Vaccination with vaccinia virus has been directly responsible for the successful eradication of smallpox (variola). Although the exact origins of vaccinia virus are uncertain, vaccinia may represent a hybrid of the variola and cowpox viruses.
Inoculation with vaccina virus produces a localized skin infection. In immunocompromised persons, vaccinia may disseminate and cause severe disease. However, adverse reactions have become increasingly rare since routine childhood immunization for smallpox in the general population was officially discontinued in the United States in 1972. Nonetheless, because news of this did not reach all health care providers and since supplies of the vaccine remained throughout the country, the vaccine continued to be administered for a few years following the official stop date.
During 2003, because of the concern for biological warfare, the United States government recommended that all first responders be vaccinated with the vaccinia virus. However, vaccination of first responders was halted upon the occurrence of vaccination-related complications, including a previously unrecognized complication, cardiomyopathy. Certain military recruits continue to receive vaccinia vaccine owing to the concern for bioterrorism. Laboratory personnel working with vaccinia and others for whom the benefits outweigh the risks of vaccination may also receive vaccinations.
History
The history of the vaccinia virus is that of smallpox, a serious illness characterized by the eruption of small pocklike lesions throughout the skin and internal organs. This is distinct from the great pox of syphilis.
The variola virus causes smallpox and may have begun infecting humans approximately 10,000 years ago. The characteristic pockmarks on 8000-year-old mummies possibly indicate smallpox infection. Smallpox was known in China during 11th century BC. The disease spread to Europe between the fifth and seventh centuries BC. Epidemics in Europe during the 17th and 18th centuries were associated with a 25%-30% mortality rate.
The Spanish are believed to have introduced smallpox to the New World, where the disease quickly spread to the native populations, causing major political consequences. Sporadic outbreaks were also reported in the American colonies during the late 18th century. During the latter part of the 20th century, major outbreaks continued to occur in Asia and Africa. At its most prevalent point, smallpox existed everywhere in the world except Australia and a few islands, causing millions of deaths nearly worldwide. Individuals who survived the disease were often left permanently disfigured by the skin lesions of the infection.
Efforts to prevent the spread of smallpox via inoculation were described as far back as the 6th century BC, when the Chinese inhaled powder derived from smallpox scabs to protect people from developing smallpox. During the late 18th century, Lady Mary Wortley Montague, the wife of a British ambassador to China, observed this custom and discussed this practice in European social circles. During the same period, a physician named Edward Jenner learned from milkmaids that those who were previously exposed to cowpox developed protection against smallpox during subsequent epidemics. While attempting to identify the responsible agent, Dr. Jenner ultimately isolated the vaccinia virus. In 1796, when Jenner made his seminal report on vaccinia, the potential benefits of vaccination became widely accepted. (Vaccinus is a Latin word relating to cows.) In the United States, Dryvax became the first approved vaccinia virus vaccine in 1931.
In 1967, the World Health Organization (WHO), in an unprecedented effort, targeted smallpox for eradication from the planet by the end of the 20th century. The WHO achieved this goal, with the last endemic case of smallpox reported in Somalia in 1977 and eradication declared in 1980. This effort was successful for several reasons, including the lack of any natural reservoir for variola virus and the ease of identifying infected individuals. The ability of sera raised against one orthopoxvirus species to cross-neutralize another species is one of the fundamental reasons for cross-protection provided by vaccination. Vaccinia virus is the species now characterized as the constituent of smallpox vaccine. The effectiveness of vaccinia virus as a vaccine paramount was in this effort. Smallpox now exists mainly in laboratories, and the first-generation vaccine known as Dryvax has been phased out.
In 2007, the ACAM2000 vaccine (Acambis, Inc.), derived from a clone of Dryvax and manufactured via cell culture, became the only approved vaccine in the United States for vaccination of individuals at high risk for smallpox infection.
Vaccinia virus is a mystery in virology. Whether vaccinia virus is the product of genetic recombination, a species derived from cowpox virus or variola virus by prolonged serial passage, or the living representative of a now extinct virus is unknown. Different strains of vaccinia virus were generated in different cities throughout Europe and Asia, complicating efforts to track the origins of the virus. Modern analysis of the vaccinia virus based on restriction mapping indicates that it is distinct from cowpox virus. The possibility that vaccinia represents a hybrid of cowpox and variola virus has been suggested. The virus was also propagated in horses and may have also been contaminated with horsepox virus.
Biology
The poxviruses are the largest known DNA viruses and are distinguished from other viruses by their ability to replicate entirely in the cytoplasm of infected cells. Poxviruses do not require nuclear factors for replication and, thus, can replicate with little hindrance in enucleated cells.
Infectious viral particles contain many of the enzymes necessary for replication within the virion itself, hence the large size of the virus. Because of its size, vaccinia was the first animal virus observed using microscopy. Specific enzymes, including DNA-dependent RNA polymerase, polyA polymerase, and several capping enzymes are all packaged within the core of the virus. The core also contains a 200-kilobase (kb), double-stranded DNA genome and is surrounded by a lipoprotein core membrane.
The life cycle of vaccinia begins when the virus fuses with the plasma membrane of a susceptible cell via a protein-based entry-fusion complex or is absorbed by cellular endosomes. No specific receptor used to facilitate entry into the cell has yet been discovered. Once the virus has entered the cell, the viral core is released into the cytoplasm of the cell, where virally packaged transcriptases initiate transcription of early genes.
The study of poxvirus entry and membrane fusion has been refreshed by new biochemical and microscopic findings, which conclude the following:
The surface of the mature virion (MV) is composed of a single lipid membrane embedded with nonglycosylated viral proteins.
The MV membrane fuses with the cell membrane, which allows the core to enter the cytoplasm and to begin gene expression.
Fusion occurs via a newly recognized group of viral protein components of the MV membrane, which are conserved in all members of the poxvirus family.
The latter MV entry/fusion proteins are required for cell-to-cell spread, requiring the disruption of the membrane wrapper of extracellular virions before fusion.
In addition, the same group of MV entry/fusion proteins is necessary for virus-induced cell-cell fusion.
Future research priorities include defining the roles of individual entry/fusion proteins and detecting and classifying cell receptors.
Within several minutes of infection, functional (ie, capped and polyadenylated) messenger RNA (mRNA) is produced and polypeptide synthesis begins. The initial proteins synthesized are used to further uncoat the virus and to begin the process of viral DNA replication. The early genes also code for factors that initiate the transcription of late genes, which function in virion construction.
Once virions are constructed and DNA is encapsulated within them, the virions are sent to the Golgi apparatus, where they acquire an envelope and are released from the cell by exocytosis as extracellular enveloped virus (EEV) particles. The cell undergoes lysis 7-24 hours after initial infection, releasing nonprocessed virions, which are visible under electron microscopy as intracellular naked virus (INV) particles. Despite the differences between EEV and INV particles, both forms are infectious. Each infected cell yields approximately 10,000 new viral particles.
Vaccinia virus is usually administered via either intradermal scarification or injection. A bifurcated needle is used to apply the vaccine by pressing in and out of the skin of the upper deltoid region of the arm 5 times for a primary vaccination and 15 times for a revaccination.
Typically, vaccinia multiplies in the basilar epithelium after vaccination, causing a local cellular reaction. A papule appears 4-5 days after vaccination secondary to local replication of the virus. The papule becomes pustular within 7-10 days and reaches a maximum size of 2-4 cm; this is known as a Jennerian pustule. At this time, associated axillary lymphadenopathy and mild fever may occur. The pustule contains fluid with live viral particles that can spread by direct contact. Two to 3 weeks after vaccination, the pustule dries from the center and forms a scab. A characteristic scar that is approximately 1 cm in diameter usually remains as evidence of prior vaccination. Revaccination yields a similar, yet accelerated, course of events. No evidence exists for systemic viremia during administration of vaccinia virus in immunocompetent individuals.
A Jennerian pustule indicates a successful primary vaccination and is classified as a major reaction. Reactions other than a Jennerian pustule are classified as equivocal and require a subsequent vaccination. Full immunity is conferred in more than 95% of persons for 5-10 years in a successful primary vaccination; successful revaccination allows 10-20 years of protection or more. Neutralizing antibodies have been found in some vaccinees up to 75 years following vaccination. Of note, antibodies to vaccinia are also protective against other Orthopox viruses (monkeypox and cowpox) and may decrease the severity of smallpox if administered within a few days of exposure.
Vaccinia virus induces immunity through both T-cell and B-cell responses. The B-cell response is evident from the presence of vaccinia-specific circulating antibodies for years after vaccination. The T-cell responses may be more important because full protection against smallpox was observed in children with agammaglobulinemia who could not mount an antibody response and who were immunized with vaccinia virus. CD8+ T-cell responses are essential for immunity, whereas CD4+ T cells are thought to contribute to long-lasting protection against vaccinia virus.
Most adverse reactions to vaccinia administration involve the skin and central nervous system (CNS). Progressive vaccinia, also known as vaccinia necrosum, is a rare complication in which viremia can lead to metastatic infection of the organs, necrosis of the skin, and, in some cases, death in immunosuppressed patients, particularly those with T-cell deficiencies. In children younger than 15 years who have eczema, vaccinia virus can also replicate rapidly in the eczematous lesions, leading to eczema vaccinatum. The sequelae of eczema vaccinatum include prolonged hospital stays and, occasionally, death.
Recent research has shown that patients with atopic dermatitis have an overabundance of a class A scavenger receptor known as macrophage receptor with collagenous structure (MARCO) on keratinocytes. Vaccinia virus bound directly to MARCO increases susceptibility to eczema vaccinatum. This breakthrough represents a potential area for future therapeutic strategies to prevent vaccinia virus infection in patients with increased susceptibility.[1]
CNS effects are also rare and include microglial encephalitis and postvaccinial encephalopathy. The former occurs most often in people older than 2 years and is characterized by fever, headaches, seizures, and coma. The latter occurs in children younger than 2 years and causes diffuse cerebral edema and cerebral hemorrhage. Permanent neurological sequelae and death can result. Adults may rarely experience a less severe CNS reaction consisting of a demyelinating process. Definite predisposing factors have not been identified for people at risk of CNS complications, but the incidence varied with the strain of vaccinia virus used.
Vaccinia virus can also be spread from draining primary vaccination sites to the eyes, eyelids, nose, and perineum, causing mild inflammatory reactions or, rarely, a more serious ocular infection. Vaccination sites should be covered with protective bandages to prevent local spread and accidental infection. Shedding of the virus can occur for up to 21 days following vaccination. Vaccinia virus should not be administered to children younger than 3 years, individuals with eczema or CNS disorders, or immunosuppressed individuals.
Individuals vaccinated within the preceding 21 days can also spread the virus to unvaccinated contacts. In particular, these individuals should avoid contact with young children, immunocompromised persons, pregnant persons, and individuals with a history of atopic dermatitis. If this contact is unavoidable, vaccinated individuals should ensure proper hand hygiene and apply an occlusive dressing to the vaccination site to prevent inadvertent transmission.[2]
Because of concerns about vaccine-related adverse events, diluted forms of both Dryvax and Pasteur were studied for safety and efficacy. The results showed that highly diluted first-generation vaccines caused less fever and loss of productivity while demonstrating similar levels of serum neutralizing antibody compared with undiluted forms of these vaccines.[3]
Recombinant vaccinia viruses
Although vaccinia virus is no longer necessary to prevent smallpox in the general population, vaccinia is now used to generate live recombinant vaccines for the treatment of other illnesses. Vaccinia virus can accept as much as 25 kb of foreign DNA, making it useful for expressing large eukaryotic and prokaryotic genes. Foreign genes are integrated stably into the viral genome, resulting in efficient replication and expression of biologically active molecules. Furthermore, posttranslational modifications (eg, methylation, glycosylation) occur normally in the infected cells.
The methods for constructing recombinant vaccinia viruses are well established. Recombinant shuttle plasmids are commonly used for placing a foreign gene into a nonessential region of the parental wild-type vaccinia virus. The plasmids contain a cloning site for insertion of the gene of interest, a selectable marker gene (eg, LacZ) or an antibiotic resistance gene, and flanking portions of a nonessential vaccinia gene. The cotransfection of the recombinant plasmid and a wild-type vaccinia virus into susceptible cells in culture results in homologous recombination between the plasmid and the vaccinia genome. Selection of recombinant viruses is possible using the selectable markers found only on the shuttle plasmid. The recombinant viruses can be purified and characterized for gene expression.
Recombinant vaccinia technology has resulted in numerous vaccine constructs targeting both infectious diseases and cancer. A recombinant vaccinia virus expressing the rabies glycoprotein was effective in preventing rabies in wild foxes. Vaccines targeted against HIV, malaria, hepatitis, and other infectious diseases have been generated and are being evaluated in clinical trials. Modified vaccinia Ankara (MVA) is being considered as a candidate pandemic influenza H5N1 vaccine.[4] The expression of human tumor antigens in vaccinia virus has been evaluated for the treatment of diverse types of cancer, including gastrointestinal tumors, malignant melanoma, breast cancer, cervical cancer, colorectal cancer, renal cell carcinoma, and hormone-refractory prostate cancer. Although these studies are in an early stage of development, the likelihood for exposure to vaccinia virus in the general population is expected to increase over the next several years.[5]
Replication-defective attenuated vaccinia viruses
Modified versions of vaccinia virus have been developed for use as recombinant vaccines. These vectors are less pathogenic than vaccinia virus and may induce a less potent neutralizing antibody response, allowing multiple immunizations.
The modified Ankara strain (MVA) of vaccinia virus was developed by repeated passage in a line of chick embryo fibroblasts. MVA has been useful as a smallpox vaccine in patients at risk for vaccinia complications. Furthermore, recombinant MVA expressing the influenza hemagglutinin gene has been shown to protect mice from infection with influenza. However, MVA lacks large-scale human safety evaluations.
As MVA begins to gain popularity in terms of use as a recombinant vector for vaccination or as a delivery vehicle for gene therapy, issues with biosafety begin to emerge. Although MVA vectors are typically regarded as safer than other vaccinia strains, certain risks must be considered for overall biosafety. When synthesized, MVA may not be completely homogeneous, and certain variants may theoretically be able to replicate in mammalian cell lines. Secondly, whatever transgene that is inserted may also present its own set of hazardous properties. Finally, the process of recombination may itself pose an additional risk of transferring a transgene with natural orthopoxviruses.[6]
NYVAC is another attenuated form of the vaccinia virus that has been used in the construction of live vaccines. NYVAC has a deletion of 18 vaccinia virus genes that renders it less pathogenic. NYVAC was used to express the Plasmodium berghei protein and elicited CD8+ T-cell responses and protection against malaria in a murine model. Like MVA, NYVAC lacks large-scale human safety studies.
A replication-defective derivative of the Lister strain of vaccinia (dVV-L) has also been shown to induce immunity comparable to MVA in mice.
Protein subunit and plasmid DNA vaccines
Subunit vaccines are another possible approach to inducing immunogenicity while reducing side effects. In mice, passive transfer of a vaccinia envelope protein antigen, H3L, demonstrates protection against smallpox. Similarly, multiple vaccinations with combinations of other envelope proteins have shown the capacity to protect mice against smallpox. In preclinical studies using mice, a recombinant interleukin-15 vaccine has been shown to provide higher immune responses, longer-lasting immunity, and greater than 1000-fold reduction in lethality.[7] A vaccine containing protein-encoding plasmid DNA is also being investigated.
Data on vaccinia complications are based on information accumulated during the 1950s and 1960s. For primary vaccination, the complication rates are as follows:
Table 1. Frequency of Complications Related to Vaccination
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See Table
International
In 1969, studies in Australia estimated similar complication rates. Reports from 2003 of inadvertent inoculation from the United States did not differ significantly from rates reported in Asia.
Mortality/Morbidity
Although complications from vaccinia vaccination are uncommon (75 per million vaccinations, death rate of 1 per million), the outcome depends on the immune status of the individual. In immunocompromised persons, mortality rates from dermal complications (eg, eczema vaccinatum, vaccinia necrosum) were reported as 10% and nearly 100%, respectively. When patients are treated with vaccinia immune globulin (VIG), the mortality rate is drastically reduced. After 1969, when VIG became available, investigations suggested mortality rates of 1% for eczema vaccinatum and 33% for vaccinia necrosum.
Individuals who previously received the vaccine and are undergoing revaccination may be at greater risk for complications than those who are immunologically naive to it.
Postvaccinial encephalitis, characterized as an encephalopathy in children, carries a mortality rate of 25%. This is usually observed in children aged 6 months to 3 years; therefore, vaccination should be postponed until children are older. Adults can experience a milder form of encephalitis characterized by perivascular demyelination. CNS complications are essentially unheard of after revaccination, are not related to underlying immunosuppression, and do not respond to VIG therapy.
Ocular keratoconjunctivitis generally responds to supportive therapy. The ophthalmic preparation of idoxuridine has been discontinued owing to a decreased need for it.
Superinfection of a vaccination site is rare and clinically difficult to distinguish from a robust take.
The most common adverse effect experienced by those receiving vaccinia vaccine is a constellation of symptoms called acute vaccinia syndrome. This is characterized by fever, headache, myalgias, and fatigue. Research suggests that a person's risk of developing fever following inoculation with vaccinia vaccine may to some extent be predicted by genetic analysis.
Mortality due to generalized vaccinia or erythematous rash has not been reported.
Differences in human morbidity and mortality associated with newer forms of vaccinia vaccine are not yet established. However, studies evaluating certain later generations of vaccinia vaccine may be associated with lower lethality and a similar ability to confer immunity.
Race
No known ethnic predilections exist for complications related to vaccinia virus.
Sex
Although a study from Australia showed a small bias for vaccinia complications in women, other studies have not confirmed this finding, and the bias may be related to the small numbers of patients studied.
Age
Vaccination was generally delayed until after the first year of life, at which point the rates of many of the complications decrease. Delay also allows for the identification of any underlying immune deficiencies, which contraindicate vaccination.
Patients should be instructed about proper wound care after vaccination with vaccinia virus. This includes changing any bio-occlusive dressings and avoiding inappropriate disposal of infected bandages.
Patients must be educated to avoid high-risk individuals during the period of maximal viral shedding, approximately 10 days after exposure to the virus.
Recent vaccination with vaccinia virus or exposure to a vaccinated person helps to make the diagnosis.
Most patients who are administered vaccinia virus experience mild pain and pruritus at the site of injection that lasts about 7-10 days. During this time, patients may also develop regional lymphadenopathy and low-grade fever, which usually resolves without intervention.
Complications that are more serious also can occur in patients with predisposing risk factors. A history of eczema, CNS disease, or immunosuppression places the patient at high risk for developing a serious complication if exposed to the virus.
As more smallpox vaccine becomes available, the safety of the live vaccine and the transmissibility of vaccina virus from recently vaccinated person to susceptible host are the central issues debated. Nosocomial transmission has been reported in the literature, with 85 secondary cases reported and an 11% fatal outcome. Nosocomial outbreaks seem to require minor contact with a source case, whereas spread within families or homes occurs more with sustained intimate exposure. This difference may be due to the immunologic and dermatologic differences among the persons exposed.
Both the rate and route of vaccinia transmission remain unknown.[8] The current plan of an occlusive dressing at the vaccination site and routine infection-control procedures is currently the most effective method to limit spread. Hypothesized routes of spread include health care workers with virus on their clothes, hands, or nasopharynx. Fomites and aerosol route have also been implicated through some secondary cases.
Vaccinia necrosum (gangrenosa), also known as progressive vaccinia, is the most severe complication of vaccinia inoculation. Vaccinia necrosum is due to the accidental or inadvertent administration of vaccinia virus to immunocompromised individuals. Exposure can be due to either direct vaccination or contact with a recently vaccinated individual. The initial site of entry results in a typical-appearing vaccinia lesion (see image below) that progresses because of the lack of local or systemic immunity. The lesion may progress for months, and secondary lesions can develop elsewhere on the body. Live vaccinia particles can be isolated easily from any of the lesions. The infection is more common in young children with unsuspected immune deficiency disorders and is generally fatal. The condition is rare, severe, and often lethal. Treatment with VIG, a pooled aggregate of vaccinia-specific antibodies, can be life-saving if administered early.
See the image below.
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This typical pustular lesion following vaccinia immunization usually appears within 5 days of vaccination and forms a scab by 10-14 days. Vaccination ....
Eczema vaccinatum occurs in patients with a history of eczema, who are unusually susceptible to infection with both the herpes simplex virus and vaccinia virus. The virus multiplies rapidly in eczematous skin. Lesions begin to appear at distant sites as the virus spreads throughout the body. The lesions are similar in appearance to smallpox but can be differentiated by a less regular pattern. As the infection progresses, however, few areas may be free of lesions. Culture assays of the virus are necessary to differentiate eczema vaccinatum from herpes infection. The disease has a 30% mortality rate, largely in infants. Treatment with VIG has some limited benefit.
Accidental/inadvertent vaccinia infection occurs when the vaccinia virus spreads from one part of the body to another. Infections of both the nose and the eyelid are most common, although other sites (eg, the perineum) can also be involved. Contamination occurs when the patient transfers the virus from a recently vaccinated site on the patient or on a vaccinated contact. Although not generally serious in people with healthy immune systems, the infection can spread from the eyelid to the cornea, resulting in permanent damage.
When transmission results from sexual contact with a vaccinated individual, painful vulvar ulcers and/or edema may develop.[9] These lesions may be accompanied by lymphadenopathy and, in some cases, pruritus and new vaginal discharge.
Erythematous rash occurs 4-17 days after vaccination and usually lasts approximately 10 days. The rash may have an appearance similar to the typical rash of roseola or erythema multiforme. The cause of the rash is not known, and full recovery without treatment is common.
Generalized vaccinia occurs in immunocompetent individuals for unknown reasons. After vaccination and before protective immunity develops, the virus spreads hematogenously and travels to ectopic sites, where it multiplies in epidermal cells. Lesions similar to the primary vaccination site appear on the skin throughout the body. The irregularity of the lesions and the healthy immune system of affected patients differentiate this disease from erythematous rash and accidental vaccinia. Recovery generally occurs without specific intervention. If symptoms last for more than 15 days, VIG can be administered.
Generalized vaccinia is a rarely reported complication of vaccinia virus vaccination, and true generalized vaccinia may be even less common because of more strict definitions. Appropriately screened individuals considering vaccinia virus vaccination may be reassured that most exanthemata after vaccination are benign.
Fetal vaccinia is a rare but often lethal condition that manifests as multiple skin lesions, including macules, papules, vesicles, pustules, scars, ulcers or areas of maceration, and epidermolysis of blisters of bullae in a fetus.
CNS complications
Postinfection encephalitis is a rare and serious complication of infection with several viruses, including measles and vaccinia. The relationship of the vaccinia virus to encephalitis is unknown. The encephalitis that develops in children younger than 2 years is characterized by an incubation period of 6-10 days and is associated with degenerative changes in ganglion cells, perivascular hemorrhage, and generalized hyperemia of the brain. Symptoms are the same as those associated with general encephalitis, including intracranial pressure, myelitis, convulsions, and muscular paralysis.
A second form of disease develops in older children and adults. This is characterized by an incubation period of 11-15 days and is associated with signs of an allergic response with perivascular demyelination.
CNS complications are rare in infants younger than 6 months and in patients who are revaccinated with vaccinia virus. Although the etiology is unknown, administration of VIG along with the primary vaccination in army recruits showed significant reduction in the incidence of this complication. Treatment is generally supportive and may include steroids for cerebral edema.
Cardiac complications
These include dilated cardiomyopathy, myocarditis and/or pericarditis, and ischemic heart disease. Cardiac deferral criteria include a history of underlying cardiac disease and at least 3 of 5 of the following major risk factors for atherosclerotic heart disease: hypertension, diabetes mellitus, hypercholesterolemia, smoking, or a history of heart disease in a first-degree relative younger than 50 years.
The Vaccine Adverse Event Reporting System (VAERS) is an available Internet resource.
The causes of vaccinia infection are generally due to intentional vaccination; however, cases of infection by direct contact with a recently vaccinated individual have been reported. Furthermore, with the increasing interest in poxviruses for foreign gene transfer, risk of accidental infection of laboratory workers and medical personnel is increasing.
The diagnosis of vaccinia virus complications is usually straightforward and depends on obtaining the history of recent vaccinia virus exposure by vaccination or contact with a vaccinated individual. A careful workup for immune deficiency should be considered in patients who do not promptly improve.
The diagnosis of CNS complications is more difficult because the signs and symptoms are nonspecific. Although rare, postvaccinial encephalitis should be considered in any patient with neurologic symptoms developing 1-2 weeks after exposure to live vaccinia virus. Vaccinia virus has not been isolated from cerebrospinal fluid (CSF) of patients with encephalitis, and CSF analysis usually produces normal results, except for increased pressure; however, CSF analysis may be indicated to exclude other causes of encephalitis.
Imaging studies are not useful in the diagnosis of vaccinia infection or a postvaccinial complication, although imaging modalities may be helpful to exclude other causes of disease (eg, MRI of the brain in cases of suspected encephalitis).
Patients who present with skin manifestations usually have live viral particles replicating in the dermal lesions. The presence of vaccinia virus can be confirmed by obtaining a biopsy of the skin lesion and examination through microscopy, plaque titer assay, Western blot, and polymerase chain reaction (PCR) analysis.
Light microscopy may reveal characteristic inclusions (ie, Guarnieri bodies) in the cytoplasm of infected cells. This is distinct from the appearance of cells infected by viruses such as herpes simplex virus, which typically demonstrate intranuclear inclusion bodies.
Treatment for the complications associated with vaccinia virus is supportive.
VIG may be helpful in selected patients, such as those with generalized vaccinia and eczema vaccinatum or those at high risk for developing complications following vaccination with vaccinia. VIG is less successful when used for treatment of progressive vaccinia and CNS complications.
VIG was developed from pooled sera collected from vaccinated patients in the 1960s and is available from the Centers for Disease Control and Prevention (CDC) in Atlanta, GA.
VIG is contraindicated in patients with allergies to VIG or sensitivity to human pooled serum.
The first drug for the treatment of smallpox, tecovirimat, was approved in July 2018 should smallpox ever be used as a bioweapon. Tecovirimat is an antiviral that inhibits the activity of the orthopoxvirus VP37 protein. The effectiveness of tecovirimat against smallpox was established by studies in animals infected with viruses closely related to variola virus, which demonstrated higher survival rates compared with those of placebo. The safety of tecovirimat was demonstrated in 359 healthy human volunteers, in whom the most frequently reported adverse effects included headache, nausea, and abdominal pain.[10]
Cidofovir and adefovir are being investigated to evaluate the clinical effect and outcomes as a secondary treatment of vaccinia-related complications that do not respond to VIG treatment. An oral form of this drug is currently under development.
To obtain tecovirimat, clinicians should contact the Centers for Disease Control and Prevention (CDC) Emergency Operations Center at 770-488-7100, which will coordinate shipment with the US government’s Strategic National Stockpile (SNS).
The antiviral agent cidofovir is available from the SNS as an investigational agent for treatment of smallpox. Cidofovir is approved in the United States for CMV retinitis.
Surgery is usually unhelpful in the treatment of complications, although debridement of nonviable tissue in cases of vaccinia necrosum may be considered. Obtaining a biopsy of suspected lesions can aid in the diagnosis.
Consultation with a dermatologist may be helpful when the diagnosis of a skin lesion is in doubt.
Suspected cases of vaccinia-related complications should be treated in consultation with an expert in infectious diseases and poxvirus virology.
Selective consultation for specific adverse events is indicated (eg, an ophthalmologist for eye complications or a neurologist for nervous system complications).
Routine vaccination with smallpox (vaccinia) vaccine, live (ACAM2000) is recommended by the CDC for occupations who directly handle cultures or animals contaminated or infected with replication-competent vaccinia virus, recombinant vaccinia viruses derived from replication-competent vaccinia strains (ie, those that are capable of causing clinical infection and producing infectious virus in humans), or other orthopoxviruses that infect humans (eg, monkeypox, cowpox, and variola).[2]
Health care personnel (eg, physicians and nurses) who currently treat or anticipate treating patients with vaccinia virus infections and whose contact with replication-competent vaccinia viruses is limited to contaminated materials (eg, dressings) and persons administering smallpox vaccine who adhere to appropriate infection prevention measures can be offered vaccination with ACAM2000, but vaccination is not recommended as routine.[2]
Avoiding vaccination of high-risk individuals (eg, immunosuppressed patients, pregnant women) can prevent vaccinia complications. Recent vaccinees also should avoid high-risk individuals for up to 21 days after vaccination. Recent evidence shows that TNF-alpha may play a role in resisting vaccinia virus infection of the skin; thus, patients on TNF-alpha-antagonists may also be at high risk.[11]
Avoid vaccination of children younger than 18 years unless indicated by a smallpox emergency.[2]
Current guidelines recommend that vaccinees defer blood donation for 21 days after vaccination or until the scab separates, whichever is later. Further studies indicate that extending the duration may be appropriate.
Contraindications to nonemergency use of smallpox vaccine include the following:[2]
Persons with a history or presence of atopic dermatitis or other active exfoliative skin conditions (eg, eczema, burns, impetigo, varicella zoster virus infection, herpes simplex virus infection, severe acne, severe diaper dermatitis with extensive areas of denuded skin, psoriasis, or Darier disease [keratosis follicularis])
Persons with conditions associated with immunosuppression (eg, HIV infection or AIDS, leukemia, lymphoma, generalized malignancy, solid organ transplantation, or therapy with alkylating agents, antimetabolites, radiation, tumor necrosis factor [TNF] inhibitors, or high-dose corticosteroids [≥2 mg/kg body weight or ≥20 mg/day of prednisone or its equivalent for ≥2 weeks], hematopoietic stem cell transplant recipients < 24 months post-transplant or ≥24 months, but who have graft-versus-host disease or disease relapse, or autoimmune disease [eg, systemic lupus erythematosus] with immunodeficiency as a clinical component)
Children younger than 1 year
Women who are pregnant or breastfeeding
Persons with a serious allergy to any component of ACAM2000
Persons with known underlying heart disease with or without symptoms (eg, CAD or cardiomyopathy)
Primary vaccinees with 3 or more known major cardiac risk factors (ie, hypertension, diabetes, hypercholesterolemia, heart disease at age 50 years in a first-degree relative, and smoking)
Immunocompetent individuals with generalized vaccinia require supportive care and isolation from immunocompromised individuals until the infection resolves.
Less severe complications (eg, accidental infections) can be treated expectantly in an outpatient setting, provided the patient can avoid contact with high-risk individuals.
Patients with minor complications related to vaccinia immunization can usually be treated in an ambulatory setting. Severe complications require hospital admission and supportive intervention.
Infected patients should be isolated in a reverse airflow setting until the diagnosis is confirmed. These patients should avoid contact with other immunosuppressed persons (eg, persons with neutropenic cancer, HIV infection). These patients should also avoid contact with pregnant women, individuals with eczema, and young children.
Note that health care workers, including nurses, phlebotomists, house staff, and nutritionists, should also avoid direct contact with infected patients.
VIG is available for amelioration of some vaccinia-related complications. VIG is produced from pooled human sera taken from vaccinia-immunized individuals and is available only from the CDC. VIG has been effective when administered early in cases of vaccinia necrosum and eczema vaccinatum. VIG has not been effective in cases of encephalopathy. The use of VIG for generalized vaccinia reactions is usually unnecessary. Vaccinia immune globulin, intravenous (VIGIV) has recently been approved by the US Food and Drug Administration.
The first antiviral for the treatment of smallpox disease, tecovirimat (TPOXX), was approved by the US Food and Drug Administration (FDA) in July 2018.[10]
Cidofovir, a nucleotide analogue of cytosine, has demonstrated antiviral activity against certain orthopoxviruses in cell-based in vitro and animal model studies. Tecovirimat and cidofovir are available from the US government’s Strategic National Stockpile (SNS).
Clinical Context:
Derived from human plasma and manufactured from pooled plasma donors who received booster immunizations with smallpox vaccine. Contains increased antibody levels against vaccinia virus. Indicated to treat rare adverse reactions caused by vaccinia virus, including aberrant infections (eg, accidental implantation in the eyes, mouth, other potentially hazardous areas), eczema vaccinatum, progressive vaccinia, severe generalized vaccinia, and vaccinia infections in immunocompromised individuals.
Clinical Context:
Antiviral agent; targets and inhibits the activity of the orthopoxvirus VP37 protein (encoded by and highly conserved in all members of the orthopoxvirus genus) and blocks its interaction with cellular Rab9 GTPase and TIP47, which prevents the formation of egress-competent enveloped virions necessary for cell-to-cell and long-range dissemination of virus. It is approved by the FDA and indicated for treatment of human smallpox disease caused by variola virus in adults and children who weigh at least 13 kg.
Clinical Context:
Not licensed for use as a treatment for smallpox. Currently approved for treatment of CMV retinitis in AIDS. Cidofovir is the first member of a group of antivirals known as acyclic phosphonate nucleotide analogs. Cidofovir diphosphate, the active intracellular metabolite of cidofovir, inhibits herpes virus polymerases at concentrations that are 8- to 600-fold lower than those needed to inhibit human cellular DNA polymerases alpha, beta, and gamma. Incorporation of cidofovir into the growing viral DNA chain results in reductions in the rate of viral DNA synthesis.
The first antiviral, tecovirimat (TPOXX), for treatment of smallpox disease was approved by the US Food and Drug Administration (FDA) in July 2018.
Cidofovir is currently approved for the treatment of cytomegalovirus (CMV) infections, but not for smallpox. However, animal models support the potential usefulness of this agent in smallpox.
Clinical Context:
Vaccine is derived from a vaccinia virus, a virus that is closely related to, but less harmful than, variola or monkeypox viruses and can protect against both of these diseases. It is indicated for prevention of smallpox and monkeypox disease in adults who are at high risk for smallpox or monkeypox infection. It is administered as a 2-dose series administered 4 weeks apart.
Before the eradication of smallpox disease, live vaccinia virus smallpox vaccine was administered routinely in all pediatric age groups, including neonates and infants. It is now used only as routine vaccination for laboratory personnel who directly handle cultures or animal care personnel whose occupations place them at risk for exposure to vaccinia and other orthopoxviruses, including recombinant vaccinia viruses.[2]
Nikesh A Patel, Medical University of South Carolina College of Medicine
Disclosure: Nothing to disclose.
Coauthor(s)
Dayna Diven, MD, Professor, Department of Dermatology, University of Texas Southwestern Austin Programs
Disclosure: Nothing to disclose.
Specialty Editors
Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference
Disclosure: Received salary from Medscape for employment. for: Medscape.
Richard B Brown, MD, FACP, Chief, Division of Infectious Diseases, Baystate Medical Center; Professor, Department of Internal Medicine, Tufts University School of Medicine
Disclosure: Nothing to disclose.
Chief Editor
John L Brusch, MD, FACP, Assistant Professor of Medicine, Harvard Medical School; Consulting Staff, Department of Medicine and Infectious Disease Service, Cambridge Health Alliance
Disclosure: Nothing to disclose.
Additional Contributors
Brenda Jones, MD, Associate Professor of Clinical Medicine, Division of Infectious Diseases, Keck School of Medicine of the University of Southern California
Disclosure: Nothing to disclose.
Acknowledgements
Ken Flanagan PhD Student, Department of Microbiology and Immunology, Albert Einstein College of Medicine
Ken Flanagan is a member of the following medical societies: American Association for Cancer Research
Disclosure: Nothing to disclose.
Howard L Kaufman, MD Chief, Division of Surgical Oncology, Columbia University College of Physicians and Surgeons
Howard L Kaufman, MD is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American College of Surgeons, American Medical Association, Association for Academic Surgery, Illinois State Medical Society, Massachusetts Medical Society, New York Academy of Sciences, and Society of Surgical Oncology
Disclosure: Nothing to disclose.
Jennifer J Lee, MD Resident Physician, Department of Dermatology, University of Texas Southwestern at Austin
Jennifer J Lee, MD is a member of the following medical societies: American Academy of Dermatology, American Medical Association, California Medical Association, and Phi Beta Kappa
Disclosure: Nothing to disclose.
Thomas W McGovern, MD Dermatologist and Mohs Surgeon, Fort Wayne Dermatology, PC
Disclosure: Nothing to disclose.
Tasneem A Poonawalla, MD Physician, Department of Dermatology, Dean Clinic
Tasneem A Poonawalla, MD is a member of the following medical societies: American College of Physicians, American Medical Association, and Texas Medical Association
Clark J, Diven D. Poxviruses. Tyring S, Moore A, Lupi O, eds. Mucocutaneous Manifestations of Viral Diseases. 2nd ed. New York, NY: Informa HealthCare; In press.
Damon I. Orthopoxviruses: Vaccinia (Smallpox Vaccine), Variola (Smallpox), Monkeypox, and Cowpox. Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 6th ed. Orlando, FL: Churchill Livingstone; 2005. 1742-55.
Friedman HM. Smallpox, Vaccinia, and Other Poxviruses. Isselbacher, et al, eds. Harrison's Principles of Internal Medicine. 13th ed. New York, NY: McGraw-Hill; 1994. 798-9.
Neff JM. Vaccinia Virus (Cowpox). Mandell GL, Bennett JE, Dolin R, eds. Mandell, Douglas, and Bennett's Principles and Practice of Infectious Diseases. 5th ed. Philadelphia, Pa: Churchill Livingstone; 2000. 1553-5.
Notice to Readers: Newly Licensed Smallpox Vaccine to Replace Old Smallpox Vaccine. MMWR Morb Mortal Wkly. 2008. 57:207-208.
This typical pustular lesion following vaccinia immunization usually appears within 5 days of vaccination and forms a scab by 10-14 days. Vaccination usually leaves a permanent indentation.
This typical pustular lesion following vaccinia immunization usually appears within 5 days of vaccination and forms a scab by 10-14 days. Vaccination usually leaves a permanent indentation.
Complication
Number of cases from 450,293 vaccinations administered between 12/13/2002 and 5/28/2003
Department of Defense rate per million vaccinees (95% confidence interval)
Historical number of cases from 1950s and 1960s
Death
0
0 (0-3.7)
Age 1 y at first vaccination - 5 per 1 million primary vaccinees
Age 1-4 y at first vaccination - 0.5 per 1 million primary vaccinees
Age 5-19 y at first vaccination - 0.5 per 1 million primary vaccinees
Age ≥ 20 y at first vaccination - No data
Encephalitis
1
2.2 (0.6-7.2)
3 per 1 million primary vaccinees
Vaccinia necrosum/progressive vaccinia
0
0 (0-3.7)
Approximately 1 patient per million during primary or revaccination
Usually fatal over a period of several months
Eczema vaccinatum
0
0 (0-3.7)
1 per 100,000 primary vaccinees
1 per 1 million revaccinees
Generalized vaccinia
36
80 (63-100)
Occasional occurrence in immunocompetent individuals
3 per 100,000 primary vaccinees
1 per 1 million revaccinees
Accidental vaccinia
48
107 (88-129)
3 per 100,000 to 1 million vaccinees
Erythematous rash
36
80 (63-100)
Approximately 1 per 100,000 primary vaccinees*
Acute myopericarditis
37
82 (65-102)
100 per 1 million vaccinees
*Incidence was slightly higher when vaccination occurred before age 1 year.
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