Smallpox was a highly contagious and often deadly disease caused by the variola virus. It spread mainly through close contact with infected people, especially by breathing in droplets released when they coughed, sneezed, or talked. The virus could also spread through contaminated bedding, clothing, or surfaces.
Without treatment, smallpox killed about 30 percent of those infected. Survivors often carried lifelong scars, and some suffered permanent blindness. Its symptoms included fever and a rash that developed into distinctive skin sores. For centuries, smallpox caused repeated outbreaks, killing millions of people and reshaping societies by influencing wars, reducing populations, and altering the course of civilizations.
In 1980, the World Health Organization announced that smallpox had been completely eradicated after a worldwide vaccination campaign. The last known natural case occurred in Somalia in 1977. This achievement is regarded as one of the greatest successes in public health and medical history.
Although smallpox no longer exists in nature, it remains important for science and history. Protection against the disease still comes from the smallpox vaccine, which uses a related virus called vaccinia to create immunity. If smallpox were to reappear—through an accident or deliberate release—control efforts would rely on vaccination, isolation of patients, and supportive treatment such as fluids, nutrition, and antiviral drugs like tecovirimat (TPOXX), cidofovir, and brincidofovir.
Forms of Smallpox?
There were two main clinical forms of smallpox: variola major and variola minor. Variola major was the more severe form and historically accounted for the majority of cases. It was associated with higher mortality rates, often killing about 30 percent of those infected, and it caused extensive scarring and complications such as blindness in many survivors. Variola minor, in contrast, was a milder form of the disease. It produced similar symptoms but with much less severity, and the fatality rate was typically below 1 percent. Although variola minor caused fewer deaths, both forms contributed to widespread illness, social disruption, and the need for mass vaccination efforts until eradication was achieved.
Causative Agent
Smallpox is caused by the variola virus, a member of the genus Orthopoxvirus within the family Poxviridae. It is a large, double-stranded DNA virus that is unique in its strict adaptation to humans, with no identified animal reservoirs. This exclusivity of human infection was a major factor that made global eradication possible.
The virus typically entered the body through the respiratory tract, where it began to replicate in the mucous membranes of the nose and throat. From there, it spread to regional lymph nodes and subsequently entered the bloodstream in a process known as viremia. This systemic spread allowed the virus to infect multiple organs and tissues, eventually reaching the skin, where the characteristic pustular rash developed.
Structurally, the variola virus is notable for its brick-shaped morphology and large genome, which encodes numerous proteins that help it evade the host immune response. Although the virus could survive outside the human body for only limited periods, particularly in scabs shed from lesions, this environmental stability was sufficient to aid person-to-person transmission. Transmission occurred primarily through inhalation of airborne droplets, but could also result from contact with contaminated materials such as clothing or bedding.
Unlike many RNA viruses, the variola virus did not mutate rapidly. Its genetic stability was a key factor in the success of vaccination, as the immunity conferred by the vaccinia virus (a related orthopoxvirus used in vaccines) remained effective across centuries of use. This stability, combined with the absence of non-human hosts, contributed to the feasibility of eradication through coordinated global vaccination campaigns.
Historical Significance
Smallpox has profoundly influenced human societies for millennia, with evidence of the disease traced back to ancient civilizations. Characteristic pockmarks identified on the mummy of Pharaoh Ramses V of Egypt (died c. 1157 BCE) suggest its presence in North Africa during antiquity. Early written records from India and China, dating as far back as the 3rd century BCE, also describe illnesses resembling smallpox, indicating its long-standing impact on human populations.
Throughout history, smallpox caused recurring epidemics with high mortality rates, contributing to population declines across Asia, Africa, Europe, and later the Americas. In Europe, major outbreaks shaped social, political, and military outcomes, weakening armies and influencing the course of wars. In the Americas, the introduction of smallpox by European colonists in the 15th and 16th centuries had catastrophic effects on Indigenous populations, who had no prior exposure or immunity to the disease. Mortality in some communities reached 70 to 90 percent, profoundly altering the demographic and cultural landscape of the continent.
The devastation caused by smallpox also spurred medical innovation. In Asia, practices resembling inoculation (variolation) were documented in China and India centuries before their introduction to Europe. These methods involved deliberate exposure to material from smallpox lesions to induce a milder infection and subsequent immunity. Building on these early practices, the English physician Edward Jenner introduced vaccination in 1796, using material from cowpox lesions to protect against smallpox. Jenner’s discovery laid the foundation for modern immunology and remains one of the most significant milestones in medical history.
In the 20th century, coordinated international efforts to eliminate smallpox began under the leadership of the World Health Organization. Through mass vaccination campaigns, surveillance, and containment strategies, smallpox transmission was gradually halted worldwide. The last naturally occurring case of variola major was reported in Bangladesh in 1975, while the final case of the milder variola minor occurred in Somalia in 1977. In 1980, the World Health Assembly officially declared smallpox eradicated.
Smallpox remains the only human infectious disease to have been eradicated globally.
Symptoms and Progression
Smallpox begins with distinct early symptoms that signal the onset of infection. These initial signs lead into a characteristic rash that follows specific stages. Complications vary in severity and may impact recovery.
Early Signs
Smallpox typically starts with high fever around 101 to 104 °F (38.3 to 40 °C). Patients often experience severe fatigue, headache, and back pain. Malaise and vomiting can also occur within the first 2 to 4 days.
During this period, the virus targets mucous membranes and skin cells. Swelling of lymph nodes (lymphadenopathy) is common and helps distinguish smallpox from similar illnesses like chickenpox.
Stages of Rash
The rash progresses in distinct phases: macules, papules, vesicles, pustules, and scabs.
- Macules: Flat, red spots appear first, usually on the face and arms.
- Papules: Raised bumps form after 1-2 days.
- Vesicles: Clear fluid-filled blisters emerge next, becoming painful.
- Pustules: These blisters fill with pus and become firm and dome-shaped.
- Scabs: Pustules crust over and eventually fall off in about 2-3 weeks.
The rash typically appears simultaneously on all parts of the body. It is often most dense on the face and extremities.
Complications
Smallpox was associated with a wide range of complications, which contributed to its high mortality and lasting impact on survivors. Secondary bacterial infections of the characteristic skin lesions were common and could lead to sepsis, significantly increasing the risk of death. Respiratory complications, such as viral or secondary bacterial pneumonia, were frequent in severe cases and represented one of the leading causes of fatal outcomes. Neurological complications, including encephalitis (inflammation of the brain), occurred less often but were often severe, sometimes resulting in long-term cognitive or motor impairments.
Permanent scarring and skin discoloration were the most visible long-term consequences among survivors, particularly on the face and extremities. Involvement of the eyes could lead to corneal ulceration, keratitis, and subsequent blindness, a recognized complication that left many survivors with partial or complete loss of vision.
The risk of complications was especially high in children, malnourished individuals, and those with weakened immune systems. Pregnant women faced particularly poor outcomes, with infection frequently leading to miscarriage, stillbirth, or neonatal death. In rare cases, severe hemorrhagic forms of smallpox developed, characterized by widespread bleeding and high fatality rates.
Transmission and Contagion
Smallpox spreads primarily through direct contact and airborne particles. The length of contagiousness and exposure risks influence how widely the disease may spread.
Modes of Transmission
The most common route of transmission was through respiratory droplets, released when an infected person coughed, sneezed, or even spoke. Because these droplets typically did not travel long distances, infection usually required prolonged, face-to-face contact.
Secondary transmission occurred via contaminated materials, including bedding, clothing, or surfaces that carried the virus from infectious scabs or bodily fluids. The virus could survive for days to weeks in scabs, making fomites (objects carrying infection) a significant source of spread in households and healthcare settings. Entry into the body typically occurred through the respiratory tract or, less frequently, through broken skin or mucous membranes.
Though less common, airborne transmission was possible, particularly in enclosed, poorly ventilated spaces such as hospitals, where the virus could remain suspended in the air for longer periods. This mode of transmission occasionally resulted in outbreaks beyond immediate close contacts, though it was not the dominant pathway. Unlike some pathogens, the smallpox virus did not persist for long outside the human body, meaning transmission generally required close or repeated exposure.
Infectious Period
Smallpox patients became contagious roughly 1 to 2 days before the rash appeared, coinciding with the onset of fever and early symptoms. The period of greatest infectivity corresponded with the rash and pustular stages, when the skin lesions contained high concentrations of virus.
Contagion persisted until the last scabs separated and the skin underneath healed, a process that typically lasted 3 to 4 weeks. During this time, patients could transmit the virus directly or indirectly. Because scabs could harbor live virus, handling contaminated materials even late in the disease carried infection risks. Effective outbreak control depended on strict isolation of infected individuals throughout the full infectious period.
Risk Factors
Several factors influenced the likelihood of infection. Close contact with a patient, especially within households or healthcare settings, posed the highest risk. Healthcare workers, caregivers, and family members were particularly vulnerable. Poor hygiene and the sharing of personal items could facilitate indirect spread, while crowded living conditions and inadequate ventilation increased the chances of transmission.
Individuals lacking prior vaccination or natural immunity were most at risk of infection and severe disease. Children, malnourished individuals, and those with compromised immune systems faced a higher probability of complications and death. Pregnant women were also especially vulnerable, as infection often led to miscarriage or stillbirth.
Diagnosis of Smallpox
Diagnosis involves identifying distinct clinical features and confirming the presence of the virus through laboratory tests. Early detection relies heavily on recognizing characteristic symptoms and rash patterns, while lab methods provide definitive evidence.
Clinical Assessment
Clinicians diagnosed smallpox primarily through recognition of its distinct clinical presentation. The illness typically began with a sudden onset of high fever, malaise, headache, and back pain, followed within two to four days by the appearance of a rash. The rash characteristically started on the face, hands, and forearms, later spreading to the trunk and legs.
The lesions of smallpox were noted for being firm, deep-seated, and well-circumscribed, progressing in a uniform manner across affected areas. The stages included macules (flat spots), papules (raised bumps), vesicles (fluid-filled blisters), pustules (pus-filled lesions), and finally scabs that detached after healing. Unlike chickenpox, in which lesions appear in successive “crops” and vary in stage, smallpox lesions progressed synchronously, meaning they developed and matured at the same time in each region of the body. Another distinguishing feature was the greater concentration of lesions on the face and extremities, including the palms and soles, compared with chickenpox, which predominantly affects the trunk.
Recognition of these clinical patterns was essential in differentiating smallpox from other vesicular diseases such as chickenpox, monkeypox, or severe drug reactions.
Laboratory Testing
While clinical features provided the first indication of smallpox, definitive diagnosis required laboratory confirmation. The polymerase chain reaction (PCR) remains the most sensitive and specific method, allowing direct detection of variola DNA in clinical samples.
Virus isolation in cell culture was historically possible but is rarely performed today due to biosafety risks, as variola virus can only be handled under the highest level of laboratory containment (Biosafety Level 4). Electron microscopy can identify orthopoxvirus particles by their characteristic “brick-shaped” morphology but cannot distinguish variola virus from other closely related orthopoxviruses such as vaccinia or monkeypox.
Serological tests, which detect antibodies, have limited value for acute diagnosis since antibodies typically appear late in the infection, often after clinical recovery has begun. Therefore, they were not useful in identifying early or active cases.
Accurate testing required proper collection of clinical specimens, most commonly obtained from vesicular or pustular fluid and scab material. Because of the potential public health implications, suspected cases of smallpox were historically treated as medical emergencies requiring immediate laboratory confirmation and public health response.
Treatment and Care
There is no known cure for smallpox, and treatment historically focused on symptom management, prevention of complications, and supportive care while the body’s immune system fought the infection. Modern medical advances, particularly the development of antiviral drugs, have added new options for treatment in the event of a re-emergence. Because of the disease’s high fatality rate and risk of spread, patient isolation and strict infection control measures were central to management.
Supportive Therapies
Supportive care formed the foundation of smallpox treatment. Maintaining adequate hydration was essential, as high fever and sweating frequently led to fluid loss. Fluids could be given orally or intravenously, depending on the severity of the patient’s condition. Fever and pain were commonly managed with antipyretics such as acetaminophen or ibuprofen.
Isolation of infected patients was critical to prevent further transmission, as individuals remained contagious until all scabs had fallen off. Wound care was required for the extensive skin lesions, which needed careful cleansing and sterile dressing to prevent secondary bacterial infections. Nutritional support was also important to preserve strength and promote recovery during the illness, particularly for children and malnourished individuals.
Antiviral Medications
Although no specific antiviral therapy was available during the era of naturally occurring smallpox, modern research has identified drugs with activity against orthopoxviruses. Tecovirimat (TPOXX), approved for smallpox treatment, prevents the virus from forming an envelope protein necessary for spreading between cells. It is most effective when administered early in infection.
Other antiviral agents, such as cidofovir and its derivative brincidofovir, have shown activity against variola virus and may be used in cases resistant to first-line treatment. Both drugs act by inhibiting viral DNA replication, thereby reducing viral load and disease severity. However, they require close monitoring, as cidofovir is associated with kidney toxicity. In most scenarios, antiviral therapy would be used in combination with supportive care to improve patient survival rates.
Management of Complications
Severe complications were common in smallpox and required targeted interventions. Secondary bacterial infections of the skin or lungs were treated with antibiotics to prevent sepsis or pneumonia. In cases of viral or bacterial pneumonia, respiratory support, including oxygen therapy or mechanical ventilation, could be necessary.
Neurological complications, such as encephalitis, required intensive care and close monitoring for seizures or altered mental status. Patients with ocular involvement needed specialized ophthalmologic treatment to reduce the risk of corneal ulceration and blindness. In critically ill patients, management also included measures to stabilize shock, organ failure, or severe systemic reactions, often requiring advanced supportive care in intensive care units.
Vaccination and Prevention
Smallpox prevention relied heavily on vaccination efforts. Development of the vaccine, strategies for its use, and methods to prevent disease after exposure all contributed to controlling the virus.
Smallpox Vaccine Development
The first smallpox vaccine was developed by Edward Jenner in 1796, who demonstrated that inoculation with the related cowpox virus provided protection against smallpox. This early method stimulated the immune system without causing the severe illness associated with variola virus infection.
Over time, the vaccine was refined to use the vaccinia virus, another orthopoxvirus closely related to smallpox. Advances in vaccine production, including lyophilization (freeze-drying), extended the shelf life and improved distribution, allowing vaccines to be stored and transported to remote regions without loss of potency.
Immunologically, the vaccine worked by triggering both antibody production and immune memory cells, providing long-term protection. A single dose was estimated to be about 95% effective, with most vaccinated individuals developing lifelong immunity or protection lasting several decades.
Vaccination Strategies
During the twentieth century, mass vaccination campaigns became the cornerstone of global smallpox control. These efforts targeted entire populations in endemic regions, aiming for at least 80% vaccination coverage to interrupt transmission chains.
Later, the ring vaccination strategy was introduced and proved critical to eradication. In this approach, health workers isolated confirmed cases and vaccinated all close contacts, neighbors, and potential secondary exposures. This created a “ring” of immunity around each case, preventing further spread.
Routine vaccination schedules typically required only a single dose, with boosters reserved for individuals at continued risk, such as laboratory staff working with orthopoxviruses. Public health authorities also monitored for adverse reactions, which, while rare, included complications such as post-vaccinal encephalitis or progressive vaccinia in immunocompromised individuals.
Post-Exposure Prophylaxis
Vaccination within 3-4 days of exposure to the virus can prevent or significantly reduce the severity of smallpox. This is because the vaccine stimulates immunity faster than the virus can replicate.
Post-exposure vaccination was used in outbreak control to limit secondary cases. Those vaccinated after exposure typically developed milder symptoms or remained asymptomatic.
Combining vaccination with quarantine and surveillance improved containment. This approach reduced transmission during outbreaks before smallpox was eradicated globally in 1980.
Smallpox Eradication
The eradication of smallpox represents one of the greatest achievements in the history of public health. It was the result of a coordinated global campaign that combined widespread vaccination, careful surveillance, and innovative containment strategies. The success of the eradication program not only eliminated a devastating human disease but also provided a model for tackling other infectious diseases.
World Health Organization Initiatives
The World Health Organization (WHO) formally launched the Intensified Smallpox Eradication Program in 1967, building on earlier national and regional control efforts. At the time, smallpox remained endemic in parts of Africa, Asia, and South America, causing millions of infections and hundreds of thousands of deaths each year.
The program emphasized surveillance and containment, marking a shift from mass vaccination alone. WHO provided standardized vaccine supplies, refrigeration systems for storage, and technical training for health workers worldwide. Vaccinators were equipped with the bifurcated needle, a simple and cost-effective tool that made vaccine administration easier and more reliable.
The ring vaccination strategy became central to the campaign. Instead of attempting to vaccinate entire populations indiscriminately, health teams identified each confirmed case of smallpox and vaccinated all close contacts, neighbors, and local community members. This approach created a protective barrier of immunity around each outbreak, halting chains of transmission more efficiently than mass campaigns.
Milestones in Eradication
The eradication campaign achieved steady progress throughout the late 1960s and 1970s. National programs, particularly in India, Bangladesh, and Ethiopia, faced challenges due to large populations, difficult geography, and political instability, yet succeeded through persistent case-finding and vaccination drives.
In October 1977, the last naturally occurring case of variola major was recorded in Ali Maow Maalin, a hospital cook in Somalia. This event marked a turning point in the program, as Somalia was among the last regions with endemic transmission.
The last known case of variola minor occurred in 1978 in Birmingham, United Kingdom, following a laboratory accident that resulted in one fatality. The incident highlighted the need for strict biosafety measures when handling dangerous pathogens, even after the disease was no longer circulating in the community.
In May 1980, the World Health Assembly officially declared smallpox eradicated worldwide. This made smallpox the first human infectious disease to be eradicated through deliberate public health action, a distinction it continues to hold.
Current Status and Research
Smallpox is officially eradicated, but research continues to address related health security concerns. Surveillance programs monitor for potential threats, while biosecurity measures focus on preventing misuse of the virus.
Smallpox in the Modern Era
Smallpox was declared eradicated in 1980. No naturally occurring cases have been reported since.
Stored virus samples exist only in two authorized laboratories: the CDC in the United States and the VECTOR Institute in Russia. These stocks are used for research into vaccines, antiviral drugs, and diagnostics.
Vaccination against smallpox is no longer routine, but certain groups, such as laboratory personnel and specific military units, may receive it. Research focuses on improving safer vaccines and treatments in case of an outbreak.
Ongoing Surveillance
Global health agencies maintain vigilance for any signs of smallpox reemergence.
Surveillance includes monitoring for unusual outbreaks of rash-fever illnesses that could mimic smallpox. Advanced laboratory methods help differentiate variola virus from other orthopoxviruses.
Public health organizations maintain emergency protocols, including stockpiles of vaccines and antiviral medications, to respond promptly if an outbreak is detected.
Bioterrorism Concerns
Smallpox remains a concern as a potential bioweapon due to its high contagion and severity.
Governments enforce strict controls on remaining viral stocks to prevent theft or misuse. International agreements regulate handling and research of the variola virus.
Research also explores countermeasures to mitigate impacts in case of bioterrorism, including better diagnostics, treatments, and rapid vaccination strategies.
Legacy and Lessons Learned
Smallpox has shaped modern medicine through its impact on disease control and vaccine science. Its eradication stands as a benchmark in public health and informs current strategies against infectious diseases.
Influence on Public Health
Smallpox eradication prompted the creation of robust vaccination programs and surveillance systems globally. The World Health Organization’s (WHO) 1967 intensified campaign utilized mass vaccination and case tracking to interrupt transmission effectively.
The success fostered international cooperation and built infrastructure for managing future outbreaks. Lessons in quarantine, contact tracing, and public communication from this campaign influenced responses to later epidemics, such as Ebola and COVID-19.
Public health policies now emphasize early detection and rapid response, directly tracing back to smallpox control. The eradication demonstrated that systematic and coordinated efforts could eliminate a contagious disease, guiding health priorities worldwide.
Vaccine Development Legacy
The smallpox vaccine was the first successful vaccine, created using the cowpox virus by Edward Jenner in 1796. This breakthrough introduced the concept of using a related, less dangerous virus to build immunity.
It established platforms for developing vaccines against other diseases, proving that live attenuated or related viruses could induce protective immune responses. The vaccine’s development refined understanding of immunity, dosage, and vaccine administration methods.
Vaccination logistics and global immunization strategies benefited from the smallpox experience. Modern vaccines for diseases like polio, measles, and influenza owe their development frameworks to techniques first implemented in smallpox vaccination programs.