Vaccine and Immunity

Objective of the course

 To learn the overall immune response to a pathological entity (pathogens, cellular

abnormalities, aberrant tolerance mechanisms) in an integrative manner

 To discuss the utilization of the immune system as a therapeutic strategy in a

variety of diseases

 To learn how the pathogens succeed in inducing disease despite the immune system
 The Science of Immunology: the beginning………

5th century BC: Thucidydes wrote of individuals who recovered from the Plaque which was
raging in Athens at that time. He observed that these people who had already contracted
the disease and recovered became “immune” or “exempt” from the disease.

10th century China/Persia,/India/Sudan: earliest recognized attempt to intentionally

induce immunity to highly infectious and deadly disease smallpox.

Small Pox:
• A Great Scourge of Mankind . Ancient Egyptian, Chinese and Indian
literature dating back to 1100 BC mentions small pox
• Two virus variants: Variola major (mean fatality 25-30%) and Variola
minor (mean fatality 15%)
• Fatality among children around 80%
 The Science of Immunology: the beginning………

Small Pox and its eradication: A case study

Immunological intervention to fight this deadly disease:

• In ancient China, Persia, Sudan , India a practice called Variolation

was in place that involved deliberate inoculation with dried small pox
pustules to initiate a mild form of the disease

• Many from different fields of life observed that those who got
infected with cowpox were protected from smallpox

• Some went as far as inoculating others with cowpox and

rechallenging them with small pox. John Fewster, Peter Plett , Benjamin
Jesty
In 1774, Benjamin Jesty, a farmer, inoculated his wife with the
vaccinia virus obtained from “farmer Elford of Chittenhall, near
Yetminster.”
The Science of Immunology: the beginning………

Edward Jenner: father of Immunology

On May 15, 1796, Edward Jenner scraped pus from

cowpox blister on the hands of Sarah Nelmes, a milkmaid
who had caught the disease from a cow named Blossom
and inoculated an 8 year old James Phipps. 6 weeks
later on July 1 Jenner challenged the boy with live
smallpox and found that he was protected

A process he termed Vaccination

Demonstrated
a) long term protection
b) protection possible from person to person
inoculation
c) well defined study that led to the advent of the
science of Immunology in its current form
 The Science of Immunology: the beginning………

Small Pox officially eradicated in 1980

The Last Patient who contracted and survived small pox

Dysfunctional Immune System: When Diseases Develop
 Recognizes, clears and remembers invading Infection
pathogens

Recognizes self as foreign and mounts Autoimmune diseases

response to self

 immunosuppressive drugs

systemic immune suppression

leaves the individual prone to
infection.
Dysfunctional Immune System: When Diseases Develop
 Recognizes, clears and remembers invading Infection
pathogens

Recognizes self as foreign and mounts Autoimmune diseases

response to self

 Recognizes cellular abnormalities and Immune evasion by cancer

employs specific mechanisms to clear them
Destruction of cancer cells by

 Irradiation
 Chemotherapy
 Surgery

a lot of surrounding healthy cells are

also killed leading to a number of
deleterious side-effects.
Immune System: The Body’s Defense Against Disease

Recognition: Recognizes danger from

pathogen, cellular abnormalities and
discriminates between self and non-self

 Diversity: can respond to a huge range of

diverse molecules, even if they differ from each
other by a few amino acid residues

Specificity: Mounts very specific response to

the exogenous or endogenous dangers thus
minimizing collateral damage

 Memory: Able to recognize and mount

response to previously encountered dangers
 The Science of Immunology: the progress………

Germ Theory vs Spontaneous Generation: Robert Koch and Louis Pasteur

In 1875, Robert Koch, inoculated the ear of a rabbit with the blood of an animal that had
died of anthrax. Demonstrated that “Infectious Disease was caused by Microorganisms”

Quite independently, Louis Pasteur began his studies of the “chicken cholera bacillus.” He
demonstrated that virulent organisms can be attenuated by artificial means and used for
protection against the disease. Pasteur worked on anthrax and rabies and developed the
first viable vaccine for anthrax and rabies.
 Progress of Immunology: Cellularists and humoralists
By the end of the 19th century Immunologists had progressed to:

 Establishment of Germ Theory

 immunity to infection could be transferred by a

soluble substance in the serum (Von Behring and
Kitasato: protection to diphtheria and tetanus to
people by inoculated animal serum)

 this soluble substance was produced by specialized

cells of the immune system and that the regulation
of this process (generation of antibodies) was
important for self-non-self discrimination (Ehrlich)

 Jules Bordet: Complement system

 Finally, the immune system responds to bacterial

pathogens by the recruitment of “phagocytes,”
which recognize, engulf, and destroy the microbes
via “phagocytosis” (Metchnikoff).
 Progress of Immunology: Some Nobel Prizes

 1901: First Nobel prize in Physiology or Medicine awarded to von Behring

“for his work on serum therapy, especially its application against diphtheria, by which
he has opened a new road in the domain of medical science and thereby placed in the
hands of the physician a victorious weapon against illness and deaths.”

 1905: Robert Koch for “his investigations and discoveries in relation to

Tuberculosis”

 1908: Metchnikoff and Ehrlich shared the Nobel prize “in recognition of their work
on immunity.”

 1919: Jules Bordet, for his discoveries related to immunity

 Progress of Immunology: Cellularists and humoralists
Between the years 1900 and 1942 the Cellularists: challenges to the prevailing view of
“Humoralists” played a dominant role antibodies alone served to confer specific
in immunology. immunity.
Delayed type hypersensitivity: Koch in 1883,
1. Antibodies Allograft rejection: Medawar, 1944
2. Complement
3. Immunopathology like serum Landsteiner and Chase, 1942
sickness , Arthus reaction etc
4. Chemistry of antigen-antibody
reactions No recall response
No transfer
5. Antibody structure in the late 1950s

Cells transferred to
Lymphocytes: Gowans et al,naïve
Initiation
guineaofpigs
immune responses by small lymphocytes. Nature
196:651-55, 1962 Recipient showed
recall response
Immunized
with Mtb serum transferred to
naïve guinea pigs No recall response
 Conceptual breakthrough: Clonal Selection Theory

Earlier hypothesis: antigen instructs the cell about the specificity of the antibody.

⮚ 1955, Jerne Selective Hypothesis: The natural-selection theory of antibody formation.

Proc. Nat. Acad. Sci. 41: 849-857, 1955,
1.every animal had a large set of natural globulins that had become diversified in some
unknown fashion
2. the function of an antigen was to combine with those globulins with
which it made a chance fit.
3. The antigen would serve to transport the selected globulins to
antibody-producing cells, which would then make many identical copies of the globulin
presented to them.

⮚ Burnet : A modification of Jerne’s theory of antibody production using the concept of

clonal selection. Aust. J. Sci. 20, 67-69, 1957
Diversity of the Antibody repertoire: Clonal Selection Theory
According to Burnet, the clonal selection theory states:
1. Animals contain numerous cells called lymphocytes.
2. Each lymphocyte is responsive to a particular antigen by virtue of specific surface
receptor molecules.
3. Upon contacting its appropriate antigen, the lymphocyte is stimulated to proliferate
(clonal expansion) and differentiate.
4. The expanded clone is responsible for the secondary response (more cells to respond)
whilethe differentiated (“effector”) cells secrete antibody.

Abbas and Janeway Cell 100:129, 2000.

 Conceptual Breakthrough:
Generation of Immunological Diversity

Somatic hypermutation: Susumu Tonegawa, 1978

Paradigm shift in Molecular genetics: genetic makeup of an organism remained

unchanged throughout ontogeny (unless altered by pathological states, such as cancer).

the immunoglobulin genes are the only genes that have been shown to undergo somatic
rearrangements
Conceptual Breakthrough: Major Histocompatibility Complex

1930s, George Snell: tumor grafts were

accepted between inbred mice, but
not between mice of different strains.
The same was true for normal tissues.
Snell termed the underlying genes
histocompatibility genes. H2 genes in
mice

1943, Peter Medawar: skin grafts in

burn victims, autografts succed while
allografts were rejected

1950s, Dausset: similar findings in

humans; HLA genes

Self:non-self discrimination
Zinkernagel and Doherty: MHC restriction
is necessary for activation cytotoxic
response
Paradigm shifting Immunological Advances:

2 signal hypothesis of lymphocyte activation