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What is the history of Smallpox and Monkeypox (Mpox) vaccine use in America?

Updated November 03, 2023


The earliest form of vaccination against smallpox, a procedure known as inoculation or variolation, involved the lancing of a smallpox pustule from an infected individual and introducing this fluid under the skin of a smallpox susceptible individual. This procedure was believed to have been practiced in China, India, and Africa hundreds of years prior to its introduction in Europe in the early 18th Century. French philosopher Voltaire reported that in ancient China, smallpox scabs were inhaled as a powder through the nose. This practice spread to Persia and Turkey, however, instead of inhalation, the scabs were ingested. 

Inoculation Introduced in Turkey and Spreads to Europe

In 1679, variolation was reportedly introduced in Turkey by a man who inoculated many children against smallpox. This practice was also believed to be used in young women who inhabited the region north of the Caucasus Mountains, near the Black Sea. The people of this region were poor and often sold their beautiful daughters to the Shahs of Persia or the Sultans of the Ottoman Empire. 

Lady Mary Wortley Montagu, the wife of Lord Edward Wortley Montagu, the British Ambassador to Turkey, was credited for introducing smallpox inoculation in Britain. At the age of 26, Lady Mary had developed smallpox and was left permanently scarred. After witnessing the practice of variolation, Lady Mary allowed for her 6 year old son to undergo the procedure on March 18, 1718, in Turkey, without consent from her husband. Three years later, in 1721, a deadly smallpox epidemic broke out in London. Lady Mary chose to have her three year old daughter Mary inoculated. This was the first time the procedure was performed in Britain and as a result of its reported success, the practice began to gain favor within the medical community. 

Early experimentation with smallpox variolation had mixed results. While some practitioners reported success with the procedure, others noted that the practice could result in complications that included death. In Britain, early practitioners would take the smallpox pus from an infected individual and inject it into the bloodstream. Eventually, they realized that superficial scratches performed in Turkey were as effective. It was at this time that it also became known that recently inoculated individuals could spread the disease on to others. 

Inoculation in Colonial America

Information on the practice of smallpox variolation in Colonial America was introduced in 1706 by a slave from North Africa. The Reverend Cotton Mather of Boston was gifted a slave who told him of the procedure. When a smallpox outbreak occurred in 1721, Mather attempted to persuade Boston physicians to perform variolation. Only one, Zabdiel Boylston, chose to try the procedure and inoculated his young son, his slave, and his slave’s son. 

The procedure was opposed by most Boston doctors but six prominent clergyman supported Boylston and his experiments. Boylston reported that of the 242 people that he inoculated, only 6 had died. The procedure was reported as having a fatality rate of 2.5 percent which was much better than the estimated 15 percent death rate from natural disease. Authorities in Boston halted Boylston’s experiments in May of 1722. Many who expressed opposition considered it a violation of God’s Will.   

In 1738, a variation to smallpox variolation was introduced in Charleston, South Carolina. When a smallpox outbreak occurred, inoculation was performed by taking pus from a person who had recently undergone variolation. It was reported that this procedure could effectively be repeated up to 6 times and was said to significantly reduce the risk of death from the disease. Scottish physician, Dr. James Kirkpatrick, was involved in the variolation activities in South Carolina, and upon return to London, he published an essay on his experience. Kirkpatrick also assisted with the founding of the Smallpox and Inoculation Hospital of London which provided free care to those afflicted with smallpox and offered inoculations to the public. 

Variolation became more widespread in the mid-18th Century in Western Europe. Members of the Russian Royal Family were inoculated and the procedure, performed by various methods depending on the practitioner, was also introduced in the Netherlands, Germany, Switzerland, Denmark, France, and Sweden. 

Smallpox inoculations were performed during the Revolutionary War in America but frequently caused the disease to spread. Certain cities and several of the 13 colonies placed restrictions or banned its practice at one time or another. 

Inoculation Standarized for Mass Production

In 1798, British physician Dr. Edward Jenner reported that exposure to cowpox, a related virus that was considered harmless, would protect a person from smallpox. 

One of Jenner’s early experiments involved infecting an eight-year-old boy with cowpox by scraping pus from lesions of a child infected with cowpox onto the skin of the boy. Jenner then twice challenged the boy’s immunity to smallpox by scraping pus from the lesions of a person with smallpox onto the boy’s skin. The boy did not develop smallpox and Jenner widely promoted his discovery and advocated cowpox inoculation as a prevention of smallpox. 

Eventually, Jenner’s procedure was modified and standardized for mass production by the pharmaceutical industry. As Jenner refined the cowpox inoculation process, a new virus called vaccinia evolved. It is still not known exactly how the vaccinia virus came into being but theories are that it is a weakened form of the smallpox or cowpox virus or, more likely, a hybrid of the two viruses.   

This procedure, which Jenner referred to as vaccination, was initially rejected by prominent physicians of the time. Despite their public opposition to Jenner’s vaccination, several doctors began performing the procedure using materials obtained from the pustules of cows. These same physicians refused to credit Jenner for his work and made attempts to stop him from furthering his research. Jenner, however, was awarded a significant amount of money from the British government to continue his work. 

Physicians from outside of Britain also criticized Jenner’s vaccination and reported that it was ineffective. Even though the procedure was criticized by many prominent physicians of the time, vaccination campaigns began outside of Britain. The procedure was introduced to the Mediterranean region in 1800 and eventually was used in areas of Italy, France, and even Russia. 

This procedure was introduced in the U.S. in 1800 by Boston physician Benjamin Waterhouse who used it to vaccinate his son, several of his house servants, and an additional eight patients. Later that year, Dr. Elisha Story vaccinated several children and adults near Boston with vaccine materials obtained from his son who procured it from a sailor in London. The substance, which was thought to be cowpox, turned out to be smallpox, and it caused an outbreak of the disease. Many of the vaccinated individuals developed smallpox and 68 people died. This outbreak caused a backlash against vaccination. 

Waterhouse was able to secure new vaccine materials from London in March of 1801 and was granted permission to use it in May of 1802. The Boston Board of Health permitted vaccination of multiple children from the poorhouse who were subsequently exposed to smallpox and did not develop the disease. As Waterhouse was the only person who possessed the vaccine, he set up a monopoly in the U.S. and would issue it only to practitioners who agreed to give him at least one-fourth of the profits from vaccination. It would take more than a year for the monopoly to be broken. It was Waterhouse who wrote to then President Thomas Jefferson and requested that he sponsor vaccine distribution in the Southern United States. 

The first vaccine shipment proved to be ineffective, however, the next shipment was reported to be effective and was used to vaccinate Jefferson’s family and many people in the surrounding area. Vaccine materials were also brought to Washington D.C. and used to vaccinate many Native Americans. 

In 1813, President James Madison appointed Dr. James Smith of Baltimore as a Federal Vaccine agent to ensure that the smallpox vaccine was effective and to distribute it to all U.S. citizens. It was Smith who discovered that smallpox vaccination did not offer lifelong protection after a previously vaccinated child developed the disease and died. Revaccination was suggested by a colleague but Smith felt that it may be better to return to variolation. Smith’s loss of confidence in vaccination called the practice into question, and in 1821, when smallpox scabs were inadvertently used in vaccination campaigns and caused disease and death, national vaccination efforts dwindled. 

For the first part of the 19th Century, vaccination was performed by an arm to arm technique. The vaccine was frequently administered to a child and then shared to others. In the mid-1840s, the vaccine was propagated in cows. Human lymph was initially used, followed by bovine lymph. In 1850, the bovine lymph was combined with glycerol to prevent the vaccine from breaking down. This vaccine was introduced in France in 1864 and distributed throughout Europe. Smallpox vaccines formulated from calf lymph were initially introduced in the U.S. in 1870 and Britain in the 1880s. Arm to arm vaccinations were finally outlawed in Britain in 1898 when the Vaccination Act was passed.   

In 1853, Britain mandated smallpox vaccination for the entire population of England, Scotland, and Wales.  The mandates, however, were not strictly imposed as there were no mechanisms in place to enforce it. By the 1860s, further legislation enabled the appointment of vaccination officers to enforce the mandate, and these stricter laws prompted the founding of the Anti-compulsory Vaccination League in London, with chapters around the country. Many who opposed vaccine mandates did so due to personal or family harm from vaccination. 

One town in particular became known as the Mecca for persons who opposed vaccination. In the 1870s and 1880s, opposition to smallpox vaccination in the town of Leicester increased significantly. In turn, vaccination officers began strict enforcement of the law and parents who refused to get their children vaccinated were prosecuted. Prosecutions increased dramatically, however, in Leicester, those who were fined and imprisoned for refusing vaccination were considered heroes. In 1886, prosecutions were finally halted and vaccination rates in Leicester plummeted. 

Conscientious exemptions to vaccination were finally permitted by law in 1898, and smallpox vaccination rates dropped considerably. Public health officials prophesized that the decrease in vaccination rates would cause an increase of smallpox outbreaks and epidemics that would result in severe illness and death; however, this did not occur. In fact, as smallpox vaccination rates declined, cases of smallpox also decreased. Additionally, other diseases such as typhus, enteric fever and scarlet fever also decreased significantly during this same time period even though there were no vaccinations for these illnesses. Improved sanitation and higher standards of living were reported as playing a major role in the decrease of disease and death. 

Jacobson v. Massachusetts 

In the U.S. in 1904, Henning Jacobson, a Lutheran Minister, objected to a Cambridge, Massachusetts Board of Health law that required all adults to get a second smallpox vaccination or pay a $5 dollar fine. Pastor Jacobson and his son had suffered severe reactions to previous smallpox vaccinations and he argued that a genetic predisposition placed him at higher risk for dying or being injured if he was revaccinated. Jacobson also concluded that smallpox vaccine ingredients were toxic and often caused injury and even death and that medical doctors were unable to predict who would be harmed. He made the ethical and legal argument that being required to get revaccinated was an assault on his person and a violation of his 14th Amendment right to liberty and equal protection under the law. 

The attorneys representing the medical doctors persuaded judges in the state court that Jacobson did not know what he was talking about and they ruled against him. Instead of simply paying a $5 fine, Jacobson appealed to the U.S. Supreme Court. In a split decision with one dissenting vote, the Court majority, including Oliver Wendell Holmes, said that citizens do not have the right under the U.S. Constitution to be free at all times because there are manifold restraints to which every person is necessarily subjected for the common good. They said that state legislatures have the constitutional authority to enact compulsory vaccination laws and exercise police power to restrict or eliminate liberty during smallpox epidemics to secure the general comfort, health and prosperity of the state. 

The judges dismissed Jacobson’s concern about being genetically susceptible to vaccine harm. Instead they chose to incorrectly affirm the infallibility of doctors and stated that: The matured opinions of medical men everywhere, and the experience of mankind, as all must know, negative the suggestion that it is not possible in any case to determine whether vaccination is safe. 

Smallpox Vaccination in the 20th Century

In 1935, Federal Public Health Officials published a listing of biological products that possessed licenses issued through the Treasury Department in accordance with the July 1, 1902 Act of Congress entitled An act to regulate the sale of viruses, serums, toxins, and analogous products in the District of Columbia, to regulate interstate traffic in said articles, and for other purposes. 

Licensing of a product was not an endorsement that the claims made by the manufacturer were accurate. However, to obtain a license, the product did undergo routine evaluation to ensure it was free of contaminants and the production facilities were inspected. In 1935, several pharmaceutical companies manufactured smallpox vaccines. These included Parke Davis & Company, Mulford Biological Laboratories, Sharp & Dohme, The Cutter Laboratory, New York City Department of Health Laboratories, Lederle Laboratories, E.R Squibb and Sons, Eli Lilly & Company, Gilli Laboratories, Commonwealth of Massachusetts Department of Health Antitoxin and Vaccine Laboratory, United States Standard Products Company, the Michigan State Department of Health Bureau of Laboratories, and the National Drug Company. 

Initiatives to eradicate smallpox in the 20th century involved the use of vaccines containing the live vaccinia virus cultured mainly on cow skins. There were many live vaccinia virus strains used in vaccination campaigns. One vaccine, a lyophilized formulation called Dryvax derived from the New York City Board of Health live vaccinia virus strain, was manufactured by Wyeth Laboratories. Dryvax, like other vaccines manufactured during this time, used preparation methods that would have produced a mixture of viruses and frequently contained bacteria and other adventitious agents. 

In the 1950s, a method was introduced that permitted the smallpox vaccine to be freeze-dried and heat-stable which enabled the vaccine to be stored long-term without the need for refrigeration. The vaccine, however, was well recognized as highly reactive and capable of causing harm and even death. Serious adverse events reported after vaccination included progressive vaccinia, generalized vaccinia, eczema vaccinatum, postvaccinial encephalitis, and death. In persons vaccinated for the first time, serious adverse reactions were ten times more likely to occur than among revaccinated individuals. Additionally, death from vaccination was four times higher in persons initially vaccinated when compared to revaccinated individuals. 

Even though Dryvax was in use for decades in the U.S., vaccine efficacy and the level of antibodies considered protective against smallpox was never determined. Public health officials believed that a single dose of smallpox would be protective for about five years or less but antibodies could persist for over ten years. Revaccination was thought to offer more protection and boost antibody levels. Routine smallpox vaccination in the U.S. came to an end in 1971 and vaccination of health care workers stopped in 1976. 

In 1982, Wyeth Laboratories discontinued production of Dryvax for use by the general population. The vaccine, however, was still in use for routine administration of all active duty military personnel. In the discontinuation notice issued by the CDC, public health officials reported that the product’s discontinuation would stop the misuse of the vaccine as a treatment or preventative for other diseases such as herpes.  By January 1982, smallpox vaccination for international travel was no longer required. 

Public health officials began recommending smallpox vaccination for laboratory workers in 1980 as a precaution against orthopoxviruses such as monkeypox and vaccinia. Vaccination was only recommended for laboratory workers who had direct contact with cultures or animals infected or contaminated with vaccinia, recombinant vaccinia viruses, or other orthopoxviruses that infect humans such as cowpox and monkeypox. Doctors and nurses who may have contact with these viruses through contaminated materials such as dressings, but who followed appropriate infection control guidelines were considered less likely to come into contact with these viruses than laboratory workers; however, they could also consider vaccination. 

As Dryvax was a live vaccinia virus vaccine, transmission of the vaccine virus from recently vaccinated individuals to close contacts occurred and frequently involved serious complications. These transmissions prompted public health officials to caution that recently vaccinated individuals avoid contact with others, especially those with immunodeficiencies, eczema, and children under the age of one.    Additionally, the vaccine virus could also be transmitted from the vaccination site to other parts of the body and cause complications especially through open skin lesions or acne. 

Risk of Bioterrorism

In response to growing international concern of bioterrorism, the CDC published guidelines on the use of smallpox vaccination. In this recommendation, laboratory workers with direct exposure to orthopoxviruses were the only population that were recommended to receive smallpox vaccination. The potential for smallpox as a bioweapon was discussed but public health officials considered it unlikely. They did, however, recommend that in the event of a bioterrorism event, the following populations would be considered for vaccination:

  • Persons initially exposed to the virus on its release;
  • Individuals who had close contact with a confirmed or suspected smallpox patient at any time between the onset of the patient's fever until all scabs had fallen off;
  • Persons directly involved in providing medical care or assistance to confirmed or suspected smallpox patients;
  • Laboratory workers involved in collecting or processing clinical specimens from confirmed or suspected smallpox patients; and
  • Additional individuals who may be at an increased risk of infection through contact with infectious materials from a smallpox patient.

In a pre-event situation, contraindications to smallpox vaccination included persons: 

  • with a presence or history of eczema or atopic dermatitis;
  • who have acute, chronic, or exfoliative skin conditions;
  • who have immunosuppression;
  • who are less than 12 months of age;
  • who are pregnant or breastfeeding; or
  • who have previously had a serious allergy to the vaccine or who are allergic to any component of the vaccine.

The vaccine was also contraindicated for persons living with household members with a presence or history of eczema, atopic dermatitis, or acute, chronic, or exfoliative skin conditions, with immunosuppressive conditions, and those who were pregnant.

Public health officials, however, stated that in the event of a smallpox emergency, no contraindications to vaccination existed as persons considered at serious risk of injury from vaccination were also at higher risk of complications and death from the disease. 

In December 2002, President George W. Bush announced that the military and government officials in high-risk areas would begin receiving smallpox vaccination. Front-line health care workers who wanted to be vaccinated would also be given the opportunity to receive the vaccine; however, the vaccine, which was not licensed at the time of his recommendation, would not yet be available for members of the general public. In his announcement, President Bush reported that while there was no known imminent threat, preparing for the possibility of a smallpox bioterrorism attack was prudent. 

The White House stated that the U.S. Department of Health and Human Services was in the process of establishing an orderly process to make unlicensed vaccine available to those adult members of the general public without medical contraindications who insist on being vaccinated either in 2003, with an unlicensed vaccine, or in 2004, with a licensed vaccine. 

Between January 24, 2003 and December 31, 2003, nearly 40,000 civilian healthcare providers received smallpox vaccination. Ninety-seven serious and 712 non-serious adverse events occurred following vaccination.  Two vaccine associated ischemic cardiac deaths were reported among civilians who received the vaccine. 

Additionally, between December 2002 and January 2004, nearly 580,000 U.S. military personnel were administered smallpox vaccines. The vaccine’s vaccinia virus was transferred to at least 30 contacts, with most cases occurring in spouses or adult intimate contacts. One breastfed infant was also infected and developed lesions in the mouth and on the face but recovered without serious complications.  At least one vaccine associated cardiac death was reported among military vaccinees. 

By June of 2003, the smallpox vaccination program was quietly halted by the CDC following reports of serious cardiac adverse events and deaths. Further, several hospitals refused to participate in the vaccination program due to concerns over the transmission vaccine virus between vaccinees and susceptible contacts, including those with immunosuppressive conditions. 

ACAM 2000 Vaccine Approval

In August 2007, the U.S. Food and Drug Administration (FDA) approved ACAM 2000, a live smallpox (vaccinia) virus vaccine, for use in persons considered at high-risk for smallpox.  Six months later, on February 29, 2008, the CDC issued a notice that distribution of ACAM 2000 had begun. In this notice, the CDC reported that Wyeth, the manufacturer of Dryvax smallpox vaccine, was withdrawing its license and requested the immediate destruction of all vaccine doses. The CDC denied that the withdrawal was related to any quality, safety, or purity concerns, but rather due to a contractual agreement between the CDC and Wyeth. 

The CDC updated their smallpox recommendations in 2015 and recommended vaccination for all laboratory personnel who directly handle cultures or animals infected or contaminated with recombinant vaccinia viruses, replication-competent vaccinia virus, or additional infectious orthopoxviruses (e.g. cowpox, monkeypox, variola). Health care personnel treating individuals with vaccinia virus infections and those administering ACAM2000 smallpox vaccine could also be offered vaccination, and revaccination was recommended at least every 10 years. In non-emergency situations, many contraindications to vaccination were reported by the CDC and included the use of the vaccine in persons: 

  • with a presence or history of eczema or atopic dermatitis;
  • who have acute, chronic, or exfoliative skin conditions;
  • who have immunosuppression;
  • who are less than 12 months of age;
  • who are pregnant or breastfeeding;
  • who have previously had a serious allergy to the vaccine or who are allergic to any component of the vaccine;
  • with known heart disease or who have three or more cardiac risk factors;
  • living with household members who have a presence or history of eczema, atopic dermatitis, or acute, chronic, or exfoliative skin conditions, those with immunosuppressive conditions, those who are pregnant and/or breastfeeding, infants under 12 months of age; or
  • under the age of 18 years.

Mpox Vaccine Approval

On September 24, 2019, the FDA approved Jynneos, a live, non-replicating smallpox and mpox vaccine for use in persons 18 years of age and older who are considered at high-risk of smallpox and monkeypox vaccine. 

The CDC has authorized use of the vaccine in persons who are at risk of occupational exposure to orthopoxviruses. This includes laboratory personnel working with orthopoxviruses, healthcare providers administering ACAM2000 or those treating individuals with orthopoxvirus infection. Booster doses of the vaccine have also been approved for persons at continued risk of exposure to orthopoxviruses, and this vaccine may be given as a booster dose for persons who received a primary series of ACAM2000. 

On August 9, 2022, the FDA authorized the JYNNEOS vaccine under Emergency Use Authorization (EUA) to be administered intradermally to individuals 18 years and older. Per the FDA, one-fifth of the standard dose can be given intradermally as a two-dose series, 28 days apart. Additionally, the FDA authorized use of the vaccine subcutaneously in persons under the age of 18 who are considered at high-risk for mpox illness.  

In October 2023, the CDC’s Advisory Committee on Immunization Practices (ACIP) voted in favor of an interim recommendation for the use of Jynneous mpox vaccine in all adults 18 years and older who are considered at risk for mpox. Those considered at risk include gay, bisexual or other men who have sex with other men, transgender and nonbinary individuals who, in the previous six months have had at least one of the following: 

  • Sex with more than one person
  • A new diagnosis of one or more sexually transmitted infections
  • Sex in affiliation with a large public event in a region where mpox transmission is occurring
  • Sex at a commercial sex site

This recommendation also includes individuals with sexual partners who meet the above criteria and people who anticipate experiences that place them at risk of mpox. 

The mpox vaccine interim recommendations will be reviewed by the CDC’s ACIP within 2-3 years. 

Jynneos mpox vaccine is currently being studied for use among adolescents aged 12 through 17 years of age. 

IMPORTANT NOTE: NVIC encourages you to become fully informed about smallpox/monkeypox (Mpox) and the smallpox/Monkeypox (Mpox) vaccine by reading all sections in the Table of Contents, which contain many links and resources such as the manufacturer product information inserts, and to speak with one or more trusted health care professionals before making a vaccination decision for yourself. This information is for educational purposes only and is not intended as medical advice.


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