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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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
•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
–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