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Core Module Immunology Doctoral Training Group GK1660 Erlangen • 2015 History of Immunology Hans-Martin Jäck Division of Molecular Immunology Dept. Of Internal Medicine III Nikolaus-Fiebiger-Center University of Erlangen-Nürnberg Ludwik Fleck 1979 It is difficult, if not impossible, to give an accurate historical account of a scientifc discipline TIMELINE - History of Immunology 1860 Pasteur 1650 1663 Leeuwenhook 1876 Koch 1800 Ehrlich 1900 B&T cells 1965 1900 2000 Cells & Germs 1796 Jenner Vaccination Behring 1890 Immunochemistry (Antibody problem) Landsteiner 1940 AK Structure 1965 Cellular Revolution Tonegawa 1976 B/T Cooperation 1985 Molecular Revolution 3 TIMELINE - History of Immunology § Discovery of cells and germs (1683 - 1884) § Prevention of Infection (1796 – today) § Start of Immunology (1890 - 1910) § Immunochemistry - The antibody problem (1910 – 1965) § Cellular revolution - B/T collaboration (1940 – 1985) § Molecular revolution - genes and molecules (1976 – today) § Translational and systems immunology ?? (2016 - ???) Doctoral Training Group GK1660 - University of Erlangen-Nürnberg 4 TIMELINE - Development of Ideas Aims Peroids Pioneers Notions Applications Phagocytosis 1870-1890 Pasture & Metchnikoff Immunization & Description Receptors 1890-1910 Behring & Ehrlich Antibodies & Cell 1910-1930 Bordet & Landsteiner 1930-1950 1950-1970 Subcellular Cellular Specificity & Haptens Mechanisms Systemic Analysis 1970-1983 Modern Immunol. 1983-present Multicellular Immune regulation Post-TCR Era Doctoral Training Group GK1660 - University of Erlangen-Nürnberg Ab synthesis & Ag temp. Clonal selection Network Cooperation Molecular Mechanisms 5 TOPICS I. The Scientific Method II. Discovery of Cells & Germs III. Prevention of infections IV. Immunochemistry V. Cellular revolution: B and T cells VI. Molecular revolution: Genes and molecules VII. Immunotherapies Doctoral Training Group GK1660 - University of Erlangen-Nürnberg 6 Core Module Immunology Doctoral Training Group GK1660 Erlangen • 2015 History of Immunology Part 2: Discovery of Cells & Germs Hans-Martin Jäck Division of Molecular Immunology Dept. Of Internal Medicine III Nikolaus-Fiebiger-Center University of Erlangen-Nürnberg MINDMAP Development of the techniques • Microscope (Leeuwenhoek) • Culture techniques (Koch) Cell theory versus Spontaneous generation Germ theory versus Miasma • Schwann, Redi, Pasteur, • Pasteur, Snow, Koch • External Desinfection • Semmelweiss, Lister Methods to treat them Discovery of the immune system • Internal desinfektion • Penicillin, Sulfonamides • Vaccination • Antibodies • Cells • Genes & Molecules 8 DISCOVERY OF CELLS Discovery of Cells - The „Cell“ (Hooke, 1663) § Discovered small compartments (lat. cellula) with a primitive microscope in a piece of cork § Actually, he only observed cell walls because cork cells are dead § Hooke drew the cells he saw and also coined the word CELL. § Hooke published his findings in his famous work, Micrographia: Physiological Descriptions of Minute Bodies made by Magnifying Glasses (1665). http://www.biblio.tu-bs.de/ausstellungen/natur.html Drawing of the structure of cork by Robert Hooke that appeared in Micrographia http://www.bio.miami.edu/~cmallery/150/unity/cell.text.htm#figure1 Doctoral Training Group GK1660 - University of Erlangen-Nürnberg 10 Discovery of Cells - Leeuwenhoek‘s microscope 1674 Linse Probe Fokussierschraube Fig.3 gives an exploded view of a van Leeuwenhoek microscope. It consists of the upper body-plate (1), the lower body-plate (2), the bracket screw (3), the square bent main bracket (4), the main screw (5), the stage (6), the specimen pin (7), the focussing screw (8), the lens (9) and five rivets 1,5 x 2 mm (10). http://www.microscopy-uk.org.uk/mag/indexmag.html?http://www.microscopy-uk.org.uk/mag/artjul07/hl-loncke2.html Doctoral Training Group GK1660 - University of Erlangen-Nürnberg 11 Cells - Visualization of live small organisms (1676) 1676 Leeuwenhoek was the first man to witness a live cell under a microscope in rain water (protozoa). He named them animalcules ("little animals“). 1683 Leeuwenhoek described in letter to the Royal Society very likely bacteria (types of animalcules) in the saliva and tooth scrapings from his mouth. 1719 Red blood cells from animals and man Antoni van Leeuwenhoek Delft, Holland 24. Oktober 1632 Delft, Holland † 27. August 1723 12 Rote Blutkörperchen des Lachses mit Zellkernen, gezeichnet von Leeuwenhoek, 1719. http://de.wikipedia.org/wiki/ Zellkern#Geschichte The left panel shows a replica of a Leeuwenhoek microscope . The photomicrographs in the center and right were taken in the early 20th century through one of Leeuwenhoek's microscope. (Source: The Leeuwenhoek Letter. Society of American Bacteriologists. Baltimore. 1937.) Doctoral Training Group GK1660 - University of Erlangen-Nürnberg 13 Cells - Improvement of the miscrocope 1773 Otto Müller (Denmark) describes different forms of bacteria with an improved microscope 14 Cells - Improvement of the miscrocope 1773 Otto Müller (Denmark) describes different forms of bacteria with an improved microscope 1820 Ernst Abbe together with Carl Zeiss and Otto Schott in Jena solve the problem of chromatic abberation 15 Cell Theory – Discoveries 1827 Brown observes agitation of suspended particles → Brownian Movement 1833 Robert Brown discovered "an opaque spot in the epidermis, the parenchyma or internal cells of orchids and in many other cells," which he named the nucleus. The same "spot" had been seen often enough before by other observers, but Brown was the first to recognize it as a component part of the vegetable cell and to give it a name. 1838 Christian Gottfried Ehrenberg introduced the name bacterium (lt. bacterium = rod, stick) 1838/9 Schwann und Leyden proposed cell theory http://www.bio.miami.edu/~cmallery/150/unity/cell.text.htm Doctoral Training Group GK1660 - University of Erlangen-Nürnberg 16 Discovery of Cells - Cell Theory (1838) § Proposal of Cell Theory (1838, Theodor Schwann) Microscopic Investigations on the Accordance in the Structure and Growth of Plants and Animals (published without Schleiden) Theodor Schwann Neuss, Germany 7 December 1810, † 11 January 1882 1. The cell is the unit of structure in all living things. 2. The cell retains a dual existence as a distinct entity and a building block in the construction of organisms. 3. Cells form by free-cell formation, similar to the formation of crystals (spontaneous generation). Note: The first two tenets are correct, but the third is wrong. § Rudolph Virchow's powerful dictum "Omnis cellula e cellula“ (all cells arise form pre-existing cells) corrected this point. § Cell Theory is to Biology as Atomic Theory is to Physics. 17 ORIGIN OF CELLS Spontaneous Generation? Living Cells from decayed organic matter (Verfaultes, Verwesenes) or Biogenesis Omnis cellula e cellula? Generation of Life (Cells) – Hypotheses § Life by Spontaneous Generation o Spontaneous generation is the hypothesis that some vital force contained in organic matter can create living cells from decayed organic matter (Verfaultes, Verwesenes) o Spontaneous generation was very popular throughout the middle ages and into the latter half of the 19th century. o The idea was attractive because this vital force was considered a strong proof of God's presence in the world. o Disproved by Pasteur’s famous swan neck-flask experiment (1859) § Biogenesis Theory http://www.microbiologytext.com http://www.brighthub.com/science/genetics/articles/21169.aspx o Living matter arises only from living matter (Virchow 1858) Doctoral Training Group GK1660 - University of Erlangen-Nürnberg 19 Spontanous Generation – Disprove 1 Francesco Redi 1626 - 1697 Doctoral Training Group GK1660 - University of Erlangen-Nürnberg 20 Spontanous Generation – Redi 1668 Exp 1 Rotten mead Exp 2 Rotten mead Exp 3 Observation o Maggots (dt., Maden) grow on air-exposed meat Hypothesis o Maggots develop from fly eggs and not from rotten meat by spontanous generation Rotten mead Rotten mead Experiment 3 § A third piece of meat was overlaid with cheesecloth (Leintuch) § Flies were able to lay the eggs into the cheesecloth, and when this was removed, no maggots developed § However, if the cheesecloth containing the eggs was placed on a fresh piece of meat, maggots developed Conclusion: Eggs "caused" maggots and not spontaneous generation http://www.microbiologytext.com 21 John Needham revives Spontanous Generation Theory for small microbes (1745/48) Ø Experiment: - Killed all living matters in broth by heating - Cooled flask and let it sit at a constant temperature Ø Result: - Thick turbid solution of microorganisms developed Ø Conclusion: - Existence of spontaneous generation. http://www.microbiologytext.com http://eglobalmed.com/core/VirtualMicrobiology/www.bact.wisc.edu/ Microtextbook/index8504.html? module=Book&func=displayarticle&art_id=27 Spontanous Generation – Pro 22 Spontanous Generation – Dispove 2 Ø Experiment: Repeated Nedham expt., but prevented air from flowing into the flask, since he suspected that the air was providing a source of contamination. Flask is covered →no air enters Ø Result: No growth occurred in Spallanzani's flasks Ø Conclusion: Needham was wrong. Ø Counter: Air was required for the “vital” force to work. Doctoral Training Group GK1660 - University of Erlangen-Nürnberg http://eglobalmed.com/core/VirtualMicrobiology/www.bact.wisc.edu/ Microtextbook/index8504.html? module=Book&func=displayarticle&art_id=27 Lazzaro Spallanzani disproves Nedham (1786) 23 Spontanous Generation – Contra Ø Experiment: Repeated Nedham expt., but prevented air from flowing into the flask, since he suspected that the air was providing a source of contamination. Ø Result: No growth occurred in Spallanzani's flasks Ø Conclusion: Needham was wrong. Ø Counter: Air was required for the “vital” force to work. Flask is covered →no air enters Doctoral Training Group GK1660 - University of Erlangen-Nürnberg http://eglobalmed.com/core/VirtualMicrobiology/www.bact.wisc.edu/ Microtextbook/index8504.html? module=Book&func=displayarticle&art_id=27 Lazzaro Spallanzani disproves Nedham (1786) 24 Pasteur once said, “There are no such things as pure and applied science; there are only science and the application of science.” Doctoral Training Group GK1660 - University of Erlangen-Nürnberg 25 Spontanous Generation – The Disprove 3 Pasteur’s Swan Neck Experiment (1859/60) Louis Pasteur 1822-1895 • Pasteur filled a flask with medium and heated it to kill all life • He drew out the neck of the flask into a long S shape. → Prevented microorganisms in the air from easily entering the flask, yet allowed some air interchange. • If the swan neck was broken or tilted, microbes entered the flask and grew http://www.microbiologytext.com Doctoral Training Group GK1660 - University of Erlangen-Nürnberg 26 Development of a theory by the scientific method Observation: Broth spoils when it is left out for a couple of days. Why? Hypothesis: Airborne organisms must fall into the broth and grow. Prediction: If one boils (and kills germs) and covers broth, it will not spoil. Experiment: Boil broth, divide it into two containers, leave one covered and one uncovered for two days and see if one spoils. Result: Only the uncovered broth spoiled. REPEAT experiment Publication: Conclusion: "Only broth that is exposed to the air after two days spoiled. The covered specimen did not." Verification: Other scientists get the same results every time. Theory: “Microorganisms from the air cause broth to spoil”. Doctoral Training Group GK1660 - University of Erlangen-Nürnberg 27 Spontanous Generation - Summary 1668 • Francesco Redi disproves spontaneous generation for large organisms (magots) 1786 • Lazzaro Spallanzani disproves Nedham for bacteria 1859 • Louis Pasteur's swan-neck flasks show that spontaneous generation does not occur. 1870 • Thomas H. Huxley supports Pasteur's claim to have experimentally disproved spontaneous generation. Doctoral Training Group GK1660 - University of Erlangen-Nürnberg 28 Summary - Timeline of Cell Theory 1655 • Hooke described small compartments (alt. cellula) in cork and named them cells 1674 • Leeuwenhoek saw the frist living organism (Einzeller – Protozoa), and 9 years later very likely bacteria. 1831/33 • Brown descibed the cell nucleus in cells of the orchid. 1838 • Christian Gottfried Ehrenberg introduced the name bacterium 1839 • Schwann und Leyden proposed cell theory 1857 • Kolliker described mitochondria. 1858 • Rudolf Virchow publishes his famous conclusion: omnis cellula e cellula [alle Zellen aus einer Zelle] Doctoral Training Group GK1660 - University of Erlangen-Nürnberg 29 Classification of Microorganisms (1872) § He used the microscope to carefully examine the world of the microbe and made many observations § Introduced the term “bacillus” as a pre-fix for microorganisms Ferdinand Cohn Breslau, Germany 24 January 1828 † 25 June 1898 § His landmark paper on the cycling of elements in nature was published in Ueber Bakterien in 1872 § In 1875, Cohn publish an early classification scheme including descriptions of Bacillus in the first volume of a journal he founded, Beitraege zur Biologie der Planzen. Doctoral Training Group GK1660 - University of Erlangen-Nürnberg 30 Development of culture conditions 1872 Oscar Brefeld growths fungal colonies from single spores on gelatin 1877 Robert Koch develops methods for staining bacteria, photographing, and preparing permanent visual records on slides. 1881 Koch develops solid culture media and the methods for obtaining pure cultures of bacteria. 1882 Angelina Fannie and Walther Hesse in Koch's laboratory develop the use of agar as a support medium for solid culture. 1884 Hans Christian Gram develops a dye system for identifying bacteria [the Gram stain]. 1887 First report of the petri plate by Julius R. Petri. Doctoral Training Group GK1660 - University of Erlangen-Nürnberg 31 Birth of Microbiology § Microbiology could be defined as the study of organisms too small to be seen with the naked eye. § However, the recent discovery of near 1 mm in size has made this definition somewhat inaccurate http://www.microbiologytext.com Doctoral Training Group GK1660 - University of Erlangen-Nürnberg 32 MICROBES ARE DISCOVERED TO CAUSE DISEASE Miasma Theory versus Germ Theory Miasma Theory versus Germ Theory Miasma theory o Diseases caused by a miasma (Gr.: "pollution"), a noxious form of "bad air“, poisonous vapor, or foul smell o In the 1850s, miasma was used to explain the spread of cholera in London and in Paris o Because predominance of the miasmatic theory among Italian scientists, the 1854 discovery by Filippo Pacini of the cholera bacillus was completely ignored (rediscovered by Robert Koch, today „Vibrio cholerae Pacini) Germ theory (Pasteur 1859) This microscope slide, prepared by Pacini in 1854, was clearly identified as containing the cholera bacillus. o Louis Pasteur, while working on sour wine and beer (which saved the French bread, beer and wine production) discovered that unwanted microbes infected the wine. o Microorganisms cause disease 34 Germ Theory versus Miasma Theory Proponents o Dr. William Farr, commissioner for the 1851 London census, believed that cholera was transmitted by air, and that there was a deadly concentration of miasmata near the River Thames' banks. o Crimean War nurse Florence Nightingale (1820–1910) who became famous for her work in making hospitals sanitary and fresh-smelling. Consequences o Helped make the connection between poor sanitation and disease. Hand-washing o Improvements in the sanitation systems Doctoral Training Group GK1660 - University of Erlangen-Nürnberg 35 Germ Theory – The Beginning Theodor Schwann 1810-1882 1837 Schwann showed that something airborne causes putrification and can be killed by heat. He excluded air. Fillipo Pacini 1854 Filippo Pacini discovered cholera bacillus (was completely ignored because of miasmatic view if Italian science. Louis Pasteur 1822-1895 1863 Pasteur showed that the Schwann‘s „something“ airborne are microorganisms that can be killed by heat → Germ Theory of Disease 36 Miasma Theory - Disproven for Cholera (1954) (Drawn by Dr John Snow about 1854; shown in Stamp, L. D. 1964, A Geography of Life and Death.). • In 1854 John Snow dispoved the miasmatic theory for cholera by following an epidemic in Soho, central London • He showed that a water pump in Broad Street was the source for the spread of cholera (he removed the handle and the epidemic stopped) • Cholera is not spread by “bad air” but rather by contaminated water Start of Epidemilogy http://en.wikipedia.org/wiki/Broad_Street_cholera_outbreak 37 Side Visit - Epidemilogy § Epidemiology is the science that studies the patterns, causes, and effects of health and disease conditions in defined populations. § It is the cornerstone of public health, and it identifies risk factors for disease and targets for preventive healthcare. http://en.wikipedia.org/wiki/Epidemiology Doctoral Training Group GK1660 - University of Erlangen-Nürnberg 38 Pasteur’s Germ Hypothesis 39 § The problem (1856) o Industry ask Pasteur to find out why wine could become sour § His hypothesis o A growing, living organism (germ) caused the problem § His findings (1857/58) o Conversion of sugar into alcohol is caused by yeast 1822-1895 France o Conversion into lactic acid is cause by a bacterial contamination § His solution to fight the disease of wine o Briefly heat (60-100oC) the liquid to kill the germs o Applied to milk, beer, wine, vinegar ► Pasteurisation o Savior of the French wine and beer industry 39 Pasteur: Linking Germs to Disease 40 § “If wine and beer are changed by germs, then the same can and must happen sometimes in men and animals” ► 1859 - Diseases can be caused by GERMS § French Silk Industry (1865) o Asked Pasteur to investigate why their silkworms die. o He discovered that a certain germ was responsible for Division of Molecular Immunology, Universitätsklinikum Erlangen 40 Germ Theory - Final Test by R. Koch (1876) 1843-1910 41 1876 Robert Koch isolates the first disease-causing pathogen (anthrax) and provides definitive proof of the germ theory 1882 Koch isolates tubercle bacillus 1884 Henle/Koch Postulates, a set of rules for the assignment of a microbe as the cause of a disease: Robert Koch Nobel price 1905 1. The agent must be present in every case of the disease. 2. The agent must be isolated and cultured in vitro. 3. The disease must be reproduced when a pure culture of the agent is inoculated into a susceptible host. 4. The agent must be recoverable from the experimentally-infected host. 41 Germ Theory § He developed the concepts of contagium vivum and contagium animatum, respectively (von den Miasmen und Kontagien , 1840) § Co-founded the theory of microorganisms as the cause of infective diseases Henle, Friedrich Fürth, Germany 19.07.1809 Göttingen, Germany 13.05.1885 § He did not find a special species of bacteria himself - this was achieved by his student Robert Koch. § The Henle-Koch postulates. Fundamental rules of cleanly defining disease-causing microbes: Doctoral Training Group GK1660 - University of Erlangen-Nürnberg 42 Discovery of Viruses - Timeline Dmitri Iwanowski (1864-1920) • Dmitri Iwanowski, a Russian botanist, reported in 1892, that extracts from diseased tobacco plants could transmit disease to other plants after passage through ceramic filters fine enough to retain the smallest known bacteria. • This is generally recognized as the beginning of Virology. • Attributed his findings to cracked filter and believed he still dealt with bacteria • In 1898, Martinus Beijerinick extended Iwanowski's results on tobacco mosaic disease Martinus Beijerinick (1851-1931) • Was the first to develop the modern idea of a pathogen different from typical bacteria, which he referred to as contagium vivum fluidum ('soluble living germ') • However, he thougt the new agent is rather an infectious liquid not a corpuscle Doctoral Training Group GK1660 - University of Erlangen-Nürnberg 43 Discovery of Viruses - Timeline • In 1898, Friedrich Loeffler & Paul Frosch showed that a similar filtratable agent was responsible for foot-and-mouth disease in cattle. Freidrich Loeffler (1852-1915) • In contrast to Iwanowski and Beijerinick, they speculated that the infectous agent was a small particle that passed through the filter • Should be credited with the discovery of a virus 1915-17 • Twort and d'Herelle discover bacterial viruses. 1957 • D. Carleton Gajdusek proposes that a slow virus is responsible for the wasting disease kuru (later prions). Doctoral Training Group GK1660 - University of Erlangen-Nürnberg 44 Infectious Diseases – Timeline Bacteria 1840s Ignaz Semmelweis shows that hand washing prevents childbirth fever. 1854 John Snow’s methods to search for the cause of the cholera epidemiy starts the field of epidemiology. 1859 Louis Pasteur develops the germ theory. 1867 Joseph Lister uses phenol to treat wounds for surgery. 1872 Robert Koch and Cohn identify Bacillus anthracis as the cause of anthrax and publish their research. 1882 Koch isolates Mycobacterium tuberculosis. 1884 Henle/Koch postulates for infectious disease. Doctoral Training Group GK1660 - University of Erlangen-Nürnberg 45 Infectious Diseases – Timeline Viruses 1892 Dmitri Ivanowski publishes the first evidence of the filterability of a pathogenic agent causing tobacco mosaic disease 1899 Martinus Beijerinck recognizes the unique nature of Ivanowski's discovery. He coins the term contagium vivum fluidum - a contagious living fluid (but not corpuscle). 1899 Friederich Loeffler and Paul Frosch discover that foot and mouth disease is caused by a filterable pathogenic corpuscle 1915-17 Twort and d'Herelle discover bacterial viruses. 1957 D. Carleton Gajdusek proposes that a slow virus is responsible for the wasting disease kuru (later prions). Doctoral Training Group GK1660 - University of Erlangen-Nürnberg 46 Core Module Immunology Doctoral Training Group GK1660 Erlangen • 2015 History of Immunology Part 3: Prevention of Infections Hans-Martin Jäck Division of Molecular Immunology Dept. Of Internal Medicine III Nikolaus-Fiebiger-Center University of Erlangen-Nürnberg TOPICS - Preventions of Infections DESINFECTION – External 1840s Ignaz Semmelweis - hand washing prevents childbirth fever 1867 Joseph Lister - carbol to treat wounds for surgery DESINFECTION – Internal (antimicrobial compounds) 1881 1909 1929 1935 E. v. Behring - unsuccessful attempts to treat infections with chemicals P. Ehrlich - First organic compound to treat syphilis (Salvarsan) Fleming - Penicillin Domagk - Sulfonamides PREVENTIVE VACCINATION 1796 Jenner - Cow pox vaccination 1880 Pasteur - cholera vaccination in chicken – generalization of Jenner’s use of cow pox vaccine. Pasteur introduces general term vaccination 1886 Pasteur - rabies vaccination Doctoral Training Group GK1660 - University of Erlangen-Nürnberg 48 TOPICS - Preventions of Infections 49 DESINFECTION – External DESINFECTION – Internal PREVENTIVE VACCINATION 1840s Ignaz Semmelweis hand washing prevents childbirth fever 1909 P. Ehrlich 1st organic compound to treat syphilis (Salvarsan) 1796 Jenner Cow pox vaccination 1867 Joseph Lister carbol (phenol) to treat wounds and equipment for surgery 1929 Fleming Penicillin 1880 Pasteur cholera vaccination in chicken general term vaccination 1935 Domagk Sulfonamides 1886 Pasteur rabies vaccination 1914 Henry Darkin Darkin’s solution Natriumhypochlorite 49 PREVENTION OF INFECTION Exernal Desinfektion Infectious Diseases – Timeline Bacteria 51 1840s Ignaz Semmelweis shows that hand washing prevents childbirth fever. 1854 John Snow’s methods to search for the cause of the cholera epidemiy starts the field of epidemiology. 1859 Louis Pasteur develops the germ theory. 1867 Joseph Lister uses phenol to treat wounds for surgery. 1872 Robert Koch and Cohn identify Bacillus anthracis as the cause of anthrax and publish their research. 1882 Koch isolates Mycobacterium tuberculosis. 1884 Henle/Koch postulates for infectious disease. Division of Molecular Immunology, Universitätsklinikum Erlangen 51 Infectious Diseases – Timeline Bacteria 52 1840s Ignaz Semmelweis shows that hand washing prevents childbirth fever. 1854 John Snow’s methods to search for the cause of the cholera epidemiy starts the field of epidemiology. 1859 Louis Pasteur develops the germ theory. 1867 Joseph Lister uses phenol to treat wounds for surgery. 1872 Robert Koch and Cohn identify Bacillus anthracis as the cause of anthrax and publish their research. 1882 Koch isolates Mycobacterium tuberculosis. 1884 Henle/Koch postulates for infectious disease. Division of Molecular Immunology, Universitätsklinikum Erlangen 52 Desinfection – Ignatz Semmelweis (1861) Founder of Hygiene Semmelweis, Ignaz (1818-1865) § Showed that child-bed fever was spread by physicians especially after an autopsy and could be prevented by hand washing with chloride of lime. Doctoral Training Group GK1660 - University of Erlangen-Nürnberg 53 Start of Hygiene (1861) Puerperal fever monthly mortality rates at the Maternity Clinic in Vienna (pathology) and Dublin (no pathology) 1784 -1849. • Advent of pathological anatomy in Wien in 1823 correllated with the incidence of fatal child bed fever • Rates for Dublin maternity hospital, which had no pathological anatomy, was lower • Rates drop markedly when Semmelweis implemented chlorine handwashing mid-May 1847 % of patients Pathology (1823) Handwash (1847) Vienna Dublin Years Doctoral Training Group GK1660 - University of Erlangen-Nürnberg 54 Start of Hygiene (Semmelweis - 1861) Puerperal fever monthly mortality rates for the First Clinic at Vienna Maternity Institution 1841-1849. • Rates drop markedly when Semmelweis implemented chlorine handwashing mid-May 1847 Handwash (1847) Doctoral Training Group GK1660 - University of Erlangen-Nürnberg 55 Germany Hospital Hygiene Standards 2011 Hygiene im Krankenhaus - Dreckspatzen in Weiß (2008) • Mindestens 500.000 Menschen infizieren sich jedes Jahr in Deutschland im Krankenhaus. • Doch ein Drittel aller Krankenhausinfektionen ließe sich vermeiden. Hygiene-Gesetz beschlossen - Zeugnis ärztlichen Scheiterns (2011) • Die Bundesregierung verabschiedet Hygiene-Regeln. • Klinikleiter werden verpflichtet, die aktuellen Hygiene-Regeln zu kennen und an ihre Mitarbeiter weiterzugeben. Doctoral Training Group GK1660 - University of Erlangen-Nürnberg 56 Desinfection – Ignatz Semmelweis (1861) Founder of Hygiene Semmelweis, Ignaz (1818-1865) § Showed that child-bed fever was spread by physicians especially after an autopsy and could be prevented by hand washing with chloride of lime. § Colleagues caused him to move from Vienna to Pest, Hungary § Involuntarily admitted to a mental institution, where he died 14 days later § Because of poor writing of the paper and his unprofessional attitude towards the big players, his work was ignored for 17 years, before Lister in England popularized his findings Doctoral Training Group GK1660 - University of Erlangen-Nürnberg 57 Desinfection – Joseph Lister (1867) Lister’s Joseph Lister (1827-1912) Carboxylic spray Sterile surgery Doctoral Training Group GK1660 - University of Erlangen-Nürnberg 58 Desinfection – Henry Darkin (1914) 59 § French pharmacists Antoine Labarraque (1822) sold his Eau de Labarraque for desinfection purposes § Rediscovered in a „screening“ experiment by Henry Darkin in 1914 (Darkin‘s solution) Henry Darking (1880-1952) England/USA o Desinfection of choice during 1st World War o Mechanism: Oxidative agent in water 1. NaClO + H2O → HClO + OH2. HClO + H+ + 2e- → Cl- + H2O § Today: Desinfection of swimming pools, household cleaners and root canal procedure • http://link.springer.com/article/10.1007%2FBF02561720#page-1 • https://de.wikipedia.org/wiki/Henry_Drysdale_Dakin 59 PREVENTION OF INFECTION “Internal” Desinfection with antimicrobial compounds THE DISCOVERY OF ANTIMICROBIAL COMPOUNDS § Salvarsan (Ehrlich 1909) § Penicillin (Fleming 1928) § Sulfonamide (Domagk 1934) P. Ehrlich – Begin of Chemotherapy (1909) • Worked with Koch and von Behring in Berlin and later in Frankfurt at his own institute Paul Ehrlich Strehlen. Germany March 14, 1854 Bad Homburg, Germany † August 20, 1915 • Sidechain Theory (1900) to explain inducibiliy and specificity of humoral immunity • Quantitation of antisera (serum titer) • Nobel price 1908 in Medicine • First synthetic organic compound to treat symphillis (1909) Nobel Medicine 1908 Founder of chemotherapy Doctoral Training Group GK1660 - University of Erlangen-Nürnberg 62 P. Ehrlich – A bullet against syphillis (1909) 1905 Schaudinn and Hoffmann (Berlin) discovered the spirochaete that causes syphilis 1907 First test of over 600 arsenic compounds synthesized by Alfred Bentheim identified compound 606 ineffective 1909 Hata, a student of Kitasato, had succeeded in infecting rabbits with syphilis, and he found that 606 was very effective. 1910 Hoechst brings 606 as Salvarsan on the market to treat syphillis (salvare – retten, sanus – gesund, heil and rest of Arsen) Doctoral Training Group GK1660 - University of Erlangen-Nürnberg 63 A. Fleming – Penicillin (1928) 1923 Isolation of the enzyme lysozyme 1928 Discovered bactericidal effect (gram-positive) of penicillin secreted by the mold Penicillium notatum (London) Fleming, Alexander Scotland 6 August 1881 London † 11 March 1955 Nobel Medicine 1945 http://www.sciencemuseum.org.uk/broughttolife/techniques/antibiotics.aspx 64 A. Felming – The landmark discovery 1929 On the antibacterial action of cultures of a penicillium with special reference to their use in the isolation of B. influenzae British Journal of Experimental Pathology Vol. 10, 226-236 (1929). http://digital.nls.uk/scientists/ pageturner.cfm?id=74491740 Key observation: „While working…., the plates … became contaminated with various micro-organims. It was noticed that around a large colony of contaminating mold that staphylococcus colonies …. were obviously undergoing lysis“. Doctoral Training Group GK1660 - University of Erlangen-Nürnberg 65 A. Felming – The landmark discovery On the antibacterial action of cultures of a penicillium with special reference to their use in the isolation of B. influenzae British Journal of Experimental Pathology Vol. 10, 226-236 (1929). http://digital.nls.uk/scientists/ pageturner.cfm?id=74491740 Key observation: „While working…., the plates … became contaminated with various micro-organims. It was noticed that around a large colony of contaminating mold that staphylococcus colonies …. were obviously undergoing lysis“. 66 A. Felming – Penicillin (1928) 1923 Isolation of the enzyme lysozyme 1928 Discovered bactericidal effect (gram-positive) of penicillin secreted by the mold Penicillium notatum (London) 1929 Publication (was not well received) 1930 Gave up research on penicillin since he failed to show that penicillin works to kill bacteria in vivo 1945 Shared the Nobel Prize with Howard Florey and Ernst Chain Fleming, Alexander Scotland 6 August 1881 London † 11 March 1955 Nobel Medicine 1945 http://www.sciencemuseum.org.uk/broughttolife/techniques/antibiotics.aspx Doctoral Training Group GK1660 - University of Erlangen-Nürnberg 67 G. Domagk – Sulfonamids (1935) § Timeline 1929 Employed by Bayer AG and IG Farben 1935 Discovered the antibacterial effect of the azo dye Prontosil against streptococcus Treated his own daughter and saved her arm 1939 Award of Nobel Prize in Medicine 1947 Received his Nobel price, but no price money Domagk, Gerhard Lagow, Germany 30. Oktober 1895 Königsfeld, Germany † 24. April 1964 Nobel Medicine 1939 § Prontosil was later replaced by penicillin § Domagk‘s research on sulfonamide led to the development of effective tuberculostatica 68 Penicillin – In Vivo Efficiency (1939) 1939 Howard Flory (born in Australia) and Ernst Chain (born in Berlin) showed that penicillin works in mice Titration curve by Florey and Chain to test the activity of purified penicillin on bacterial growth in vitro Doctoral Training Group GK1660 - University of Erlangen-Nürnberg 69 Penicillin – In Vivo Efficiency (1939) 1939 Howard Flory (born in Australia) and Ernst Chain (born in Berlin) showed that penicillin works in mice Importance of animal experiments Titration curve by Florey and Chain to test the activity of purified penicillin on bacterial growth in vitro Doctoral Training Group GK1660 - University of Erlangen-Nürnberg 70 Penicillin – In Vivo Efficiency (1939) 1939 Howard Flory (born in Australia) and Ernst Chain (born in Berlin) showed that penicillin works in mice 1941 Mass production starts in US by Merck 1942 1st patient was treated 1942 Enough U.S. penicillin to treat 10 patients. 1943 After a worldwide search, a moldy cantaloupe in a Peoria, Illinois, market was found to produce the best and highest-quality penicillin Titration curve by Florey and Chain to test the activity of purified penicillin on bacterial growth in vitro 1942 12 Million doses of penicillin ready for D-day to cure infected wounds and to treat gonorrhoea and syphilis of allied soldiers 1945 Shared the Nobel Prize with Howard Florey and Ernst Chain Doctoral Training Group GK1660 - University of Erlangen-Nürnberg 71 Penicillin – Mechanism of Action http://de.wikipedia.org/wiki/Penicillin Penicillin is bicyclic dipeptide betweeb Cys and Val, interfers with the biosynthesis of the bacterial cell wall http://digital.nls.uk/scientists/biographies/ alexander-fleming/index.html http://flexikon.doccheck.com/Penicillin#Wirkung • After being taken up by the bacterium, the beta-lactam ring opens up and binds to the enzyme D-alanine transpeptidase (only in procaryotes) • This blocks the cross-linking of the peptidoglykane moties and the formation of the cell wall • Osmotic lysis of bacterium 72 Penicillin – Resistance § Penicillinase (Beta-lactamase) produced by some bacteria inactivates penicillin by opening the beta-lactam ring § Penicillinase was the first β-lactamase to be identified by Abraham and Chain in 1940 from Gram-negative E. coli even before penicillin entered clinical use § Clavulanic acid (Claxo-Smith) is competitive inhibitor Clavulanic acid http://en.wikipedia.org/wiki/Beta-lactamase 73 PREVENTION OF INFECTION The power of vaccination Immune System – Barriers against Microbes & etc 75 (Immunitas, lat.: ‚exemption from any burden, duty or obligation‘) bacteria protozoa virus fungi worms tumors B A R R I E R S Innate Adaptive Memory http://archives.microbeworld.org/microbes/virus_bacterium.aspx 75 Boosting Adaptive Immunity 76 Adaptive Immunity natural artificial Active Active (infection) (vaccination) Memory No or less severe course of disease 76 Immunological Memory – 2 branches 77 Capacity of the immune system to respond more rapidly and strongly to pathogens that have been encountered previously during an infection or an active vaccination Long-lived effector cells & circulating effector molecules Antigen-specific memory B cells and T cells Inactivation of pathogens Accelerated response No or less severe course of disease 77 Vaccination 78 Adaptive Immunity natural artificial Passive Active Active Passive (placenta) (infection) (vaccination) (serotherapy) Memory No or less severe course of disease 78 Vaccination 79 Passive Vaccination • Transfer of a trained defense „team“ in form of cells or soluble factors • Immediatedly available • But only temporary protection • e.g., acute intoxication, slow-acting viruses (rabies, Ebola), Rh incompatibilty Active Vaccination • Induction of better barriers after application of an active or inactivated pathogen (or parts of it) • Protection after 10-14 days • And memory was generated Vorlesung Immunologie 6. Semester Humanmedizin 1/6, Emmerich, Leipzig 79 Vaccination – Passive immunization § Characteritics o Übertragung von Serum, Gammaglobulinen oder Antikörpern aus anderen Individuen oder Tieren o Die Schutzwirkung tritt bei dieser Art der Immunisierung sofort ein, allerdings sind heterologe Immunglobuline nur relativ kurz wirksam (Halbwertszeit t/2 = 20 Tage) o Nebenreaktionen durch eine Immunantwort gegen das verabreichte fremde Protein mit sich bringen (Serumkrankheit, Anaphylaxie) o Homologe Präparate (von anderen Menschen) bergen dagegen wieder die Gefahr der Übertragung von Hepatitis bzw. HIV. § Naturally aquired passive immunity o placental transport of maternal IgG from mother in the fetus through o Transfer if maternal IgA into newborn through milk § Artifically induced passive immunisation o Injection or transfusion of gammaglobulin from other individuals or animals o Treatment of an acute infection (diphtherie, tetanus, rabies, FSME, rubella (Röteln) …) o Posions (Insects, snake, scorpions, botulinus) o Prophylactic before travel to foreign countries o Rhesus prophylactic Doctoral Training Group GK1660 - University of Erlangen-Nürnberg 80 Vaccination Passive Vaccination • Transfer of a trained defense „team“ in form of cells or soluble factors • Immediatedly available • But only temporary protection • e.g., acute intoxication, slow-acting viruses (rabies, Ebola), Rh incompatibilty 81 Active Vaccination • Induction of better barriers after application of an active or inactivated pathogen (or parts of it) • Protection after 10-14 days • And memory was generated Vorlesung Immunologie 6. Semester Humanmedizin 1/6, Emmerich, Leipzig Memory 81 Immune Memory – The first description 82 § Thucydides (Description of plaque 430 B.C.) o the same man was never attacked twice -- never at least fatally. o they were for the future safe from any disease whatsoever First description of adaptive immunity and memory 82 First Descriptions – Immunity § Thucydides (430 B.C.) • Patients who survived epidemics did not get sick during a second epidemics § Marcus Annaeus Lucanus (65 B.C.) • Used “immunes” to describe a habit of African tribes to protect themselves against snake bites by injecting dried poison snake glands § Mithradates VI (1. century B.C.) • Used increasing amounts of poison to protect himself against assassinations Silverstein, Arthur M. (1989) History of Immunology, Academic Press. First description of memory and adaptive immunity 83 Small Poxs – Timeline of Variolation Ca. 1000 Chinese inoculated children with material from infected people (Variolation, „Variola“ from lat. varius = engl. colored, blotchy=fleckig) Ca. 1500 Variolation introduced into Turkish harems Lady Mary Montagu, wife of the British ambassodour to Turkey, 1717 Lady Mary Montagu introduced smallpox inoculation to Europe. 1760 Variolation of the families of Maria Theresia und George III. popularized variolation 1776 Washington began variolating the Continental Army 84 Small Pox - Disease § Dt., Pocken, Blattern; engl. Small pox; lat., Variola § The German word „Pocken“ originated from Germanic „poccas“ and means Beutel, Tasche, Blase (= Blatter) und is related to the Engl. pocket/pox/pocks § „Variola“ from lat. varius = dt. bunt, scheckig, fleckig § Highly contagious viral and very often fatal disease § 10% of all children before the age of 10 died of small pox Doctoral Training Group GK1660 - University of Erlangen-Nürnberg 85 Small Pox - Disease § The disease killed as many as 30% of those infected • Queen Mary II of England, Emperor Joseph I of Austria, King Luis I of Spain, Tsar Peter II of Russia, and King Louis XV of France) § Between 65–80% of survivors were “pox-marked” § Very old disease • Originated in China and India 3000 years ago • Symptoms are already mentioned in Old Testament • • • • Mumy of Pharao Ramses II. of Egypt showed pox scars Reached Europe around 165 through Roman legions returning from „Irak“ Antoninische Pest , 1st recorded 24 year-long epidemy Worldwide since the 16th century http://www.microbiologybytes.com/introduction/introduction.html Doctoral Training Group GK1660 - University of Erlangen-Nürnberg 86 Small Poxs – Variolation & Vaccination § Variolation o Oriental habit to protect children through intentional infection with lymph or pustules from a person that recovered from a mild infection of small pox. o Common practice before vaccination o Worked if exposed to a weak strain of smallpox o Wrong treatments could kill or be ineffective. o Strains of small pox differ in mortality rate (1-20%) § Vaccination o Edward Jenner discovered that cowpox could protect against smallpox with less complications than variolation. o Louis Pasteur coined the term vaccination (from lat, vacca = cow) as a general procedure o immunize people against other disease Doctoral Training Group GK1660 - University of Erlangen-Nürnberg 87 88 The Beginning of Scientific Active Vaccinations Jenner (1796) Pasteur (1885) 88 Vaccination 89 Adaptive Immunity natural artificial Passive Active Active Passive (placenta) (infection) (vaccination) (serotherapy) Memory No or less severe course of disease 89 Vaccination – The Jenner Experiment (1796) 90 § Country lore (Bauernweisheit)/Obervation Cowpox pustule on the hand of the dairymaid Sarah Nelmes http://www.jennermuseum.com/Jenner/cowpox.html o “Milkmaids who caught cowpox from their cows could not catch smallpox”. o Milk maids infected by cowpox have on their hands scars very similar to smallpox scars. 90 Vaccination – The Jenner Experiment (1796) 91 § Country lore (Bauernweisheit)/Obervation § Hypothesis Cowpox pustule on the hand of the dairymaid Sarah Nelmes o Cowpox infection protects from small pox § The experiment (May 14, 1796) o Infected a boy with the lymph of a cowpoxinfected milkmaid. o On 1st July, Jenner infected (variolated) the boy with small pox § Result o Boy did not get sick http://www.jennermuseum.com/Jenner/cowpox.html o “Milkmaids who caught cowpox from their cows could not catch smallpox”. o Milk maids infected by cowpox have on their hands scars very similar to smallpox scars. Jenner infects James Phipps, the son of his gardener who had not yet suffered smallpox with Sarah’s lymph. James became mildly ill 91 § Conclusion o Cow pox infection protects against small pox § Problems o Human experiment o Controls § Publication o 1797, rejected by Transactions of the Royal Society of London. o 1801, published “The Origin of the Vaccine Inoculation” 92 Baxby D. 1999. Edward Jenner's Inquiry; a bicentenary analysis. Vaccine. 1999 Jan 28;17(4):301-7. Vaccination – The Jenner Experiment (1796) “Pasteur introduced VACCINATION (from lt. vacca = cow) as a general term for the procedure to protect individuals with weaken pathogens (Pasteur: Trans. 7th Session Internat. Med. Congr. (1881) 92 § Conclusion o Cow pox infection protects against small pox § Problems o Human experiment o Controls The first “scientific” vaccination o 1797, rejected by Transactions of the Royal § Publication Society of London. o 1801, published “The Origin of the Vaccine Inoculation” 93 Baxby D. 1999. Edward Jenner's Inquiry; a bicentenary analysis. Vaccine. 1999 Jan 28;17(4):301-7. Vaccination – The Jenner Experiment (1796) “Pasteur introduced VACCINATION (from lt. vacca = cow) as a general term for the procedure to protect individuals with weaken pathogens (Pasteur: Trans. 7th Session Internat. Med. Congr. (1881) 93 Humoralists Keep the body's humors in balance: Contagionists Restrict contact: o leave the disease-ridden area o impose quarantine o remove sources of fomites Miasmatists Cleanse the air: o remove sources of foul smells o flush the air with smoke o breathe in aromatic substances o perform routine blood-letting o administer medicines that cause sweating, urination, bowel evacuation In 1798, a new way to control the spread of a disease (smallpox): Vaccinatists Vaccinate: o purposefully infect the population with another, less virulent disease Modified after B. J. Becker: Infectious and Epidemic Disease in History , Department of History, University of California, Irvine Doctoral Training Group GK1660 - University of Erlangen-Nürnberg 94 Disease protection before Jenner 95 Keep the body's humors in balance: Humoralists QUARANTINE o perform routine blood-letting o administer medicines that cause sweating, urination, bowel evacuation • Originates from ital. quarantina di giorni (40 days) Restrict contact: Contagionists o leave the disease-ridden area o impose quarantine o remove sources of fomites • 1st quarantine (30 days) o 1374 Venice (Lazzaretto Nuovo) ??? Cleanse the air: Miasmatists o 1377 Republic Ragusa (Dubrovnik) (historically proven) o remove sources of foul smells o 1383o Marseille flush the air with smoke o breathe in aromatic substances • 1642 - Quarantaine from 30 to 40 days In 1798, a new way to control the spread of a disease (smallpox): (very likely origination of word quarantine ??) Vaccinate: o purposefully infect the population with another, less virulent disease https://de.wikipedia.org/wiki/Quarant%C3%A4ne Vaccinatists Modified after B. J. Becker: Infectious and Epidemic Disease in History , Department of History, University of California, Irvine Division of Molecular Immunology, Universitätsklinikum Erlangen 95 Disease protection before Jenner Humoralists Keep the body's humors in balance: Contagionists Restrict contact: o leave the disease-ridden area o impose quarantine o remove sources of fomites Miasmatists Cleanse the air: o remove sources of foul smells o flush the air with smoke o breathe in aromatic substances o perform routine blood-letting o administer medicines that cause sweating, urination, bowel evacuation In 1798, a new way to control the spread of a disease (smallpox): Vaccinatists Vaccinate: o purposefully infect the population with another, less virulent disease Modified after B. J. Becker: Infectious and Epidemic Disease in History , Department of History, University of California, Irvine Doctoral Training Group GK1660 - University of Erlangen-Nürnberg 96 Small Pox – Jenner‘s Clinic and ?? side effects ?? Roitt p 346 Doctoral Training Group GK1660 - University of Erlangen-Nürnberg 97 Vaccination – Techniques § Vaccination gun o No need for needle replacement and sterilisation. o Required too much maintenance § Disposable 'bifurcated needle‘ o Has a narrow, flattened forked end o Draws vaccine by capillary action o Was then jabbed repeatedly into the skin Doctoral Training Group GK1660 - University of Erlangen-Nürnberg 98 Eradication of small poxs 1796 Jenner’s 1st vaccination against small pox 1801 Jenner: “The eradication of small pox must be the goal of future vaccinations” 1807 -74 Mandatory (gesetzliche) vaccination against small pox in Bavaria (1807), Denmark (1810), Prussia (1835), German Empire (1874) and Great Britain (1853) 1870-71 Small poxs epidemics during the German-French war of 1870/71 • • French were not vaccinated ►23,400 dead Germans were vaccinated ► only 278 dead Division of Molecular Immunology, Universitätsklinikum Erlangen 99 Eradication of small poxs 1960 Up to 15 million cases of smallpox each year. 1967 the World Health Organization (WHO) launched its campaign to eradicate smallpox worldwide. 1977 Ali Maow Maalim from Somali was the last person on Earth to catch smallpox by natural transmission 1980 WHO formally declared: "Smallpox is Dead!” Doctoral Training Group GK1660 - University of Erlangen-Nürnberg 100 Gründe für Eliminierung § Highly visible disease o Short incubation period → can’t spread very far before it’s noticed. o Easily recognizable rash (WHO photo campaign, see below) 101 Beispiel: POCKEN § Combination of focused surveillance and ring vaccination o WHO workers quickly identifying smallpox patients by displaying pictures of people with the smallpox rash and asking if anyone nearby had a similar rash o “Ring vaccination” - anyone who could have been exposed to a smallpox patient was vaccinated as quickly as possible, § Only humans can transmit and catch smallpox (no animal reservoir) o Yellow fever is transmitted by mosquitos and infects humans and monkeys o So even if the entire population of the planet could somehow be vaccinated against yellow fever, its eradication could not be guaranteed because disease could still be circulating among monkeys, o Smallpox has nowhere to hide. Division of Molecular Immunology, Universitätsklinikum Erlangen 101 Tetanus – nicht ausrottbar Division of Molecular Immunology, Universitätsklinikum Erlangen 102 102 Jenner’s Contribution to Medicine 103 Nabel (2013). Designing Tomorrow’s Vaccines. NEJM 368:6, 551 103 “Jenner is acknowledged as the Father of Vaccination Pasteur - Vaccination against chicken cholera 1879 CHOLERA • • caused by a bacterium, vibrio cholerae, produces a toxin that affects the intestines. devastating epidemics worldwide through-out history. 105 Pasteur - Vaccination against chicken cholera 1879 CHOLERA • • caused by a bacterium, vibrio cholerae, produces a toxin that affects the intestines. devastating epidemics worldwide through-out history. 1881 VACCINATION Pasteur introduced VACCINATION (from lt. vacca = cow) as a general term for the procedure to protect individuals with weaken pathogens Pasteur: Trans. 7th Session Internat. Med. Congr. (1881) 106 Pasteur – Vaccination against Anthrax Anthrax Vaccine Trial (1881) http://www.historyofvaccines.org/content/timelines/pasteur Sheep were treated by attenuating the anthrax bacteria with carbolic acid or left untreated 107 Pasteur – Vaccination against rabies (1885) Rabies • viral disease that causes acute inflammation of the brain in humans and other warm-blooded animals. • Symptoms: violent movements, loss of consciousness. Vaccination against rabies (The case of Johann Meister) Vaccinated with the spinal cord of a rabbit that died of rabies • Once symptoms appear it nearly always results in death. • T h e t i m e p e r i o d b e t w e e n contracting the disease and the start of symptoms can be from one week (usually 1 mts) to more than one year (usually 3 mths) • Incubation time depends on time virus needs to reach the central nervous system http://en.wikipedia.org/wiki/Rabies 108 Vaccination – Another success story 109 § Polio vaccination o 1955 (Salk) – USA o 1960 (Sabin) DDR o 1962 (Sabin) - BRD H.P.Pöhn, G.Rasch, bga Schriften Statistik meldepflichtiger übertragbarer Krankheiten.Vom Beginn der Aufzeichnungen bis heute, MMV Medizin Verlag, München, 1994 Division of Molecular Immunology, Universitätsklinikum Erlangen 109 Impfung – Timeline 110 Nabel (2013). Designing Tomorrow’s Vaccines. NEJM 368:6, 551 110 Data in graph are based on Vaccination – Another success story the following public-cation Centers for Disease Control and Prevention (CDC): Impact of Vaccination Universally Recommended for Children – United States, 1900–1998. In: MMWR, Morbitity and Mortality Weekly Report. 48, Nr. 12, April 1999, S. 243–248. PMID 10220251. Abgerufen am 4. Dezember 2011. 111 § Polio vaccination o 1955 (Salk) – USA o 1960 (Sabin) DDR o 1962 (Sabin) - BRD H.P.Pöhn, G.Rasch, bga Schriften Statistik meldepflichtiger übertragbarer Krankheiten.Vom Beginn der Aufzeichnungen bis heute, MMV Medizin Verlag, München, 1994 Division of Molecular Immunology, Universitätsklinikum Erlangen 111 THE PRE-IMMUNE ERA “Though Pasteur and Koch knew that vaccines worked, no one then in the world of science knew how it worked!” Mechnikov, Roux, Yersin, Bordet, et al. Behring, Ehrlich, Nissen, Wernicke et al. Integrated Research Training Group TRR130: B Cells and Beyond 112 Vaccination – Another success story 113 § Polio vaccination o 1955 (Salk) – USA o 1960 (Sabin) DDR o 1962 (Sabin) - BRD H.P.Pöhn, G.Rasch, bga Schriften Statistik meldepflichtiger übertragbarer Krankheiten.Vom Beginn der Aufzeichnungen bis heute, MMV Medizin Verlag, München, 1994 Division of Molecular Immunology, Universitätsklinikum Erlangen 113 Impfung – Timeline 114 Nabel (2013). Designing Tomorrow’s Vaccines. NEJM 368:6, 551 114 Data in graph are based on Vaccination – Another success story the following public-cation Centers for Disease Control and Prevention (CDC): Impact of Vaccination Universally Recommended for Children – United States, 1900–1998. In: MMWR, Morbitity and Mortality Weekly Report. 48, Nr. 12, April 1999, S. 243–248. PMID 10220251. Abgerufen am 4. Dezember 2011. 115 § Polio vaccination o 1955 (Salk) – USA o 1960 (Sabin) DDR o 1962 (Sabin) - BRD H.P.Pöhn, G.Rasch, bga Schriften Statistik meldepflichtiger übertragbarer Krankheiten.Vom Beginn der Aufzeichnungen bis heute, MMV Medizin Verlag, München, 1994 Division of Molecular Immunology, Universitätsklinikum Erlangen 115 Impfung – Erfolgsgeschichte der Medizin 116 USA Disease Smallpox Annual Morbitity (year) 48,164 (1900-04) Vaccination Introduced Morbitity in 1998 % Decrease 18xx (Deutschland) 0 100 Diphtheria 175,885 (1920-22) 1923 1 100 Pertussis 147,271 1926 6279 95,7 tetanus 1314 (1922-26) 34 97.4 Polio 16,316 (1951-54) 1955 0 100 Measles 503,282 (1958) 1963 89 99,9 Mumps 152,209 (1968) 606 99,6 Centers for Disease Control and Prevention (CDC): Impact of Vaccination Universally Recommended for Children – United States, 1900– 1998. In: MMWR, Morbitity and Mortality Weekly Report. 48, Nr. 12, April 1999, S. 243–248. PMID 10220251. Abgerufen am 4. Dezember 2011. Division of Molecular Immunology, Universitätsklinikum Erlangen 116 Impfung – Erfolgsgeschichte der Medizin 117 Nabel (2013). Designing Tomorrow’s Vaccines. NEJM 368:6, 551 Division of Molecular Immunology, Universitätsklinikum Erlangen 117 THE PRE-IMMUNE ERA “Though Pasteur and Koch knew that vaccines worked, no one then in the world of science knew how it worked!” Mechnikov, Roux, Yersin, Bordet, et al. Behring, Ehrlich, Nissen, Wernicke et al. Integrated Research Training Group TRR130: B Cells and Beyond 118 Discovery of Inducible and Soluble Immunity - Antitoxins or Antibodies • • • • • Behring Ehrlich Nissen Wernicke et al. BOOKS - History Doctoral Training Group GK1660 - University of Erlangen-Nürnberg 120