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.
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.
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. 
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. 
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. 
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.  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. 
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.
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.  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 (Open Table in a new window)
|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.|
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.
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.
No known ethnic predilections exist for complications related to vaccinia virus.
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.
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.
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