Introduction

Smallpox vaccine live is a live virus vaccine containing replication-competent vaccinia virus derived from a plaque-purified clone of the New York City Board of Health vaccinia strain.

Uses for Smallpox Vaccine Live

Smallpox vaccine live has the following uses:

Smallpox vaccine live is indicated for active immunization against smallpox disease in individuals determined to be at high risk for smallpox infection.

Smallpox Vaccine Live Dosage and Administration

General

Smallpox vaccine live (ACAM2000) is available in the following dosage form(s) and strength(s):

Multiple-dose vial containing lyophilized vaccine and vial containing diluent. After reconstitution with the diluent as directed by the manufacturer, each vaccine vial provides approximately 100 doses; each dose of 0.0025 mL contains 2.5 x 10⁵ to 12.5 x 10⁵ plaque-forming units (PFU) of vaccinia virus.

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

• Administer smallpox vaccine live (ACAM2000) only after being trained on the safe and effective administration of the vaccine by the percutaneous route (scarification).

• Do not administer intradermally, subcutaneously, IM, or IV.

• One droplet of reconstituted smallpox vaccine live is administered by the percutaneous route (scarification) using 15 jabs of a bifurcated needle.

• The droplet (0.0025 mL) of smallpox vaccine live is picked up with a bifurcated needle by dipping the needle into the vial of reconstituted vaccine.

• See the manufacturer's labeling for complete instructions for vaccine preparation and administration (including handling precautions and disposal instructions) and instructions for interpreting the response to vaccination (including vaccination failures).

• Give the FDA-approved patient labeling (Medication Guide) to the vaccinee and provide instructions on vaccination site care. (See Advice to Patients.)

• Revaccination may be recommended (e.g., every 3 years) in individuals at continued high risk of exposure to smallpox (e.g., research laboratory workers handling variola virus).

Contraindications

• There are very few absolute contraindications to smallpox vaccine live (ACAM2000) for those at high risk for smallpox. The risk for experiencing serious vaccination complications must be weighed against the risk of experiencing a potentially fatal smallpox infection. (See Serious Vaccination Complications and Death under Cautions.)

• Severe localized or systemic infection with vaccinia (progressive vaccinia) may occur following receipt of smallpox vaccine live (ACAM2000) in individuals with weakened immune systems. Individuals with severe immunodeficiency who are not expected to benefit from smallpox vaccine live should not receive the vaccine. This may include individuals undergoing bone marrow transplantation and those with primary or acquired immunodeficiency who require isolation.

Warnings/Precautions

Serious Vaccination Complications and Death

Smallpox vaccine live (ACAM2000) contains live, replication-competent vaccinia virus. Individuals at greatest risk of experiencing serious complications following receipt of a replication-competent smallpox vaccine are often those at greatest risk for death from smallpox, and the risk for serious vaccination complications must be weighed against the risk for a potentially fatal smallpox infection.

Serious complications that may occur following primary vaccination or revaccination with replication-competent smallpox vaccine live include myocarditis and/or pericarditis, encephalitis, encephalomyelitis, encephalopathy, progressive vaccinia (vaccinia necrosum), generalized vaccinia, severe vaccinial skin infections, erythema multiforme major (including Stevens-Johnson syndrome), eczema vaccinatum, and blindness. These complications may rarely lead to severe disability, permanent neurological sequelea, and death. Fetal death can occur if replication-competent smallpox vaccine live is administered to pregnant women (see Pregnancy under Cautions).

Based on clinical trials of ACAM2000, symptoms of suspected myocarditis or pericarditis (such as chest pain, raised troponin/cardiac enzymes, or ECG abnormalities) occur in 5.7 per 1000 primary vaccinations (95% CI: 1.9-13.3). This finding includes cases of acute symptomatic or asymptomatic myocarditis or pericarditits or both.

Historically, death following vaccination with live vaccinia virus is a rare event; approximately 1 death per million primary vaccinations and 1 death per 4 million revaccinations have occurred after vaccination with live vaccinia virus. Death is most often the result of sudden cardiac death, postvaccinial encephalitis, progressive vaccinia, or eczema vaccinatum. Death has also been reported in unvaccinated contacts accidentally infected by individuals who have been vaccinated.

Data on the incidence of adverse events among US military personnel and civilian first responders vaccinated with a previously available smallpox vaccine live containing replication-competent vaccinia virus (i.e., New York City Board of Health strain; Dryvax) during vaccination programs initiated in December 2002 are shown in Table 1. The incidence of preventable adverse events (eczema vaccinatum, contact transmission, and autoinoculation) reported in these programs was notably lower compared with data collected in the 1960s when smallpox vaccination was routinely recommended in the US population; this difference presumably is because of better vaccination screening procedures and routine use of protective bandages over the inoculation site. Myocarditis and pericarditis were not commonly reported following smallpox vaccination in the 1960s, but emerged as a more frequent event based on more active surveillance in the military and civilian programs.

Department of Defense program as of January 2005 (n = 730,580): 71% primary vaccinations; 89% male; median age 28.5 years.

Department of Health and Human Services program as of January 2004 (n = 40,422): 36% primary vaccinations; 36% male; median age 47.1 years.

Cardiovascular Events

In clinical trials involving 2983 individuals who received smallpox vaccine live (ACAM2000) and 868 individuals who received a previously available smallpox vaccine live (Dryvax), 10 cases of suspected myocarditis (7 out of 2983 ACAM2000 recipients [0.2%] and 3 out of 868 Dryvax recipients [0.3%]) were identified. The mean time to onset of suspected myocarditis and/or pericarditis after vaccination was 11 days (range: 9–20 days). All individuals who experienced these cardiac events were naive to vaccinia. Of these 10 cases, 2 were hospitalized; none of the remaining 8 required hospitalization or treatment with medication. Of the 10 cases, 8 were subclinical and detected only by ECG abnormalities with or without associated elevations of cardiac troponin I. These cases resolved by 9 months, with the exception of one female in the Dryvax group who had persistent borderline abnormal left ventricular ejection fraction on ECG.

The best estimate of risk for myocarditis and pericarditis in recipients of replication-competent smallpox vaccine live is derived from the phase 3 clinical trials comparing ACAM2000 and Dryvax where there was active monitoring for potential myocarditis and pericarditis. Among vaccinees naive to vaccinia, 8 cases of suspected myocarditis and pericarditis were identified across both vaccine groups, for a total incidence rate of 6.9 per 1000 vaccinees (8 out of 1162). The rate for the ACAM2000 group was 5.7 (95% CI: 1.9-13.3) per 1000 vaccinees (5 out of 873 vaccinees) and the rate for the Dryvax group was 10.4 (95% CI: 2.1-30.0) per 1000 vaccinees (3 out of 289 vaccinees). No cases of myocarditis and/or pericarditis were identified in 1819 previously vaccinated individuals. The long-term outcome of myocarditis and pericarditis following smallpox vaccine live vaccination is currently unknown.

Ischemic cardiac events, including fatalities, have been reported following smallpox vaccination; the relationship of these events, if any, to vaccination has not been established. In addition, cases of non-ischemic, dilated cardiomyopathy have been reported following smallpox vaccination; the relationship of these cases to smallpox vaccination is unknown.

There may be increased risk of adverse events following vaccination with smallpox vaccine live in individuals with known cardiac disease, including those diagnosed with previous myocardial infarction, angina, congestive heart failure, cardiomyopathy, chest pain or shortness of breath with activity, stroke or transient ischemic attack, or other heart conditions. In addition, risk of adverse events may be increased in individuals who have been diagnosed with 3 or more of the following risk factors for ischemic coronary disease: high blood pressure, elevated blood cholesterol, diabetes mellitus or high blood sugar, first degree relative (e.g., mother, father, brother, sister) who had a heart condition before 50 years of age, or history of smoking cigarettes.

Ocular Complications and Blindness

Accidental infection of the eye (ocular vaccinia) following vaccination with replication-competent smallpox vaccine live may result in ocular complications including keratitis, corneal scarring and blindness. Patients who are using corticosteroid eye drops may be at increased risk of ocular complications.

Congenital or Acquired Immune Deficiency Disorders

Severe localized or systemic infection with vaccinia (progressive vaccinia) may occur following vaccination with replication-competent smallpox vaccine live in individuals with weakened immune systems, including those with leukemia, lymphoma, organ transplantation, generalized malignancy, HIV/AIDS, or cellular or humoral immune deficiency, and those receiving radiation therapy or treatment with antimetabolites, alkylating agents, high-dose corticosteroids (more than 10 mg of prednisone daily or equivalent for 2 weeks or longer), or other immunomodulatory drugs. Smallpox vaccine live is contraindicated in individuals with severe immunodeficiency (see Contraindications under Cautions). Vaccinees with close contacts who have these conditions may be at increased risk because live vaccinia virus can be shed and then transmitted from the vaccinee to these close contacts.

History or Presence of Eczema and Other Skin Conditions

Individuals with eczema of any description, such as atopic dermatitis, neurodermatitis, and other eczematous conditions, regardless of severity of the condition, and individuals who have a history of these conditions at any time in the past, are at higher risk of developing eczema vaccinatum following vaccination with replication-competent smallpox vaccine live. Close contacts who have eczematous conditions may be at increased risk because the live vaccinia virus can be shed and then transmitted from the vaccinee to these close contacts.

Vaccinees with other active acute, chronic, or exfoliative skin disorders (e.g., burns, impetigo, varicella zoster, acne vulgaris with open lesions, Darier’s disease, psoriasis, seborrheic dermatitis, erythroderma, pustular dermatitis) or household contacts having such skin disorders might also be at higher risk for eczema vaccinatum.

Hypersensitivity to the Vaccine or its Components

Smallpox vaccine live contains trace amounts of neomycin and polymyxin B. Individuals allergic to these components may be at higher risk for adverse events after vaccination.

Management of Smallpox Vaccination Complications

The US Centers for Disease Control and Prevention (CDC) can assist clinicians in the diagnosis and management of patients with suspected complications of vaccinia (smallpox) vaccination. Vaccinia immune globulin (VIG) is indicated for treatment of certain complications following vaccination with replication-competent smallpox vaccine live. If VIG and/or antivirals are needed or additional information is required, clinicians should contact the CDC emergency operations center at 770-488-7100.

Prevention of Transmission of Live Vaccinia Virus

The most important measure to prevent inadvertent autoinoculation and contact transmission following vaccination with a replication-competent smallpox vaccine live is thorough hand washing after changing the bandage or after any other contact with the vaccination site.

Individuals susceptible to adverse effects of vaccinia virus (i.e., those with cardiac disease, eye disease, immunodeficiency states [including HIV infection], eczema, pregnant women, infants) should be identified and measures should be taken to avoid contact between such individuals and those who have received replication-competent smallpox vaccine live and have active vaccination lesions.

Recently vaccinated healthcare personnel should avoid contact with patients, particularly those with immunodeficiencies, until the scab at the vaccination site has separated from the skin. However, if continued contact with patients is unavoidable, vaccinated healthcare workers should ensure that the vaccination site is well covered and follow good hand-washing technique. In this setting, a more occlusive dressing may be used. Semipermeable polyurethane dressings are effective barriers to shedding of vaccinia. However, exudate may accumulate beneath the dressing, and care must be taken to prevent viral spread when the dressing is changed. In addition, accumulation of fluid beneath the dressing may increase skin maceration at the vaccination site. Accumulation of exudate may be decreased by first covering the vaccination site with dry gauze, then applying the dressing over the gauze. The dressing should be changed every 1–3 days.

Blood and Organ Donation

Blood and organ donation should be avoided for at least 30 days following vaccination with replication-competent smallpox vaccine live.

Laboratory Test Interference

Smallpox vaccine live (ACAM2000) may induce false-positive tests for syphilis. Positive rapid plasma reagin (RPR) test results should be confirmed using a more specific test, such as the fluorescent treponemal antibody (FTA) assay.

Smallpox vaccine live (ACAM2000) may induce temporary false-negative results for the tuberculin skin test (purified protein derivative [PPD]) and may also affect blood tests for tuberculosis. Tuberculin testing should be delayed, if possible, for 1 month following smallpox vaccination.

Limitations of Vaccine Effectiveness

Vaccination with smallpox vaccine live may not protect all recipients following exposure to smallpox.

Specific Populations

Pregnancy

Smallpox vaccine live (ACAM2000) has not been studied in pregnant women. Live vaccinia virus vaccines can cause fetal harm and fetal death when administered to a pregnant woman. Congenital infection, principally occurring during the first trimester, has been observed after vaccination with replication-competent smallpox vaccine live, although the risk may be low. Generalized vaccinia of the fetus, early delivery of a stillborn infant, or a high risk of perinatal death has been reported.

The only setting in which vaccination of pregnant women should be considered is when exposure to smallpox is considered likely. If smallpox vaccine live is administered to a pregnant woman or if the vaccinee lives in the same household with or has close contact with a pregnant woman, the vaccinee should be apprised of the potential hazard to the fetus. Pregnant women who are close contacts of vaccinees may be at increased risk because live vaccinia virus can be shed and then transmitted to close contacts.

Healthcare providers, state health departments, and other public health staff should report to the National Smallpox Vaccine in Pregnancy Registry all pregnant women who, from 42 days prior to conception onward, received replication-competent smallpox vaccine live or had close contact with an individual who received replication-competent smallpox vaccine live within the previous 28 days. Civilian women should contact their healthcare provider or state health department for help enrolling in the registry. All civilian and military cases should be reported to the US Department of Defense by telephone (619-553-9255), the Defense Switched Network (DSN) 553-9255, fax (619-533-7601), or e-mail ([email protected]).

Lactation

Smallpox vaccine live (ACAM2000) has not been studied in lactating women. It is not known whether vaccine virus or antibodies are distributed into human milk.

Live vaccinia virus can be inadvertently transmitted from a vaccinated breast-feeding mother to her infant. Infants are at high risk of developing serious complications from live vaccinia smallpox vaccination.

Pediatric Use

The safety and effectiveness of smallpox vaccine live (ACAM2000) have not been established in the age groups from birth to 16 years of age. The use of the vaccine in all pediatric age groups is supported by evidence from adequate and well-controlled studies in adults and additional historical data on use of live vaccinia virus smallpox vaccines in children.

Before the eradication of smallpox disease, live vaccinia smallpox vaccine was administered routinely in all pediatric age groups, including neonates and infants, and was effective in preventing smallpox disease. During that time, live vaccinia virus vaccines were occasionally associated with serious complications in children, the highest risk being in infants younger than 12 months of age.

Vaccinees who have close contact with infants (e.g., breast-feeding) must take precautions to avoid inadvertent transmission of live vaccinia virus to infants.

Geriatric Use

Clinical studies of smallpox vaccine live (ACAM2000) did not include sufficient numbers of individuals 65 years of age or older to determine whether they respond differently than younger individuals. There are no published data to support use of the vaccine in geriatric individuals older than 65 years of age.

Common Adverse Effects

Information regarding the safety of smallpox vaccine live (ACAM2000) has been derived from clinical trials evaluating the vaccine, data compiled during the era when routine smallpox vaccination was recommended using previously available replication-competent vaccinia vaccines (e.g., Dryvax), and adverse event data obtained from military and civilian smallpox vaccination programs during 2002–2005 that used Dryvax.

Common adverse events following vaccination with replication-competent smallpox vaccine live include inoculation site signs and symptoms, lymphadenitis, and constitutional symptoms (e.g., malaise, fatigue, fever, myalgia, headache). These adverse events are less frequent in revaccinated individuals than in those receiving the vaccine for the first time.

Inadvertent inoculation at other sites is the most frequent complication of replication-competent vaccinia vaccination. The most common sites involved are the face, nose, mouth, lips, anus, and genitalia.

Self-limited skin rash (e.g., urticaria and folliculitis) not associated with vaccinia replication in skin may occur following vaccination.

General

Smallpox vaccine live (ACAM2000) is available in the following dosage form(s) and strength(s):

Multiple-dose vial containing lyophilized vaccine and vial containing diluent. After reconstitution with the diluent as directed by the manufacturer, each vaccine vial provides approximately 100 doses; each dose of 0.0025 mL contains 2.5 x 10⁵ to 12.5 x 10⁵ plaque-forming units (PFU) of vaccinia virus.

Dosage

It is essential that the manufacturer's labeling be consulted for more detailed information on dosage and administration of this drug. Dosage summary:

Adults

Dosage and Administration

• Administer smallpox vaccine live (ACAM2000) only after being trained on the safe and effective administration of the vaccine by the percutaneous route (scarification).

• Do not administer intradermally, subcutaneously, IM, or IV.

• One droplet of reconstituted smallpox vaccine live is administered by the percutaneous route (scarification) using 15 jabs of a bifurcated needle.

• The droplet (0.0025 mL) of smallpox vaccine live is picked up with a bifurcated needle by dipping the needle into the vial of reconstituted vaccine.

• See the manufacturer's labeling for complete instructions for vaccine preparation and administration (including handling precautions and disposal instructions) and instructions for interpreting the response to vaccination (including vaccination failures).

• Give the FDA-approved patient labeling (Medication Guide) to the vaccinee and provide instructions on vaccination site care. (See Advice to Patients.)

• Revaccination may be recommended (e.g., every 3 years) in individuals at continued high risk of exposure to smallpox (e.g., research laboratory workers handling variola virus).

Specific Drugs

It is essential that the manufacturer's labeling be consulted for more detailed information on interactions with this drug, including possible dosage adjustments. Interaction highlights:

There are no data evaluating the simultaneous administration of smallpox vaccine live with other vaccines.