Use of JYNNEOS (Smallpox and Monkeypox Vaccine, Live, Nonreplicating) for Preexposure Vaccination of Persons at Risk for Occupational Exposure to Orthopoxviruses

Recommendations of the Advisory Committee on Immunization Practices -- United States, 2022

Agam K. Rao, MD; Brett W. Petersen, MD; Florence Whitehill, DVM; Jafar H. Razeq, PhD; Stuart N. Isaacs, MD; Michael J. Merchlinsky, PhD; Doug Campos-Outcalt, MD; Rebecca L. Morgan, PhD; Inger Damon, MD, PhD; Pablo J. Sánchez, MD; Beth P. Bell, MD


Morbidity and Mortality Weekly Report. 2022;71(22):734-742. 

In This Article

Abstract and Introduction


Certain laboratorians and health care personnel can be exposed to orthopoxviruses through occupational activities. Because orthopoxvirus infections resulting from occupational exposures can be serious, the Advisory Committee on Immunization Practices (ACIP) has continued to recommend preexposure vaccination for these persons since 1980,[1] when smallpox was eradicated.[2] In 2015, ACIP made recommendations for the use of ACAM2000, the only orthopoxvirus vaccine available in the United States at that time.[3] During 2020–2021, ACIP considered evidence for use of JYNNEOS, a replication-deficient Vaccinia virus vaccine, as an alternative to ACAM2000. In November 2021, ACIP unanimously voted in favor of JYNNEOS as an alternative to ACAM2000 for primary vaccination and booster doses. With these recommendations for use of JYNNEOS, two vaccines (ACAM2000 and JYNNEOS) are now available and recommended for preexposure prophylaxis against orthopoxvirus infection among persons at risk for such exposures.

Orthopoxviruses are large, double-stranded DNA viruses (Genus Orthopoxvirus, Family Poxviridae) that comprise multiple species, including Variola virus, Vaccinia virus, Monkeypox virus, Cowpox virus, and newly discovered species (e.g., Akhmeta virus and Alaskapox virus).[4] Infection with an orthopoxvirus or immunization with an orthopoxvirus vaccine lends immunologic cross-protection against other viruses in the genus.[3] Until 1971, children in the United States received an orthopoxvirus vaccine (to prevent smallpox) as part of their routine childhood vaccines. However, with the World Health Organization (WHO) declaration of the eradication of smallpox (the infection caused by Variola virus) in 1980,[2] recommendations for routine vaccinations ended worldwide.

A small subset of persons in the United States continues to receive orthopoxvirus vaccination:[3] persons at occupational risk for exposure to orthopoxvirus infections and certain U.S. military personnel. The first group (those with occupational risk for exposure) are within the purview of ACIP and the focus of this report. Regular booster doses are recommended for persons with ongoing occupational risk for exposure to orthopoxvirus infections. Designated public health and health care worker response teams approved by public health authorities should receive booster vaccination only at the time of an event, rather than at regular intervals.*

Poxviruses are increasingly being used in a wide range of biomedical research.[3] Vaccinia virus is the most frequently studied poxvirus and serves as the prototype of the orthopoxvirus genus. This orthopoxvirus is used in basic virologic research, and because of its ability to serve as a vector for the expression of foreign genetic material, it is often used as an immunology tool and potential vaccine vector. Vaccinia virus is considered one of the less virulent orthopoxviruses, and possibly because of this perception, many laboratorians who work with this virus do not receive preexposure prophylaxis. CDC has received reports of occupational exposures to Vaccinia virus over the years and in some cases, morbidity has not been insignificant[5,6] In nearly all cases, infections with Vaccinia virus occurred in persons who were unvaccinated or previously vaccinated but not up to date with recommended booster doses.

In addition to less virulent viruses like Vaccinia virus, some researchers work with more virulent orthopoxviruses, including Variola virus (in some CDC laboratories) and Monkeypox virus. ACIP has historically recommended more frequent booster vaccination doses for persons working with more virulent orthopoxviruses than for those working with less virulent orthopoxviruses.[3]

Replication-competent poxvirus strains can cause clinical infection in humans as well as produce infectious virus that can be transmitted to others.[3] Replication-deficient poxvirus strains, including modified vaccinia Ankara (MVA), TROVAC, and ALVAC, do not produce infectious virus in humans, and therefore do not cause clinical infection; as such, replication-deficient poxvirus strains pose a substantially lower risk of adverse events compared with replication-competent strains. During 2015–2019, ACAM2000 was the only orthopoxvirus vaccine licensed by the Food and Drug Administration (FDA); ACIP recommendations for use of ACAM2000 in the United States were published in 2015.[3] ACAM2000 is a replication-competent Vaccinia virus vaccine derived from a plaque-purified clone of the same New York City Board of Health strain that was used to manufacture Dryvax vaccine, one of the vaccines used in the eradication of smallpox. Because ACAM2000 is replication-competent, there is a risk for serious adverse events (e.g., progressive vaccinia and eczema vaccinatum) with it; myopericarditis also occurs with ACAM2000 (estimated rate of 5.7 per 1,000 primary vaccinees based on clinical trial data), but the underlying mechanism is unknown.[7,8]

In 2019, FDA licensed JYNNEOS, a replication-deficient MVA vaccine, for prevention of smallpox or monkeypox disease in adults aged ≥18 years determined to be at high risk for infection with these viruses. JYNNEOS is administered by subcutaneous injection as a 2-dose series delivered 28 days apart. There is no major cutaneous reaction, also known as a "take" (a vaccine site lesion often used as a marker of successful vaccination with replication-competent vaccines such as ACAM2000), following vaccination with JYNNEOS and consequently no risk for inadvertent inoculation or autoinoculation. The effectiveness of JYNNEOS was inferred from the immunogenicity of JYNNEOS in clinical studies and from efficacy data from animal challenge studies. Occurrences of serious adverse events are expected to be minimal because JYNNEOS is a replication-deficient virus vaccine. However, because the mechanism for myopericarditis following receipt of ACAM2000 is thought to be an immune-mediated phenomenon, it is not known whether the antigen or antigens that precipitate autoantibodies are present in JYNNEOS as well. ACIP began considering discussing the data for JYNNEOS in February 2020. This report describes the ACIP recommendations for the use of JYNNEOS for preexposure prophylaxis in persons at occupational risk for exposure to orthopoxviruses.