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
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)
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
>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
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
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
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
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
All immune cells are derived from a singlehemopoietic stem cell
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
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
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
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
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
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)
Molecular Biology of the Cell
How were the first experiments performed to understand T cell recognition of foreign antigen?
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?
sites.google.com/site/stratikos/mhc
T cells are constantly scanning self/host cellsfor expression of ‘foreign’ peptides
MHC
peptide
Molecular Biology of the Cell
B cells proliferate and secrete antibody after encounter with foreign antigen (need CD4 help)
Molecular biology of the cell
Immune response is always greater after secondary exposure to the same antigen
(principle of booster immunizations)
Naïve cell
Activated cellMemory cell
Immuneresponse is
always greaterafter
secondaryexposure to thesame antigen
Activated cell
Memory cell
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
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
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
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)
Class activity - interpret this table
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
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
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)
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
Recombinant Viral and DNA Vaccines
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
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
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!
Next weekLecture 2: Vaccination and autism
Top Related