Its hallmark symptom is a distinctive rash that changes in appearance as the disease progresses. (1,2) Smallpox is deadly, killing around 3 in 10 people who are infected. Some experts estimate that in the 20th century alone, smallpox was responsible for 300 million deaths. (3) A global smallpox immunization campaign led to the eradication of the disease in the late 1970s. Today, two government research laboratories — one in the United States, the other in Russia — hold the last remaining stores of the virus responsible for smallpox. (4) The first symptoms are usually:
High feverHeadachesBody aches, including backachesVomiting
These symptoms typically last two to four days and are severe enough to prevent normal day-to-day activities. Other possible symptoms may include:
ChillsSevere abdominal painFatigueDeliriumDiarrheaMalaiseNauseaExcessive bleeding (1,5,6)
After the first symptoms of headaches, fever, and body aches, the next sign of the disease to appear is a rash, beginning with small, flat red spots on the tongue and in the mouth. The rash develops into sores that break open. Typically within a day, the rash spreads to the face and then to the arms and legs, followed by the hands, feet, and the rest of the body. As the rash develops, the fever may go down, causing infected people to feel like they’re getting better. Within a couple of days, the rash turns into small red bumps that look like blisters. By the fourth day of the rash, the spots transform into sores that fill with a thick, opaque fluid and have a dent in the center. The fever may then resume for the duration of the rash. The crater-like sores turn into pustules (pus-filled lesions), becoming sharply raised, round, and firm to the touch. These pustules may break open, oozing and becoming bloody. After about five days, the pustules begin to form a crust and then scab over. Most sores reach this stage by the end of the second week of the rash. The scabs fall off after about one more week, leaving deep pockmarks. (5,7,8) There are two species of variola virus — Variola major and Variola minor. The first can lead to life-threatening illness, while the second rarely results in death. (1) Humans are the only known carriers of the variola virus. Other Orthopoxvirus viruses are normally transmitted to humans from infected animals. (6)
How Is Smallpox Transmitted?
Smallpox is most contagious after the rash develops. Transmission occurs through:
Prolonged face-to-face contact with someone infected with the variola virus, who may spread it through saliva by coughing, sneezing, or speakingContact with an infected person’s bodily fluids, especially fluid from blisters on the skinTouching items that have been contaminated with the variola virus (via scabs or fluid from sores), such as blankets, towels, or clothes — the virus can survive outside the body for up to 24 hours (1)Breathing in the virus if it has become airborne and circulated through a ventilation system, such as one in a small office, bus, or train (9,10,11)
According to the Centers for Disease Control and Prevention (CDC), the major diagnostic criteria for smallpox are:
A fever of at least 101 degrees F (38.3 degrees C), which develops one to four days before a rash and is accompanied by at least one other symptom, including extreme weakness, headache, backache, chills, vomiting, or severe abdominal painClassic smallpox lesions as described aboveLesions that are in the same stage of development on any one part of the body (such as having only pustules on the arms, rather than a mix of pustules and blisters)
If a person meets the above criteria it’s highly likely they have smallpox. Minor diagnostic criteria (lower likelihood) include:
A rash with the greatest concentration of lesions on the face and extremitiesLesions that first appear in the mouth or on the face or forearmsExtreme illnessRash that evolves into different forms slowlyLesions on the palms of the hands or soles of the feet
Laboratory tests can rule out other potential diagnoses, such as chicken pox, and confirm a smallpox diagnosis. (12)
How Does Smallpox Differ From Chicken Pox?
Though both smallpox and chicken pox cause fever and rash, the two diseases are not the same. Chicken pox is caused by the varicella zoster virus, a type of alpha herpesvirus (not belonging to the Orthopoxvirus genus). Though chicken pox can sometimes cause serious complications, the illness is often mild. (13) There are also differences between smallpox and chicken pox rashes. Chicken pox rash often develops soon after other symptoms begin (if there are any) and looks like small blisters; the itchy lesions develop one after another, rather than all at once in a single area; and the lesions change rapidly, usually forming scabs within 24 hours. (14,15) Initial symptoms last for two to four days and typically include high fever, headaches and body aches, and sometimes vomiting. The person may be contagious during this phase. A person is most contagious over the next four days, when a red rash appears and spreads, then turns into fluid-filled sores. The next phase, in which the sores become pustules, then form into scabs, lasts about 10 days. It takes about six days for the scabs to fall off. At this point the person is no longer contagious. (5,9) But in recent years, researchers have developed antiviral medications for smallpox. In 2018, the U.S. Food and Drug Administration (FDA) approved the drug tecovirimat (TPOXX) to treat smallpox. The drug works by inhibiting the activity of a protein called p37, which ultimately prevents viral particles from leaving an infected cell and spreading to other cells. (18) Research shows that tecovirimat is effective against the variola virus in laboratory settings (in cell cultures) and can treat diseases similar to smallpox in animals. Studies also show tecovirimat is safe, with the most frequent side effects being headache, nausea, and abdominal pain. But since the drug was developed after the eradication of smallpox, it hasn’t been tested on human subjects, causing some uncertainty about how well it would work in the unlikely event of an outbreak. Other studies have shown that the antiviral drugs cidofovir (currently used to treat an eye infection called cytomegalovirus retinitis in people with AIDS) and brincidofovir (an experimental drug also used to treat cytomegalovirus retinitis as well as adenovirus) are effective against smallpox in lab settings and can treat smallpox-related diseases in animals. Neither cidofovir nor brincidofovir have been tested on people with smallpox. Scientists continue to study the drugs’ effectiveness and toxicity. The CDC has stockpiles of tecovirimat and cidofovir in case of a public-health emergency. (19)
Prevention of Smallpox
Healthcare workers no longer routinely administer smallpox vaccines to the general public. The CDC recommends smallpox vaccination only for laboratory researchers who study the variola virus or its close relatives. Still, the CDC has stockpiles of smallpox vaccine — enough to give one to every person in the United States if necessary. (20) The original smallpox vaccine contains live vaccinia virus, which is in the same Orthopoxvirus genus as the variola virus but causes a less severe illness. Exposure to the vaccinia virus prompts the immune system to produce antibodies that are also effective against the variola virus. This method of gaining smallpox immunity was first developed by the English doctor Edward Jenner. In 1796, after observing that milkmaids who got cowpox never developed smallpox, he took material from a cowpox sore and inoculated it into the hand of his gardener’s 9-year-old son. Then he repeatedly exposed the boy to the variola virus — and the child did not develop smallpox. Sometime in the 1800s, the virus used to make the smallpox vaccine switched from cowpox to vaccinia. (4) The smallpox vaccine prevents infection in 95 percent of those who receive it, and is also able to prevent or lessen infection when given within a few days of exposure to variola virus. The smallpox vaccine can’t help people with advanced infection who are already developing a rash. (21) Since the eradication of smallpox, scientists have developed a newer version of the vaccine that uses attenuated (weakened) viral strains. This vaccine is suitable for people who can’t take the original vaccine, such as those who are pregnant, have a weakened immune system, or have had a bone-marrow transplant. The new smallpox vaccine hasn’t been tested against the variola virus in people, so its effectiveness is still unproven. (22)
Side Effects of the Smallpox Vaccine
Unlike most other vaccines, the smallpox vaccine does not involve an injection or “shot.” Instead, it’s administered with a bifurcated (two-pronged) needle that is first dipped into the vaccine solution. A doctor uses the needle to prick the skin (usually in the upper arm) multiple times in a few seconds. A successful vaccination causes a red and itchy lesion to develop at the vaccine site within three to four days. This lesion turns into a large blister that fills with pus and begins to drain in the first week. It begins to dry and scab over in the second week and then falls off (leaving a small scar) in the third week. (21) During this process, the vaccinia virus can be easily transferred to another part of the body or even another person through touch. Touching the vaccination sore and then the eye can lead to a serious infection that can threaten vision. The vaccination sore may also develop into a serious toxic or allergic rash. Rarely, people develop other significant or even life-threatening reactions to the vaccine, including:
Inflammation of the heart, heart lining, or bothHeart pain and heart attackSerious rash called eczema vaccinatum (in people with preexisting skin conditions, particularly eczema or atopic dermatitis, who got infected with the vaccinia virus from someone else who was vaccinated)Progressive vaccinia, or a buildup of inflamed tissue at the vaccination site, in people with a weakened immune systemBrain inflammation
Research suggests these complications kill one or two people out of every million vaccinated for smallpox. But most people who get the smallpox vaccine experience only mild reactions. These may include:
Pain and redness at the vaccination siteSwollen lymph nodes in the armpitsLow-grade feverTrouble sleepingGeneral malaise that interferes with daily activities (1,23)
When sores in the mouth break open, the virus infects the trachea and lungs. But before the virus can spread much farther, it needs to replicate. Research suggests this likely happens in the lymphoid organs, specifically the spleen, bone marrow, and lymph nodes. After replication, the virus can move into the bloodstream, causing secondary infections of other organs:
The cells lining the small blood vessels of the liver often become swollen and die, and the liver becomes much heavier than normal.Certain cells in the bone marrow and spleen become enlarged.The spleen becomes engorged and fills with many large lymphoid cells.The brain may become inflamed (encephalitis).
Smallpox can also cause eye infections, pneumonia, arthritis, and bone infections. (1) Death from smallpox usually results from high blood pressure, issues with blood coagulation, and cardiovascular collapse. Some people develop a severe, rare form of smallpox called hemorrhagic smallpox, which causes bleeding, especially of the skin, the mucous membranes throughout the body, and the gastrointestinal tract. (24) Most people diagnosed with smallpox survive, but they can be left deeply scarred or blind. For people at heightened risk, such as those who are pregnant or immunocompromised, smallpox can be fatal. (10) But the virus can be found inside laboratories for research purposes. In 1981, just four labs — in the United States, England, Russia, and South Africa — kept variola virus. By 1984, England and South Africa had either destroyed their variola stocks or transferred them to other approved labs, leaving only two labs with the virus: the CDC, headquartered in Atlanta, and the State Research Center of Virology and Biotechnology (VECTOR Institute) in Koltsovo, Russia. (4) There is some concern that these stores could be stolen and used in a bioterrorism attack. While this risk is low, the CDC has an emergency plan in place and continues to develop new vaccines and medications. (25) In an unsettling 2014 incident, scientists cleaning out an old laboratory on the National Institutes of Health campus in Bethesda, Maryland, found vials labeled “variola.” The CDC collected the vials and brought them to Atlanta. (26) A similar incident occurred in November 2021, at a Merck vaccine research facility in Pennsylvania, but no one was exposed. RELATED: Vials Labeled ‘Smallpox’ Found at Merck Facility Outside Philadelphia
History of Smallpox
While no one has smallpox now, this disease has been a threat to public health for thousands of years. Archaeologists found smallpox-like rashes in three Egyptian mummies from the third century B.C., as well as on the mummy of Ramses V, who died in 1157 B.C. But these lesions may have been caused by many other diseases, including those produced by other poxviruses. Ancient Indian treatises provide the first reliable descriptions of smallpox, though it’s unclear how old these medical texts are. Some experts date the treatises to the sixth century B.C, while others claim they go all the way back to the 15th century B.C. In China, the first reliable description of smallpox was in the fourth century A.D., though some evidence suggests the disease first appeared there in the third century B.C. (27) Exploration and trade over the centuries helped smallpox go global. Smallpox reached Japan in the sixth century A.D.; northern Africa, Spain, and Portugal in the seventh century; and Central and South America in the 16th century. North America saw its first cases of smallpox in the 17th century and Australia in the 18th century. In 1959, the World Health Organization initiated a vaccination program to rid the world of smallpox and launched renewed efforts in 1967 with its intensified eradication program. In 1975, a 3-year-old girl from Bangladesh named Rahima Banu was the last person on the planet to naturally acquire variola major; in 1977, a hospital cook in Somalia named Ali Maow Maalin was the last person to have naturally acquired variola minor. In 1978, a woman named Janet Parker became the last known person to die of smallpox. A medical photographer at the Birmingham University Medical School in England, Parker worked on a floor above a microbiology lab that was researching variola virus. Scientists suspect she contracted the disease by visiting the lab or through airborne virus that traveled through the building’s ventilation system. (4) In 1520, a Spanish ship sailing from Cuba, which was carrying an infected enslaved African, arrived in Mexico. Academics believe this marked the arrival of smallpox in the Americas. The disease began to circulate, and rapidly wiped out an estimated 90 percent of Native Americans. European populations had gained increased immunity to the disease, thanks to repeated exposure, but Native Americans had no immune defense for the virus. (28,29,30) In Australia, the first recorded major smallpox epidemic broke out in 1789. Most of the British colonists there had been exposed to smallpox as children and were unaffected, but the disease ravaged the Aboriginal community, killing up to 70 percent of that population. (31) The slave trade also spread smallpox across Africa. Historians have traced smallpox infections to traders’ caravan routes. In 1713, after exposure to smallpox from Europeans, whole clans of Khoisan people died, making it easier for Europeans to wrest control of their land. (30) Until 1977, smallpox outbreaks were still common in South America, Africa, and Asia. (4,30,32) The leading public health institute in the United States, the CDC works to protect citizens from threats like smallpox. Its website is a go-to resource for information about smallpox, including vaccines and bioterrorism risk. Mayo Clinic Based in Rochester, Minnesota, Mayo Clinic is a nonprofit dedicated to clinical practice, education, and research. Its website offers an overview of smallpox, including information on symptoms, diagnosis, and treatment. MedlinePlus MedlinePlus is part of the U.S. National Library of Medicine, the world’s largest biomedical library. The MedlinePlus homepage for smallpox has a brief introduction to the disease with links to other websites for details on symptoms and prevention. Another page on the website has a helpful explainer on smallpox. National Institute of Allergy and Infectious Diseases (NIAID) NIAID supports research — basic, preclinical, and clinical — to advance product development for biodefense and emerging infectious diseases, including new vaccines and treatments for smallpox. The NIAID website also delves into smallpox prevention and treatment. World Health Organization (WHO) Founded in 1948, the World Health Organization is a United Nations specialized agency focused on international public health. Its website delivers extensive information on smallpox, including the methods that resulted in the eradication of the disease and current efforts to prevent outbreaks. CDC Emergency Preparedness and Response This website provides information on diseases like smallpox as well as natural disasters like tornados. The CDC has separate pages about potential smallpox bioterrorism and smallpox bioterrorism response planning. U.S. Food and Drug Administration (FDA) The FDA website collects news on smallpox and facts about the disease; information about the FDA’s role in smallpox emergency preparedness and response; basic info and links regarding smallpox vaccines, treatments, and diagnostic procedures; and emergency contact numbers. Additional reporting by Shira Feder.
