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Lecture I:
Immunology of Vaccination
BIOL 485 A - SENIOR SEMINAR IN CELLULAR,
MOLECULAR AND
DEVELOPMENT
Hot Topics in Disease Prevention: From single cells toglobal health
Ingunn Stromnes, PhDPostdoctoral fellow
Department of Immunology
Lecture I
March 30, 2010
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Foundation of vaccination and immunology
stem from infectious disease
Smallpox virionClinical
manifestation20th Century ~ 300-500
million deaths
Variola major
(~30% fatality)
1721 - variolation
introduced in Europe(1% fatality)
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Edward Jenner
17 May 1749 26 January 1823
Observation: milkmaids do not get smallpox and are
continuously exposed to cows with Cowpox
Hypothesis: pus in Cowpox blisters that milkmaids receive from
cows protect them from Smallpox
Dont think, act.
William Harvey, 16th
century
First empirical proof of protective immunity
Experiment :
1. Inoculated 8 year-old James Phipps with material
from the cowpox blisters of the hand of Sarah
Nelmes, a milkmaid who had caught cowpox.
2. Infected James with Smallpox (varioulos
material).
3. James did not get Smallpox.
Vacca - cow
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>4,000 BC
Smallpox
originates in
India/China,
Middle Eastor Africa
1400
European
fatalities
>500,000/yr(1400-1800)
1823
Variolationoutlawed
1950
Freeze
driedvaccine
WHO
supports
further
research
20021520
Aztec
empire
collapses(Cortez)
1096
Crusaders
bring
Smallpox toEurope
(1096-1200)
Mass
production
of vacciniain calf skin
1863 1978
Last
Smallpox
fatality
2001
USA retains
Variola
stock atCDC
Adapted from Smith and McFadden, Nature Revews Immunology, 2002
History of Smallpox
1993
Variola
genomesequenced
1977
Last natural
case ofSmallpox
1967
WHO
intensifies
eradicationprogram
1723
Variolation
introduced inEurope
Smallpox
eradicated
19791796
Vaccination
by Jenner
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How was the eradication Smallpox possible?
Smallpox vaccine was effective against all strains of variola
viruses
High fidelity DNA polymerase, variola viruses were unable
to undergo antigenic variation to escape existing immunity(Contrasts with RNA viruses such as HIV and influenza which undergo high mutation
rates due to error prone RNA polymerases)
Smallpox infection was restricted to humans(virus did not persist in animal reservoirs)
Smallpox does not cause a latent or persistent infection(once infected, either a person died ~30-40% in the case ofVariola major, or recovered)
Symptoms of Smallpox were readily detectable(Contrasts with HIV- long latency period, spread throughout the populationto epidemic proportions prior to the diagnosis of AIDS)
Immunological reasons CD4 T cell-dependent neutralizing
antibodies to vaccinia antigens are cross-reactive with smallpox antigens,
cross-reactive CD8 cytotoxic T cell response may also contribute
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How is prior exposure to a similar pathogen
protecting from disease?
1. Specificity- generating an immune response
to a specificpathogen
2. Memory- Maintaining that response over
time in order to prevent re-infection with asimilar pathogen
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The immune system is composed of innate
and adaptive immunity
Innate immune response (myeloid cells)
First line of defense
Programs the adaptive immune response
Adaptive immune response (lymphocytes)
Specificity
Immunological memory
Autoimmune
diseases(MS, RA)
Resistance to
infection
Resistance to
cancer progression
Chronic inflammatory
diseases
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thymus
bone
marrow
T Cells
B Cells
CD4+ helper T cells
CD8+ cytotoxic T cells
Myeloid cells
(DCs.,etc..)
Adaptive
Lymphocytes
BB cell receptor(BCR)
Antibody(secretedBCR)
T TTCR
CD8
TCR
CD4
Blood & Tissues
Innate
Myeloid cells
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All immune cells are derived from a single
hemopoietic stem cell
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InfectionInnate
Response
Inductionof adaptive
response
Adaptive
immune responseMemory
Level of
microorganism
Threshold
level of
antigen to
detect aresponse
Entry of
microorgansim
Pathogen
cleared
Duration of infection
Adapted from Immunobiology
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Immunological principles of vaccination
Adaptive immunity established before infection
Immunity that is induced must be robust and durable enoughin order to be clinically relevant
Immunological mechanisms of protection:
I. Protective antibodies
major mechanism for protection by most currentvaccines
block colonization and/or spread of infection
II. T cell responses CD4 helper T cells- enhance antibody response and
formation of CTL memory
CD8 CTL- anti-viral immunity
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What happens when you get
infected with a pathogen? depends on the pathogen
www.hubtesting.net/.../bacteria.94120838_std.jpg
Extracellular pathogens
(bacteria, parasites)
Intracellular pathogens
(often viruses)
https://reader009.{domain}/reader009/html5/0501/5ae89b1fb4a75/5ae89b299b863.jpg
Replicates outside of the cell Replicates inside of the cell
Cytotoxic T cells
(CTLs) are requiredto eliminate
infected cells
Antibodies are
required toneutralize
extracellular
pathogens
Humoral immunity
(ie., antibodies) is
essential
Cell-mediated
immunity (ie., CTLs, is
essential) antibodies
help too
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1.Virus
infects
APC
2. APC presents
viral antigen
3. APC activates
CD4 T cell
4. Helper CD4 T cell
helps CTL and B cells
5. Antigen-specific
B cells are activated
6. Antigen-specifi
B cells secrete
antibody
8. CD8 CTLs kill
Infected cells
7. Antibodies attach to virus,
signal for virus destruction
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Antigen-specific
T cell
virus
Antigen
presenting cell
PRR
MHC/Antigen
Cytokines and chemokinesCostimulatory molecules
Migrated to lymph node
Present antigen to T cells
Proliferate
Migrate to sites of infected tissues
Activate B cells
Form immunological memory
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How do cells of the innate immune response
recognize pathogens? Implications for vaccine design.
Innate cell recognition depends on molecular differences
between host cells and the infectious organism
Innate immune cells express pattern recognition
receptors (PRRs) that recognize pathogen-associated
molecular patterns (PAMPS) expressed by pathogens (forexample, TLR-4 receptor recognizes LPS)
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Molecular Biology of the Cell
How were the first experiments performed to
understand T cell recognition of foreign antigen?
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T Cell
Target cell
(adapted from Eur.J. Immunol. 1975, Berke G.)
**
T cell recognition of
infected cell
T cell lysis
of target cell
TCR
peptide
MHC
Molecular basis of
T cell recognition
How do T cells recognize foreign antigen?
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sites.google.com/site/stratikos/mhc
T cells are constantly scanning self/host cells
for expression of foreign peptides
MHC
peptide
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Molecular Biology of the Cell
B cells proliferate and secrete antibody after
encounter with foreign antigen (need CD4 help)
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Molecular biology of the cell
Immune response is always greater after
secondary exposure to the same antigen
(principle of booster immunizations)
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Nave cell
Activated cellMemory cell
Immune
response isalways greater
after
secondary
exposure to the
same antigen
Activated cell
Memory cell
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Original Rabies vaccine (early 1900s)
Designing an effective and safe
vaccine - it is just not that simple.
Caused paralysis in some recipients
However, the vaccine also generated an immune
response to the rabbit brain tissue (myelin sheath) in
some individuals
High homology between rabbit myelin and human myelin
proteins
Immune response that generated to rabbit brain, cross-
reacted with human myelin tissue- autoimmunit
Vaccine was made from inoculated rabbit brain
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Failure of HIV Vaccine STEP trial (2008)
Designing an effective and safe
vaccine - it is just not that simple.
Vaccine may have increased risk among people who had
pre-existing immunity to the common cold virus
??? Unknown - challenged the field to understand vector-
based immunity
HIV vaccine - modified adenovirus type 5 (recombinant
vaccine) that contained 3 HIV genes
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SafetyEfficacy
Safety standards are much
higher for preventative treatments
compared to therapeutic
treatments
Live-attenuated vaccines - live
vaccines that have been
weakened can be more effective
than non-replicating vaccines, but
also pose more risks
Vaccine design: Balance between
efficacy and safety
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Modern Day Vaccine Design
Antigen(s) - any protein, peptide, substance, etc., that
stimulates an immune response (SPECIFIC to the
pathogen of interest)
Adjuvant - a substance that enhances the immune
response to a weakly immunogenic antigen (non-specific)
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Class activity - interpret this table
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Types of Vaccines
Live-attenuated vaccines
Naturally occurring - vaccinia
Intentionally weakened - (Influenza, MMR, oral Polio, BCG,Rotavirus, Rabies)
Advantages
mimic natural infection - stimulate PRRs on innate cellsInduce antibodies, CD4 and CD8 T cells for live viral vaccines. CTL are
induced effectively because viral proteins are synthesized inside of the cells
and thus efficiently loaded onto MHC class I in cells this does not occur
with killed or subunit vaccines.
Disadvantages
May cause disease in immunocompromised hosts
Passive maternal antibodies may interfere with efficacy
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How is Attenuation Achieved?
The old way - serial passage in different host cells in culture
Cold-adapted influenza (Flu-mist)
Recombinant live-attenuated vaccines
Mutate virulence proteins, introduce new antigens
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Types of Vaccines
Whole organism vaccineOrganisms contain microbial pattarns that stimulate innate immune response
Attenuated (live) or inactivated (dead/killed, ie., treated with formalin)
Examples (Pertussis, Influenza, Hep A, Poliovirus)
Disadvantages
Inactivation may destroy protective antigensDo not induce a CD8 T cell response (no MHC class I presentation)
Examples of bad ones- inactivated measles, RSV
Subunit vaccinesComposed of purified microbial antigens, not whole organisms
Examples-Tetanus and diphtheria toxoids, HepB
Advantages
reduce risk of adverse effects no risk of infection or spread to unintendedbystanders
may be more simple to produce
Disadvantages
must know the antigens to which protective immunity is directed
do not induce CD8 CTL responses (no presentation via MHC class I)
usually require addition of an adjuvant(s)
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Recombinant DNA technology for new vaccines
Reassortment vaccine for rotavirus (diarrheal pathogen)human rotaviral antigens placed into animal rotavirus genome
First recombinant vaccine -Hepatitis B vaccine (yeast) Made in Yeast
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Recombinant Viral and DNA Vaccines
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Public Health Issues of Vaccination
Goals1. Prevent infection and transmission
protects individual and reduces risk of unimmunized frominfection (herd immunity)
2. Prevent disease and/or transmission May not prevent infection, but prevents clinical disease
Risk vs. Benefit1. Individual or society
2. Always relative, changes with time
Ethics and Vaccine Utilization
1. Universal-mandated vaccines compared torecommended/optional vaccines
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Vaccine Safety Real vs. Perceived
Higher standard of safety needed for vaccines than therapies
No vaccine is completely safe
Next week- example -MMR lead to decrease rate measles
vaccine uptake fell in response to false assertion of role in risk forautism rate of measles increased
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Future of Vaccines
Major Global Infectious Diseases (chronic diseases) HIV, hepatitis C, malaria (Jennifer), more effective tuberculosis
vaccine, cancer (3rd Lecture -HPV, Marcia)
Obstacles Clarity of goals - must we prevent infection or is prevention of
disease sufficient?
Understanding essential mechanisms of protective immunity (ifthey exist)
Strategies
Innate immune response Greater understanding of tissue-specific regulation of immunity
New adjuvants
Recombinant DNA approaches - CTL immunity
HUGE CHALLENGE!
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Next week
Lecture 2: Vaccination and autism
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