The disease

What is smallpox?

Smallpox is a virus. It is a type of poxvirus that belongs to a large group of viruses known as orthopoxviruses, which include monkeypox, cowpox, and vaccinia virus, among others. Smallpox virus only infects people.

Symptoms of smallpox begin with a two- to five-day period of:

• High fever
• Malaise, meaning feeling “out of sorts”
• Backache 

These symptoms are followed by the development of a rash. The rash begins in the lining of the mouth and throat as well as on the face and forearms before spreading to the trunk and legs.  

The rash changes over time:

• First, red bumps that are flat to the skin develop.
• The flat bumps change to raised bumps.
• The bumps become liquid-filled blisters.
• Finally, the blisters become scabs. 

The time from the beginning of the rash to the formation of scabs is about two weeks.

Smallpox lesions occur in the deep layers of skin. As a result, survivors often have lifelong pockmarks on the skin after they recover. These pockmarks were so disfiguring that mirrors were often removed from the homes of women who recovered from smallpox.

Smallpox was also a deadly disease. About 30 of every 100 people infected with smallpox died from the disease.

How do you catch smallpox?

Smallpox spreads from one person to another by large droplets from the mouth and throat of people who have the disease. This means two things:

• The virus is spread by coughing, sneezing or talking. 
• Contact has to be fairly close, within about 6 feet, of the infected person for spread to occur.

Smallpox is different from chickenpox in how it spreads. Whereas chickenpox virus (varicella) can spread before the rash occurs, smallpox only spreads after the rash has developed. The virus that is spread from one person to another is contained in the blisters in the mouth and throat. It can also spread through contact with the fluid or scabs from the blisters, such as by direct contact or on contaminated items, but this type of spread is less common.

Usually, it takes about 12 days from the time a person is exposed to the virus to the start of symptoms.

The vaccine

The smallpox vaccine was the first vaccine. People were protecting themselves and their families against smallpox for many years using a technique called “variolation.” Variolation involved taking pus from the sore of a person with smallpox and inoculating it into someone who did not have immunity. While this approach likely saved many people from having smallpox, it was dangerous because there was no standard for what was inoculated from one person to another, and as a result, some people died simply trying to protect themselves from smallpox.

Edward Jenner is often credited with developing the first vaccine. His approach moved people away from variolation. Jenner was a family physician who lived in southern England. He noticed that every few years, when smallpox would sweep across the English countryside, women who milked cows (milkmaids) did not get smallpox. He reasoned that these women were getting infected with cowpox, an orthopoxvirus that, as its name suggests, infects cows. When the milkmaids came in contact with blisters on the udders of cows during milking, the milkmaids would develop cowpox infections. The immunity from these infections protected them from infection with smallpox. 

In 1796, Jenner published the results of experiments in which he tested his theory. To do this, Jenner took fluid from the blisters of cows and injected it into several people, including his 15-month-old son, to see if they would then be protected against smallpox. It worked.

See an illustrated story of Edward Jenner’s experiment.

Vaccination continued until smallpox was virtually eradicated. The last natural case occurred in the U.S. in 1949, but cases could still be imported, so vaccination continued. Vaccination of the general population was stopped in the U.S. in 1972. Administration to healthcare workers was discontinued in 1976, and administration to international travelers was discontinued in 1982.

What is the smallpox vaccine and how is it made?

Over time, vaccination using cowpox virus was replaced with a vaccine that relied on live, weakened vaccinia virus, another orthopoxvirus. These vaccinia virus vaccines were the type used during the eradication of smallpox. 

Today, even though most people are not at risk for smallpox, some are at risk for mpox. So, the vaccinia virus vaccine can be used to protect against infection with monkeypox virus. While two vaccinia-based vaccines are approved for use in the U.S., only one is currently used:

• Jynneos — This vaccine is made using a live, weakened vaccinia virus that has been altered so it cannot reproduce. The vaccine became available in 2019 and is given in two doses separated by 28 days. This is the version of orthopoxvirus vaccine available in the U.S. today.
• ACAM2000 — This vaccine is made using a live, weakened vaccinia virus. Because this virus can still reproduce, people experience more side effects from this vaccine, including the development of a sore at the injection site. Because the sore contains live, weakened virus, people can accidentally inoculate themselves causing lesions on other parts of the body, such as their face or genitals, or they can spread the virus to others, causing them to develop an infection. For this reason, ACAM2000 is not currently available. This vaccine is, however, part of the national stockpile, and in the event of a bioterrorist attack, it could be used to protect more people in an emergency. 

How is the smallpox vaccine administered?

Jynneos

This vaccine is given in one of two ways:

• In the fat layer below the skin, called “subcutaneous” injection
• Between the layers of skin, called “intradermal” injection

You can find out more about these two methods of administration and the considerations for each in the “Other questions you might have” section on the “Mpox: The Disease & Vaccines” page of our website.

ACAM2000

Previous smallpox vaccines, including ACAM2000, were administered in a unique manner. A drop of the vaccine virus was placed on the upper arm. The drop was then inoculated into the skin using a two-pronged, stainless-steel needle. The needle was used to puncture the skin three or 15 times depending on whether the person was vaccinated in the past. People getting their first vaccine got three punctures, whereas those getting a booster dose of vaccine received 15 punctures. ACAM2000 is administered as a single dose with 15 punctures of the skin regardless of whether it is the first time for vaccination or not. 

The vaccination done in this way causes a lesion and a residual, lifelong scar. In fact, many people over 50 years of age can still see the scar on their arm. 

Does the smallpox vaccine have side effects?

Jynneos

People who get this vaccine may have injection site reactions, like pain, redness and itching. If the vaccine is given between the layers of skin, they may also develop a lesion. When the vaccine is given between the fat layers below the skin, development of a lesion is less likely.

Other side effects can include:

• Fever
• Headache
• Tiredness
• Nausea
• Chills
• Muscle aches

ACAM2000

This vaccine initially causes a red, raised bump at the site of inoculation. This bump usually appears between two and five days after vaccination. The bump progresses to a blister and eventually a scab. The scab then separates from the skin about two to three weeks after inoculation.

Side effects from the vaccine include: 

• Fever (more commonly in children than adults)
• Swelling of the lymph node in the armpit near the site of inoculation between three and 10 days after vaccination and lasting for a few weeks after the skin lesion has healed
• Itching
• Sore arm
• Headache
• Body aches
• Mild rash 
• Tiredness

Severe side effects following administration of this vaccine do occur but are relatively uncommon:

• In a small number of people, the smallpox vaccine can cause swelling of the heart or the tissue that surrounds it (myocarditis and pericarditis), leading to chest pain or pressure, fast or irregular heartbeat, or breathing problems. These can occur up to four weeks after receipt of the vaccine and should be brought to the attention of a healthcare provider as they can cause a medical emergency.
• Swelling of the brain or spinal cord.
• Stevens-Johnson syndrome (SJS), a condition that causes flu-like symptoms as well as severe blistering and detachment of the skin.
• Overwhelming infection that spreads throughout the body and includes a widespread rash, more common in people with eczema.
• Skin and tissue death at the site of injection; more common in people who are immune compromised, such as from HIV or an organ transplant.
• Bacterial infection of the vaccination site.
• Spread of the virus to other parts of the body, or even to other people, particularly if the recipient scratches the injection site and then touches another part of their body without washing their hands. This spread can occur in the eye and cause damage to the cornea, including blindness.
• Fetal death if given during pregnancy.
• Severe allergic reaction shortly after receipt of the vaccine, called anaphylaxis.
• Death resulting from some of these severe side effects.

While anyone can experience side effects, some people are at greater risk. These include people who:

• Have eczema, atopic dermatitis or other skin issues
• Have heart conditions or a family history of heart problems, including history of heart attack, congestive heart failure, stroke or other conditions
• Smoke
• Have high blood pressure, high cholesterol, diabetes, or high blood sugar
• Are pregnant or breastfeeding
• Are less than 1 year old
• Are using steroid-based eye medications
• Had allergic reactions to previous doses or are allergic to neomycin or polymyxin B

ACAM2000 is no longer routinely used in the U.S. because of the number and severity of potential side effects and the large number of people more likely to experience them. However, during a bioterrorist event when large numbers of people could require protection quickly, and given the high death rate from smallpox infections, the stockpile of this vaccine could be an important tool.

Who should get the smallpox vaccine?

Since smallpox has been eradicated, most people are not recommended for vaccination to protect themselves against smallpox. However, protection against one orthopoxvirus often means having protection against other orthopoxviruses. Therefore, three reasons exist for keeping vaccines that can protect against smallpox available. The vaccine recommendations are informed by these reasons: 

1. Other orthopoxviruses, such as monkeypox virus, can cause disease. To see who is recommended for vaccination due to risk for mpox, check the “Mpox: The Disease & Vaccines” page of our website.
2. Smallpox has been considered as a possible weapon of bioterrorism. For this reason, some members of the military are vaccinated.
3. Some people work with orthopoxviruses in labs, so they are recommended for vaccination as well.

If a bioterrorist attack were to occur, vaccine recommendations would likely be considered for the public.

Other questions you might have

How long does immunity to smallpox last?

The smallpox vaccine was discontinued for routine use in the U.S. in 1972. So, most people in this country younger than 50 years of age have never been vaccinated against smallpox. But what about people older than 50? Does immunity to smallpox last 50 years or longer?

The best study to answer this question was performed in England in the early 1900s. An outbreak of smallpox affecting more than 1,000 people occurred in Liverpool between 1902 and 1903. People infected with smallpox were divided into two groups: Those who got smallpox vaccine in infancy and those who did not. The death rate for 30- to 49-year-olds was 3.7% in the vaccinated group and 54% in the unvaccinated group. For those older than 50 years of age, the fatality rate was 5.5% in the vaccinated group and 50% in the unvaccinated group.

Therefore, smallpox vaccine protected against disease caused by smallpox, even 50 years after vaccination.

Is smallpox the only disease to be eradicated?

Smallpox was the first human infection to be successfully eradicated. Eradication, which means elimination from the face of the earth, was accomplished by vaccination and public health procedures to track and contain the disease. The last case of natural smallpox occurred in Somalia in 1977, and the WHO declared it eradicated in 1980. The success in eradicating smallpox provided hope for the eradication of other devastating diseases, such as polio, rubella and measles. 

For more about the public health efforts that eradicated smallpox, check the book, House on Fire: The Fight to Eradicate Smallpox, by Dr. William Foege.

To date, the only other viruses to be eradicated include: 

• Rinderpest — A virus that infected cattle. 
• Type 2 poliovirus — Unfortunately, a vaccine-derived variant of type 2 polio virus still causes disease in some people because of its use in the oral polio vaccine (OPV). While no longer used in the U.S., OPV is still used in some other countries. This version contains live, weakened polio virus. Because the vaccine virus replicates in the intestine, recently vaccinated people can shed the virus in their feces causing its spread to other people. As a result, while type 2 polio virus no longer spreads in the environment (i.e., naturally), the vaccine virus does. This version is known as “vaccine-derived polio virus,” or VDPV, because it was introduced by the vaccine.

Relative risks and benefits

Do the benefits of the smallpox vaccine outweigh its risks?

No. Smallpox infections no longer occur in the world. Currently, the risks of the vaccine to prevent smallpox clearly outweigh its benefits for most people. However, if smallpox infections were to occur again in the U.S., the relationship between vaccine risks and benefits would change dramatically.

Disease risks

Although smallpox is deadly, no cases occur anywhere in the world, so the risk today is zero. Because there is no risk of smallpox, this is a situation in which the use of a vaccine does NOT outweigh the risks of disease.

Vaccine risks

Jynneos has minor side effects, but it is not used to prevent smallpox because there is no risk.

ACAM2000 has several risks, including some potentially severe and life-threatening effects, including:

• Inflammation of heart or tissues surrounding heart
• Infection of the inoculation site
• Inadvertent inoculation of another site or other people
• Swelling of brain or spinal cord
• Severe allergic reaction
• Rarely, death

For these reasons, this vaccine is not currently used in the U.S. It is, however, part of the national stockpile and could be used in the event of a bioterrorist event.

References

Orenstein WA, Offit PA, Edwards KM and Plotkin SA. Smallpox and Vaccinia in Plotkin’s Vaccines, 8th Edition. 2024, 1057-1086.

Cohen, J. Smallpox vaccinations: how much protection remains? Science 2001: 294:885.

Reviewed by Paul A. Offit, MD, on March 4, 2026