INTRODUCTION — Replication-competent vaccinia virus was the live poxvirus that was used as the smallpox vaccine. The development of this vaccine was an important step in the successful eradication of smallpox, an infection characterized by fever, rash, and constitutional symptoms, with a high rate of morbidity and mortality.

This topic will address the virology of vaccinia virus, available vaccines, vaccination procedures, contraindications, and adverse events. Vaccinia virus in the research setting is discussed elsewhere. (See "Vaccinia virus in the research setting".)

HISTORICAL BACKGROUND — Attempts at control of smallpox began after it was noted that accidental exposure to smallpox by a scratch on the skin reduced the severity of infection. This led to the practice of "variolation," which involved intentional administration of pustular fluids from smallpox scabs to uninfected persons. The practice of variolation began in China and India in the tenth century; deaths were reported as a complication of this procedure.

In 1796, Edward Jenner showed that inoculation with cowpox virus protected against smallpox and carried less risk of illness than variolation. Subsequently, vaccinia virus became the basis for the smallpox vaccine. The origins of vaccinia virus are uncertain. Successful vaccination was highly protective for development of any disease for five years and could protect from death or severe smallpox for up to 20 years. Periodic revaccination was necessary for optimal protection.

In 1959, the World Health Assembly adopted a program aimed at global eradication of smallpox. The development of stable, freeze-dried vaccine meant that vaccination programs could reach less-developed tropical countries. By 1967, efforts towards eradication were intensified.

Key components of the eradication strategy included surveillance, quarantine of infected patients, and vaccination of contacts and others living in the immediate area. Eradication was ultimately successful for a number of reasons. Smallpox has a long incubation period, which allows vaccination to modify the course of the illness. The lack of a reservoir for variola, other than humans, the ease of clinical diagnosis, and the fact that variola does not establish latent or persistent infection, were additional important contributors to the success of the eradication effort.

By 1985, less than 10 years after the last reported case, routine vaccination against smallpox was abandoned throughout the world. However, some laboratory researchers (those who work with replication-competent vaccinia virus and other pathogenic poxviruses), some health care workers, some first responders, and military personnel continue to be vaccinated. In addition, several experimental vaccines employ replication-competent vaccinia virus as a vaccine vector and as an oncolytic virus. Thus, the complications from replication-competent vaccinia virus vaccination are still seen. (See 'Adverse events' below.)

A detailed discussion of the types of vaccine is found below. (See 'Modified vaccinia Ankara vaccine' below and 'Smallpox (vaccinia) vaccine' below.)

VIROLOGY — Vaccinia virus is a large, double-stranded DNA virus that carries out its entire life cycle in the cytoplasm of infected cells [1]. The virus is in the same family as variola virus, the causative agent of smallpox and monkeypox. (See "Variola virus (smallpox)" and "Monkeypox".)

However, unlike variola virus, which is easily spread through respiratory secretions, vaccinia virus is spread by direct contact through broken or abraded skin or mucosal membranes. The only natural host for the variola virus is humans. By contrast, the natural host for vaccinia virus is unknown, and it has the ability to infect numerous cell types from a vast number of animals. This property of infecting multiple cell lines from a broad range of species is one of the major reasons why vaccinia virus is widely used in research laboratories.

The virus has also been extensively studied as a model system to understand gene regulation and expression. With the advent of recombinant DNA technology and cloning, vaccinia virus became a research tool for the expression of foreign proteins in vitro and in vivo [2]. Recombinant vaccinia viruses expressing foreign proteins may have future applications in vaccinating animals or people against infectious diseases or cancer [3-5]. In recent years, many laboratories have been using highly attenuated poxviruses that do not produce infectious virus in mammalian cells. Because this type of virus does not produce infectious progeny, it has an excellent safety profile, even in immunocompromised hosts [6]. This highly attenuated strain of vaccinia virus has gained approval for use as a smallpox/monkeypox vaccine in the United States. (See 'Modified vaccinia Ankara vaccine' below.)

BIOTERRORISM AND THE SMALLPOX VACCINE — Prior to the eradication of smallpox, the smallpox vaccination campaign was very effective. Administration of the smallpox vaccine markedly reduced the smallpox attack rate compared with unvaccinated individuals (99.9, 99.5, 88, and 50 percent at 1, 3, 10, and 20 years after vaccination, respectively). (See 'Historical background' above.)

With the worldwide eradication of smallpox, routine vaccination with vaccinia virus is no longer performed. However, after the anthrax bioterrorism attack in October 2001, the United States government has gone to great lengths to improve preparedness for the intentional or accidental release of and exposure to variola virus. Initially, this began with attempts to vaccinate potential first responders and health care workers [7,8]. There has also been funding for the development and production of a modern-day smallpox vaccine, as well as the development of antipoxvirus therapeutics. (See 'Modified vaccinia Ankara vaccine' below and 'Antiviral agents' below.)

Smallpox vaccine has also been purchased by the United States government for stockpiling. Identification of a case of smallpox would be a public health emergency, and in that setting, vaccine would be distributed by the Department of Health and Human Services.

AVAILABLE VACCINES — There are two available smallpox vaccines, a replication-deficient modified vaccinia Ankara vaccine (MVA) and a replication-competent smallpox vaccine (ACAM2000). Dryvax, which was first approved in 1931, was used in the United States prior to the eradication of smallpox. This vaccine was a replication-competent vaccine that was cultivated in lymph and skin of inoculated animals and is no longer being used.

●In the United States, the MVA vaccine (Jynneos) was approved for use as a smallpox/monkeypox vaccine in September 2019 [9]. It was approved as a smallpox vaccine in Canada and the European Union in 2013. This vaccine differs from replication-competent vaccines in that it does not produce infectious progeny virus. (See 'Modified vaccinia Ankara vaccine' below.)

●ACAM2000 was approved by the US Food and Drug Administration (FDA) in 2007. In the United States, ACAM2000 is only available through the Centers for Disease Control and Prevention (CDC). In 2008, this cell culture-grown smallpox vaccine replaced stockpiles of Dryvax [10-12]. (See 'Smallpox (vaccinia) vaccine' below.)

The discussion below focuses primarily on the use of ACAM2000. Additional information on the MVA vaccine will be forthcoming once guideline recommendations are issued.

MODIFIED VACCINIA ANKARA VACCINE — A modified vaccinia Ankara (MVA) vaccine (sold under the trade names Imvamune in Canada, Imvanex in Europe, and Jynneos in the United States) is made from a highly attenuated, nonreplicating vaccinia virus and has an excellent safety profile, even in immunocompromised people and those with skin disorders. This vaccine can be used for prevention of both smallpox and monkeypox. The initial vaccination series with MVA (0.5 mL) is administered as a subcutaneous injection at zero and four weeks.

In Germany, the MVA vaccine was used to vaccinate 100,000 people during the smallpox eradication program in the 1970s. This vaccine, which was given subcutaneously or intramuscularly rather than through scarification, was not associated with significant adverse events. Further clinical trials have supported the safety and immunogenicity of this vaccine [13-20]. Common adverse events seen after vaccination with MVA include injection site reactions, headache, myalgia, and lymphadenopathy [18,20].

The potential efficacy of this vaccine against smallpox was demonstrated in an open-label trial that analyzed immune responses and cutaneous reactions induced by the ACAM2000 vaccine, as a surrogate marker [20]. In this trial, 440 volunteers were randomly assigned to receive a single dose of ACAM2000, or two doses of the MVA vaccine four weeks apart followed by a challenge dose of ACAM2000 four weeks later. Almost 98 percent of those who received ACAM2000 alone developed the expected major cutaneous reaction with median maximum lesion areas of 76 mm² (95% CI 70-87). By contrast, the median maximum lesion areas from ACAM2000 given to the group that first received MVA vaccination were 0 mm² (95% CI 0-2), indicating protection from poxvirus challenge.

Because of its safety profile, it is expected that this vaccine will replace ACAM2000 when vaccination is used for pre-exposure prophylaxis of smallpox, particularly in groups such as the military, research laboratory workers, and laboratory response network laboratory personnel who work with variola virus, monkeypox virus, and replication-competent vaccinia virus.

SMALLPOX (VACCINIA) VACCINE — The United States Advisory Committee on Immunization Practices (ACIP) has published recommendations for smallpox vaccination with the replication-competent ACAM2000 in emergency and routine nonemergency settings [6,21,22]. The discussion below will only address the routine nonemergency use of the vaccine. The use of the smallpox vaccine in the setting of suspected smallpox bioterrorism should be done only after consultation with state and local health officials along with the Centers for Disease Control and Prevention (CDC). (See 'Bioterrorism and the smallpox vaccine' above.)

Vaccine administration — Vaccination with ACAM2000 is carried out as a scarification; an infectious dose is placed on a bifurcated sterile needle and gently penetrated 15 times into the epidermis of the deltoid region of the arm. Two to five days after primary vaccination, a papule forms and then becomes a vesicle two to three days later. The vesicle reaches a maximum size by day 8 to 10. A scab forms within two weeks leaving behind a scar when healing is complete. Mild fever and localized lymphadenopathy are often present during the first two weeks after vaccination.

Viral shedding from the vaccine site is highest during the first two weeks, but virus can still be cultured until the scab falls off. While a semiocclusive dressing may prevent contact and environmental spread of the vaccine, it is recommended to cover the vaccine site with dry gauze, which decreases secondary pox lesions around the inoculation site [23].

Cutaneous inoculation has been performed for two main reasons.

●The resulting scar served as a method to verify vaccination during the smallpox eradication program.

●Immune responses to vaccine given by means other than scarification were found to be inferior.

Vaccinated individuals maintain long-lasting cellular and humoral immune responses. In one report, more than 90 percent of volunteers who were vaccinated 25 to 75 years previously maintained substantial humoral and/or cellular immunity against vaccinia [24]. Antibody responses remained stable throughout this period, while T cell responses gradually declined with a half-life of 8 to 15 years.

Vaccination against smallpox and monkeypox — With the worldwide eradication of smallpox and the suspension of vaccinia virus as a routine vaccine, there is a growing population that is susceptible to smallpox. Concerns have been raised that variola virus might be used as a biological warfare agent [25].

Due to these concerns, some first responders have been vaccinated. In 2003, about 39,000 civilians in the United States were vaccinated in a government-sponsored Pre-Event Vaccination Program [26]. In addition, some countries choose to continue to vaccinate military recruits with vaccinia virus. However, this policy is not without risk [27].

After a large outbreak of monkeypox in Africa that mainly affected children and young adults who had never been vaccinated against smallpox, there was some discussion about vaccinating civilians in the affected region who were at risk of exposure to monkeypox [25,28-30]. Vaccination was not recommended at that time. However, during an outbreak of monkeypox in North America [31], multiple people were given the smallpox vaccine [32]. (See "Monkeypox".)

Adverse events — A review of historical data and more contemporary vaccination studies in the wake of bioterrorism concerns has highlighted a number of important adverse events.

Historical data — During the smallpox eradication program, numerous reports described the complications of vaccination in the United States [33-36]. Historically, vaccinia adverse reactions have included eczema vaccinatum, progressive vaccinia, fetal vaccinia, generalized vaccinia, erythema multiforme major, and postvaccinial encephalitis [37]. (See 'Specific complications' below.)

Contemporary data — In 2003, the US Department of Health and Human Services (DHHS) implemented a smallpox vaccination program with Dryvax for potential first responders through a comprehensive safety monitoring system [37]. More than 38,000 doses of vaccine were administered with 822 reported adverse events, 100 of which were considered serious. Adverse events included generalized vaccinia (2 cases); one case of postvaccinial encephalitis; and the rediscovery of myocarditis and/or pericarditis (21 cases) and unexpected ischemic cardiac events (10 cases).

No further cardiac events were identified in the DHHS vaccine program after initiation of the additional deferral criteria, which included:

●History of cardiac disease.

●Presence of three major risk factors for atherosclerotic heart disease (hypertension, diabetes, hypercholesterolemia, smoking, or a history of heart disease in first-degree relatives before age 50 years).

Risk of complications and vaccine status — Historical data from a 1968 surveillance study demonstrated that approximately 75 complications occurred per million vaccinations with an overall death rate of one per million doses in people receiving the vaccine for the first time suggesting an overall acceptable rate of adverse events in healthy people in the setting of naturally occurring smallpox (table 1) [35].

Studies have differed, however, as to whether the risk of complications increases in patients who have received vaccine in the past [35,37]. In the 1968 national surveillance study, complications were 10 times more likely to occur in the primary vaccine group compared to those being revaccinated. Revaccination was also associated with fewer acute adverse reactions compared with primary vaccination, including significantly smaller skin lesions and a significantly lower incidence of fever [38,39]. In contrast, in the DHHS vaccine safety monitoring program discussed above, serious adverse events were more common among older revaccinees than younger first-time vaccinees.

Contraindications — In the nonemergency setting, some of the vaccine-related adverse events discussed above can be prevented by avoiding vaccination in high-risk hosts, including:

●Patients with immunodeficiencies (natural, acquired, or drug-induced)

●Individuals with a history of eczema or other exfoliative skin condition

●Pregnant women [40,41]

●Individuals younger than 18 years of age

●Individuals with a history of anaphylaxis to polymyxin B sulfate and neomycin since the vaccine contains trace amounts of these agents

●Close contacts with immunocompromised patients [42]

In addition, to avoid cardiac events, patients should be asked about heart disease, and in the nonemergency setting, vaccination should not be administered to individuals with:

●A history of cardiac disease (eg, coronary artery disease or cardiomyopathy) [43]

●The presence of three major risk factors for atherosclerotic heart disease (eg, hypertension, diabetes, hypercholesterolemia, smoking, a history of heart disease in first-degree relatives before age 50 years)

The contraindications to smallpox vaccination after a suspected bioterrorism attack are different, and are addressed in the CDC document that provides clinical guidance for smallpox vaccine use in a postevent vaccination program [22].

Specific complications

Acute vaccinia syndrome — Approximately 13 percent develop acute vaccinia syndrome (AVS), characterized by fatigue, headache, muscle aches, and fever [44]. One study found an association between AVS and specific polymorphisms in the interleukin-1 gene complex, an integral mediator of febrile responses in humans [45,46].

Postvaccinial encephalitis — In the 1968 national surveillance study, a variety of disorders that were temporally related to vaccination were classified as postvaccinial encephalitis; the estimated rate was 2.9 cases per million in primary vaccinated individuals [35]. Mortality from this complication was high, and there was significant potential for permanent neurologic sequelae. Of the 16 reported cases, 15 occurred in subjects who were less than seven years old. The only adult patient found to have central nervous system (CNS) complications was 42 years old, and his prior vaccination status was unknown.

Two distinct clinicopathologic syndromes of postvaccinial encephalitis have been identified [47].

●Microglial encephalitis is more frequent in persons older than two years of age; it is characterized by fever and headache followed by onset of seizures and coma. On histologic examination, widespread demyelination of subcortical white matter is seen.

●Postvaccinial encephalopathy occurs mainly in children younger than two years of age and presents with fulminant seizures and paralysis. These patients have diffuse cerebral edema and perivascular hemorrhages; virus is sometimes isolated from brain or cerebrospinal fluid.

Surveillance for neurologic adverse events during the 2002-2004 United States smallpox vaccination program identified three cases of suspected encephalitis for an observed rate of five per million vaccinations [47]. No virus was isolated from cerebrospinal fluid and all patients recovered. No reports of encephalitis occurred more than 14 days after vaccination.

These data from the United States on CNS disease following vaccination are in striking contrast to statistics from European countries where a different strain of vaccinia virus was used and rates of postvaccinial encephalitis were as high as one in 4000 in adult primary vaccinees [48]. This leads some to suggest that development of postvaccinial encephalitis could be very high in adults undergoing primary vaccination [49].

There are no data on specific therapy of this generally rare complication. It has been suggested that hyperimmune antivaccinia virus immune globulin (VIG) would be unlikely to be effective because postvaccinial encephalitis is thought to be an immune-mediated disorder, rather than direct vaccinial infection of the central nervous system [50]. Although not recommended for this indication, VIG may reduce the incidence of postvaccinial encephalitis (from 13 to 3 cases in a randomized trial of over 106,000 Dutch military recruits) [51].

Progressive vaccinia — Progressive vaccinia (also called vaccinia necrosum and vaccinia gangrenosum) is the most dreaded complication of vaccination and was universally fatal prior to the introduction of VIG [33]. It occurs in vaccinees with immunodeficiencies such as agammaglobulinemia or T cell deficiencies, as well as those who receive immunosuppressive therapy including steroids or radiation therapy. After vaccination, there is progressive destruction of local areas of skin, subcutaneous tissue, and other underlying structures with metastatic lesions appearing at other cutaneous sites that can ultimately result in death.

This complication can occur after both primary and revaccination. In the 1968 national surveillance study, the majority of progressive vaccinia cases developed in patients over the age of 15 years who became immunosuppressed (two of five primary vaccinees and five of six revaccinees) [35]. All of these patients were given VIG, which appeared to decrease mortality. (See 'Vaccinia immune globulin' below.)

The efficacy of VIG was evaluated in a 2004 literature review of 64 patients with progressive vaccinia who were treated with VIG; no randomized controlled trials have been performed [50]. The following findings were noted:

●Fourteen patients died, which represents a mortality rate of 22 percent.

●Progressive vaccinia was lethal in infants despite treatment with VIG because they lack cellular immune function. In comparison, progressive vaccinia resolved after VIG in many adults with acquired immune deficiencies and in 8 of 14 with isolated hypogammaglobulinemia or agammaglobulinemia.

In 2009, the first case of progressive vaccinia since 1987 was reported the United States [52,53]. The patient was a 20 year old military recruit who had undiagnosed acute myelogenous leukemia (AML). Progressive vaccinia developed after he received chemotherapy to treat AML, and presented as an expanding lesion at the vaccine site (figure 1). He received all available treatments for orthopoxvirus infections (see 'Treatment of complications' below). While he ultimately survived, he developed numerous complications related to prolonged hospitalization and treatment of his cancer.

Eczema vaccinatum — Eczema vaccinatum (EV), also called Kaposi varicelliform eruption, is local or disseminated vaccinia that occurs in patients who have a history of eczema or other types of atopic dermatitis [35]. In patients with EV, vaccinia virus may disseminate to cause an extensive vesiculopustular rash with systemic illness [54].

Eczema vaccinatum has developed in patients whose eczema was in complete remission at the time of vaccination. As a result, a history of eczema is considered a contraindication for vaccination. Individuals with other types of dermatitis are also at risk of eczema vaccinatum, and they should not be vaccinated until the skin condition is completely cleared. (See 'Contraindications' above.)

The vast majority of patients developing eczema vaccinatum in both the primary and revaccination groups were infants and children in the 1968 national surveillance study, with only 20 of the 126 cases occurring in people over 15 years of age (table 1) [35]. While usually less severe than progressive vaccinia, eczema vaccinatum resulted in hospitalization in 60 percent of vaccinees with this complication; hospital stays were occasionally prolonged [35]. Treatment with VIG may decrease the severity of and mortality from eczema vaccinatum, although there are no controlled trials evaluating efficacy [33,50,55]. (See 'Vaccinia immune globulin' below.)

Individuals with eczema who come into close contact with a person who has been recently vaccinated can also develop severe eczema vaccinatum, presumably due to inoculation at multiple sites. Approximately 80 percent of contacts acquiring this complication required hospitalization [35,56].

The first case report of eczema vaccinatum in the United States since 1988 was a two-year-old child with a history of severe eczema, who was hospitalized because of a generalized vesicular rash (picture 1) [56,57]. The rash developed after he was exposed to his father, who had recently been vaccinated with a replication-competent smallpox vaccine in preparation for military service. However, the history was not initially obtained by his doctors.

Due to the delayed diagnosis of eczema vaccinatum, the child's hospital course was complicated by hypothermia and hemodynamic instability. The patient was treated serially with intravenous VIG, mechanical ventilation, cidofovir, and an investigational drug, ST-246 (now called tecovirimat) under an emergency investigational drug application. (See 'Antiviral agents' below.)

The patient eventually recovered and was discharged after 48 days of hospitalization. Given the rapid initiation of serial interventions, it was difficult to determine the potential contributions of each agent to the patient's recovery [57].

The patient's mother also developed vesicular lesions on her face that were probably related to physical contact with her son's lesions. An environmental assessment of the home five days after hospitalization of the child demonstrated the presence of viable virus on household items (eg, drinking cup, toys).

Generalized vaccinia — Some patients develop a vesicular rash that can be extensive following vaccination. This complication is referred to as generalized vaccinia, which is usually self-limited and not life-threatening. Of the 143 cases compiled in the 1968 national surveillance study, the majority of cases of generalized vaccinia occurred among infants and children receiving primary vaccination [35]. However, 9 of 10 cases that occurred in the revaccination group were in people 20 years or older. While no serious sequelae from generalized vaccinia have been reported, extensive scars can develop. Because of the generally benign outcome, no studies have evaluated the possible efficacy of therapies such as VIG [50].

Myocarditis and myopericarditis — Cardiac complications of smallpox vaccination have been reported since the initiation of vaccination in the 1950s in Europe. The complications range from asymptomatic T-wave changes to fatal myocarditis or myopericarditis. The cause of myocarditis and myopericarditis is unknown, but believed to be immune mediated. While this has yet to be proven, it was found that after vaccinations, some subjects developed a false positive test to syphilis [58].

During the smallpox vaccination program of civilian first responders in the United States in 2003, 21 of 36,217 civilian vaccinees developed myopericarditis (6 per 10,000) [59]. The rate was 1.3 per 10,000 vaccinees if only probable cases were included and 5.5 per 10,000 vaccinees if suspected cases were included [37]. Among military vaccinees, the rate was lower (1.2 per 10,000), probably reflecting a highly selected, very fit population [60]. The true incidence of myopericarditis is probably somewhat higher since these cases represented symptomatic disease, which limited duty. This complication has led to its inclusion on a black box warning on the ACAM2000 package insert.

The diagnosis and treatment of this entity are discussed elsewhere. (See "Myopericarditis", section on 'Vaccinia-associated myopericarditis'.)

Superinfection — Superinfection of a smallpox vaccination site is clinically difficult to distinguish from a large normal vaccination reaction or "robust take." A robust take is cellulitis caused by the replicating vaccinia virus.

The frequency of superinfection was addressed in a retrospective review of 36,043 United States civilian smallpox vaccinees; 48 cases of severe local reactions consistent with possible superinfection were identified [61]. However, only 2 of the 48 cases (0.6 per 10,000) met the definition of superinfection and were effectively treated with antibiotics.

Accidental inoculation — Accidental inoculation, which results in a normal vaccinial lesion in an inappropriate site, was the most commonly reported complication of vaccination in the 1968 national surveillance study [35]. It usually occurred after autoinoculation of the eye or surrounding structures (74 percent). The importance of education of vaccine recipients about proper hand washing after bandage changes cannot be over-emphasized. One study demonstrated that vaccinia virus can still be detected through day 21 after vaccination [62].

The vast majority of autoinoculation complications occurred in infants and children in the primary vaccine group. Prior immunization may prevent inadvertent eye infection since only seven cases were described in the revaccination group.

Vaccinial keratitis from acute inflammatory changes can cause prolonged disability [63]. As a result, some of the 143 patients in the national surveillance study with eye inoculations were given idoxuridine eye drops with or without VIG [35]. In another series that only analyzed ocular infections, 4 of 22 patients with corneal involvement had mild residual defects; in comparison, residual defects were rare in patients whose corneas were not affected [64].

The possible role of VIG therapy in such patients is not known. In a review of eight reports with information about VIG therapy, there were no fatalities [50]. Although healing of vaccinial keratitis has been described after VIG therapy [63], there are experimental data in rabbits showing that daily administration of VIG in vaccinial keratitis resulted in larger eye lesions with more persistent scarring, possibly due to immune complex disease [65].

It is recommended that VIG should be considered in patients with severe ocular vaccinia, after keratitis has been excluded, and that the presence of keratitis is not an absolute contraindication to VIG in patients with a comorbid complication requiring such therapy [50].

Sexual transmission of vaccinia virus — Case reports have described sexual transmission of vaccinia virus [66-68]:

●A vaginal lesion secondary to vaccinia virus occurred in a female approximately 10 days after sexual contact with a military recruit who was vaccinated against smallpox [66]. The mode of transmission was thought to be lack of hand washing after rebandaging the vaccination site immediately before intercourse.

●Vaccinia virus was apparently genitally transmitted by a sexual partner who had received the replication-competent smallpox vaccine three days prior to sexual intercourse [67].

●An individual who received the vaccinia vaccine and who did not use an occlusive dressing transmitted vaccinia to a sexual partner, who developed a painful perianal rash, a lesion on the upper lip, fever, malaise, nausea, and vomiting [68]. The individual who acquired secondary vaccinia then transmitted it sexually to another individual, who developed malaise, sore throat, and nasal congestion, as well as lesions of the penis, groin, and arm. Vaccinia virus DNA was detected by the polymerase chain reaction from skin lesions of the secondary and tertiary case patients.

Vulvar vaccinia infections are characterized by painful ulcers and/or vesicles and vulvar edema with occasional lymphadenopathy [67]. Patients may also complain of vaginal discharge or pruritus. The lesions are often misdiagnosed as genital herpes.

Healthcare providers should educate patients about the importance of using an occlusive dressing and of hand washing after contact with the vaccination site to prevent transfer to other parts of the body and to other individuals.

Reporting guidelines — Any adverse event after smallpox vaccination should be reported to state health departments and the Vaccine Adverse Events Reporting System (VAERS) [69]. Any adverse reaction that requires treatment with VIG, cidofovir, or new antivirals should be reported immediately (see 'Antiviral agents' below). Adverse events that meet the regulatory criteria for "serious" (eg, those resulting in hospitalization, permanent disability, life-threatening illness, or death) should be reported within 48 hours. Officials should be notified of all other events within one week.

Reports can be submitted to VAERS at www.vaers.hhs.gov, 877-721-0366, or P.O. Box 1100, Rockville, MD 20849-1100. Forms and telephone assistance are available from VAERS (800-822-7967).

Treatment of complications — In the United States, VIG is the only treatment that is approved by the Food and Drug Administration (FDA) for the management of complications resulting from the replication-competent smallpox vaccine [50]. Off-label use of the newer antiviral agents for treatment of smallpox such as tecovirimat and brincidofovir has also been given to treat complications resulting from the replication-competent smallpox vaccine. Idoxuridine eye drops had been used for the treatment of ocular vaccinia; however, this ophthalmic preparation is no longer available.

Vaccinia immune globulin — An intravenous formulation of vaccinia immune globulin (VIG) derived from the plasma of smallpox vaccines was approved by the US FDA in February 2005 [70]. VIG was tested in 111 healthy volunteers and was well tolerated. Mild to moderate adverse effects included headache, hives, and other rashes. VIG-IV, which is only available through the CDC (404-639-3670), is administered in a dose of 2 mL/kg (100 mg/kg), given as an intravenous infusion. As discussed above, VIG appears to reduce the morbidity and mortality from progressive vaccinia, eczema vaccinatum, and possibly severe generalized vaccinia and ocular inoculation in the absence of keratitis [50]. The concern about keratitis is based in part upon experimental data in rabbits showing that daily administration of VIG in vaccinial keratitis resulted in larger eye lesions with more persistent scarring, possibly due to immune complex disease [65].

Antiviral agents — Novel therapies to treat orthopoxvirus infections have been developed to counter vaccine complications and to treat smallpox infection. These include:

●Tecovirimat – Tecovirimat (ST-246) targets an envelope protein required for viral maturation and inhibits release of the infectious form of orthopoxvirus from infected cells. This drug is approved by the US FDA for treatment of smallpox [71] and has been added to CDC's Strategic National Stockpile. The use of this agent is discussed in a separate topic review. (See "Variola virus (smallpox)", section on 'Tecovirimat'.)

Tecovirimat has demonstrated efficacy against vaccinia virus in animal models, even when administered at later stages of illness [72,73]. It has also been given to humans in small safety trials [74] and, prior to its approval, was administered as an Emergency Investigational Drug to a severely ill child with eczema vaccinatum [56,57] and to a military recruit with progressive vaccinia [52]. Tecovirimat, along with VIG, was used as preemptive treatment of a military recruit who, soon after vaccinia virus vaccination, was diagnosed with leukemia [75]. This combination was also used to treat a patient with vaccinia virus infection resulting from a laboratory-related needlestick [76]. In all of these cases, tecovirimat was generally well tolerated, but its effect on clinical outcomes could not be determined.

●Brincidofovir (CMX001) – Brincidofovir is an analog of the antiviral agent cidofovir, which can be given orally and does not appear to have renal toxicity [77]. In the United States, this agent was approved for treatment of smallpox in June 2021 [78]. This agent is discussed in detail elsewhere. (See "Variola virus (smallpox)", section on 'Brincidofovir'.)

●Cidofovir – Cidofovir inhibits viral DNA polymerase. The United States Army Medical Research Institute of Infectious Diseases reported that cidofovir has in vitro activity against poxviruses and thus might be useful therapeutically [79]. However, the CDC considers cidofovir a second-line therapy for severe vaccinia infection due to the risk of nephrotoxicity. (See "Cidofovir: An overview" and "Cidofovir: An overview", section on 'Toxicity'.)

The possible efficacy of cidofovir was evaluated in a model of progressive vaccinia in immunocompromised mice [80]. Both topical and parenteral cidofovir delayed death compared with placebo. Topical therapy was more effective than parenteral therapy; however, the greatest effect was seen with combined topical and parenteral therapy.

●Other agents – Several other agents are being investigated. Thiosemicarbazone (Marboran) has been used as an agent to prevent smallpox, as well as some of the complications of vaccinia virus vaccination [81,82]; however, it is not available in the United States. Other antiviral agents that have activity against vaccinia virus and have been considered for the treatment of serious vaccine complications include adefovir and ribavirin [79,83].

Prevention of complications — In addition to its use in the treatment of complications, VIG has also been used to prevent complications in vaccinated individuals at high risk for complications. Included in the group are children less than one year of age, eczema, burns, chickenpox, and congenital or acquired immunosuppression [50]. There are no randomized trials to demonstrate efficacy in these settings. However, since VIG has a very low incidence of serious complications, prophylaxis is probably warranted in the above groups if vaccination is essential [50].

A potential concern with VIG use in these patients is that it might attenuate the development of active immunity after vaccination. However, the available data suggest that VIG does not diminish the response to smallpox vaccination [50,51]. Similarly, treatment of mice with the experimental drug ST-246 [84] or CMX001 [85] during smallpox vaccination did not compromise protective immunity elicited by the vaccine.

Some preliminary data suggest that there may be a genetic basis for adverse events after smallpox vaccination. Volunteers who received vaccinia virus vaccine underwent genotyping for 1442 single-nucleotide polymorphisms (SNPs) [86]. Genetic polymorphisms in two genes were associated with adverse reactions to smallpox immunization. Although further research is needed to confirm these findings, such an approach might allow screening before vaccinia virus administration to minimize complications.

SUMMARY AND RECOMMENDATIONS

●Smallpox vaccine helped to eliminate smallpox disease worldwide. (See 'Introduction' above.)

●Smallpox vaccine is derived from vaccinia virus, a large, double-stranded DNA virus that carries out its entire life cycle in the cytoplasm of infected cells. The virus is in the same family as variola virus, the causative agent of smallpox and monkeypox. (See 'Virology' above.)

●With the worldwide eradication of smallpox, routine vaccination with vaccinia virus is no longer performed. However, after the anthrax bioterrorism attack in 2001, large numbers of healthcare workers and potential first responders were vaccinated against smallpox in the United States. (See 'Bioterrorism and the smallpox vaccine' above.)

●Two available smallpox vaccines are part of the strategic stockpile in the United States; one is a replication-deficient modified vaccinia Ankara vaccine (MVA), and the other is a replication-competent smallpox vaccine (ACAM2000). Dryvax, which was first approved in 1931, was used in the United States prior to the eradication of smallpox, but it is no longer being used.

●The MVA vaccine is made from a highly attenuated, nonreplicating vaccinia virus and has an excellent safety profile, even in immunocompromised people and those with skin disorders. This vaccine was approved for use in the United States in September 2019 and will likely replace ACAM2000 when vaccination is used for pre-exposure prophylaxis.

●The replication-competent smallpox vaccine, ACAM2000, was approved for use in the United States in 2007. In the United States, it is only available through the Centers for Disease Control and Prevention (CDC).

•Vaccination with replication-competent smallpox vaccine (ACAM2000) is given by cutaneous inoculation with scarification, since this route of administration is associated with optimal cellular and humoral immune responses. (See 'Vaccine administration' above.)

•Serious adverse events associated with the replication-competent smallpox vaccine have included progressive vaccinia, eczema vaccinatum, myocarditis, pericarditis, and ischemic cardiac events. No further cardiac events have been described after the addition of deferral criteria for immunization, including a history of cardiac disease or risk factors for coronary artery disease (eg, hypertension, diabetes, hypercholesterolemia). (See 'Adverse events' above.)

•Vaccination with the replication-competent smallpox vaccine is contraindicated in immunosuppressed hosts, individuals with allergies to any of the two antibiotics used within the vaccine formulation, and in children younger than 18 years of age. (See 'Contraindications' above.)

•Postvaccinial encephalitis associated with the replication-competent smallpox vaccine is rare in the United States but has been reported in greater frequency in Europe where a different strain of vaccinia has been used to make the vaccine. (See 'Postvaccinial encephalitis' above.)

•Some self-limited complications have been associated with the replication-competent smallpox vaccine, such as the acute vaccinia syndrome, characterized by fatigue, headache, muscle aches, and fever and generalized vaccinia, which can lead to widespread vesicular lesions. (See 'Acute vaccinia syndrome' above.)

•Other complications include bacterial superinfection and accidental autoinoculation or accidental inoculation of close contacts. Vaccine recipients should be educated about proper hand washing after bandage changes to avoid contamination of other body parts, particularly the eye. (See 'Accidental inoculation' above.)

•Any adverse event associated with the replication-competent smallpox vaccine should be reported to state health departments and the Vaccine Adverse Events Reporting System (VAERS). (See 'Reporting guidelines' above.)

•In the United States, vaccinia immune globulin (VIG) is the only treatment that is approved by the US Food and Drug Administration (FDA) for the management of complications resulting from the replication-competent smallpox vaccine. With the FDA approval of tecovirimat and brincidofovir for the treatment of smallpox, these drugs are also available to manage significant complications from smallpox vaccination. (See 'Treatment of complications' above.)