Vaccines to prevent smallpox, mpox (monkeypox), and other orthopoxviruses

INTRODUCTION — Replication-competent vaccinia virus vaccine was used to help eradicate smallpox, a disease with a high rate of morbidity and mortality. Although smallpox has been eradicated, there is still a role for vaccinia virus vaccines to help prevent smallpox and mpox (previously referred to as monkeypox) in select populations.

This topic will address the virology of vaccinia virus, available vaccines, vaccination procedures, contraindications, and adverse events. Topic reviews that discuss the individual infections are presented elsewhere. (See "Variola virus (smallpox)" and "Treatment and prevention of mpox (monkeypox)".)

HISTORICAL BACKGROUND OF ORTHOPOXVIRUS VACCINES — 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 10^th 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 resource-limited 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 (a strategy called ring vaccination). 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.

With the eradication of smallpox, routine vaccination against smallpox was abandoned throughout the world because the risk of vaccination with replication-competent vaccinia virus outweighed the benefits. However, some groups have continued to be vaccinated in the decades since eradication. This includes laboratory researchers who work with pathogenic poxviruses and replication-competent vaccinia virus as well as certain health care workers and first responders. In addition, the United States military has continued to vaccinate personnel during certain periods of time.

After the anthrax bioterrorism attack in October 2001, the United States government improved preparedness for the intentional or accidental release of and/or exposure to variola virus. Since production of the smallpox vaccine ended after the eradication of smallpox (in the United States, that vaccine was called Dryvax), new stocks of smallpox vaccine produced in cell culture were developed, stockpiled, and approved; this vaccine is called ACAM2000. More recently, a second generation smallpox vaccine with an improved safety profile was developed and approved (modified vaccinia Ankara [MVA]/JYNNEOS). In the United States, these vaccines are distributed by the Department of Health and Human Services. Detailed discussions of these vaccines are found below. (See 'Modified vaccinia Ankara (non-replicating) vaccine' below and 'Vaccinia virus (replication-competent) vaccine' below.)

Vaccinia virus vaccines are also being utilized as pre- and post-exposure prophylaxis during the global outbreak of mpox that started in May 2022. This is discussed in detail elsewhere. (See "Treatment and prevention of mpox (monkeypox)", section on 'Pre-exposure prophylaxis with orthopoxvirus vaccines' and "Treatment and prevention of mpox (monkeypox)", section on 'Post-exposure prophylaxis' and "Treatment and prevention of mpox (monkeypox)", section on 'Post-exposure management'.)

VACCINIA VIRUS — Vaccinia virus is a large, double-stranded DNA virus that carries out its entire replication cycle in the cytoplasm of infected cells [1]. The virus is in the same family as variola virus, the causative agent of smallpox, and immunization with a vaccine derived from vaccinia virus provides protection against smallpox, mpox, and other diseases caused by members of the orthopoxvirus family. (See 'Modified vaccinia Ankara (non-replicating) vaccine' below and 'Vaccinia virus (replication-competent) vaccine' below.)

Because vaccinia virus has the ability to infect numerous cell types from a vast variety of animals, it 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].

Many laboratories have also been using a highly attenuated vaccinia virus that does not produce infectious virus in mammalian cells. This virus was initially developed in Germany in the 1970's by serial passage in chick embryo fibroblasts. The resulting virus, modified vaccinia Ankara [MVA], contained large deletions in the genome. These deletions resulted in a virus that replicates in chicken embryo fibroblasts but does not form infectious virus particles in mammalian cells. Because this type of virus does not produce infectious progeny in mammalian cells, 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/mpox vaccine in several countries, including the United States.

INDICATIONS FOR VACCINATION — The indications for vaccination with an orthopoxvirus vaccine depends upon the setting (outbreak versus routine nonemergency setting).

There are two available orthopoxvirus vaccines that can be used for prevention of smallpox and mpox: a replication-deficient modified vaccinia Ankara (MVA) vaccine and a replication-competent smallpox vaccine (ACAM2000). (See 'Modified vaccinia Ankara (non-replicating) vaccine' below and 'Vaccinia virus (replication-competent) vaccine' below.)

●MVA vaccine – The MVA vaccine (JYNNEOS in the United States, IMVANEX in the European Union, and IMVAMUNE in Canada) is made from a highly attenuated, non-replicating vaccinia virus and has an excellent safety profile, even in immunocompromised people and those with skin disorders. The MVA vaccine is administered as two doses four weeks apart. In the United States, this vaccine is approved for the prevention of smallpox and mpox. (See 'Modified vaccinia Ankara (non-replicating) vaccine' below.)

●ACAM2000 – ACAM2000 is a replication-competent smallpox vaccine that can only be used in select patients and is associated with more adverse events than the MVA vaccine. It is administered as a single dose. In the United States, ACAM2000 is approved for the prevention of smallpox. It can be used for prevention of mpox under an expanded-access investigational new drug (IND) application through the United States Centers for Disease Control and Prevention (CDC). (See 'Vaccinia virus (replication-competent) vaccine' below.)

Emergency/outbreak settings — The indications for vaccination in an emergency or outbreak setting vary depending upon the specific pathogen (eg, smallpox versus mpox), the type of exposure, and the risk of complications. The approach to vaccination in an emergency setting is determined by public health authorities.

During the global outbreak of mpox in 2022, vaccination is being used for post-exposure prophylaxis, and when resources allow, it is also being offered to communities at high risk for exposure to monkeypox virus (the causative agent of mpox). (See "Treatment and prevention of mpox (monkeypox)", section on 'Pre-exposure prophylaxis with orthopoxvirus vaccines' and "Treatment and prevention of mpox (monkeypox)", section on 'Post-exposure prophylaxis'.)

In the setting of a smallpox outbreak or bioterrorism attack, the United States Advisory Committee on Immunization Practices (ACIP) has published recommendations for vaccination with the replication-competent smallpox vaccine (ACAM2000) [7].

Routine nonemergency indications — Vaccination against orthopoxvirus infections with either the modified vaccinia Ankara vaccine (JYNNEOS) or the replication-competent vaccine (ACAM2000) is indicated in occupational settings for people working with virulent orthopoxviruses like variola virus (eg, in WHO-sanctioned BSL-4 labs at the CDC in the United States and Vector Institute in Russia) and monkeypox virus as well as less virulent orthopoxviruses like cowpox and replication-competent vaccinia virus. These groups include research laboratory workers, laboratory response network laboratory personnel, and members of select health care worker response teams [8]. In such persons, it can also be used for management after an exposure.

While the United States ACIP does not make recommendations regarding which vaccine should be used, we suggest vaccination with the MVA strain of vaccinia virus because of its safety profile. If the MVA vaccine is not available, vaccination with the replication-competent vaccine should be considered in the occupational setting [9] as well as for post-exposure prophylaxis. However, contraindications to vaccination must be carefully evaluated, and the risk of severe adverse reactions must be weighed against the risk for severe orthopoxvirus infection. (See 'Contraindications and precautions' below and 'Complications' below.)

MODIFIED VACCINIA ANKARA (NON-REPLICATING) VACCINE — The modified vaccinia Ankara (MVA) vaccine has been approved for prevention of both smallpox and mpox.

Dosing and administration — The preferred route of administration for the MVA vaccine is subcutaneously. However, in an outbreak situation when vaccine supplies might be limited, intradermal administration can be used as it requires a lower dose and allows more doses per vial. (See 'Standard dosing' below and 'Dose-sparing regimen' below.)

Standard dosing — The MVA vaccine series consists of two doses; the second dose is ideally administered 28 to 35 days after the first dose. However, if the second dose is delayed beyond 35 days, an additional dose (ie, after the second dose) is not required [10]. Peak immunity is expected 14 days after the second dose of vaccine.

The MVA vaccine (0.5 mL/dose) is administered as a subcutaneous injection. Subcutaneous injection delivers 0.5x10⁸ to 3.95x10⁸ plaque forming units (PFUs). Subcutaneous administration involves injecting the vaccine into the fatty tissue, typically over the triceps in those 12 months and older or in the anterolateral thigh for children younger than 12 months of age. The manufacturer of the MVA vaccine notes that it is acceptable to administer this vaccine in the subcutaneous tissue over the triceps area, even though the package insert states the preferred site of administration is the "deltoid" [10].

The duration of immunity after two doses of the MVA vaccine is unknown. For those at risk of an occupational exposure, the United States Advisory Committee on Immunization Practices (ACIP) recommends a booster dose (0.5 mL/dose) every two years for persons at continued risk of exposure to more virulent species of orthopoxvirus (eg, variola virus, monkeypox virus) or at least every 10 years for those at risk of exposure to less virulent species (eg, vaccinia virus, cowpox virus) [8]. Recommendations for booster doses in other populations have not yet been established.

The MVA vaccine may be used as a booster dose for those persons who received a primary series with the replication-competent smallpox vaccine (ACAM2000 or Dryvax) and who are at continued risk for exposure.

Dose-sparing regimen — In the United States, emergency use authorization (EUA) has been granted for intradermal administration of the MVA vaccine in persons ≥18 years for prevention of mpox (0.1 mL/dose at zero and four weeks). Persons ≥18 who received the initial dose using the standard subcutaneous regimen may receive the second dose with the intradermal regimen to complete the vaccine series. However, intradermal administration should generally be avoided in persons who have a history of developing keloid scars [10].

Intradermal vaccine is typically administered on the volar (inner side) of the forearm. A video of intradermal administration can be found on the CDC website. If a person presents for their second MVA vaccine dose and is still experiencing erythema or induration at the site of the first vaccine, the second dose should be administered intradermally in the contralateral forearm; other options include the upper back below the scapula or in the deltoid area.

Intradermal administration uses a lower dose compared with the standard subcutaneous route, extending the amount of available vaccine when supplies are limited [11]. In a trial of 528 individuals that evaluated the immunogenicity of different vaccine formulations and routes of administration in persons ≥18 years, the immunogenicity of the liquid formulation was similar between those who received subcutaneous versus intradermal vaccine 14 and 180 days after the second dose of vaccine [12].

In another study that examined immune responses in humans after MVA was given by various routes of vaccination, intradermal injection of 10⁷ PFUs resulted in similar immunogenicity to subcutaneous injection of 10⁸ PFUs [13]. In an open-label follow-up that analyzed cutaneous reactions induced after subsequent challenge with the historical smallpox vaccine (Dryvax), eight of the nine participants who had previously received 10⁷ PFUs of MVA vaccine by the intradermal route had an attenuated cutaneous response to Dryvax challenge, while all of the placebo-vaccinated subjects had a full cutaneous response to Dryvax challenge, providing evidence of protection from a poxvirus challenge [14].

Administration errors and deviations — Sometimes a vaccine may be administered at the incorrect site, via the incorrect route, or at the incorrect interval. Other types of errors include incorrect dosages or storage. The need to repeat the vaccine dose depends upon the specific type of error or deviation. Detailed information can be found on the United States Centers for Disease Control and Prevention (CDC) website.

Administration with other vaccines — There are no studies evaluating co-administration of the MVA vaccine with other vaccines. In general, the MVA vaccine may be administered without regards to timing of other vaccines since it is a nonreplicating virus vaccine.

One exception may be delaying the COVID-19 vaccine in patients who recently (eg, in the last four weeks) received the MVA vaccine. This exception is based on a theoretical risk of myocarditis after a vaccinia virus vaccine. The ACAM2000 vaccine and the COVID-19 vaccine have both been associated with myocarditis. Although there is no evidence at this time that the MVA vaccine is associated with myocarditis, it is a vaccinia virus vaccine, and avoiding co-administration is reasonable pending more experience with this vaccine combination.

However, if someone recently received the COVID-19 vaccine and then had an exposure to mpox, the MVA vaccine should not be delayed. (See "Treatment and prevention of mpox (monkeypox)", section on 'Post-exposure management'.)

Vaccination of persons who develop mpox — During the mpox outbreak that started in 2022, some patients developed mpox after receiving the first dose of the MVA vaccine. (See "Treatment and prevention of mpox (monkeypox)", section on 'Indications after a known exposure'.)

In this setting, additional vaccination is not needed for most patients because recent mpox likely confers additional immune protection [15]. However, it may be reasonable to administer the second dose to an immunocompromised patient who is diagnosed with mpox. We consider this approach for those with primary immunodeficiencies (eg, genetic/hereditary conditions) or secondary immunodeficiencies (eg, patients on active chemotherapy or HIV with a CD4 count <200 cells/microL).

Adverse reactions — Common adverse events seen after vaccination with MVA include injection site reactions (erythema, pain, induration, hyperpigmentation), headache, myalgia, and lymphadenopathy [16,17]. Some reactions, such as hyperpigmentation, may persist for several weeks or months [10]. Local side effects may be more severe with intradermal administration compared with subcutaneous administration [12]. (See 'Dose-sparing regimen' above.)

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 of this vaccine [16-23].

Contraindications and precautions — The MVA vaccine is contraindicated in those with a serious allergic reaction after a previous MVA vaccine dose. Intradermal administration should generally be avoided in those who have a history of developing keloid scars [10]. (See 'Dose-sparing regimen' above.)

In an outbreak situation, the decision to vaccinate those with a history of a severe allergic reaction (eg, anaphylaxis) to ciprofloxacin or gentamicin must be determined on a case-by-case basis since the vaccine contains trace amounts of these agents. Similarly, it should be used with caution in patients with an egg allergy since the vaccine virus is grown in chicken embryo fibroblasts [24]. Consultation with an allergist may be helpful in these settings but a long delay in vaccination should be avoided. The timing of vaccination for post-exposure prophylaxis during the global mpox outbreak is discussed separately. (See "Treatment and prevention of mpox (monkeypox)", section on 'Post-exposure prophylaxis'.)

Although the safety and effectiveness of the MVA vaccine during pregnancy and in those <18 years is not known, there are no contraindications to the use of this vaccine in these populations in the emergency setting. In the United States, the MVA vaccine has been made available for children under 18 years who have been exposed to mpox under an emergency use authorization (EUA) [11].

Immunogenicity — 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 [17]. 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.

Additional information on the efficacy of the MVA vaccine for prevention of mpox is presented elsewhere. (See "Treatment and prevention of mpox (monkeypox)", section on 'Pre-exposure prophylaxis with orthopoxvirus vaccines' and "Treatment and prevention of mpox (monkeypox)", section on 'Orthopoxvirus vaccines'.)

VACCINIA VIRUS (REPLICATION-COMPETENT) VACCINE — ACAM2000 is a replication-competent smallpox vaccine that was approved by the US Food and Drug Administration (FDA) in 2007 for the prevention of smallpox. In the United States, ACAM2000 is only available through the Centers for Disease Control and Prevention (CDC). This plaque-purified, cell culture-grown smallpox vaccine replaced stockpiles of Dryvax [25-27]. 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 produced in lymph and skin of inoculated animals and is no longer being distributed.

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 [6,7,28]. 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 CDC.

This vaccine has been made available for prevention of mpox under an expanded access investigational new drug (IND) protocol during the 2022 worldwide mpox outbreak; this is discussed in a separate topic review. (See "Treatment and prevention of mpox (monkeypox)".)

Vaccine administration — Vaccination with ACAM2000 is carried out as a scarification; an infectious dose (approximately 2.5 to 12.5x10⁵ plaque forming units [PFUs]) 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. Peak immunity is expected approximately four weeks after vaccine administration.

Patients should be educated about the importance of using an occlusive dressing and hand washing after contact with the vaccination site to prevent transfer to other parts of the body and to other individuals.

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 [29].

Cutaneous inoculation is performed since immune responses to vaccine given by means other than scarification were found to be inferior [30]. In addition, the resulting scar served as a method to verify vaccination during the smallpox eradication program.

The ACIP recommends routine nonemergency revaccination with ACAM2000 every three years for those working with pathogenic orthopoxviruses (ie, variola and monkeypox virus) and every 10 years for those working with less pathogenic orthopoxviruses (ie, cowpox and vaccinia virus) [9]. However, most 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 [31]. Antibody responses remained stable throughout this period, while T cell responses gradually declined with a half-life of 8 to 15 years.

Adverse events — Historically, adverse reactions with this vaccine have included eczema vaccinatum, progressive vaccinia, fetal vaccinia, generalized vaccinia, erythema multiforme major, and postvaccinial encephalitis [32-36]. (See 'Complications' below.)

In response to perceived increased geopolitical threat, in 2003 the United States Department of Health and Human Services (DHHS) implemented a smallpox vaccination program with Dryvax for potential first responders through a comprehensive safety monitoring system [36]. 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 a history of cardiac disease and the 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). More detailed information on the contraindications to vaccination is discussed below. (See 'Contraindications and precautions' below.)

Complications

Types of complications

●Acute vaccinia syndrome – Approximately 13 percent develop acute vaccinia syndrome (AVS), characterized by fatigue, headache, muscle aches, and fever [37]. One study found an association between AVS and specific polymorphisms in the interleukin-1 gene complex, an integral mediator of febrile responses in humans [38,39].

●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 [34]. 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 complications was 42 years old, and his prior vaccination status was unknown.

Two distinct clinicopathologic syndromes of postvaccinial encephalitis have been identified [40].

•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 to 2004 United States smallpox vaccination program, which was limited to adults, identified three cases of suspected encephalitis for an observed rate of five per million vaccinations [40]. 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 central nervous system 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 [41]. This leads some to suggest that development of postvaccinial encephalitis could be very high in adults undergoing primary vaccination [42].

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 [43]. 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) [44]. Additional information on the use of VIG for treatment and prevention of complications is found below. (See 'Vaccinia immune globulin' below.)

●Progressive vaccinia – Progressive vaccinia (also called vaccinia necrosum and vaccinia gangrenosum) is one of the most severe complications of vaccination and was universally fatal prior to the introduction of VIG [32]. 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 re-vaccinees) [34]. All of these patients were given VIG, which appeared to decrease mortality. (See 'Vaccinia immune globulin' below.)

In 2009, the first case of progressive vaccinia since 1987 was reported the United States [45,46]. 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 and prevention 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 [34]. In patients with EV, vaccinia virus may disseminate to cause an extensive vesiculopustular rash with systemic illness [47].

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 in the nonsmallpox emergency situation. 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 and precautions' below.)

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) [34]. 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 [34]. Treatment with VIG may decrease the severity of and mortality from eczema vaccinatum, although there are no controlled trials evaluating efficacy [32,43,48]. (See 'Vaccinia immune globulin' below.)

Individuals with eczema who have direct contact with a person who has been recently vaccinated can also develop severe eczema vaccinatum. Approximately 80 percent of contacts acquiring this complication required hospitalization [34,49].

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 in 2007 because of a generalized vesicular rash (picture 1) [49,50]. 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 [50].

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, a majority occurred among infants and children receiving primary vaccination [34]. 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 [43].

●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 is 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 [51].

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) [52]. 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 [36]. Among military vaccinees, the rate was lower (1.2 per 10,000), probably reflecting a highly selected, very fit population [53]. 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 [54]. However, only 2 of the 48 cases (0.6 per 10,000) met the definition of superinfection and were effectively treated with antibiotics.

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) [34].

Studies have differed, however, as to whether the risk of complications increases in patients who have received the vaccine in the past [34,36]. 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 [55,56]. In contrast, in the DHHS vaccine safety monitoring program, serious adverse events were more common among older re-vaccinees than younger first-time vaccinees.

Treatment and prevention of complications — In the United States, VIG is the only treatment that is approved by the FDA for the management of complications resulting from the replication-competent smallpox vaccine [43]. It can also be used to prevent complications in select patients at risk for developing complications.

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; although this ophthalmic preparation is no longer available, other agents (eg, triflourodine, vidarabine) can be used.

Some 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 [57]. 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.

This section will review therapeutic agents to treat and prevent vaccine-related adverse events. Contraindications to vaccination to reduce the risk of developing complications are found below. (See 'Contraindications and precautions' below.)

Vaccinia immune globulin

●For treatment of complications – An intravenous (IV) formulation of vaccinia immune globulin (VIG) derived from the plasma of smallpox vaccinees was approved by the US FDA in February 2005 [58]. 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 IV infusion.

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 [43]. VIG was tested in 111 healthy volunteers and was well tolerated. Mild to moderate adverse effects included headache, hives, and other rashes.

There have been concerns about its use in treatment of keratitis, 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 [59]. However, the presence of keratitis is not an absolute contraindication to VIG in patients with a comorbid complication requiring VIG therapy [43].

The efficacy of VIG for progressive vaccinia, one of the most severe complications of smallpox vaccination, was evaluated in a 2004 literature review of 64 patients who were treated with VIG; no randomized controlled trials have been performed [43]. In this report, 14 patients died, which represents a mortality rate of 22 percent. Progressive vaccinia was lethal in infants with deficiencies in cellular immunity despite treatment with VIG. In comparison, progressive vaccinia resolved after VIG in many adults with acquired immune deficiencies and in 8 of 14 with isolated hypogammaglobulinemia or agammaglobulinemia. A more detailed discussion of progressive vaccinia is found above. (See 'Complications' above.)

●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. This includes children less than one year of age as well as those with eczema, burns, chickenpox, or congenital/acquired immunodeficiencies [43]. 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 [43].

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 in animal models suggest that VIG does not diminish the response to smallpox vaccination [43,44]. Similarly, treatment of mice with ST-246 (tecovirimat) [60] or CMX001 (brincidofovir) [61] during smallpox vaccination did not compromise protective immunity elicited by the vaccine.

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

●Tecovirimat – Tecovirimat (ST-246) targets an envelope protein required for viral maturation and inhibits release of an infectious form of orthopoxvirus from infected cells. This drug is approved by the US FDA for treatment of smallpox [62] and has been added to CDC's Strategic National Stockpile. The use of this agent is discussed in separate topic reviews. (See "Variola virus (smallpox)", section on 'Tecovirimat' and "Treatment and prevention of mpox (monkeypox)", section on 'Antiviral therapy'.)

Tecovirimat has demonstrated efficacy against vaccinia virus in animal models, even when administered at later stages of illness [63,64]. It has also been given to humans in small safety trials [65] and, prior to its approval, was administered as an Emergency Investigational Drug to a severely ill child with eczema vaccinatum [49,50] and to a military recruit with progressive vaccinia [45]. Tecovirimat, along with VIG, was used as preemptive treatment of a military recruit who, soon after vaccinia virus vaccination, was diagnosed with leukemia [66]. This combination was also used to treat a patient with vaccinia virus infection resulting from a laboratory-related needlestick [67]. In all of these cases, tecovirimat was generally well tolerated, but its effect on clinical outcomes could not be determined.

●Cidofovir/Brincidofovir – 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 [68]. 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 [69]. 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.

Brincidofovir is an analog of the antiviral agent cidofovir, which can be given orally and does not appear to have renal toxicity [70]. In the United States, this agent was approved for treatment of smallpox in June 2021 [71], but it is not yet available for use. This agent is discussed in detail elsewhere. (See "Variola virus (smallpox)", section on 'Brincidofovir'.)

●Trifluridine (and vidarabine) eye drops or ointments – In patients with ocular lesions, off-label use of trifluridine (or vidarabine) eye drops or ointments can be used. Drops or ointments can be applied every four hours for 7 to 10 days [72].

●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 [73,74]; 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 [68,75].

Contraindications and precautions — Contraindications to vaccination with replication-competent vaccinia virus depend upon the setting. In the routine, nonemergency setting (eg, pre-exposure prophylaxis to prevent infection in the occupational setting), contraindications and precautions are more restrictive, whereas in the emergency setting, the benefits of vaccination are often more likely to outweigh the risk for adverse events and complications, as described above.

●Nonemergency setting – To prevent smallpox or mpox in the nonemergency setting, some of the vaccine-related adverse events discussed above can be prevented by avoiding vaccination with ACAM2000 in high-risk hosts, including:

•Persons with immunodeficiencies (natural, acquired, or drug-induced)

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

•Pregnant and breastfeeding persons [76,77]

•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 [78]

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) [79].

•The presence of 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).

●Smallpox emergency – In the setting of a smallpox outbreak or bioterrorism attack, the only contraindication to ACAM2000 is being severely immunocompromised (eg, bone marrow transplant recipients within four months of transplantation, persons with HIV with CD4 cell counts <50 cells/microL, persons with severe combined immunodeficiency, complete DiGeorge syndrome) [7].

The decision to vaccinate others who may be at risk for serious adverse events depends upon the level of exposure to variola virus and the availability of alternative vaccines. As an example, routine vaccination with ACAM2000 is contraindicated in persons <18 years of age; however, in an emergency setting, replication-competent smallpox vaccine should be considered since the benefits of vaccination may outweigh the risks. Prior to the eradication of smallpox, this vaccine was routinely used in those 12 months of age [6].

More detailed information on the contraindications to smallpox vaccination after a suspected bioterrorism attack are addressed in the CDC document that provides clinical guidance for smallpox vaccine use in a post-event vaccination program [7].

●Mpox outbreak – During an outbreak of mpox (eg, the global outbreak that started in 2022), ACAM2000 may be an option for certain persons after a known exposure. (See "Treatment and prevention of mpox (monkeypox)", section on 'Post-exposure management'.)

However, ACAM2000 is contraindicated in [80]:

•Those with a history of a severe allergic reaction (eg, anaphylaxis) after a previous dose of ACAM2000

•Patients with immunodeficiencies (natural, acquired, or drug-induced; vaccination should be avoided regardless of immune status)

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

•Persons who are pregnant or breastfeeding [76,77]

•Infants <12 months of age

•Three or more major cardiac risk factors (hypertension, diabetes, hypercholesterolemia, heart disease at age ≤50 years in a first-degree relative, or smoking)

•Eye disease treated with topical steroids

By contrast, ACAM2000 can be considered on a case-by-case basis in certain patients that may be less likely to develop severe complications such as:

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

•Moderate or severe acute illness, with or without fever

•Children and adolescents ages 1 through 16 years

•Close contacts with immunocompromised patients [78]

Additional considerations

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 [34]. 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 [81].

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 [82]. 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 [34]. 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 [83].

The possible effect of VIG therapy in such patients is not known. In a review of eight reports with information about VIG therapy, there were no fatalities [43]. Although healing of vaccinial keratitis has been described after VIG therapy [82], 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 [59].

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 [43].

Sexual transmission of vaccinia virus — Case reports have described sexual transmission of vaccinia virus [84-86]:

●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 [84]. 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 [85].

●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 [86]. 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 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 [85]. Patients may also complain of vaginal discharge or pruritus. The lesions are often misdiagnosed as genital herpes.

REPORTING GUIDELINES — Any adverse event after smallpox vaccination should be reported to state health departments and the Vaccine Adverse Events Reporting System (VAERS) [87]. Any adverse reaction that requires treatment with vaccinia immune globulin (VIG) or antiviral therapy should be reported immediately (see 'Antiviral agents' above). 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 877-721-0366 or P.O. Box 1100, Rockville, MD 20849-1100. Forms and telephone assistance are available from VAERS (800-822-7967).

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Orthopoxvirus (smallpox and monkeypox)".)

SUMMARY AND RECOMMENDATIONS

●Role of vaccinia virus – There are two available orthopoxvirus vaccines: one is a replication-deficient modified vaccinia Ankara (MVA) vaccine, 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. (See 'Historical background of orthopoxvirus vaccines' above.)

Smallpox vaccines are 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 immunization with a vaccine derived from vaccinia virus provides cross-protection to other orthopoxviruses. (See 'Vaccinia virus' above.)

●Indications – With the eradication of smallpox, routine vaccination with vaccinia virus is no longer offered to most persons. However, vaccination continues to be indicated for persons at high-risk for occupational exposures (eg, select laboratory and health care workers). (See 'Routine nonemergency indications' above and 'Indications for vaccination' above.)

During an emergency/outbreak situation, vaccination may be indicated for larger populations. As an example, during the worldwide outbreak of mpox (previously referred to as monkeypox) in 2022, vaccination is being offered to certain communities at high risk for exposure to monkeypox virus in addition to being used as post-exposure prophylaxis. (See 'Emergency/outbreak settings' above and "Treatment and prevention of mpox (monkeypox)", section on 'Post-exposure management' and "Treatment and prevention of mpox (monkeypox)", section on 'Pre-exposure prophylaxis with orthopoxvirus vaccines'.)

●The modified vaccinia Ankara vaccine – The MVA vaccine is made from a highly attenuated, non-replicating vaccinia virus and has an excellent safety profile, even in immunocompromised people and those with skin disorders. It is administered as two doses four weeks apart. It was approved for use in the United States in 2019 for the prevention of smallpox and mpox. In the United States, it is only available through the Centers for Disease Control and Prevention (CDC). (See 'Modified vaccinia Ankara (non-replicating) vaccine' above.)

●Vaccinia virus (replication-competent) vaccine – The replication-competent smallpox vaccine, ACAM2000, was approved for use in the United States in 2007 for the prevention of smallpox. In the United States, it is only available through the CDC. (See 'Vaccinia virus (replication-competent) vaccine' above.)

•Vaccination with the 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. (See 'Adverse events' above.)

•The contraindications to ACAM2000 vary depending upon the setting.

-In the nonemergency setting (eg, vaccination of laboratory workers to prevent occupational exposure), vaccination with the replication-competent smallpox vaccine is contraindicated in immunocompromised hosts, people with eczema and atopic dermatitis, individuals with allergies to any of the two antibiotics used within the vaccine formulation, pregnant persons, and in children younger than 18 years of age. It should also be avoided in those with a history of cardiac disease or risk factors for coronary artery disease (eg, hypertension, diabetes, hypercholesterolemia).

-In the setting of a smallpox outbreak or bioterrorism attack, the only contraindication to vaccination with ACAM2000 is severe immunocompromise. Other contraindications depend upon the level of exposure to variola virus and the availability of alternative vaccines. (See 'Contraindications and precautions' above.)

By contrast, during an outbreak of mpox, in which the risk of developing severe disease is low, ACAM2000 is still contraindicated in many patients. However, it can be considered on case-by-case basis in certain groups who may be less likely to develop complications. Additional information on the use of this vaccine during the global mpox outbreak that started in 2022 is presented separately. (See "Treatment and prevention of mpox (monkeypox)", section on 'Post-exposure management'.)

•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. Antiviral agents such tecovirimat, cidofovir, and brincidofovir are also available to manage significant complications from smallpox vaccination. (See 'Treatment and prevention of complications' above.)