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How Effective is Smallpox and Monkeypox (Mpox) Vaccine?

Updated January 20, 2023

There are two smallpox vaccines approved by the U.S. Food and Drug Administration (FDA): ACAM 2000, a live smallpox (vaccinia) vaccine, developed and manufactured by Emergent Product Development Gaithersburg, Inc., and JYNNEOS, a live, non-replicating, smallpox and monkeypox (Mpox) vaccine, developed and manufactured by Bavarian Nordic.1

Smallpox (Vaccinia) Vaccine, Live (ACAM 2000)

The ACAM 2000 smallpox vaccine does not contain smallpox virus (variola) and can’t cause or transmit smallpox. The vaccine contains the vaccinia virus, which is a member of the same family of viruses as smallpox (the orthopoxvirus genus). Vaccine-acquired immunity from the vaccinia virus found in ACAM 2000 may offer protection against the smallpox (variola) virus through cross-protection.

The vaccinia virus in ACAM 2000 causes an infection of the epidermis, dermal, subcutaneous tissues, and lymph nodes at the injection site. Health experts report that successful vaccination against smallpox with the ACAM 2000 vaccinia virus is determined by the development of a vesicular skin lesion at the injection site, referred to as a “take.”

The virus replicates within the body’s cells and neutralizing antibodies and T and B cells are believed to provide protection against smallpox, although the level of neutralizing antibody protection is not known. According to the vaccine manufacturer, it is estimated that more than 95 percent of individuals vaccinated with smallpox vaccine for the first time develop neutralizing antibodies to vaccinia.2

There are two types of smallpox vaccine responses that have been identified by the World Health Organization (WHO) and the CDC’s Advisory Committee on Immunization Practices (ACIP). The first is the skin reaction or “take” considered to be an indication of successful vaccination. The second is an equivocal reaction and this is usually associated with prior smallpox vaccination. An equivocal reaction mean that the vaccine was not properly administered or the administered vaccine was rendered inactive and incapable of producing an immune response.3 4 5

Smallpox and Monkeypox (Mpox) Vaccine, Live, Non-Replicating (JYNNEOS)

The effectiveness of JYNNEOS vaccine against smallpox was inferred by comparing the immunogenicity of this vaccine to ACAM 2000 smallpox vaccine. The outcomes were supported by efficacy data collected through animal challenge studies. Vaccine effectiveness against monkeypox (Mpox) was inferred from the immunogenicity of the vaccine from efficacy data from animal challenge studies and in a clinical study. In immunogenicity clinical studies, JYNNEOS was considered non-inferior to ACAM 2000.6 In July 2022, the World Health Organization (WHO) acknowledged a lack of data on the effectiveness of the JYNNEOS vaccine against Mpox. Additionally, health officials from WHO admitted that any individual who receives the JYNNEOS vaccine is essentially involved in a clinical study to determine how effective the vaccine is against Mpox.7

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.


[1] U.S. Food and Drug Administration. Vaccines Licensed for Use in the United States. July 5, 2022.

[2] Emergent Product Development Gaithersburg, Inc. ACAM2000 – Package Insert. U.S. Food and Drug Administration Dec. 13, 2019.

[3] Tan X, Chun S, Pablo J. et al. Failure of the smallpox vaccine to develop a skin lesion in vaccinia virus-naïve individuals is related to differences in antibody profiles before vaccination, not after. Clin Vaccine Immunol. Mar. 2012;19(3) :418-28.

[4] Emergent Product Development Gaithersburg, Inc. ACAM2000 – Package Insert. U.S. Food and Drug Administration. Dec. 13, 2019.

[5] Capriotti T. Smallpox vaccine revisited. Dermatol Nurs. Dec. 2002;14(6):387-91.

[6] Bavarian Nordic A/S. JYNNEOS – Package Insert. U.S. Food and Drug Administration Sept. 2, 2022.

[7] Phillips J. WHO Admits Everyone Who Gets Monkeypox Vaccine Part of ‘Clinical Trial’ to Collect Data. The Epoch Times July 25, 2022.

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