artificial induction of immunity

{{Main|Variolation|Smallpox}}

The earliest recorded artificial induction of immunity in humans was by variolation or inoculation, which is the controlled infection of a subject with a less lethal natural form of smallpox (known as Variola Minor) to make him or her immune to re-infection with the more lethal natural form, Variola Major. This was practiced in ancient times in China and India, and imported into Europe, via Turkey, around 1720 by Lady Montagu and perhaps others. From England, the technique spread rapidly to the Colonies, and was also spread by African slaves arriving into Boston.{{cite web |publisher=National Institutes of Health |work=Smallpox – A Great and Terrible Scourge |url=https://www.nlm.nih.gov/exhibition/smallpox/sp_variolation.html |title=Variolation |access-date=21 March 2018 |archive-date=2 May 2019 |archive-url=https://web.archive.org/web/20190502065059/https://www.nlm.nih.gov/exhibition/smallpox/sp_variolation.html |url-status=live }}{{cite book |first=Andrew Dickson |last=White |title=A History of the Warfare of Science with Theology |chapter=Theological Opposition to Inoculation, Vaccination and the use of Anaesthetics |location=New York |publisher=D. Appleton and Company |year=1898 |chapter-url=http://abob.libs.uga.edu/bobk/whitem10.html |access-date=13 March 2006 |archive-date=17 September 2008 |archive-url=https://web.archive.org/web/20080917184044/http://abob.libs.uga.edu/bobk/whitem10.html |url-status=dead }}

Variolation had the disadvantage that the inoculating agent used was still an active form of smallpox and, although less potent, could still kill the inoculee or spread in its full form to others nearby. However, as the risk of death from inoculation with Variola Minor was just 1% to 2%, as compared to the 20% risk of death from the natural form of smallpox, the risks of inoculation were generally considered acceptable.{{cite journal |doi=10.1258/jrsm.2008.08k008 |title=Zabdiel Boylston's evaluation of inoculation against smallpox |year=2008 |last1=Boylston |first1=A. |last2=Williams |first2=A. |journal=Journal of the Royal Society of Medicine |volume=101 |issue=9 |pages=476–7|pmc=2587382 |pmid=18779251}}Lettres Philosophiques. Voltaire.In fact, the mortality rate of the Varoiola Minor form of smallpox then found in Europe was 1–3% as opposed to 30–50% for the Variola Major type found elsewhere; however, blindness, infertility, and severe scarring were common. Figures from "The Search for Immunisation", In Our Time, BBC Radio 4 (2006).Letter of Lady Montagu reproduced at {{cite web|url=http://www.foundersofscience.net/lady_mary_montagu.htm |title=Letter of Lady Mary Montagu|access-date=2013-04-18 |url-status=dead |archive-url=https://web.archive.org/web/20040102183753/http://www.foundersofscience.net/lady_mary_montagu.htm |archive-date=2 January 2004 }} viewed 18 March 2006{{cite journal |doi=10.1136/bmj.325.7361.430 |title=Anti-vaccinationists past and present |year=2002 |last1=Wolfe |first1=R. M |journal=BMJ |volume=325 |issue=7361 |pages=430–32 |pmid=12193361 |last2=Sharp |first2=LK |pmc=1123944}}

{{Main|Smallpox vaccine|Edward Jenner}}

In 1796, Edward Jenner FRS, a doctor and scientist who had practiced variolation, performed an experiment based on the folk-knowledge that infection with cowpox, a disease with minor symptoms which was never fatal, also conferred immunity to smallpox.Harris F "Edward Jenner and Vaccination" World Wide School [http://www.worldwideschool.org/library/books/tech/medicine/EdwardJennerAndVaccination/chap1.html Full text] {{Webarchive|url=https://web.archive.org/web/20010708050608/http://www.worldwideschool.org/library/books/tech/medicine/EdwardJennerAndVaccination/Chap1.html |date=8 July 2001 }} The idea was not new; it had been demonstrated some years earlier by Benjamin Jesty, who had not publicized his discovery.{{cite journal|last=Pead|first=Patrick P.|title=Benjamin Jesty; new light in the dawn of vaccination|journal=Lancet|year=2003|volume=362|issue=9401|pages=2104–09|pmid=14697816|doi=10.1016/s0140-6736(03)15111-2|s2cid=4254402}} In 1798, Jenner extended his observations by showing that cowpox could be passed from a lesion on one patient to others through four arm to arm transfers and that the last in the series was immune by exposing him to smallpox. Jenner described the procedure, distributed his vaccine freely, and provided information to help those hoping to establish their own vaccines. In 1798 he published his information in his famous Inquiry into the Causes and Effects...of the Cow Pox. He is credited with being the first to start detailed investigations of the subject and of bringing it to the attention of the medical profession.{{cite journal|last=Baxby|first=Derrick|author-link = Derrick Baxby|title=Edward Jenner's Inquiry; a bicentenary analysis|journal=Vaccine|year=1999|volume=17|issue=4|pages=302–07|pmid=9987167|doi=10.1016/s0264-410x(98)00207-2}} Despite some opposition vaccination took over from variolation.

Jenner, like all members of the Royal Society in those days, was an empiricist.{{cite journal |doi=10.1016/j.revmed.2006.09.024 |title=Histoire de la vaccination: De l'empirisme aux vaccins recombinants |trans-title=History of vaccination: from empiricism towards recombinant vaccines |language=fr |year=2007 |last1=Guérin |first1=N. |journal=La Revue de Médecine Interne |volume=28 |issue=1 |pages=3–8 |pmid=17092612}}Vaccines – a Biography edited by Andrew W. Artenstein {{ISBN|978-1-4419-1107-0}}{{page needed|date=April 2013}}{{cite web |url=http://sydney.edu.au/science/hps/empiricism/ |title=Empiricism and the Life Sciences in Early Modern Thought |last1=Gal |first1=O. |last2=Wolfe |first2=C. |publisher=The University of Sydney |access-date=18 April 2013 |archive-date=2 January 2023 |archive-url=https://web.archive.org/web/20230102004227/https://www.sydney.edu.au/science/schools/school-of-history-and-philosophy-of-science.html |url-status=live }} The theory to support further advances in vaccination came later.

Main articles: Pasteur Louis Pasteur; Germ Theory: Germ theory of disease

In the second half of the 1800s Louis Pasteur perfected experiments which disproved the then-popular theory of spontaneous generation and from which he derived the modern theory of (infectious) disease. Using experiments based on this theory, which posited that specific microorganisms cause specific diseases, Pasteur isolated the infectious agent from anthrax. He then derived a vaccine by altering the infectious agent so as to make it harmless and then introducing this inactivated form of the infectious agents into farm animals, which then proved to be immune to the disease.{{Cite book |last=Smith |first=Alice Lorraine |url=https://books.google.com/books?id=5NRpAAAAMAAJ |title=Principles of Microbiology |date=1985 |publisher=Times Mirror/Mosby College Pub. |isbn=978-0-8016-4685-0 |language=en |access-date=10 October 2016 |archive-date=14 January 2023 |archive-url=https://web.archive.org/web/20230114130555/https://books.google.com/books?id=5NRpAAAAMAAJ |url-status=live }}

Pasteur also isolated a crude preparation of the infectious agent for rabies. In a brave piece of rapid medicine development, he probably saved the life of a person who had been bitten by a clearly rabid dog by performing the same inactivating process upon his rabies preparation and then inoculating the patient with it. The patient, who was expected to die, lived, and thus was the first person successfully vaccinated against rabies.René Dubos, Louis Pasteur: Freelance of Science, Little, Brown and Company, 1950.{{ISBN?}}{{page needed|date=July 2021}}

Anthrax is now known to be caused by a bacterium, and rabies is known to be caused by a virus. The microscopes of the time could reasonably be expected to show bacteria, but imaging of viruses had to wait until the development of electron microscopes with their greater resolving power in the 20th century.

{{Main|Toxoid}}

Some diseases, such as tetanus, cause disease not by bacterial growth but by bacterial production of a toxin. Tetanus toxin is so lethal that humans cannot develop immunity to a natural infection, as the amount of toxin and time required to kill a person is much less than is required by the immune system to recognize the toxin and produce antibodies against it.{{cite web|title=Pathogenic Clostridia, including Botulism and Tetanus (page 3)|url=http://textbookofbacteriology.net/clostridia_3.html|publisher=Todar's Online Textbook of Bacteriology|access-date=21 March 2010|archive-date=15 May 2021|archive-url=https://web.archive.org/web/20210515060205/http://textbookofbacteriology.net/clostridia_3.html|url-status=live}} However the tetanus toxin is easily denatured losing its ability to produce disease, but leaving it able to induce immunity to tetanus when injected into subjects. The denatured toxin is called a toxoid.{{cite book|title=Essential Immunology 3rd Edition|last1=Roitt|first1=I.M.|year=1977|publisher=Blackwell Scientific Publications|isbn=063200276X|url=https://archive.org/details/essentialimmunole3roit}} {{page needed|date=April 2013}}

{{Main|Adjuvant}}

The use of simple molecules such as toxoids for immunization tends to produce a low response by the immune system, and thus poor immune memory. However, adding certain substances to the mixture, for example adsorbing tetanus toxoid onto alum, greatly enhances the immune response (see Roitt etc. below). These substances are known as adjuvants. Several different adjuvants have been used in vaccine preparation. Adjuvants are also used in other ways in researching the immune system.{{cite web|url=http://www.nal.usda.gov/awic/pubs/antibody/overview.htm |title=Overview |access-date=2013-04-18 |url-status=dead |archive-url=https://web.archive.org/web/20130713005218/http://www.nal.usda.gov/awic/pubs/antibody/overview.htm |archive-date=13 July 2013 }}{{full citation needed|date=April 2013}}

A more contemporary approach for "boosting" the immune response to simpler immunogenic molecules (known as antigens) is to conjugate the antigens. Conjugation is the attachment to the antigen of another substance which also generates an immune response, thus amplifying the overall response and causing a more robust immune memory to the antigen. For example, a toxoid might be attached to a polysaccharide from the capsule of the bacteria responsible for most lobar pneumonia.{{cite web |title=Full Prescribing Information - Pneumovax 23 |date=April 2021 |publisher=Merck Sharp & Dohme Corp |url=http://www.merck.com/product/usa/pi_circulars/p/pneumovax_23/pneumovax_pi.pdf}} {{Webarchive|url=https://web.archive.org/web/20230102004250/https://www.merck.com/product/usa/pi_circulars/p/pneumovax_23/pneumovax_pi.pdf |date=2 January 2023 }}{{cite report|last1=Nuorti|first1=J.P.|last2=Whitney|first2=C.G.|date=10 December 2010|title=Prevention of Pneumococcal Disease Among Infants and Children – Use of 13-Valent Pneumococcal Conjugate Vaccine and 23-Valent Pneumococcal Polysaccharide Vaccine|url=https://www.cdc.gov/mmwr/preview/mmwrhtml/rr5911a1.htm?s_cid=rr5911a1_e|publisher=Centers for Disease Control and Prevention (CDC)}}

{{Main|Immunoglobulin}}

File:Platypus.jpg lack placental transfer of immunity]]

Temporary immunity to a specific infection can be induced in a subject by providing the subject with externally produced immune molecules, known as antibodies or immunoglobulins. This was first performed (and is still sometimes performed) by taking blood from a subject who is already immune, isolating the fraction of the blood which contains antibodies (known as the serum), and injecting this serum into the person for whom immunity is desired. This is known as passive immunity, and the serum that is isolated from one subject and injected into another is sometimes called antiserum. Antiserum from other mammals, notably horses, has been used in humans with generally good and often life-saving results, but there is some risk of anaphylactic shock and even death from this procedure because the human body sometimes recognizes antibodies from other animals as foreign proteins.

Passive immunity is temporary, because the antibodies which are transferred have a lifespan of only about 3–6 months. Every placental mammal (which includes humans) has experienced temporarily induced immunity by transfer of homologous antibodies from its mother across the placenta, giving it passive immunity to whatever its mother became immune to.Ehrlich, P. (1892) Ueber Immunitaet durch Vererbung und Saeugung. Z. Hyg. Infect. Kr. 12, 183.{{cite journal |pmid=7438556 |year=1980 |last1=Pitcher-Wilmott |first1=RW |last2=Hindocha |first2=P |last3=Wood |first3=CB |title=The placental transfer of IgG subclasses in human pregnancy |volume=41 |issue=2 |pages=303–08 |pmc=1537014 |journal=Clinical and Experimental Immunology}} This allows some protection for the young while its own immune system is developing.

Synthetic (recombinant or cell-clone) human immunoglobulins can now be made, and for several reasons (including the risk of prion contamination of biological materials) are likely to be used more and more often. However, they are expensive to produce and are not in large-scale production as of 2013.{{Cite web |url=http://www.antibodyengineering.co.uk/?gclid=CN2ZxfLFz7YCFWbKtAod-TAADQ |title=Engineers of small-scale humanised antibody production. Prices on application. |access-date=16 April 2013 |archive-date=10 March 2016 |archive-url=https://web.archive.org/web/20160310213105/http://www.antibodyengineering.co.uk/?gclid=cn2zxflfz7ycfwbktaod-taadq |url-status=dead }} In the future it might be possible to artificially design antibodies to fit specific antigens, then produce them in large quantities to induce temporary immunity in people in advance of exposure to a specific pathogen, such as a bacterium, a virus, or a prion. At present, the science to understand this process is available but not the technology to perform it.Immunisation article in Ganfyd, the online collaborative textbook of medicine. http://www.ganfyd.org/index.php?title=Artificial_induction_of_immunity

• Herd immunity
• Pox party
• Coronavirus party

{{Reflist}}

• Pier GB, Lyczak JB, and Wetzler LM. (2004). Immunology, Infection, and Immunity. ASM Press. {{ISBN|1-55581-246-5}}
• {{usurped|1=[https://web.archive.org/web/20110722110047/http://www.ganfyd.org/index.php?title=Category:Therapeutic_antibody Therapeutic antibodies]}} Ganfyd on-line collaborative medical textbook.

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Category:History of immunology