Vaccinia
Encyclopedia
Vaccinia virus is a large, complex, enveloped
Viral envelope
Many viruses have viral envelopes covering their protein capsids. The envelopes typically are derived from portions of the host cell membranes , but include some viral glycoproteins. Functionally, viral envelopes are used to help viruses enter host cells...

 virus
Virus
A virus is a small infectious agent that can replicate only inside the living cells of organisms. Viruses infect all types of organisms, from animals and plants to bacteria and archaea...

 belonging to the poxvirus family. It has a linear, double-stranded DNA
DNA
Deoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms . The DNA segments that carry this genetic information are called genes, but other DNA sequences have structural purposes, or are involved in...

 genome
Genome
In modern molecular biology and genetics, the genome is the entirety of an organism's hereditary information. It is encoded either in DNA or, for many types of virus, in RNA. The genome includes both the genes and the non-coding sequences of the DNA/RNA....

 approximately 190 kbp
Base pair
In molecular biology and genetics, the linking between two nitrogenous bases on opposite complementary DNA or certain types of RNA strands that are connected via hydrogen bonds is called a base pair...

 in length, and which encodes for approximately 250 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...

s. The dimensions of the virion are roughly 360 × 270 × 250 nm, with a mass of approximately 5-10 fg. Vaccinia virus is well-known for its role as a vaccine
Vaccine
A vaccine is a biological preparation that improves immunity to a particular disease. A vaccine typically contains an agent that resembles a disease-causing microorganism, and is often made from weakened or killed forms of the microbe or its toxins...

 (its namesake) that eradicated the smallpox
Smallpox
Smallpox was an infectious disease unique to humans, caused by either of two virus variants, Variola major and Variola minor. The disease is also known by the Latin names Variola or Variola vera, which is a derivative of the Latin varius, meaning "spotted", or varus, meaning "pimple"...

 disease, making it the first human disease to be successfully eradicated by science. This endeavour was carried out by the World Health Organization
World Health Organization
The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...

 under the Smallpox Eradication Program. Post eradication of smallpox, scientists study Vaccinia virus to use as a tool for delivering genes into biological tissues (gene therapy
Gene therapy
Gene therapy is the insertion, alteration, or removal of genes within an individual's cells and biological tissues to treat disease. It is a technique for correcting defective genes that are responsible for disease development...

 and genetic engineering
Genetic engineering
Genetic engineering, also called genetic modification, is the direct human manipulation of an organism's genome using modern DNA technology. It involves the introduction of foreign DNA or synthetic genes into the organism of interest...

).

In the early 21st century, due to concerns about smallpox being used as an agent for bioterrorism
Bioterrorism
Bioterrorism is terrorism involving the intentional release or dissemination of biological agents. These agents are bacteria, viruses, or toxins, and may be in a naturally occurring or a human-modified form. For the use of this method in warfare, see biological warfare.-Definition:According to the...

, there was renewed interest in studying the Vaccinia virus.

Classification

Vaccinia infections may be divided into the following types:
  • Generalized vaccinia
    Generalized vaccinia
    Generalized vaccinia is a cutaneous condition that occurs 6-9 days after vaccination, characterized by a generalized eruption of skin lesions, and caused by the vaccinia virus....

  • Eczema vaccinatum
    Eczema vaccinatum
    Eczema vaccinatum is a rare severe adverse reaction to smallpox vaccination.It is characterized by serious local or disseminated, umbilicated, vesicular, crusting skin rashes in the face, neck, chest, abdomen, upper limbs and hands, caused by widespread infection of the skin in people with previous...

  • Progressive vaccinia
    Progressive vaccinia
    Progressive vaccinia is a rare cutaneous condition caused by the vaccinia virus, characterized by painless, but progressive, necrosis and ulceration....

     (Vaccinia gangrenosum, Vaccinia necrosum)
  • Roseola vaccinia
    Roseola vaccinia
    Roseola vaccinia is a cutaneous condition characterized by a prominent rim of erythema surround the site of vaccination injection....


Origin

Vaccinia virus is closely related to the virus that causes Cowpox
Cowpox
Cowpox is a skin disease caused by a virus known as the Cowpox virus. The pox is related to the vaccinia virus and got its name from the distribution of the disease when dairymaids touched the udders of infected cows. The ailment manifests itself in the form of red blisters and is transmitted by...

; historically the two were often considered to be one and the same. The precise origin of Vaccinia virus is unknown, however, due to the lack of record-keeping as the virus was repeatedly cultivated and passaged in research laboratories for many decades. The most common notion is that Vaccinia virus, Cowpox virus, and Variola virus (the causative agent of smallpox), were all derived from a common ancestral virus. There is also speculation that Vaccinia virus was originally isolated from horse
Horse
The horse is one of two extant subspecies of Equus ferus, or the wild horse. It is a single-hooved mammal belonging to the taxonomic family Equidae. The horse has evolved over the past 45 to 55 million years from a small multi-toed creature into the large, single-toed animal of today...

s.

Basic biology

Poxviruses are unique among DNA virus
DNA virus
A DNA virus is a virus that has DNA as its genetic material and replicates using a DNA-dependent DNA polymerase. The nucleic acid is usually double-stranded DNA but may also be single-stranded DNA . DNA viruses belong to either Group I or Group II of the Baltimore classification system for viruses...

es because they replicate
DNA replication
DNA replication is a biological process that occurs in all living organisms and copies their DNA; it is the basis for biological inheritance. The process starts with one double-stranded DNA molecule and produces two identical copies of the molecule...

 only in the cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...

 of the host cell
Host (biology)
In biology, a host is an organism that harbors a parasite, or a mutual or commensal symbiont, typically providing nourishment and shelter. In botany, a host plant is one that supplies food resources and substrate for certain insects or other fauna...

, outside of the nucleus
Cell nucleus
In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...

. Therefore, the large genome is required for encoding various enzymes and proteins involved in viral DNA replication and gene transcription
Transcription (genetics)
Transcription is the process of creating a complementary RNA copy of a sequence of DNA. Both RNA and DNA are nucleic acids, which use base pairs of nucleotides as a complementary language that can be converted back and forth from DNA to RNA by the action of the correct enzymes...

. During its replication cycle, VV produces four infectious forms which differ in their outer membranes
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...

: intracellular mature virion (IMV), the intracellular enveloped virion (IEV), the cell-associated enveloped virion (CEV) and the extracellular enveloped virion (EEV). Although the issue remains contentious, the prevailing view is that the IMV consists of a single lipoprotein
Lipoprotein
A lipoprotein is a biochemical assembly that contains both proteins and lipids water-bound to the proteins. Many enzymes, transporters, structural proteins, antigens, adhesins, and toxins are lipoproteins...

 membrane, while the CEV and EEV are both surrounded by two membrane layers and the IEV has three envelopes. The IMV is the most abundant infectious form and is thought to be responsible for spread between hosts. On the other hand, the CEV is believed to play a role in cell-to-cell spread and the EEV is thought to be important for long range dissemination within the host organism.

Host resistance

Vaccinia contains within its genome several protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...

s that give the virus resistance to interferon
Interferon
Interferons are proteins made and released by host cells in response to the presence of pathogens—such as viruses, bacteria, or parasites—or tumor cells. They allow communication between cells to trigger the protective defenses of the immune system that eradicate pathogens or tumors.IFNs belong to...

s. K3L is a protein with homology
Homology (biology)
Homology forms the basis of organization for comparative biology. In 1843, Richard Owen defined homology as "the same organ in different animals under every variety of form and function". Organs as different as a bat's wing, a seal's flipper, a cat's paw and a human hand have a common underlying...

 to the protein eukaryotic initiation factor 2 (eIF-2alpha). K3L protein inhibits the action of PKR, an activator of interferons. E3L is another protein encoded by Vaccinia. E3L also inhibits PKR activation; and is also able to bind to double stranded RNA.

Use as a vaccine

A Vaccinia virus infection is very mild and is typically asymptomatic in healthy individuals, but it may cause a mild rash and fever
Fever
Fever is a common medical sign characterized by an elevation of temperature above the normal range of due to an increase in the body temperature regulatory set-point. This increase in set-point triggers increased muscle tone and shivering.As a person's temperature increases, there is, in...

. Immune responses generated from a Vaccinia virus infection protects the person against a lethal smallpox
Smallpox
Smallpox was an infectious disease unique to humans, caused by either of two virus variants, Variola major and Variola minor. The disease is also known by the Latin names Variola or Variola vera, which is a derivative of the Latin varius, meaning "spotted", or varus, meaning "pimple"...

 infection. For this reason, Vaccinia virus was, and is still being used as a live-virus vaccine against smallpox. Unlike vaccines that use weakened forms of the virus being vaccinated against, the Vaccinia virus vaccine cannot cause a smallpox infection because it does not contain the smallpox virus. However, certain complications and/or vaccine adverse effects occasionally arise. The chance of this happening is significantly increased in people who are immunocompromised. Approximately one in one million individuals will develop a fatal response to the vaccination
Vaccination
Vaccination is the administration of antigenic material to stimulate the immune system of an individual to develop adaptive immunity to a disease. Vaccines can prevent or ameliorate the effects of infection by many pathogens...

. Currently, the vaccine is only administered to health care workers or research personnel who have a high risk of contracting Vaccinia virus, and to the military personnel of the United States of America. Due to the present threat of smallpox-related bioterrorism
Bioterrorism
Bioterrorism is terrorism involving the intentional release or dissemination of biological agents. These agents are bacteria, viruses, or toxins, and may be in a naturally occurring or a human-modified form. For the use of this method in warfare, see biological warfare.-Definition:According to the...

, there is a possibility the vaccine may have to be widely administered again in the future. Therefore, scientists are currently developing novel vaccine strategies against smallpox which are safer and much faster to deploy during a bioterrorism event.

On September 1, 2007, the U.S. Food and Drug Administration
Food and Drug Administration
The Food and Drug Administration is an agency of the United States Department of Health and Human Services, one of the United States federal executive departments...

 (FDA) licensed a new vaccine
Vaccine
A vaccine is a biological preparation that improves immunity to a particular disease. A vaccine typically contains an agent that resembles a disease-causing microorganism, and is often made from weakened or killed forms of the microbe or its toxins...

 ACAM2000
ACAM2000
ACAM2000 is a smallpox vaccine developed by . It was approved for use in the United States by the U.S. Food and Drug Administration on 31 August 2007. It contains live vaccinia virus, cloned from the same strain used in an earlier vaccine, Dryvax...

 against smallpox
Smallpox
Smallpox was an infectious disease unique to humans, caused by either of two virus variants, Variola major and Variola minor. The disease is also known by the Latin names Variola or Variola vera, which is a derivative of the Latin varius, meaning "spotted", or varus, meaning "pimple"...

 which can be produced quickly upon need. Manufactured by Acambis of Cambridge
Cambridge
The city of Cambridge is a university town and the administrative centre of the county of Cambridgeshire, England. It lies in East Anglia about north of London. Cambridge is at the heart of the high-technology centre known as Silicon Fen – a play on Silicon Valley and the fens surrounding the...

, England
England
England is a country that is part of the United Kingdom. It shares land borders with Scotland to the north and Wales to the west; the Irish Sea is to the north west, the Celtic Sea to the south west, with the North Sea to the east and the English Channel to the south separating it from continental...

, and Cambridge
Cambridge, Massachusetts
Cambridge is a city in Middlesex County, Massachusetts, United States, in the Greater Boston area. It was named in honor of the University of Cambridge in England, an important center of the Puritan theology embraced by the town's founders. Cambridge is home to two of the world's most prominent...

, Massachusetts
Massachusetts
The Commonwealth of Massachusetts is a state in the New England region of the northeastern United States of America. It is bordered by Rhode Island and Connecticut to the south, New York to the west, and Vermont and New Hampshire to the north; at its east lies the Atlantic Ocean. As of the 2010...

, the U.S. Centers for Disease Control and Prevention
Centers for Disease Control and Prevention
The Centers for Disease Control and Prevention are a United States federal agency under the Department of Health and Human Services headquartered in Druid Hills, unincorporated DeKalb County, Georgia, in Greater Atlanta...

 stockpiled 192.5 million doses of the new vaccine (see list of common strains below).

History

The original vaccine for smallpox, and the origin of the idea of vaccination, was Cowpox
Cowpox
Cowpox is a skin disease caused by a virus known as the Cowpox virus. The pox is related to the vaccinia virus and got its name from the distribution of the disease when dairymaids touched the udders of infected cows. The ailment manifests itself in the form of red blisters and is transmitted by...

, reported on by Edward Jenner
Edward Jenner
Edward Anthony Jenner was an English scientist who studied his natural surroundings in Berkeley, Gloucestershire...

 in 1796. The Latin
Latin
Latin is an Italic language originally spoken in Latium and Ancient Rome. It, along with most European languages, is a descendant of the ancient Proto-Indo-European language. Although it is considered a dead language, a number of scholars and members of the Christian clergy speak it fluently, and...

 term used for Cowpox was variolae vaccinae, essentially a direct translation of "cow-related pox". That term lent its name to the whole idea of vaccination. When it was realized that the virus used in smallpox vaccination was not, or was no longer, the same as the Cowpox virus, the name 'vaccinia' stayed with the vaccine-related virus. (See OED.) Vaccine potency and efficacy prior to the invention of refrigerated methods of transportation was unreliable. The vaccine would be rendered impotent by heat and sunlight, and the method of drying samples on quills and shipping them to countries in need often resulted in an inactive vaccine. Another method employed was the "arm to arm" method. This involved vaccinating an individual then transferring it to another as soon as the infectious pustule forms, then to another, etc. This method was used as a form of living transportation of the vaccine, and usually employed orphans as carriers. However, this method was problematic due to the possibility of spreading other blood diseases, such as hepatitis and syphilis. 41 Italian children contracted syphilis after being vaccinated by the arm to arm method in 1861.

In 1913, E. Steinhardt, C. Israeli, and R. A. Lambert grew vaccinia virus in fragments of guinea pig cornea
Cornea
The cornea is the transparent front part of the eye that covers the iris, pupil, and anterior chamber. Together with the lens, the cornea refracts light, with the cornea accounting for approximately two-thirds of the eye's total optical power. In humans, the refractive power of the cornea is...

l tissue culture
Tissue culture
Tissue culture is the growth of tissues or cells separate from the organism. This is typically facilitated via use of a liquid, semi-solid, or solid growth medium, such as broth or agar...

.

In 1939 Alan Downie showed that the smallpox vaccines being used in the 20th century and cowpox virus were not the same , but some sorts of cousins.

Recent cases

In March 2007, a 2-year-old Indiana boy and his mother contracted a life-threatening vaccinia infection from the boy's father. The boy developed the telltale rash over 80 percent of his body after coming into close contact with his father, who was vaccinated for smallpox before being deployed overseas by the United States Army
United States Army
The United States Army is the main branch of the United States Armed Forces responsible for land-based military operations. It is the largest and oldest established branch of the U.S. military, and is one of seven U.S. uniformed services...

. The United States military resumed smallpox vaccinations in 2002. The child acquired the infection due to eczema
Eczema
Eczema is a form of dermatitis, or inflammation of the epidermis . In England, an estimated 5.7 million or about one in every nine people have been diagnosed with the disease by a clinician at some point in their lives.The term eczema is broadly applied to a range of persistent skin conditions...

, which is a known risk factor for vaccinia infection. The boy was treated with intravenous immunoglobulin
Intravenous immunoglobulin
Intravenous immunoglobulin is a blood product administered intravenously. It contains the pooled IgG extracted from the plasma of over one thousand blood donors. IVIG's effects last between 2 weeks and 3 months...

, cidofovir
Cidofovir
Cidofovir is an injectable antiviral medication for the treatment of cytomegalovirus retinitis in patients with AIDS. It suppresses CMV replication by selective inhibition of viral DNA polymerase and therefore prevention of viral replication and transcription...

, and an experimental drug being developed by SIGA Technologies. On April 19, 2007, he was sent home with no after effects except for possible scarring of the skin.

In 2010, the Centers for Disease Control and Prevention
Centers for Disease Control and Prevention
The Centers for Disease Control and Prevention are a United States federal agency under the Department of Health and Human Services headquartered in Druid Hills, unincorporated DeKalb County, Georgia, in Greater Atlanta...

 (CDC) reported that a woman in Washington had contracted vaccinia virus infection after digital vaginal contact with her boyfriend, a military member who had recently been vaccinated for smallpox. The woman had a history of childhood eczema, but she had not been symptomatic as an adult. The CDC indicated that it was aware of four similar cases in the preceding 12 months of vaccinia infection after sexual contact with a recent military vaccinee.

Common strains

This is a list of some of the well-characterized vaccinia strains used in research and immunizations.
  • Western Reserve
  • Copenhagen
  • Dryvax
    Dryvax
    Dryvax is a freeze-dried calf lymph smallpox vaccine. It is the world's oldest smallpox vaccine, created in the late 19th century by American Home Products, a predecessor of Wyeth. By the 1940s, Wyeth was the leading US manufacturer of the vaccine and the only manufacturer by the 1960s...

     (also known as "Wyeth"): the vaccine strain previously used in the United States
    United States
    The United States of America is a federal constitutional republic comprising fifty states and a federal district...

    , produced by Wyeth
    Wyeth
    Wyeth, formerly one of the companies owned by American Home Products Corporation , was a pharmaceutical company. The company was based in Madison, New Jersey, USA...

    . It was replaced in 2008 by ACAM2000 (see below), produced by Acambis. It was produced as preparations of calf
    Calf
    Calves are the young of domestic cattle. Calves are reared to become adult cattle, or are slaughtered for their meat, called veal.-Terminology:...

     lymph
    Lymph
    Lymph is considered a part of the interstitial fluid, the fluid which lies in the interstices of all body tissues. Interstitial fluid becomes lymph when it enters a lymph capillary...

     which was freeze-dried and treated with antibiotics.
  • ACAM2000
    ACAM2000
    ACAM2000 is a smallpox vaccine developed by . It was approved for use in the United States by the U.S. Food and Drug Administration on 31 August 2007. It contains live vaccinia virus, cloned from the same strain used in an earlier vaccine, Dryvax...

    : The current strain in use in the USA, produced by Acambis. ACAM2000 was derived from a clone
    Cloning
    Cloning in biology is the process of producing similar populations of genetically identical individuals that occurs in nature when organisms such as bacteria, insects or plants reproduce asexually. Cloning in biotechnology refers to processes used to create copies of DNA fragments , cells , or...

     of a Dryvax virus by plaque purification
    Viral plaque
    A viral plaque is a visible structure formed within a cell culture, such as bacterial cultures within some nutrient medium . The bacteriophage viruses replicate and spread, thus generating regions of cell destructions known as plaques....

    . It is produced in cultures of Vero cells
    Vero cells
    Vero cells are lineages of cells used in cell cultures.The Vero lineage was isolated from kidney epithelial cells extracted from an African green monkey...

    .
  • Modified vaccinia Ankara
    Modified vaccinia Ankara
    Vaccinia viruses re-engineered to express foreign genes are robust vectors for production of recombinant proteins, the most common being a vaccine delivery system for antigens. Concerns about the safety of the vaccinia virus have been addressed by the development of vectors based on attenuated...

    : a highly attenuated (not virulent) strain created by passaging vaccinia virus several hundred times in chicken
    Chicken
    The chicken is a domesticated fowl, a subspecies of the Red Junglefowl. As one of the most common and widespread domestic animals, and with a population of more than 24 billion in 2003, there are more chickens in the world than any other species of bird...

     embryo
    Embryo
    An embryo is a multicellular diploid eukaryote in its earliest stage of development, from the time of first cell division until birth, hatching, or germination...

     fibroblasts. Unlike some other vaccinia strains it does not make immunodeficient mice sick and therefore may be safer to use in humans who have weaker immune systems due to being very young, very old, having HIV/AIDS, etc.

External links

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