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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
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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
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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
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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.)
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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
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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)
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Spontanous Generation – Disprove 1
Francesco Redi
1626 - 1697
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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.”
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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
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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”.
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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
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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]
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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.
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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.
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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
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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
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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
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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
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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
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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).
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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.
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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
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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