Lecture i Immunology of Vaccination 3863

7/31/2019 Lecture i Immunology of Vaccination 3863

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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

Lecture i Immunology of Vaccination 3863

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