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

Disclosures

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

Abstract and Introduction

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.

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Abstract and Introduction
Methods
Summary of Findings and Rationale for Recommendations
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Future Research
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*https://www.cdc.gov/smallpox/pdfs/revaccination-memo.pdf

Table 1. Recommendations for ACAM2000 and JYNNEOS vaccines for persons at occupational risk for exposure to orthopoxviruses — Advisory Committee of Immunization Practices, United States, 2022
Recommendations	Vaccine product
Recommendations	ACAM2000	JYNNEOS
Who should receive the vaccine?	Persons at risk for occupational exposure to orthopoxviruses*
Who should be offered the vaccine?	Persons who administer ACAM2000 or care for patients with infection with replication-competent viruses
Populations for whom booster vaccination is recommended at specific intervals	Persons who are at ongoing risk^† for occupational exposure to orthopoxviruses
Booster frequency^§
Persons working with more virulent orthopoxviruses (e.g., Variola virus or Monkeypox virus)	Every 3 years	Every 2 years
Persons working with less virulent orthopoxviruses (e.g., Vaccinia virus or Cowpox virus)	At least every 10 years

*Research laboratory personnel, clinical laboratory personnel performing diagnostic testing for orthopoxviruses, designated response team members, and health care personnel who administer ACAM2000 (Smallpox [Vaccinia] Vaccine, Live) or care for patients infected with orthopoxviruses.
^†Ongoing risk due to occupational work performed; response personnel are not considered at "sustained risk" for orthopoxvirus infections.
^§Booster doses are recommended for response personnel only once an event is identified.

Table 2. Distinctions between ACAM2000 and JYNNEOS that might facilitate decision-making among vaccinees at risk for orthopoxvirus infections — United States, 2022
Characteristic	Vaccine product
Characteristic	ACAM2000*	JYNNEOS
Vaccine virus	Replication-competent vaccinia virus	Replication-deficient modified vaccinia Ankara
"Take" following vaccination^†	Yes	No
Risk for inadvertent inoculation and autoinoculation	Yes	No
Risk for serious adverse event	Yes	No significant events identified during clinical trials
Risk for cardiac adverse events	Myopericarditis in 5.7 per 1,000 primary vaccinees	Clinical trial data limited in evaluating this outcome; however, no significant events in data abstracted from single study arms^§
Assessment of effectiveness	FDA assessed by comparing immunologic response and take rates to Dryvax*	FDA assessed by comparing immunologic response to ACAM2000 and animal studies
Administration	Percutaneously using a bifurcated needle by multiple puncture (scarification) technique,^¶ single dose	Subcutaneously, 2 doses 28 days apart

Abbreviation: FDA = Food and Drug Administration.
*Both ACAM2000 and Dryvax are derived from the New York City Board of Health strain of vaccinia; ACAM2000 is a second generation smallpox vaccine derived from a clone of Dryvax, purified, and produced using modern cell culture technology.
^†A "take" is postvaccination lesion often used as a marker of successful vaccination after ACAM2000.
^§Because JYNNEOS is a replication-deficient virus vaccine, serious adverse events are believed to be fewer. However, the mechanism of myopericarditis in persons who receive ACAM2000 is poorly understood; for this reason, it is unknown whether persons who receive JYNNEOS might experience myopericarditis.
^¶https://www.fda.gov/media/75792/download

Table 3. Contraindication to administration of ACAM2000 and JYNNEOS to recipients or their household contacts with certain conditions — United States, 2022
Clinical characteristic	Contraindication to receipt of ACAM2000			Contraindication to receipt of JYNNEOS
	Vaccine recipient with condition		Household contact with condition*
	Primary vaccination	Revaccination	Household contact with condition*
History or presence of atopic dermatitis	Y	Y	Y	—
Other active exfoliative skin conditions^†	Y	Y	Y	—
Immunosuppression^§	Y	Y	Y	—
Pregnancy^¶	Y	Y	Y	—
Age <1 year**	Y	Y	Y	—
Breastfeeding^††	Y	Y	—	—
Serious vaccine component allergy	Y	Y	—	Y
Known underlying heart disease (e.g., coronary artery disease or cardiomyopathy)	Y	Y	—	—
≥3 known major cardiac risk factors^§§	Y	—	—	—

Abbreviation: Y = yes.
*Household contacts include persons with prolonged intimate contact with the potential vaccinee (e.g., sexual contacts) and others who might have direct contact with the vaccination site or with potentially contaminated materials (e.g., dressings or clothing). JYNNEOS is a replication-deficient vaccine and therefore should not present a risk of transmission to household contacts.
^†Conditions include eczema, burns, impetigo, varicella-zoster, herpes, severe acne, severe diaper dermatitis with extensive areas of denuded skin, psoriasis, or Darier disease (keratosis follicularis). Studies evaluating JYNNEOS in persons with atopic dermatitis have demonstrated immunogenicity in eliciting a neutralizing antibody response and did not reveal any significant safety concerns.
^§Conditions include HIV; AIDS; leukemia; lymphoma; generalized malignancy; solid organ transplantation; therapy with alkylating agents, antimetabolites, radiation, tumor necrosis factor inhibitors, or high-dose corticosteroids; being a recipient of a hematopoietic stem cell transplant <24 months ago or ≥24 months ago but with graft-versus-host disease or disease relapse; or having autoimmune disease with immunodeficiency as a clinical component. Immunocompromised persons, including those receiving immunosuppressive therapy, may have a diminished immune response to JYNNEOS because of their immunocompromised status.
^¶Available human data on JYNNEOS administered to pregnant women are insufficient to determine vaccine-associated risks in pregnancy. However, animal models, including rats and rabbits, have shown no evidence of harm to a developing fetus.
**ACAM2000 is contraindicated in infants aged <1 year. Caution should be used when considering the administration of ACAM2000 or JYNNEOS to children and adolescents aged <18 years. JYNNEOS is not licensed for persons aged <18 years and has not been rigorously evaluated in this population.
^††The safety and efficacy of JYNNEOS has not been evaluated in breastfeeding women. It is not known whether JYNNEOS is excreted in human milk and data are not available to assess the impact of JYNNEOS on milk production or safety of JYNNEOS in breastfed infants. However, JYNNEOS vaccine is replication-deficient and therefore should not present a risk of transmission to breastfed infants. Caution should be used when considering the administration of JYNNEOS to breastfeeding women.
^§§Major cardiac risk factors include hypertension, diabetes, hypercholesterolemia, heart disease at age ≤50 years in a first-degree relative, and smoking. Clinical studies have not detected an increased risk of myopericarditis in recipients of JYNNEOS. Persons with underlying heart disease or ≥3 major cardiac risk factors should be counseled on the theoretical risk of myopericarditis given the uncertain etiology of myopericarditis associated with replication-competent smallpox vaccines.

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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

Abstract and Introduction

Introduction

Tables

Tables

Tables

References

Authors and Disclosures

Authors and Disclosures

Sidebar

Sidebar

Summary

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