Lymphadenopathy or lymph node pain is a common adverse effect of the smallpox and mpox vaccine. Among 873 primary vaccine recipients who received the smallpox and mpox vaccine, 8% had lymphadenopathy and 57% had lymph node pain. Among 1,371 previously vaccinated subjects who got revaccinated with the smallpox and mpox vaccine, 6% had lymphadenopathy and 19% had lymph node pain. Severe lymph node pain and lymphadenopathy were rare (less than 1%).[33515]

An injection site reaction is an expected and desired adverse reaction of the smallpox and mpox vaccine. Major cutaneous reactions are desired and are characterized by a large area of erythema, induration, and streaking inflammation of draining lymphatics. Injection site reactions were common among 873 primary vaccine recipients who received the smallpox and mpox vaccine; 92% had pruritus, 74% had erythema, 67% had pain, and 48% had swelling. Injection site signs and symptoms are less frequent in revaccinated persons than persons receiving the vaccine for the first time. Among 1,371 previously vaccinated subjects who got revaccinated with the smallpox and mpox vaccine, 82% had pruritus, 61% had erythema, 37% had pain, and 28% had swelling. Benign and malignant lesions have been reported to occur at the smallpox and mpox vaccination site. Any lesion other than a smooth scar, regardless of duration since vaccination, warrants further evaluation. Major cutaneous reactions at the site of inoculation may resemble cellulitis. One percent of vaccinia-naive and less than 1% of previously vaccinated subjects (receiving the smallpox and mpox vaccine) experienced at least 1 severe dermatologic adverse event. Erythema and rash accounted for all severe events except for 1 case of contact dermatitis and 1 case of urticaria. Generalized rashes are common after smallpox and mpox vaccination and are presumed to be hypersensitivity reactions in patients without underlying illnesses. In general, rashes are self-limited and do not require treatment. Rashes of many different types have been associated with smallpox and mpox vaccination with the most common being erythema multiforme, maculopapular rash, urticarial rash, papulovesicular, and blotchy erythematous eruptions. Most rashes clear without therapy.[27217] [33515] Serious dermatologic complications that may follow either primary live vaccinia smallpox and mpox vaccination or revaccination include severe vaccinial skin infections, erythema multiforme major (including Stevens-Johnson syndrome), and eczema vaccinatum. Eczema vaccinatum is a sometimes serious adverse reaction to the smallpox and mpox vaccine in patients with a history of atopic dermatitis (e.g., eczema). Vaccinial lesions usually occur at all or most areas of the skin that is or has been afflicted with atopic dermatitis. Eczema vaccinatum occurs more frequently in younger children (1 to 5 years of age) and in males. Vaccinia immune globulin (VIG) can be used to treat this condition.[27217] [27218] Rarely, eczema vaccinatum leads to severe disability, permanent neurological sequelae, and death. One fatality may be expected per 1 million persons receiving primary vaccination and 0.25 deaths per million persons receiving revaccination. Death is most often the result of sudden cardiac death, postvaccinial encephalitis, progressive vaccinia, or eczema vaccinatum.[33515]

Focal and generalized folliculitis is reported to be a common adverse reaction in patients receiving the smallpox and mpox vaccine for the first time. Folliculitis was noticed during a multicenter, randomized controlled study (n =148) evaluating the efficacy of various dilutions of the vaccine. Generalized folliculitis was observed in 2.7% of patients and focal folliculitis in 7.4%. Cultured sample lesions were negative for vaccinia. Skin biopsy from 1 subject with generalized rash showed suppurative folliculitis without evidence of viral infection. All lesions were benign and resolved without scarring.[27621]

Chills and fatigue are common adverse reactions associated with the smallpox and mpox vaccine.[27216] Among 873 primary vaccine recipients receiving the smallpox and mpox vaccine, 37% had malaise, 48% had fatigue, and 32% reported feeling hot. Malaise, fatigue, and fever are less frequent in revaccinated persons than persons receiving the vaccine for the first time. Among 1,371 previously vaccinated subjects who got revaccinated with the smallpox and mpox vaccine, 28% had malaise, 34% had fatigue, and 20% reported feeling hot.[33515]

Among 873 primary vaccine recipients who received the smallpox and mpox vaccine, 19% had nausea, 16% had diarrhea, 6% had constipation, and 5% had vomiting. Among 1,371 previously vaccinated subjects who got revaccinated with the smallpox and mpox vaccine, nausea occurred in 10%, diarrhea in 12%, constipation in 6%, and vomiting in 3%. Severe abdominal pain, nausea, vomiting, constipation, or diarrhea occurred in less than 1% of patients.[33515]

Among 873 primary vaccine recipients who received the smallpox and mpox vaccine, 46% had myalgia. Myalgia appears to be less common among revaccinated persons as compared with patients receiving the vaccine for the first time. For example, among 1,371 previously vaccinated subjects who got revaccinated with the smallpox and mpox vaccine, 27% had myalgia. Severe, vaccine-related myalgia was seen in 1% of vaccinia-naive subjects and in less than 1% of previously vaccinated subjects. Back pain, arthralgia, and extremity pain occurred in 2% or less of either vaccinia-naive or previously vaccinated patients.[33515]

Myocarditis or pericarditis may occur after primary vaccination or revaccination with the smallpox and mpox vaccine. Patients naive to vaccinia who received the smallpox and mpox vaccine (ACAM2000) (5 of 873) or Dryvax (3 of 289) vaccine and were actively monitored had suspected myocarditis and pericarditis. Of the 3 Dryvax cases, 2 were asymptomatic. The rate of myocarditis and pericarditis for the ACAM2000 group (5.7, 95% CI: 1.9 to 13.3 per 1,000 vaccinees) was similar to the rate for the Dryvax group (10.4, 95% CI: 2.1 to 30 per 1,000 vaccinees). No cases of myocarditis and/or pericarditis were identified in 1,819 previously vaccinated subjects. Among phase 3 trial recipients, 7 of 2,983 patients who got ACAM2000 and 3 of 868 patients who got Dryvax had suspected myocarditis. The mean time to onset of suspected myocarditis or pericarditis from vaccination was 11 days (range, 9 to 20 days), and all patients with myocarditis/pericarditis were naive to vaccinia. Most (8 of the 10) patients were asymptomatic and only had raised troponin/cardiac enzymes and/or ECG abnormalities; some patients had chest pain (unspecified). Myocarditis/pericarditis resolved by 9 months in 9 patients; 1 patient had persistent borderline abnormal left ventricular ejection fraction on echocardiogram after getting the Dryvax vaccine.[33515] Among 540,824 military personnel who got the Dryvax vaccine, 67 were evaluated for myopericarditis at a mean of 10.4 days (range, 3 to 25 days) after vaccination. All patients presented with chest pain or substernal pressure, and 57 were evaluated with echocardiography during the acute illness. Thirty-two percent had mild to moderate depression of ejection fraction, and 12% had pericardial effusion. At follow-up echocardiography (n = 40), no patient had an ejection fraction less than 54%, and no patient had evidence of ventricular dilatation, diastolic dysfunction, regional wall motion abnormality, or pericardial effusion. Fourteen percent of patients reported continued subjective symptoms such as chest discomfort, fatigue, and headache.[33487] The long-term outcome of myocarditis and pericarditis after vaccination is currently unknown. In addition to myocarditis and pericarditis, non-ischemic, dilated cardiomyopathy, and ischemic cardiac events including fatalities have been reported after smallpox and mpox vaccination; the relationship of these events, if any, to vaccination has not been established. Patients with cardiac or cerebrovascular disease (prior myocardial infarction, angina, heart failure, stroke) or risk factors for these diseases may have increased risks of adverse events from the smallpox and mpox vaccine.[33515]

Receipt of the smallpox and mpox vaccine may cause generalized vaccinia, which is a secondary, widespread, vesicular, vaccinia rash. This rash results from dissemination of the virus through the blood. Generalized vaccinia is usually self-limiting. In severe cases, vaccinia immune globulin (VIG) can been used.[27217] Rarely, generalized vaccinia leads to severe disability, permanent neurological sequelae, and death. One fatality may be expected per 1 million persons receiving primary vaccination and 0.25 deaths per million persons receiving revaccination. Death is most often the result of sudden cardiac death, postvaccinial encephalitis, progressive vaccinia, or eczema vaccinatum.[33515]

Vaccinia necrosum (progressive vaccinia) (also known as vaccinia gangrenosa) is a serious complication of smallpox and mpox vaccine that occurred in both primary and revaccinees. It is frequently fatal in patients with immune deficiency disorders. In cases of vaccinia gangrenosa, the vaccinial lesion fails to heal and progresses to involve adjacent skin with necrosis of tissue. The infection spreads to other parts of the skin, to bones, and to viscera. Vaccinia immune globulin (VIG) has been used to treat this complication.[27217] Rarely, progressive vaccinia leads to severe disability, permanent neurological sequelae, and death. One fatality may be expected per 1 million persons receiving primary vaccination and 0.25 deaths per million persons receiving revaccination. Death is most often the result of sudden cardiac death, postvaccinial encephalitis, progressive vaccinia, or eczema vaccinatum.[33515]

Congenital infection, primarily occurring during the first trimester, was observed after vaccination with live vaccinia smallpox vaccines during the era of routine smallpox vaccination. Pregnant individuals who are close contacts of vaccinees may be at risk of adverse fetal outcomes since ACAM2000 live vaccinia virus can be transmitted from vaccinees. When fetal vaccinia does occur, it usually results in fetal death (stillbirth) or death of the infant soon after delivery. Generalized vaccinia of the fetus, early delivery of a stillborn infant, or a high risk of perinatal death have been reported.[33515]

Headache is a common adverse effect of the smallpox and mpox vaccine and is usually transient. Among 873 primary vaccine recipients who got the smallpox and mpox vaccine, 50% had a headache. Headache appears to be less common among revaccinated persons as compared with patients receiving the vaccine for the first time. For example, among 1371 previously vaccinated subjects who got revaccinated with smallpox and mpox vaccine, 32% had a headache. Less than 1% of patients experienced severe headaches. Other neurological adverse events that were temporally associated with smallpox vaccination included non-serious limb paresthesias (17 cases), pain (13 cases), and dizziness or vertigo (13 cases). Photophobia has been reported to occur after smallpox vaccination. Serious neurologic adverse events included 13 cases of suspected meningitis, 3 cases of suspected encephalitis or myelitis, 11 cases of Bell palsy, 9 seizures (including 1 death), and 3 cases of Guillain-Barre syndrome. Among these 39 events, 27 occurred in primary vaccinees, and all but 2 occurred within 12 days of vaccination. Serious complications that may follow either primary smallpox and mpox vaccination or revaccination include encephalitis, encephalomyelitis, and encephalopathy.[33515] Symptoms associated with postvaccinial encephalopathy occur between 8 and 15 days after vaccination and include drowsiness, fever, headache, nausea/vomiting, and sometimes spastic muscle paralysis, meningitis, coma, and seizures. Cerebrospinal fluid usually shows a pleocytosis. Recovery may be complete or associated with residual paralysis and other CNS symptoms and sometimes death.[27217] Encephalitis, encephalomyelitis, or encephalopathy may rarely lead to severe disability, permanent neurological sequela, and death. One fatality may be expected per 1 million persons receiving primary vaccination and 0.25 deaths per million persons receiving revaccination. Death is most often the result of sudden cardiac death, postvaccinial encephalitis, progressive vaccinia, or eczema vaccinatum.[33515]

The risk of experiencing serious vaccination complications must be weighed against the risks of experiencing a potentially fatal smallpox or mpox infection. Persons at greatest risk of experiencing serious vaccination complications are often those at greatest risk for death from smallpox or mpox. Virus is shed from the vaccination site during the period starting with the development of a papule (day 2 to 5); shedding ceases when the scab separates and the lesion is re-epithelialized, which occurs 3 to 6 weeks after vaccination. Steps should be taken to reduce the risk of accidental infection of other sites in the vaccinated patient and of contact spread to other individuals. Inadvertent inoculation of close contacts and autoinoculation, especially eyelid, face, genital, anal, and periocular inoculation, have occurred. Accidental infection of the eye (ocular vaccinia/ocular infection) may cause keratitis, corneal scarring, and blindness. Death has been reported in unvaccinated contacts accidentally infected by individuals who have been vaccinated. Fatal adverse reactions are more frequent in infants. Proper management of the vaccination site is imperative.[33515]

Patients with eczema (atopic dermatitis, neurodermatitis, and other eczematous conditions), a history of eczema, or other acute or chronic exfoliative skin conditions are at an increased risk of severe adverse reactions from smallpox and mpox vaccine that may cause severe disability, permanent neurological sequelae, or death. Examples of severe adverse reactions include encephalitis, encephalomyelitis, encephalopathy, progressive vaccinia, generalized vaccinia, severe vaccinial skin infections, erythema multiforme major, and eczema vaccinatum. Because of the increased risk for eczema vaccinatum, routine primary and booster vaccinations with smallpox and mpox vaccine are contraindicated for nonemergency vaccine use in persons with eczema to any degree, including those with a past history of eczema, those with household contacts with active eczema, or whose household contacts have a past history of eczema. Routine primary and booster vaccinations are also contraindicated for nonemergency vaccine use in patients with other acute, chronic, or exfoliative skin conditions such as atopic dermatitis, wounds, burns, impetigo, or Varicella zoster. Other persons with acute or chronic skin conditions or exfoliative dermatitis (e.g., atopy, herpes infection, psoriasis, severe acne vulgaris, severe diaper dermatitis with extensive areas of denuded skin, seborrheic dermatitis, erythroderma, pustular dermatitis, varicella (chickenpox), or Darier's disease (keratosis follicularis)) may also be at increased risk for eczema vaccinatum via inadvertent inoculation of the skin and should not be routinely vaccinated until the condition resolves. Household contacts of such persons should also not be vaccinated.[27212] [33514] [33515] Identify household contacts of patients with eczema and take measures to avoid contact between a patient with eczema and persons with active vaccination lesions.

Patients with known heart conditions, including those diagnosed with previous myocardial infarction, angina, congestive heart failure, cardiomyopathy, chest pain or shortness of breath with activity, and stroke or transient ischemic attack may have increased risks of adverse events from the smallpox and mpox vaccine. Also, patients with at least 3 of the following risk factors for ischemic coronary artery disease may have increased risks of adverse events with smallpox and mpox vaccine: hypertension, hypercholesterolemia, diabetes mellitus, hyperglycemia, first degree relative who had a heart condition before the age of 50, or tobacco smoking. Identify household contacts of patients with cardiac disease and take measures to avoid contact between a patient with cardiac disease and persons with active vaccination lesions. Reports of cardiac events have occurred after smallpox and mpox vaccination, but it is not clear whether smallpox and mpox vaccine is the cause. Acute myopericarditis has been observed after smallpox and mpox vaccine administration to healthy adults, and suspected cases of myocarditis and/or pericarditis have been observed at an approximate rate of 5.7 per 1,000 (95% CI, 1.9 to 13.3) in healthy adult primary vaccinees. Inform individuals receiving smallpox and mpox vaccination that myopericarditis is a potential complication of smallpox and mpox vaccination and that they should seek medical attention if they develop chest pain, shortness of breath, or other symptoms of cardiac disease within 2 weeks after vaccination.[33515]

The smallpox and mpox vaccine is contraindicated for use by patients with severe immunodeficiency/immunosuppression who are not expected to benefit from the vaccine. This may include patients undergoing bone marrow transplantation or those with primary or acquired immunodeficiency who require isolation.[33515] Patients with congenital or acquired immune deficiency disorders, including leukemia, lymphoma, organ transplant, generalized neoplastic disease, human immunodeficiency virus (HIV) infection, acquired immunodeficiency syndrome (AIDS), cellular or humoral immune deficiency (e.g., agammaglobulinemia, severe combined immunodeficiency (SCID)), patients receiving radiation therapy, chemotherapy, high-dose corticosteroid therapy (2 mg/kg or more or 20 mg/day of prednisone for 2 weeks or longer), or other immunosuppressive medications, are at an increased risk of severe adverse reactions that may cause severe disability, permanent neurological sequelae, or death. Examples of severe adverse reactions include encephalitis, encephalomyelitis, encephalopathy, progressive vaccinia, generalized vaccinia, severe vaccinial skin infections, erythema multiforme major, and eczema vaccinatum; these events have occurred after primary vaccination or revaccination. Wait at least 1 month after discontinuation of high-dose corticosteroid therapy given for more than 2 weeks and at least 3 months after completion of other immunosuppressive medications before administering smallpox and mpox vaccine. Patients with severe clinical manifestations of autoimmune disease (e.g., systemic lupus erythematosus (SLE)) might have a degree of immunocompromise as a component of the disease. Do not vaccinate household contacts of such persons. Identify household contacts of patients with immunosuppression and take measures to avoid contact between a patient with immunosuppression and persons with active vaccination lesions. Also, advise healthcare workers who have been vaccinated to avoid contact with immunocompromised patients until the scab has separated from the skin at the vaccination site.[33514] [33515] [65107]

Use smallpox and mpox vaccine cautiously, if at all, in patients with polymyxin hypersensitivity or neomycin hypersensitivity. Trace amounts of neomycin and polymyxin B are present in the smallpox and mpox vaccine. Appropriate medical treatment must be immediately available to manage potential anaphylactic reactions following vaccine administration.[33515]

Patients who receive smallpox and mpox vaccine and have an ocular disease treated with topical steroids may be at an increased risk of severe adverse reactions including keratitis, corneal scarring, and blindness. Persons with inflammatory ocular disease might be at increased risk for inadvertent inoculation as a result of touching or rubbing the eye. Therefore, deferring vaccination is prudent for persons with inflammatory ocular diseases requiring steroid treatment until the condition resolves and the course of therapy is complete. Identify household contacts with ocular disease and take measures to avoid contact between a patient with ocular disease and persons with active vaccination lesions.[33514] [33515]

The smallpox and mpox vaccine for either primary vaccination or revaccination is contraindicated for use in a nonemergency scenario during pregnancy, in patients who are suspected to be pregnant, and in household contacts of pregnant individuals. Identify household contacts of vaccinees who are pregnant and take measures to avoid contact between a pregnant patient and persons with active vaccination lesions. The smallpox and mpox vaccine is known to cause fetal harm when administered to pregnant patients. The vaccine has rarely been reported to cause fetal infection, usually after primary immunization of the pregnant patient. When fetal vaccinia does occur, it usually results in fetal death (stillbirth) or death of the infant soon after delivery. Administration of the vaccine to pregnant patients during the first trimester may be most problematic. However, use of the vaccine in pregnant patients may be warranted in some cases (e.g., epidemic circumstances) given the high risk of adverse outcomes associated with smallpox or mpox infection, which may be more severe in pregnant vs. nonpregnant patients. Individuals of childbearing potential who receive the smallpox and mpox vaccine are recommended to take precautions against becoming pregnant or getting their partner pregnant for 6 weeks after vaccination. If the smallpox and mpox vaccine is inadvertently administered to a pregnant person or if pregnancy occurs within 6 weeks of receiving the vaccine, apprise the vaccinee of the potential risks to the fetus. Report all cases of pregnant persons who received the smallpox and mpox vaccine within 42 days before conception, during pregnancy, or were exposed to a person who received the vaccine within 28 days after vaccination to the National Smallpox Vaccine in Pregnancy Registry and Department of Defense by calling 619-553-9255.[27212] [33514] [33515] [65107]

The safety and effectiveness of smallpox and mpox vaccine vaccine have not been established in neonates, infants, children, or adolescents younger than 16 years old. Smallpox and mpox vaccine should not be used in infants unless they are at risk of contracting smallpox or mpox. Data regarding the use of smallpox and mpox vaccine in pediatric patients are limited, and infants are at an increased risk of severe adverse reactions that may cause severe disability, permanent neurological sequelae, or death. Examples of severe adverse reactions include encephalitis, encephalomyelitis, encephalopathy, progressive vaccinia, generalized vaccinia, severe vaccinial skin infections, erythema multiforme major, and eczema vaccinatum. The Advisory Committee on Immunization Practices (ACIP) advises against nonemergency (elective) use of smallpox and mpox vaccine in patients younger than 18 years of age. Advise vaccine recipients to avoid contact with any infant until active vaccination lesions have resolved. Use of the vaccine in pediatric patients may be warranted in some cases (e.g., bioterrorism or known exposure to the smallpox or mpox virus) given the high risk of adverse outcomes associated with smallpox or mpox infection.[27212] [33514] [33515]

Although excretion of vaccine virus and/or antibodies into human milk is unknown, the smallpox and mpox vaccine is contraindicated in patients who are breast-feeding. The close contact that occurs during nursing increases the risk of inadvertent inoculation of the breast-fed infant. Given the risk of adverse outcomes associated with smallpox and mpox infection, vaccination of smallpox and mpox-susceptible mothers may be needed if the potential for exposure is high; in these cases, patients are advised to discontinue breast-feeding. Handling of any infant by vaccine recipients should be avoided until the scab has separated from the vaccination site (at least 3 to 4 weeks).[33514] [33515] [65107]

The product labeling for smallpox and mpox vaccine recommends avoiding blood donation and organ donation for at least 6 weeks after vaccination. Some people who are given blood or blood products from patients who have recently received the smallpox and mpox vaccine, may experience harmful effects. The risk of transmission of vaccinia virus through transfused blood or plasma is uncertain. FDA guidance recommends smallpox and mpox vaccine recipients without vaccine complications be deferred from donating blood for at least 21 days or until the scab has spontaneously separated. Blood donation should be deferred for 2 months after vaccination if the scab was removed before separating spontaneously. Smallpox and mpox vaccine recipients with vaccine complications or persons who have experienced complications of vaccinia infection acquired through close contact with a vaccine recipient should be deferred from donating blood for 14 days after all vaccine complications have completely resolved. Persons who acquire a clinically recognizable vaccinia virus infection (localized skin lesions with no other symptoms or complications) by close contact with a vaccine recipient and whose scab did NOT spontaneously separate should not donate blood for at least 3 months from the date of vaccine recipient vaccination; no deferral period for blood donation is needed if the scab spontaneously separates and is no longer present. If the vaccine recipient vaccination date is not known but could have been within the last 3 months, defer blood donation for 2 months from the present time.[27231] [33514] [33515]

A patient who receives the smallpox and mpox vaccine may have a false-negative test result for the tuberculin skin test (purified protein derivative (PPD)) and for tuberculosis blood tests. Suppression of PPD reactivity has been demonstrated after administration of the smallpox and mpox vaccine. If possible, delay tuberculin testing for 6 weeks after smallpox and mpox vaccination.[33514] [33515]

During the first 6 weeks after vaccination, a patient who is vaccinated with smallpox and mpox vaccine may have a false-positive test result for syphilis. If the RPR test result is positive, confirm the result by the use of a more specific test, such as the fluorescent treponemal antibody absorption (FTA-ABS) assay.[33515]