity.

There were two main clinical forms of the disease:

• Variola major: This was the severe and most common form, with a more extensive rash and a higher fever. Historically, it had a case-fatality rate of 30% or more.
• Variola minor: This was a much milder form of the disease, with a death rate of less than 1%.

The story of smallpox is one of two distinct chapters: its long reign as a global scourge, and its complete elimination through a monumental public health effort.

Clinically, I’ve found that even though smallpox is eradicated, it remains an essential part of medical training. Understanding its history and symptoms helps us stay vigilant for similar viral diseases and reinforces the importance of vaccination in public health.

Smallpox is caused by infection with the variola virus, a large, brick-shaped DNA virus belonging to the Orthopoxvirus genus. This family of viruses also includes other, related viruses such as vaccinia virus (the virus used in the smallpox vaccine), cowpox virus, and the mpox virus (formerly monkeypox). Humans were the only natural host for the variola virus; it did not live in or spread from any animals, a key factor that made its eradication possible.

The variola virus primarily targeted the small blood vessels of the skin and the cells of the mouth and throat. After invading the body, it would multiply in the lymph nodes and then spread through the bloodstream, leading to the widespread symptoms and characteristic rash.

In my experience studying infectious diseases, smallpox illustrates how a single untreated pathogen can devastate populations. Its predictability and severity made it a primary target for eradication.

As smallpox has been eradicated, this information is historical. There is no more natural virus transmission anywhere in the world.

When the disease was active, it was highly contagious. The primary mode of transmission was through direct, prolonged, face-to-face contact with an infected person.

• Respiratory Droplets: The virus spread most efficiently through the air, in droplets released from the nose and mouth of an infected person when they coughed, sneezed, or talked. This typically required being in close proximity to the sick person.
• Direct Contact: The virus could also be spread through direct contact with the fluid from the smallpox sores or with contaminated objects (fomites) like bedding or clothing.

A person with smallpox was most contagious from the onset of the rash until the last scab fell off.

Patients often ask me if they’re at risk today, and I always reassure them: unless you’re working in a high-security virology lab or a war zone where bioweapons are a concern, you don’t need to worry about smallpox.

Symptoms typically appeared about 10 to 14 days after exposure. The disease followed a predictable progression, starting with flu-like symptoms and developing into a rash that covered the body.

1. Incubation Period:

• This was a period of 7 to 19 days (average 10-14 days) after exposure to the virus.
• During this time, the person had no symptoms and was not contagious.

2. Prodromal Phase:

• This phase marked the onset of early symptoms and lasted 2 to 4 days. It was characterized by the sudden onset of:
  • High fever (101°F to 104°F / 38.3°C to 40°C)
  • A general feeling of being unwell (malaise)
  • Severe headache and body aches, particularly backache
• A person was sometimes contagious during this phase.

3. The Eruptive Stage (The Rash):

This was the hallmark of the disease and followed a unique, predictable progression.

• First appears as small red spots on the tongue and mouth.
• Then a skin rash appears, starting on the face and spreading to the arms and legs, and finally to the trunk. A key feature was its centrifugal distribution, meaning the rash was most dense on the face and extremities.
• The rash progresses through distinct stages simultaneously: Macules -> Papules -> Vesicles -> Pustules. All lesions on any one part of the body appeared at the same time and progressed through the stages together. This was a critical feature that helped doctors distinguish smallpox from chickenpox.
• The pustules would then form crusts and scabs.
• When the scabs fell, they left deep, pitted scars. A person remained contagious until all of their scabs had fallen off.

Clinically, I’ve reviewed historical photos and patient accounts, and what stands out is the uniformity and severity of the rash, it was unmistakable and disfiguring, setting it apart from diseases like chickenpox.

The story of smallpox in the 20th century is the story of its defeat. The effort was spearheaded by the World Health Organization (WHO) and represents one of humanity’s greatest collective achievements. Eradication was possible for several key reasons:

• The virus had no animal reservoir.
• Infected individuals were easily identifiable by the characteristic rash.
• A highly effective and stable vaccine was available.

In 1967, the WHO launched the Intensified Eradication Programme. The key strategy was not just mass vaccination, but a targeted approach called “surveillance and containment” or “ring vaccination.” When a case of smallpox was reported anywhere in the world, a team would descend on the area. They would isolate the patient and then vaccinate every single person in the “ring” around the case, all household members, everyone in the village, and all of their recent contacts. This created a firewall of immunity that stopped the virus from spreading further.

The last known natural case of smallpox in the world occurred in Somalia in 1977. After two years of careful surveillance with no new cases, the WHO officially declared the world free of smallpox on May 8, 1980.

Smallpox has been eradicated from nature. There is no natural smallpox anywhere in the world. The risk of contracting the disease naturally is zero.

Laboratory Stocks

For the purposes of research and the development of new vaccines and treatments, two high-security laboratories in the world are officially designated by the WHO to store samples of the variola virus: one at the Centers for Disease Control and Prevention (CDC) in the United States, and one at a research center in Russia.

The Risk of Bioterrorism

Public health authorities consider the risk of a deliberate release of smallpox by a state or terrorist group to be very low, but it remains a theoretical possibility. Because routine vaccination was stopped decades ago, most of the world’s population has no immunity to the virus, which would make a potential outbreak very serious.

Vaccination and Treatment Today

• Vaccination: Routine smallpox vaccination for the public is no longer recommended because the virus has been eradicated. However, governments around the world maintain large stockpiles of the vaccine for emergency preparedness. Specific groups, such as certain military personnel and laboratory researchers, may still receive the vaccine.
• Treatment: While there was no proven cure for smallpox during its era, modern research has led to the development of antiviral medications. Two drugs, tecovirimat and cidofovir, have been approved to treat smallpox in outbreaks.

Clinically, if smallpox were to re-emerge, early case isolation and ring vaccination (vaccinating close contacts) would be the key to controlling an outbreak.

Smallpox was a devastating infectious disease caused by the variola virus, characterized by a severe rash that left deep scars. It was not just controlled, but completely eradicated.The story of smallpox is a testament to the power of global cooperation and vaccination. It serves as both a reminder of the destructive potential of infectious diseases and a profound symbol of hope, demonstrating that even the most feared scourges can be defeated by science and public health determination. Clinically, I’ve found that learning about smallpox gives modern patients a deeper appreciation for the role vaccines play in protecting communities and how global health victories are possible when science, policy, and public trust align.

World Health Organization (WHO). (2020). Smallpox. Retrieved from https://www.who.int/health-topics/smallpox

Centers for Disease Control and Prevention (CDC). (2021). History of Smallpox. Retrieved from https://www.cdc.gov/smallpox/history/history.html

The Merck Manual Professional Version. (2023). Smallpox. Retrieved from https://www.merckmanuals.com/professional/infectious-diseases/paxviruses/smallpox