Vaccinia virus (
VACV or
VV) is a large, complex,
envelopedMany 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...
virusA virus is an infectious agent too small to be seen directly with a light microscope. They are not made of cells and can only replicate inside the cells of another organism . 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
DNADeoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms and some viruses. The main role of DNA molecules is the long-term storage of information...
genomeIn modern molecular biology the genome refers to all of its hereditary information encoded in DNA .The genome includes both the genes and the non-coding sequences of the DNA. The term was adapted in 1920 by Hans Winkler, Professor of Botany at the University of Hamburg, Germany...
approximately 190
kbpIn molecular biology, two nucleotides on opposite complementary DNA or RNA strands that are connected via hydrogen bonds are called a base pair . In the canonical Watson-Crick base pairing, adenine forms a base pair with thymine , as does guanine with cytosine in DNA. In RNA, thymine is replaced...
in length, and which encodes for approximately 250
geneA gene is the basic unit of heredity in a living organism. All living things depend on genes. Genes hold the information to build and maintain their cells and pass genetic traits to offspring...
s. The dimensions of the virion are roughly 360 × 270 × 250 nm, with a weight of approximately 5-10 fg. Vaccinia virus is well-known for its role as a
vaccineA vaccine is a biological preparation that improves immunity to a particular disease. A vaccine typically contains a small amount of an agent that resembles a microorganism...
that eradicated the
smallpoxSmallpox is 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.
Vaccinia virus (
VACV or
VV) is a large, complex,
envelopedMany 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...
virusA virus is an infectious agent too small to be seen directly with a light microscope. They are not made of cells and can only replicate inside the cells of another organism . 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
DNADeoxyribonucleic acid is a nucleic acid that contains the genetic instructions used in the development and functioning of all known living organisms and some viruses. The main role of DNA molecules is the long-term storage of information...
genomeIn modern molecular biology the genome refers to all of its hereditary information encoded in DNA .The genome includes both the genes and the non-coding sequences of the DNA. The term was adapted in 1920 by Hans Winkler, Professor of Botany at the University of Hamburg, Germany...
approximately 190
kbpIn molecular biology, two nucleotides on opposite complementary DNA or RNA strands that are connected via hydrogen bonds are called a base pair . In the canonical Watson-Crick base pairing, adenine forms a base pair with thymine , as does guanine with cytosine in DNA. In RNA, thymine is replaced...
in length, and which encodes for approximately 250
geneA gene is the basic unit of heredity in a living organism. All living things depend on genes. Genes hold the information to build and maintain their cells and pass genetic traits to offspring...
s. The dimensions of the virion are roughly 360 × 270 × 250 nm, with a weight of approximately 5-10 fg. Vaccinia virus is well-known for its role as a
vaccineA vaccine is a biological preparation that improves immunity to a particular disease. A vaccine typically contains a small amount of an agent that resembles a microorganism...
that eradicated the
smallpoxSmallpox is 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 OrganizationThe World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public 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 therapyGene therapy is the insertion of genes into an individual's cells and tissues to treat a disease, such as a hereditary disease in which a deleterious mutant allele is replaced with a functional one. Although controversial, Gene Therapy can also be used for human genetic enhancement changing one's...
and
genetic engineeringGenetic engineering, recombinant DNA technology, genetic modification/manipulation and gene splicing are terms that apply to the direct manipulation of an organism's genes. Genetic engineering is different from traditional breeding, where the organism's genes are manipulated indirectly...
).
In the early 21st century, due to concerns about smallpox being used as an agent for
bioterrorismBioterrorism is terrorism by intentional release or dissemination of biological agents ; these may be in a naturally-occurring or in a human-modified form.-Definition:...
, there was renewed interest in studying the Vaccinia virus.
Classification
Vaccinia infections may be divided into the following types:
- 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 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 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 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
CowpoxCowpox is a disease of the skin that is caused by a virus known as the Cowpox virus. The pox is related to the vaccinia virus, and got its name from dairymaids touching the udders of infected cows. The ailment manifests itself in the form of red blisters and is transmitted by touch from infected...
; 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
horseThe horse is a hoofed mammal, a subspecies of one of seven extant species of the 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 virusA 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
replicateDNA replication, the basis for biological inheritance, is a fundamental process occurring in all living organisms to copy their DNA. This process is "semiconservative" in that each strand of the original double-stranded DNA molecule serves as template for the reproduction of the complementary strand...
only in the
cytoplasmThe cytoplasm is the part of a cell that is enclosed within the cell membrane. In eukaryotic cells, the cytoplasm contains organelles, such as mitochondria, which are filled with liquid that is kept separate from the rest of the cytoplasm by biological membranes. The contents of the cell nucleus...
of the
host cellIn 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
nucleusIn cell biology, the nucleus , also sometimes referred to as the "control center", 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...
. Therefore, the large genome is required for encoding various enzymes and proteins involved in viral DNA replication and gene
transcriptionTranscription, or RNA synthesis, is the process of creating an equivalent 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 in the presence of the correct enzymes...
. During its replication cycle, VV produces four infectious forms which differ in their outer
membranesThe cell membrane is the biological membrane separating the interior of a cell from the outside environment....
: 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
lipoproteinA lipoprotein is a biochemical assembly that contains both proteins and lipids. The lipids or their derivatives may be covalently or non-covalently 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
proteinProteins are organic compounds made of amino acids arranged in a linear chain and folded into a globular form. The amino acids in a polymer chain are joined together by the peptide bonds between the carboxyl and amino groups of adjacent amino acid residues...
s that give the virus resistance to
interferonInterferons are natural cell-signaling proteins produced by the cells of the immune system of most vertebrates in response to challenges such as viruses, parasites and tumor cells. They belong to the large class of glycoproteins known as cytokines and are produced by a wide variety of cells in...
s. K3L is a protein with
homologyIn evolutionary biology, homology refers to any similarity between characteristics of organisms that is due to their shared ancestry. The word homologous derives from the ancient Greek ομολογειν, 'to agree'. There are examples in different branches of biology...
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
feverFever is a frequent medical sign that describes an increase in internal body temperature to levels above normal...
. Immune responses generated from a Vaccinia virus infection protects the person against a lethal
smallpoxSmallpox is 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
vaccinationVaccination is the administration of antigenic material to produce immunity to a disease. Vaccines can prevent or ameliorate the effects of infection by a pathogen. Vaccination is generally considered to be the most effective and cost-effective method of preventing infectious diseases...
. 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
bioterrorismBioterrorism is terrorism by intentional release or dissemination of biological agents ; these may be in a naturally-occurring or in a human-modified form.-Definition:...
, 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 AdministrationThe Food and Drug Administration is a Government agency of the United States Department of Health and Human Services and is responsible for regulating and supervising the safety of foods, tobacco products, dietary supplements, Medication drugs, vaccines, Biopharmaceutical, blood transfusion,...
(FDA) licensed a new
vaccineA vaccine is a biological preparation that improves immunity to a particular disease. A vaccine typically contains a small amount of an agent that resembles a microorganism...
ACAM2000ACAM2000 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
smallpoxSmallpox is 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
CambridgeThe 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. It is also at the heart of the high-technology centre known as Silicon Fen....
,
EnglandEngland 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 and the North Sea to the east, with the English Channel to the south separating it from continental...
, and
CambridgeCambridge 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, a nexus of the Puritan theology embraced by the town's founders. Notably, Cambridge is home to two internationally prominent...
,
MassachusettsThe Commonwealth of Massachusetts is a state in the New England region of the northeastern United States. 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. Most of its population of...
, the U.S.
Centers for Disease Control and PreventionThe Centers for Disease Control and Prevention is a United States federal agency under the Department of Health and Human Services based in Atlanta, Georgia. It works to protect public health and safety by providing information to enhance health decisions, and it promotes health through...
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
CowpoxCowpox is a disease of the skin that is caused by a virus known as the Cowpox virus. The pox is related to the vaccinia virus, and got its name from dairymaids touching the udders of infected cows. The ailment manifests itself in the form of red blisters and is transmitted by touch from infected...
, reported on by
Edward JennerEdward Jenner was an English scientist who studied his natural surroundings in Berkeley, Gloucestershire, England. Jenner is widely credited as the pioneer of smallpox vaccine, and is sometimes referred to as the 'Father of Immunology'...
in 1796. The
LatinLatin is an Italic language originally spoken in Latium and Ancient Rome. Through the Roman conquest, Latin spread throughout the Mediterranean and a large part of Europe...
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.)
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 ArmyThe United States Army is the branch of the United States Military responsible for land-based military operations. It is the largest and oldest established branch of the U.S. military and is one of seven uniformed services...
. The United States military resumed smallpox vaccinations in 2002. The child acquired the infection due to
eczemaEczema is a disease in a form of dermatitis, or inflammation of the epidermis. The term eczema is broadly applied to a range of persistent skin conditions. These include dryness and recurring skin rashes that are characterized by one or more of these symptoms: redness, skin edema , itching and...
, which is a known risk factor for vaccinia infection. The boy was treated with
intravenous immunoglobulinIntravenous immune globulin 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...
,
cidofovirCidofovir 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 synthesis...
, 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.
Common strains
This is a list of some of the well-characterized vaccinia strains used in research and immunizations.
- Western Reserve
- Copenhagen
- Dryvax
Dryvax is a freeze-dried calf lymph smallpox vaccine. It is the world's oldest smallpox vaccine, created in the late 1800s 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 StatesThe United States of America is a federal constitutional republic comprising fifty states and a federal district...
, produced by WyethWyeth, formerly known as American Home Products , was one of the largest pharmaceutical companies in the world. The company is based in Madison, New Jersey...
. It was replaced in 2008 by ACAM2000 (see below), produced by Acambis. It was produced as preparations of calfCalves are the young of domestic cattle. Calves are reared to become adult cattle, or are slaughtered for their meat, called veal.-Terminology:...
lymphLymph is the interstitial fluid found between the cells of the human body. It enters the lymph vessels by filtration through pores in the walls of capillaries...
which was freeze-dried and treated with antibiotics.
- 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 cloneCloning in biology is the process of producing 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 organisms...
of a Dryvax virus by plaque purificationA 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 cellsVero cells are lineages of cells used in cell cultures.The Vero lineage was isolated from kidney epithelial cells extracted from an African green monkey . The lineage was developed on 27 Mar 1962, by Yasumura and Kawakita at the Chiba University in Chiba, Japan...
.
- 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 chickenThe chicken is a domesticated fowl. 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 bird...
embryoAn 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