Cowpox

Last updated
Cowpox virus
Cowpox virus.jpg
Electron micrograph of three Cowpox virus particles
Virus classification Red Pencil Icon.png
(unranked): Virus
Phylum: incertae sedis
Class: incertae sedis
Order: incertae sedis
Family: Poxviridae
Genus: Orthopoxvirus
Species:
Cowpox virus
Cowpox
Cowpox eruption.jpg
Cowpox lesions on patient’s forearm on day 7 after onset of illness. The hemagglutinin gene of the isolate clustered with a Russian cowpox virus strain, and the more distantly, with other cowpox and vaccinia virus strains. The patient’s dog had orthopoxvirus-specific antibodies, indicating a possible transmission route. [1]
Specialty Infectious disease   Blue pencil.svg

Cowpox is an infectious disease caused by the cowpox virus. The virus, part of the genus Orthopoxvirus , is closely related to the vaccinia virus. The virus is zoonotic, meaning that it is transferable between species, such as from animal to human. The transferral of the disease was first observed in dairymaids who touched the udders of infected cows and consequently developed the signature pustules on their hands. [2] Cowpox is more commonly found in animals other than bovines, such as rodents. Cowpox is similar to, but much milder than, the highly contagious and often deadly smallpox disease. [2] Its close resemblance to the mild form of smallpox and the observation that dairy farmers [3] were immune from smallpox inspired the first smallpox vaccine, created and administered by English physician Edward Jenner. [4]

Orthopoxvirus is a genus of viruses in the family Poxviridae and subfamily Chordopoxvirinae. Vertebrates, including mammals and humans, and arthropods serve as natural hosts. Currently, 10 species are in this genus, including the type species Vaccinia virus. Diseases associated with this genus include smallpox, cowpox, horsepox, and monkeypox. The most infamous member of the genus is Variola virus, which causes smallpox. It was eradicated using Vaccinia virus as a vaccine.

Vaccinia species of virus

Vaccinia virus is a large, complex, enveloped virus belonging to the poxvirus family. It has a linear, double-stranded DNA genome approximately 190 kbp in length, and which encodes approximately 250 genes. The dimensions of the virion are roughly 360 × 270 × 250 nm, with a mass of approximately 5–10 fg.

Zoonosis infectious disease that is transmitted between species (sometimes by a vector) from animals other than humans to humans or from humans to other animals

Zoonoses are infectious diseases that can be naturally transmitted between animals and humans.

Contents

The word “vaccination,” coined by Jenner in 1796, [4] is derived from the Latin root vaccinus, meaning of or from the cow. [5] Once vaccinated, a patient develops antibodies that make them immune to cowpox, but they also develop immunity to the smallpox virus, or Variola virus . The cowpox vaccinations and later incarnations proved so successful that in 1980, the World Health Organization announced that smallpox was the first disease to be eradicated by vaccination efforts worldwide. [5] Other orthopox viruses remain prevalent in certain communities and continue to infect humans, such as the cowpox virus (CPXV) in Europe, vaccinia in Brazil, and monkeypox virus in Central and West Africa.

Vaccination administration of a vaccine to protect against disease

Vaccination is the administration of a vaccine to help the immune system develop protection from a disease. Vaccines contain a microorganism in a weakened or killed state, or proteins or toxins from the organism. In stimulating the body's adaptive immunity, it helps prevent sickness from an infectious disease. When a sufficiently large percentage of a population has been vaccinated, herd immunity results. The effectiveness of vaccination has been widely studied and verified. Vaccination is the most effective method of preventing infectious diseases; widespread immunity due to vaccination is largely responsible for the worldwide eradication of smallpox and the elimination of diseases such as polio, measles, and tetanus from much of the world.

In biology, immunity is the balanced state of multicellular organisms having adequate biological defenses to fight infection, disease, or other unwanted biological invasion, while having adequate tolerance to avoid allergy, and autoimmune diseases.

Smallpox vaccine vaccine

Smallpox vaccine, the first successful vaccine to be developed, was introduced by Edward Jenner in 1796. He followed up his observation that milkmaids who had previously caught cowpox did not later catch smallpox by showing that inoculated cowpox protected against inoculated smallpox.

Medical use

Naturally occurring cases of cowpox were not common, but it was discovered that the vaccine could be “carried” in humans and reproduced and disseminated human-to-human. Jenner's original vaccination used lymph from the cowpox pustule on a milkmaid, and subsequent “arm-to-arm” vaccinations applied the same principle. As this transfer of human fluids came with its own set of complications, a safer manner of producing the vaccine was first introduced in Italy, The new method used cows to manufacture the vaccine using a process called “retrovaccination,” in which a heifer was inoculated with humanized cowpox virus, and it was passed from calf to calf to produce massive quantities efficiently and safely. This then led to the next incarnation, “true animal vaccine,” which used the same process but began with naturally-occurring cowpox virus, and not the humanized form.

This method of production proved to be lucrative and was taken advantage of by many entrepreneurs needing only calves and seed lymph from an infected cow to manufacture crude versions of the vaccine. W. F. Elgin of the National Vaccine Establishment presented his slightly refined technique to the Conference of State and Provincial Boards of Health of North America. A tuberculosis-free calf, stomach shaved, would be bound to an operating table, where incisions would be made on its lower body. Glycerinated lymph from a previously inoculated calf was spread along the cuts. After a few days, the cuts would have scabbed or crusted over. The crust was softened with sterilized water and mixed with glycerin, which disinfected it, then stored hermetically-sealed in capillary tubes for later use.

Tuberculosis infectious disease caused by the bacterium Mycobacterium tuberculosis

Tuberculosis (TB) is an infectious disease usually caused by Mycobacterium tuberculosis (MTB) bacteria. Tuberculosis generally affects the lungs, but can also affect other parts of the body. Most infections do not have symptoms, in which case it is known as latent tuberculosis. About 10% of latent infections progress to active disease which, if left untreated, kills about half of those affected. The classic symptoms of active TB are a chronic cough with blood-containing sputum, fever, night sweats, and weight loss. It was historically called "consumption" due to the weight loss. Infection of other organs can cause a wide range of symptoms.

At some point, the virus in use was no longer cowpox, but vaccinia. Scientists have not determined exactly when the change or mutation occurred, but the effects of vaccinia and cowpox virus as vaccine are nearly the same. [6]

The virus is found in Europe, and mainly in the UK. Human cases today are very rare and most often contracted from domestic cats. The virus is not commonly found in cattle; the reservoir hosts for the virus are woodland rodents, particularly voles. From these rodents, domestic cats contract and transmit the virus to humans. [7] Symptoms in cats include lesions on the face, neck, forelimbs, and paws, and less commonly upper respiratory tract infections. [8] Symptoms of infection with cowpox virus in humans are localized, pustular lesions generally found on the hands and limited to the site of introduction. The incubation period is 9 to 10 days. The virus is prevalent in late summer and autumn.

Europe Continent in the Northern Hemisphere and mostly in the Eastern Hemisphere

Europe is a continent located entirely in the Northern Hemisphere and mostly in the Eastern Hemisphere. It is bordered by the Arctic Ocean to the north, the Atlantic Ocean to the west and the Mediterranean Sea to the south. It comprises the westernmost part of Eurasia.

Feline zoonosis

Feline zoonosis are the viral, bacterial, fungal, protozoan, nematode and arthropod infections that can be transmitted to humans from the domesticated cat, Felis catus. Some of these are diseases are reemerging and newly emerging infections or infestations caused by zoonotic pathogens transmitted by cats. In some instances, the cat can display symptoms of infection and sometimes the cat remains asymptomatic. There can be serious illnesses and clinical manifestations in people who become infected. This is dependent on the immune status and age of the person. Those who live in close association with cats are more prone to these infections. But those that do not keep cats as pets are also able to acquire these infections because of the transmission can be from cat feces and the parasites that leave their bodies.

Cat domesticated feline

The cat is a small carnivorous mammal. It is the only domesticated species in the family Felidae and often referred to as the domestic cat to distinguish it from wild members of the family. The cat is either a house cat, kept as a pet, or a feral cat, freely ranging and avoiding human contact. A house cat is valued by humans for companionship and for its ability to hunt rodents. About 60 cat breeds are recognized by various cat registries.

Origin

Cowpox (vaccina) pustules on a cow's udder Cowpox Engraving (detail).png
Cowpox (vaccina) pustules on a cow's udder

Discovery

In the years from 1770 to 1790, at least six people who had contact with a cow had independently tested the possibility of using the cowpox vaccine as an immunization for smallpox in humans. Amongst them were the English farmer Benjamin Jesty, in Dorset in 1774 and the German teacher Peter Plett in 1791. [9] Jesty inoculated his wife and two young sons with cowpox, in a successful effort to immunize them to smallpox, an epidemic of which had arisen in their town. His patients who had contracted and recovered from the similar but milder cowpox (mainly milkmaids), seemed to be immune not only to further cases of cowpox, but also to smallpox. By scratching the fluid from cowpox lesions into the skin of healthy individuals, he was able to immunize those people against smallpox. Reportedly, farmers and people working regularly with cattle and horses were often spared during smallpox outbreaks. Investigations by the British Army in 1790 showed that horse-mounted troops were less infected by smallpox than infantry, due to probable exposure to the similar horse pox virus ( Variola equina ). By the early 19th century, more than 100,000 people in Great Britain had been vaccinated. The arm-to-arm method of transfer of the cowpox vaccine was also used to distribute Jenner's vaccine throughout the Spanish Empire. Spanish king Charles IV's daughter had been stricken with smallpox in 1798, and after she recovered, he arranged for the rest of his family to be vaccinated. In 1803, the king, convinced of the benefits of the vaccine, ordered his personal physician Francis Xavier de Balmis, to deliver it to the Spanish dominions in North and South America. To maintain the vaccine in an available state during the voyage, the physician recruited 22 young boys who had never had cowpox or smallpox before, aged three to nine years, from the orphanages of Spain. During the trip across the Atlantic, de Balmis vaccinated the orphans in a living chain. Two children were vaccinated immediately before departure, and when cowpox pustules had appeared on their arms, material from these lesions was used to vaccinate two more children. [10]

Benjamin Jesty British farmer and doctor

Benjamin Jesty was a farmer at Yetminster in Dorset, England, notable for his early experiment in inducing immunity against smallpox using cowpox.

Dorset County of England

Dorset is a county in South West England on the English Channel coast. The ceremonial county comprises the non-metropolitan county, which is governed by Dorset County Council, and the unitary authority areas of Poole and Bournemouth. Covering an area of 2,653 square kilometres (1,024 sq mi), Dorset borders Devon to the west, Somerset to the north-west, Wiltshire to the north-east, and Hampshire to the east. The county town is Dorchester which is in the south. After the reorganisation of local government in 1974 the county's border was extended eastward to incorporate the Hampshire towns of Bournemouth and Christchurch. Around half of the population lives in the South East Dorset conurbation, while the rest of the county is largely rural with a low population density.

Peter Plett was a German teacher and pioneer of smallpox vaccine from Schleswig-Holstein. His work with smallpox vaccine, undertaken in the early 1790s before similar studies by Edward Jenner, was not acknowledged until many years later.

In 1796, British medical practitioner Edward Jenner tested the theory that cowpox could protect someone from being infected by smallpox. There had long been speculation regarding the origins of Jenner’s variolae vaccine, until DNA sequencing data showed close similarities between horsepox and cowpox viruses. Jenner noted that farriers sometimes milked cows and that material from the equine disease could produce a vesicular disease in cows from which variolae vaccinae was derived. Contemporary accounts provide support for Jenner’s speculation that the vaccine probably originated as an equine disease called "grease". [11] Although cowpox originates on the udder of cows, Jenner took his sample from a milkmaid, Sarah Nelmes. Jenner extracted the pus of one of the lesions formed by cowpox on Nelmes to another individual who never had smallpox, James Phipps. He eventually developed a scab and fever that was manageable. Approximately six weeks later, Jenner then introduced an active sample of the smallpox virus into Phipps to test the theory. After being observed for an extended amount of time, it was recorded that Phipps did not receive a reaction from it. Although Jenner was not the first person to conceive the notion of cowpox protecting against the smallpox virus, his experiment proved the theory. This vaccination worked temporarily. It was later discovered that the cowpox vaccination only worked temporarily against the invasion of smallpox and the procedure would need to be repeated several times through ones' lifetime to remain smallpox free. In later years, Jenner popularized the experiment, calling it a vaccination from the Latin for cow, vacca. The amount of vaccinations among people of that era increased drastically. It was widely considered to be a relatively safer procedure compared to the mainstream inoculation. Although Jenner was propelled into the spotlight from the vaccination popularity, he mainly focused on science behind why the cowpox allowed persons to not be infected by smallpox.The honor of the discovery of the vaccination is widely accepted to be given to Benjamin Jesty. He is considered to be the first to use cowpox as a vaccination, though the term vaccination was not invented yet. During the midst of the smallpox outbreak, Jesty transferred pieces of cow udder which he knew had been infected with cowpox into the skin of his family members in the hopes of protecting them. Jesty did not publicize his findings, and Jenner, who performed his first inoculation 22 years later and publicized his findings, assumed credit. It is said that Jenner made this discovery by himself, possibly without knowing previous accounts 20 years earlier. Although Jesty may have been the first to discover it, Jenner made vaccination widely accessible and has therefore been credited for its invention. [12]

Opposition

The majority of the population at the time accepted the up-and-coming vaccination. However, there were still opposition from individuals who were reluctant to change from the inoculations. In addition, there became a growing concern from parties who were worried about the unknown repercussions of infecting a human with an animal disease. One way individuals expressed their discontent was to draw comics that sometimes depicted small cows growing from the sites of vaccination. Others publicly advocated for the continuance of the inoculations; however this was not because of their discontent for the vaccinations. Some of their reluctance had to do with an apprehensiveness for change. They had become so familiar with the process, outcome, positives, and negatives of inoculations that they did not want to be surprised by the outcome or effects of the vaccinations. Jenner soon eased their minds after extensive trials. However, others advocated against vaccinations for different reason. Because of the high price of inoculation, Jenner experienced very few common folk who were not willing to accept the vaccination. Due to this, Jenner found many subjects for his tests. He was able to publish his results in a pamphlet in 1798: An Inquiry into the Causes and Effects of Variolae Vaccinae, a Disease, Discovered in some of the Western Counties of England particularly Gloucestershire, and known by the Name of Cow Pox. [13]

Historical use

In The Cow-Pock--or--the Wonderful Effects of the New Inoculation! (1802), James Gillray caricatured recipients of the vaccine developing cow-like appendages. The cow pock.jpg
In The Cow-Pock—or—the Wonderful Effects of the New Inoculation! (1802), James Gillray caricatured recipients of the vaccine developing cow-like appendages.

After inoculation, vaccination using the cowpox virus became the primary defense against smallpox. After infection by the cowpox virus, the body (usually) gains the ability to recognize the similar smallpox virus from its antigens and is able to fight the smallpox disease much more efficiently.

The cowpox virus contains 186 thousand base pairs of DNA, which contains the information for about 187 genes. This makes cowpox one of the most complicated viruses known. Some 100 of these genes give instructions for key parts of the human immune system, giving a clue as to why the closely related smallpox is so lethal. [14] The vaccinia virus now used for smallpox vaccination is sufficiently different from the cowpox virus found in the wild as to be considered a separate virus. [15]

British Parliament

While the vaccination's popularity increased exponentially, so did its monetary value. This was realized by the British Parliament, which compensated Jenner 10,000 pounds for the vaccination. In addition, they later compensated Jenner an additional 20,000 pounds. In the coming years, Jenner continued advocacy for his vaccination over the still popular inoculation. Eventually, in 1840, the inoculation became banned in England and was replaced with the cowpox vaccination as the main medical solution to combat smallpox. The cowpox vaccination saved the British Army thousands of soldiers, by making them immune to the effects of smallpox in upcoming wars. The cowpox also saved the United Kingdom thousands of pounds. [16]

Kinepox

Kinepox is an alternative term for the smallpox vaccine used in early 19th-century America. Popularized by Jenner in the late 1790s, kinepox was a far safer method for inoculating people against smallpox than the previous method, variolation, which had a 3% fatality rate.

In a famous letter to Meriwether Lewis in 1803, Thomas Jefferson instructed the Lewis and Clark expedition to "carry with you some matter of the kine-pox; inform those of them with whom you may be, of its efficacy as a preservative from the smallpox; & encourage them in the use of it..." [17] Jefferson had developed an interest in protecting Native Americans from smallpox, having been aware of epidemics along the Missouri River during the previous century. A year before his special instructions to Lewis, Jefferson had persuaded a visiting delegation of North American Indian chieftains to be vaccinated with kinepox during the winter of 1801–1802. Unfortunately, Lewis never got the opportunity to use kinepox during the pair's expedition, as it had become inadvertently inactive—a common occurrence in a time before vaccines were stabilized with preservatives such as glycerol or kept at refrigeration temperatures.

Prevention

Today, the virus is found in Europe, mainly in the UK. Human cases are very rare (though in 2010 a laboratory worker contracted cowpox [18] ) and most often contracted from domestic cats. Human infections usually remain localized and self-limiting, but can become fatal in immunosuppressed patients. The virus is not commonly found in cattle; the reservoir hosts for the virus are woodland rodents, particularly voles. [19] Domestic cats contract the virus from these rodents. Symptoms in cats include lesions on the face, neck, forelimbs, and paws, and, less commonly, upper respiratory tract infections. Symptoms of infection with cowpox virus in humans are localized, pustular lesions generally found on the hands and limited to the site of introduction. The incubation period is 9 to 10 days. The virus is most prevalent in late summer and autumn.

Immunity to cowpox is gained when the smallpox vaccine is administered. Although the vaccine now uses vaccinia virus, the poxviruses are similar enough that the body becomes immune to both cow- and smallpox.

Related Research Articles

Edward Jenner English physician, scientist and pioneer of vaccination

Edward Jenner, FRS FRCPE was an English physician and scientist who was the pioneer of smallpox vaccine, the world's first vaccine. The terms "vaccine" and "vaccination" are derived from Variolae vaccinae, the term devised by Jenner to denote cowpox. He used it in 1796 in the long title of his Inquiry into the Variolae vaccinae known as the Cow Pox, in which he described the protective effect of cowpox against smallpox.

Vaccine biological preparatory medicine that improves immunity to a particular disease

A vaccine is a biological preparation that provides active acquired 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, its toxins, or one of its surface proteins. The agent stimulates the body's immune system to recognize the agent as a threat, destroy it, and to further recognize and destroy any of the microorganisms associated with that agent that it may encounter in the future. Vaccines can be prophylactic, or therapeutic.

Monkeypox viral disease

Monkeypox is an infectious disease caused by the monkeypox virus that can occur in certain animals including humans. Symptoms begin with fever, headache, muscle pains, swollen lymph nodes, and feeling tired. This is followed by a rash that forms blisters and crusts over. The time from exposure to onset of symptoms is around 10 days. The duration of symptoms is typically 2 to 5 weeks.

Eczema vaccinatum

Eczema vaccinatum is a rare severe adverse reaction to smallpox vaccination.

James Phipps English child given cowpox vaccine

James Phipps was the first person given the cowpox vaccine by Edward Jenner. Jenner knew of a local belief that dairy workers who had contracted a relatively mild infection called cowpox were immune to smallpox.

Artificial induction of immunity is the artificial induction of immunity to specific diseases – making people immune to disease by means other than waiting for them to catch the disease. The purpose is to reduce the risk of death and suffering.

Rabbitpox is a disease of rabbits caused by a virus of the genus Orthopoxvirus and the family Poxviridae. Rabbitpox was first isolated at the Rockefeller Institute in New York in 1933, following a series of epidemics in the laboratory rabbits. It is an acute disease only known to infect laboratory rabbits as no cases have been reported in wild rabbits; it also cannot infect humans.

The history of smallpox extends into pre-history, the disease likely emerged in human populations about 10,000 BC. The earliest credible evidence of smallpox is found in the Egyptian mummies of people who died some 3000 years ago. Smallpox has had a major impact on world history, not least because indigenous populations of regions where smallpox was non-native, such as the Americas and Australia, were rapidly decimated and weakened by smallpox during periods of initial foreign contact, which helped pave the way for conquest and colonization. During the 18th century the disease killed an estimated 400,000 Europeans each year, including five reigning monarchs, and was responsible for a third of all blindness. Between 20 and 60% of all those infected—and over 80% of infected children—died from the disease.

Variolation or inoculation was the method first used to immunize an individual against smallpox (Variola) with material taken from a patient or a recently variolated individual in the hope that a mild, but protective infection would result. The procedure was most commonly carried out by inserting/rubbing powdered smallpox scabs or fluid from pustules into superficial scratches made in the skin. The patient would develop pustules identical to those caused by naturally occurring smallpox, usually producing a less severe disease than naturally acquired smallpox. Eventually, after about two to four weeks, these symptoms would subside, indicating successful recovery and immunity. The method was first used in China and the Middle East before it was introduced into England and North America in the 1720s in the face of some opposition. The method is no longer used today. It was replaced by smallpox vaccine, a safer alternative. This in turn led to the development of the many vaccines now available against other diseases.

William Woodville English botanist

William Woodville (1752–1805) was an English physician and botanist.

Dr John Fewster (1738–1824) was a surgeon and apothecary in Thornbury, Gloucestershire. Fewster, a friend and professional colleague of Edward Jenner, played an important role in the discovery of the smallpox vaccine. In 1768 Fewster realized that prior infection with cowpox rendered a person immune to smallpox.

Vaccinia immune globulin (VIG) is made from the pooled blood of individuals who have been inoculated with the smallpox vaccine. The antibodies these individuals developed in response to the smallpox vaccine are removed and purified. This results in VIG. It can be administered intravenously. It is used to treat individuals who have developed progressive vaccinia after smallpox vaccination. It was also used along with cidofovirinfor the 2003 Midwest monkeypox outbreak as concomitant therapy to reduce the serious side effects of smallpox vaccine.

The terms inoculation, vaccination, and immunization are often used synonymously to refer to artificial induction of immunity against various infectious diseases. However, there are some important historical and current differences. In English medicine, inoculation referred only to the practice of variolation until the very early 1800s. When Edward Jenner introduced smallpox vaccine in 1798, this was initially called cowpox inoculation or vaccine inoculation. Soon, to avoid confusion, smallpox inoculation continued to be referred to as variolation and cowpox inoculation was referred to as vaccination. Then, in 1891, Louis Pasteur proposed that the terms vaccine and vaccination should be extended to include the new protective procedures being developed. Immunization refers to the use of all vaccines but also extends to the use of antitoxin, which contains preformed antibody such as to diphtheria or tetanus exotoxins. Inoculation is now more or less synonymous in nontechnical usage with injection and the like, and questions along the lines of "Have you had your flu injection/vaccination/inoculation/immunization?" should not cause confusion. The focus is on what is being given and why, not the literal meaning of the technique used.

References

  1. Pelkonen PM, Tarvainen K, Hynninen A, Kallio ER, Henttonen K, Palva A, Vaheri A, Vapalahti O (November 2003). "Cowpox with severe generalized eruption, Finland". Emerging Infectious Diseases. 9 (11): 1458–61. doi:10.3201/eid0911.020814. PMC   3035531 . PMID   14718092.
  2. 1 2 Vanessa Ngan, "Viral and Skin Infections", 2009
  3. "What's The Real Story About The Milkmaid And The Smallpox Vaccine?". NPR.org. Retrieved 2018-02-02.
  4. 1 2 Thomas Cooper Library, University of South Carolina: "Edward Jenner and the Discovery of Vaccination", exhibition, 1996
  5. 1 2 Abbas K (2003). Cellular and Molecular Immunology (Fifth ed.). Philadelphia: Saunders. ISBN   978-0-7216-0008-6.
  6. Willrich M (2011). Pox. New York: Penguin Books.
  7. Chomel BB (July 2014). "Emerging and Re-Emerging Zoonoses of Dogs and Cats". Animals. 4 (3): 434–45. doi:10.3390/ani4030434. PMC   4494318 . PMID   26480316.
  8. Mansell JK, Rees CA (2005). "Cutaneous manifestations of viral disease". In August, John R. Consultations in Feline Internal Medicine Vol. 5. Elsevier Saunders. ISBN   978-0-7216-0423-7.
  9. Plett PC (2006). "[Peter Plett and other discoverers of cowpox vaccination before Edward Jenner]". Sudhoffs Archiv (in German). 90 (2): 219–32. PMID   17338405.
  10. Tucker JB (2001). Scourge: The Once and Future Threat of Smallpox. New York: Atlantic Monthly Press. p. 31. ISBN   978-0-87113-830-9.
  11. Noyce RS, Lederman S, Evans DH (2018-01-19). Thiel V, ed. "Construction of an infectious horsepox virus vaccine from chemically synthesized DNA fragments". PLOS One. 13 (1): e0188453. Bibcode:2018PLoSO..1388453N. doi:10.1371/journal.pone.0188453. PMC   5774680 . PMID   29351298.
  12. Science and the practice of medicine in the nineteenth century. Cambridge.
  13. Lindemann M. Medicine and Society in Early Modern Europe.
  14. Moore P (2001). Killer Germs: Rogue Diseases of the Twenty-First Century. London: Carlton. ISBN   978-1-84222-150-1.
  15. Yuan, Jenifer The Small Pox Story
  16. Riedel S (January 2005). "Edward Jenner and the history of smallpox and vaccination". Proceedings. 18 (1): 21–5. doi:10.1080/08998280.2005.11928028. PMC   1200696 . PMID   16200144.
  17. "Jefferson's Instructions to Lewis and Clark (1803)". Archived from the original on 2007-08-07. Retrieved 2007-08-10.
  18. "Cowpox infection in US lab worker called a first".
  19. Kurth A, Wibbelt G, Gerber HP, Petschaelis A, Pauli G, Nitsche A (April 2008). "Rat-to-elephant-to-human transmission of cowpox virus". Emerging Infectious Diseases. 14 (4): 670–1. doi:10.3201/eid1404.070817. PMC   2570944 . PMID   18394293.

Sources

Classification
D