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Lecture Notes
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Vaccines and Tolerance
2016 3/18
C.K.Shieh
§ Routine vaccination for common infectious diseases changes the life of every
human being in our world. In this lecture, we will discuss about the vaccines in use
and the strategies that have been used to develop useful vaccines. In addition we
will discuss about one of the complex and essential characters of acquired immunity,
antigen-specific tolerance.
Vaccination, the Most Successful Medical Practice
Many diseases have disappeared (small pox) or become rare (measles, poliomyelitis) due
to successful nationwide vaccination programs.
Vaccination Schedule in Taiwan
Not including: Human papilloma vaccine, pneumococcal vaccine. Including: HBV, BCG.
(When compared with vaccination schedule in the US)
Types of Vaccine Preparations
• Live organisms
• Non-living organism
• Subcellular fragments
• Toxoids
• Recombinant proteins
Live Vaccines
Important ones: polio (Sabin), measles, mumps, rubella (MMR), BCG, Rota virus
How a Live Attenuated Vaccine Is Prepared
Continuous culture in the cell lines or animals. Adequate mutations accumulate in the
live organism to attenuate its pathogenesis mechanisms.
Killed Organisms as Vaccines
More toxicity, low efficacy. Not often used now. Still in use in some countries:
pertussis (bacteria), polio (virus)
Vaccines Made From Subcellular Fragments
Important ones: HBV surface proteins, Hib, meningococcus and pneumococcus capsule
Toxoids
Diphtheria, tetanus (DT)
Recombinant viruses as vaccines
Strategy for future vaccines
Adjuvants for Vaccines
Only Al(OH)3 (Alum) is used in humans, acting as a reservoir in the injection site and
also as a pro-inflammatory stimulator (an inflammasome activator) at the same time.
Other adjuvants to boost the favored immune responses are being developed.
Non-specific Immunotherapy
Cytokines and other immunostimulants
Safety Problems
For live vaccines: reverse mutation to pathogenic microbes; fatal infection for
immunodeficient patients
For killed vaccines: contamination, strong reactions…
CNS effects for pertussis vaccine
Intussusception for Rota virus vaccine
Future Vaccines

Vaccines prepared from recombinant, non-virulent viruses (e.g. vaccinia virus)

Vaccines with immunomodulaing activities

Vaccines make from anti-idiotype antibodies
DNA Vaccines
Bare DNA (DNA without protein coating) is a form of “future vaccines” that is stable and
cheap. Bare DNA should enter the cells of hosts and be transcribed and translated.
The produced proteins then become the immunogens. The approach has the theoretical
advantage that it might induce stronger T cell responses than extracellular antigens.
Cancer Vaccines
• Coley used bacterial filtrate to stimulate immune system in order to reject tumors one
century ago.
• The idea of non-specific immune stimulation has attracted enormous amount of
imagination and efforts from both the scientific community and general public. Little
success was documented.
• New strategies based on insights in immune response to tumors will be used to design
approaches for “therapeutic vaccines”.
Regarding anti-idiotype antibodies as vaccines…
1. Balance of idiotype anti-idiotype network was believed to be an important basis for
immune responses and homeostasis between the body and the immune system.
Although this theory is no longer in the mainstream of immunology, some previous
findings remain true.
2. As the binding surface (idiotope) of an antibody may be the complementary image of
the original antigen, some anti-idiotope antibodies may bear similar antigenicity to the
original antigens. They may thus be used as vaccines. This idea, however, remains
more of theoretical interest than practical use. In some situation like production of high
affinity antibody against carbohydrate antibody, anti-idiotype Ab as a surrogate vaccine
appears more attractive.
Immunological Tolerance
1. Tolerance is one of the central characters of the immune system (along with memory
and specificity).
2. Location: Central tolerance and peripheral tolerance
3. Cell type: T cell tolerance and B cell tolerance
4. Mechanisms: deletion, anergy, immune deviation (ignorance), cell mediated
immunoregulation
5. Lack of appropriate co-stimulation as a way an antigen-specific tolerance induction
through different mechanisms.
Central and Peripheral Immunological Tolerance
1. Theoretically, most endogenous antigens can tolerize the immune cells during their
maturation in the “central” lymphoid organs. AIRE gene play an important role in
inducing the expression of various genes in the thymus.
2. Exogenous antigens usually are encountered in the peripheral tissues. e.g. food
antigens, air allergens
Regulatory T cells regulate immune responses in an antigen specific manner
through suppression at different levels.
1. Immunosuppressive cytokines: IL-10, TGF-, IL-35 etc.
2. IL-2 consumption
3. Direct cytolysis
4. Modulation of dendritic cells
Regulatory T cells regulate immune responses in an antigen specific manner
through suppression at different levels.
1. Anergy
2. Deletion
3. Receptor editing
4. Exclusion from sites for maturation