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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 to global health Ingunn Stromnes, PhD Postdoctoral fellow Department of Immunology Lecture I March 30, 2010
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Page 1: Lecture I: Immunology of Vaccination

Lecture I:Immunology of Vaccination

BIOL 485 A - SENIOR SEMINAR IN CELLULAR,MOLECULAR ANDDEVELOPMENTHot Topics in Disease Prevention: From single cells toglobal health

Ingunn Stromnes, PhDPostdoctoral fellow

Department of ImmunologyLecture I

March 30, 2010

Page 2: Lecture I: Immunology of Vaccination

Foundation of vaccination and immunology stem from infectious disease

Smallpox virion Clinical manifestation 20th Century ~ 300-500

million deaths

Variola major(~30% fatality)

1721 - variolationintroduced in Europe(1% fatality)

Page 3: Lecture I: Immunology of Vaccination

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 fromcows protect them from Smallpox

“Don’t think, act.”William Harvey, 16thcentury

First empirical proof of protective immunity

Experiment :1. Inoculated 8 year-old James Phipps with materialfrom 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

Page 4: Lecture I: Immunology of Vaccination

>4,000 BC

Smallpoxoriginates inIndia/China,Middle East

or Africa

1400

Europeanfatalities

>500,000/yr(1400-1800)

1823

Variolationoutlawed

1950

Freezedried

vaccine

WHOsupportsfurther

research

20021520

Aztecempire

collapses(Cortez)

1096

Crusadersbring

Smallpox toEurope

(1096-1200)

Massproductionof vacciniain calf skin

1863 1978

LastSmallpox

fatality

2001

USA retainsVariolastock at

CDC

Adapted from Smith and McFadden, Nature Revews Immunology, 2002

History of Smallpox

1993

Variolagenome

sequenced

1977

Last naturalcase of

Smallpox

1967

WHOintensifieseradication

program

1723

Variolationintroduced in

Europe

Smallpoxeradicated

19791796

Vaccinationby Jenner

Page 5: Lecture I: Immunology of Vaccination

How was the eradication Smallpox possible?

• Smallpox vaccine was effective against all strains of variolaviruses

• High fidelity DNA polymerase, variola viruses were unableto undergo antigenic variation to escape existing immunity(Contrasts with RNA viruses such as HIV and influenza which undergo high mutationrates 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 of Variola major, or recovered)

• Symptoms of Smallpox were readily detectable(Contrasts with HIV- long latency period, spread throughout the population to 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

Page 6: Lecture I: Immunology of Vaccination

How is prior exposure to a similar pathogen protecting from disease?

1. Specificity- generating an immune responseto a specific pathogen

2. Memory- Maintaining that response overtime in order to prevent re-infection with asimilar pathogen

Page 7: Lecture I: Immunology of Vaccination

The immune system is composed of innateand adaptive immunity

Innate immune response (myeloid cells)

• First line of defense• Programs the adaptive immune response

Adaptive immune response (lymphocytes)• Specificity• Immunological memory

Autoimmunediseases(MS, RA)

Resistance toinfection

Resistance tocancer progression

Chronic inflammatorydiseases

Page 8: Lecture I: Immunology of Vaccination

thymus

bone marrow

T Cells

B Cells

CD4+ helper T cells

CD8+ cytotoxic T cells

Myeloid cells(DCs.,etc..)

AdaptiveLymphocytes

BB cell receptor(BCR)

Antibody(secretedBCR)

T TTCR

CD8

TCR

CD4

Blood & Tissues

InnateMyeloid cells

Page 9: Lecture I: Immunology of Vaccination

All immune cells are derived from a singlehemopoietic stem cell

Page 10: Lecture I: Immunology of Vaccination

InfectionInnate

Response

Induction of adaptiveresponse

Adaptive immune response Memory

Level of microorganism

Threshold level of

antigen to detect a response

Entry of microorgansim

Pathogen cleared

Duration of infection

Adapted from Immunobiology

Page 11: Lecture I: Immunology of Vaccination

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 infectionII. T cell responses

• CD4 helper T cells- enhance antibody response andformation of CTL memory

• CD8 CTL- anti-viral immunity

Page 12: Lecture I: Immunology of Vaccination

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)

http://www.healthjockey.com/images/flu-virus.jpg

Replicates outside of the cell Replicates inside of the cell

Cytotoxic T cells(CTLs) are requiredto eliminateinfected cells

Antibodies arerequired to‘neutralize’extracellularpathogens

‘Humoral’ immunity(ie., antibodies) isessential

‘Cell-mediatedimmunity’ (ie., CTLs, isessential) antibodieshelp too

Page 13: Lecture I: Immunology of Vaccination

1.Virus infects APC

2. APC presents viral antigen

3. APC activates CD4 T cell

4. Helper CD4 T cellhelps CTL and B cells

5. Antigen-specific B cells are activated

6. Antigen-specific B cells secreteantibody

8. CD8 CTLs kill Infected cells

7. Antibodies attach to virus, signal for virus destruction

Page 14: Lecture I: Immunology of Vaccination

Antigen-specific T cell

virus

Antigen presenting cell

PRR

MHC/AntigenCytokines and chemokinesCostimulatory moleculesMigrated to lymph nodePresent antigen to T cells

ProliferateMigrate to sites of infected tissuesActivate B cellsForm immunological memory

Page 15: Lecture I: Immunology of Vaccination

How do cells of the innate immune response recognize pathogens? Implications for vaccine design.

• Innate cell recognition depends on molecular differencesbetween host cells and the infectious organism

• Innate immune cells express pattern recognitionreceptors (PRRs) that recognize pathogen-associatedmolecular patterns (PAMPS) expressed by pathogens (forexample, TLR-4 receptor recognizes LPS)

Page 16: Lecture I: Immunology of Vaccination

Molecular Biology of the Cell

How were the first experiments performed to understand T cell recognition of foreign antigen?

Page 17: Lecture I: Immunology of Vaccination

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?

Page 18: Lecture I: Immunology of Vaccination

sites.google.com/site/stratikos/mhc

T cells are constantly scanning self/host cellsfor expression of ‘foreign’ peptides

MHC

peptide

Page 19: Lecture I: Immunology of Vaccination

Molecular Biology of the Cell

B cells proliferate and secrete antibody after encounter with foreign antigen (need CD4 help)

Page 20: Lecture I: Immunology of Vaccination

Molecular biology of the cell

Immune response is always greater after secondary exposure to the same antigen

(principle of booster immunizations)

Page 21: Lecture I: Immunology of Vaccination

Naïve cell

Activated cellMemory cell

Immuneresponse is

always greaterafter

secondaryexposure to thesame antigen

Activated cell

Memory cell

Page 22: Lecture I: Immunology of Vaccination

Original Rabies vaccine (early 1900’s)

Designing an effective and safevaccine - it is just not that simple….

• Caused paralysis in some recipients

• However, the vaccine also generated an immuneresponse to the rabbit brain tissue (myelin sheath) insome individuals

• High homology between rabbit myelin and human myelinproteins

• Immune response that generated to rabbit brain, cross-reacted with human myelin tissue- autoimmunit

• Vaccine was made from inoculated rabbit brain

Page 23: Lecture I: Immunology of Vaccination

Failure of HIV Vaccine STEP trial (2008)

Designing an effective and safevaccine - it is just not that simple….

• Vaccine may have increased risk among people who hadpre-existing immunity to the common cold virus

??? Unknown - challenged the field to understand vector-based immunity

• HIV vaccine - modified adenovirus type 5 (recombinantvaccine) that contained 3 HIV genes

Page 24: Lecture I: Immunology of Vaccination

SafetyEfficacy

• Safety standards are muchhigher for preventative treatmentscompared to therapeutictreatments

• Live-attenuated vaccines - livevaccines that have beenweakened can be more effectivethan non-replicating vaccines, butalso pose more risks

Vaccine design: Balance betweenefficacy and safety

Page 25: Lecture I: Immunology of Vaccination

Modern Day Vaccine Design

• Antigen(s) - any protein, peptide, substance, etc., thatstimulates an immune response (SPECIFIC to thepathogen of interest)

• Adjuvant - a substance that enhances the immuneresponse to a weakly immunogenic antigen (non-specific)

Page 26: Lecture I: Immunology of Vaccination

Class activity - interpret this table

Page 27: Lecture I: Immunology of Vaccination

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 cells•Induce antibodies, CD4 and CD8 T cells for live viral vaccines. CTL areinduced effectively because viral proteins are synthesized inside of the cellsand thus efficiently loaded onto MHC class I in cells – this does not occurwith killed or subunit vaccines.

•Disadvantages•May cause disease in immunocompromised hosts•Passive maternal antibodies may interfere with efficacy

Page 28: Lecture I: Immunology of Vaccination

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

Page 29: Lecture I: Immunology of Vaccination

Types of Vaccines…

• Whole organism vaccine• Organisms 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 antigens•Do not induce a CD8 T cell response (no MHC class I presentation)• Examples of bad ones- inactivated measles, RSV

• Subunit vaccines•Composed 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)

Page 30: Lecture I: Immunology of Vaccination

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

Page 31: Lecture I: Immunology of Vaccination

Recombinant Viral and DNA Vaccines

Page 32: Lecture I: Immunology of Vaccination

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 society2. Always relative, changes with time

Ethics and Vaccine Utilization1. Universal-mandated vaccines compared torecommended/optional vaccines

Page 33: Lecture I: Immunology of Vaccination

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

Page 34: Lecture I: Immunology of Vaccination

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 (if

they 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 weekLecture 2: Vaccination and autism