eMedicine Specialties > Infectious Diseases > Viral Infections

Vaccinia

Author: Tasneem A Poonawalla, MD, Staff Physician, Department of Internal Medicine, University of Texas Medical Branch at Galveston
Coauthor(s): Dayna Diven, MD, Clinical Professor, Department of Dermatology, University of Texas Medical Branch at Galveston; Howard L Kaufman, MD, Chief, Division of Surgical Oncology, Columbia University; Ken Flanagan, BS, Department of Microbiology and Immunology, Albert Einstein College of Medicine
Contributor Information and Disclosures

Updated: Aug 24, 2006

Introduction

Background

Vaccination with vaccinia virus has been directly responsible for the successful eradication of smallpox (variola). Although the exact origins of vaccinia virus are uncertain, the possibility that vaccinia represents a hybrid of cowpox and variola virus has been suggested. Inoculation with vaccina virus produces a localized skin infection. In persons who are immunocompromised, vaccinia may disseminate and cause severe disease. Adverse reactions have been rare because routine childhood immunization was discontinued in the United States during 1972.

New uses of vaccinia virus could result in more frequent administration and in the reappearance of complications. Military recruits are now vaccinated because of concerns about biologic warfare. Vaccinia virus also has new uses as a vector for the expression of foreign genes derived from other infectious microorganisms and tumor cells. These recombinant vaccinia viruses are in the early phases of clinical testing as vaccines for rabies, malaria, hepatitis, Epstein-Barr virus infection, human immunodeficiency virus (HIV) infection, and cancer. The expanded use of vaccinia virus in the laboratory and clinical setting suggests that physicians should understand the pathophysiology of this virus and should know how to treat the adverse effects associated with vaccinia administration.

History

The history of the vaccinia virus is linked to that of smallpox, a serious illness characterized by the eruption of small pocklike lesions throughout the skin and internal organs. This disease 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 are indicative of smallpox infection. The disease was a scourge in Europe during the 17th and 18th centuries, with intermittent endemics associated with a 25-30% mortality rate. Individuals surviving the disease often were left permanently disfigured by the skin lesions of the infection.

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 also were reported in the American colonies during the late 18th century.

Smallpox was known in China during 11th century BC, and inoculation was described as far back as the 6th century BC, when Chinese people inhaled powder derived from smallpox scabs to protect people from developing smallpox. During the late 18th century, Lady Mary Wortley Montague, wife of the British ambassador to China, observed this custom and discussed this practice in European social circles.

In 1796, when Edward Jenner made his seminal report, the full potential of vaccination became accepted widely. Jenner observed that milkmaids exposed to cowpox developed protection against smallpox during subsequent epidemics. In attempts to produce the agent responsible for smallpox protection resulting from exposure to cows, Jenner ultimately isolated the vaccinia virus. (Vaccinus is a Latin word relating to cows.)

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. Modern analysis of the vaccinia virus based on restriction mapping indicates that vaccinia 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.

Different strains of vaccinia virus were generated in different cities throughout Europe and Asia, making it difficult to track the origins of the virus. The various strains were used to vaccinate individuals after acceptance of Jenner's initial studies.

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 was of paramount importance in this effort. Smallpox now exists mainly in laboratories.

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. The receptors used for viral entry have not been identified for the vaccinia virus; however, the myxoma virus (ie, rabbit pox) has been shown to use chemokine receptors for entry into host cells. Once fused, 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 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 are 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 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.

Pathophysiology

Vaccinia virus usually is administered by 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.

In the usual course of events, 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 individuals who are immunocompetent.

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.

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. Protection is nearly complete for 1-3 years after vaccination, but partial immunity may be present for 20 years or longer.

Most adverse reactions to vaccinia administration involve the skin and CNS. A progressive vaccinia infection can occur in patients who are immunosuppressed, particularly with T-cell deficiencies.

In affected individuals, infection of almost any organ follows viremia. The skin usually is involved, and continued replication of the virus can result in a severe necrotizing infection. Vaccinia virus also can replicate rapidly in eczematous lesions, leading to infections that are more serious.

CNS effects include encephalitis, which has been reported most often in children aged 6 months to 2 years. Adults may 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 also can be spread from draining primary vaccination sites to the eyes and perineum, causing mild inflammatory reactions. Vaccination sites should be covered with protective bandages to prevent local spread and accidental infection. Vaccinia virus should not be administered to children younger than 3 years, individuals with eczema or CNS disorders, or individuals who are immunosuppressed.

Recombinant vaccinia viruses

Although vaccinia virus no longer is necessary to prevent smallpox in the general population, vaccinia now is 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 commonly are 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. 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, and cervical 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.

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.

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 render 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.

Future research in the development of modified vaccinia viruses and the development of nonreplicating poxviruses (eg, fowlpox virus, canarypox virus [ALVAC]) likely will lead to further exposure of the human population to poxviruses.

Frequency

United States

Data on vaccinia complications are based on information accumulated during the 1950s and 1960s. For primary vaccination, the complication rates are as follows:

Frequency of Complications Related to Vaccination

Open table in new window

*Incidence was slightly higher when vaccination occurred before age 1 year.

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 virus exposure are not common, 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 have suggested mortality rates of 1% for eczema vaccinatum and 33% for vaccinia necrosum.

Postvaccinial encephalitis, characterized as an encephalopathy in children, is the other major complication; it 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 mild form of encephalitis characterized as a perivascular demyelinating disease, which usually has a milder course. These complications are essentially unheard of after revaccination. The nervous system complications are not related to underlying immunosuppression and do not respond to VIG therapy.

Mortality due to generalized vaccinia or erythematous rash has not been reported. Ocular keratoconjunctivitis generally responds to supportive therapy.

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 generally was 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.

Clinical

History

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 also may 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. 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.

Physical

• Dermal complications
  • 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 1) 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, may be of limited benefit.
  • 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 from 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) also can 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.
  • 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 generally is supportive and may include steroids for cerebral edema.
• Cardiac complications 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.

Causes

The causes of vaccinia infection generally are due to intentional vaccination; however, cases of infection by direct contact with a recently vaccinated individual are reported. Furthermore, with the increasing interest in poxviruses for foreign gene transfer, risk of accidental infection of laboratory workers and medical personnel is increasing.

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