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Immunotherapy and
Vaccination
Immunotherapy:
Chapter 14
Vaccination is most familiar
Using Immune system to fight disease
Also see on-line Influenza
resource at
http://www.influenzareport.com/ir/vacci
nes.htm
The Parents' Guide to Childhood
Immunizations
http://www.cdc.gov/nip/publications/Par
ents-Guide/2005-parents-guide.pdf
Self-Test
Questions:
Intro: both
A: 1 – 5, 7, 8
B: 1 - 8
C - G: all
Disease
Virus
Small pox
Cow pox
Chicken pox
variola
vaccinia
varicella
Immunotherapy
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Edward Jenner and the
origin of Immunotherapy
(vaccination)
Small pox caused by ‘variola virus’
Induced immunity dates to ancient Chinese
-- practiced ‘Variolation’
-- brought to England in 1700s
-- lead to the ‘Royal experiment’
Jenner discovered protective effect of cow pox
-- ‘vaccinia virus’
-- ‘vacca’ Latin for cow - vaccination
WHO irradicated small pox in 1970s
Immunotherapy
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What are different types of
immunization?
Passive Immunization
-- direct transfer of protective antibodies
-- no immunological memory
Active Immunization
-- activation of immune response
-- immunological memory
Therapeutic Immunization
-- treat existing disease
Immunotherapy
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Passive Immunization to treat Fetal Erythroblastosis
Conditions: mother Rh—; father, 1st and 2nd fetuses are Rh+
Rh
Immune hemolysis
Rhogam
Given 24-48 hours
after 1st pregnancy
Immunotherapy
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Active Vaccination: What are
some important considerations
in the design of vaccines?
Characteristics of pathogen & disease
Intra- vs extra-cellular
short or long incubation
acute or chronic disease
Antigenic stability
route of infection
Characteristics of vaccine
appropriate response
booster
safety
stability, cost
Characteristics of patient
Infants (vs adults) have lower…
-- GC activity
-- Plasma cell production
-- TH1 response
Maternal Ab black responses
Immunotherapy
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What are the recommended childhood vaccines?
Combined vaccines
Why are boosters needed?
Other vaccines for
special needs
TB, anthrax, plague,
yellow fever, etc
Immunotherapy
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Vaccine efficacy
vs
Efficacy – under trial conditions
incidence among those administered
1- ------------------------------------------- ------------------------------------------incidence among those not administered
Example efficacies
Diphtheria: 87%-96%
Tetanus: >90%
Oral polio: 90%-100%
Mumps/Measles/Rubella:
90%-95%
HIV vaccine trials
150 vaccines developed
6 have made it to efficacy testing
2009: 1st with efficacy (31%)
[2007 had negative efficacy]
Malaria vaccine trial
2011: 45 – 56%
effectiveness
Calculated under “field” conditions
i.e., real world conditions
-- religious/cultural opposition
-- available medical facilities
-- etc
Is 100% efficacy necessary?
-- “herd immunity”
Diphtheria
Hib (<5 yrs old)
Measles
Mumps
Pertussis
Polio (paralytic)
Rubella
Smallpox
Tetanus
Immunotherapy
Cases per Year
before
in
(average)
2003
175,885
1
20,000 (est.)
259
503,282
56
152,209
231
147,271
11,647
16,316
0
47,745
7
48,164
0
1,314
20
Decrease
in Cases
per Year
99.9%
98.8%
99.9%
99.9%
92.1%
100.0%
99.9%
100.0%
98.5%
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How are vaccines made?
Dead (inactivated) pathogens
IPV – Inactivated polio vaccine – ‘Salk’ vaccine
[old pertussis of DPT -- Bordetella pertussis]
Live attenuated pathogens
MMR – measles, mumps, rubella viruses
OVP -- oral polio vaccine – ‘Sabin’ vaccine
Cell cultured virus
Subunit / Peptide components
HBsAG -- Hepititis B surface antigen
Flu – purified HA & NA antigens
Conjugates (polysaccharides coupled to protein carrier)
HiB – Haemophilus influenzae type B
PCV – pneumococcal conjugate vaccine
Remember Adjuvants?
Toxoids
DTaP -- diphtheria, tetanus toxoids
[ + “acellular pertussis” molecular component]
-- increase immune response
e.g., aluminum hydroxide
McGraw-Hill
Vaccines
Immunotherapy
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What are pros and cons of different types of vaccines?
Dead (inactivated) pathogens
pros
may be safer; more stable than attenuated
cons
weaker cell mediated response; boosters
contaminants – pertussis endotoxin in old DPT
Live attenuated pathogens
pros
better cell-mediated response
cons
reversion -- Sabin polio (Types 1 & 2)
infection in immunodeficient patients
less stable
Molecular components
pros
No living pathogen present
very stable
cons
fewer epitopes
weaker cell mediated response
Vaccine type
Example reactions
Vaccines from
Chicken eggs and cell
cultures
Allergic reactions
Contaminating pathogens
Vaccines with
Preservatives
Allergic reactions
Live attenuated
Susceptibility during preganncy
and among immunodepressed
Dead whole cell
Contamination with toxins
Immunotherapy
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Why do we not have vaccines for
serious protozoal diseases
-- malaria, African sleeping sickness
Plasmodium causes Malaria
-- Anopholes mosquito is vector
Trypanosoma cause ASS
-- tsetse fly is vector
Complex life cycles
Chronic diseases
Undergo “Antigenic Shift”
Trypanosoma carries ~1000 VSG genes
(variant surface glycoprotein)
~1% of parasites shift AG
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Influenza: the disease
Principal virus subtypes -- A & B
Key surface antigens
Hemaglutinin -- HA
Neuraminidase – NA
-- numbered 1,2,3, etc
Causes of seasonality unclear:
Δ antigenicity/ infectiousness
social interactions
environmental conditions
Current circulating forms
H3N2*, H1N1, H1N2,
~36K deaths
~200,000 hospitalizations
Immunotherapy
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Influenza con’t:
Circulating stains vary annually
-- “antigenic drift”
-- vaccine must accommodate
Recent vaccines contain
A -- New Caledonia/20/99 (H1N1)
A -- Wisconsin/67/2005 (H3N2)
B -- Malaysia/2506/2004
Vaccines types
Injection – inactivated whole virus or
purified HA & NA antigens
Nasal spray “FluMist”
-- cold adapted attenuated
Prepared in eggs
Capacity only ~ 300 x 106 doses
Immunotherapy
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Pandemic Flu
“Antigenic-Shift” can occur
History
1918 Spanish Flu (H1N1; 40 mil dead)
1957 Asian Flu (H2N2; ~1 mil+ dead
1968 Hong Kong Flu (~0.75 mil dead)
-- AG-shift from H2N2 to H3N2
Swine Flu 2009
H1N1 vaccine (influenza A/California/07/2009)
15 μg HA or
106.5-107.5 pfu of live attenuated virus
Challenges to vaccination
Development time
Production capacity (use of eggs?)
Distribution
Economics
Vaccination strategy
Current spread of H5H1
Immunotherapy
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Modern Immunotherapies
Rituximab mechanisms
Immunotherapies for
Autoimmune disorders / transplant rejection
1) B-cell elimination
-- e.g., Rituximab:
-- mAb against CD-20 (Ca++ channel?)
-- triggers B-cell destruction
At advent of Cancer Immunotherapy
-- Long history: “Coley’s Toxins”
-- immune activation
What are “Cancer Antigens”?
Immunotherapy
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Other Types of Cancer
Immunotherapies
Checkpoint inhibitors
2) Checkpoint inhibitors
-- Why do many cancers evade
immune destruction?
3) Cancer vaccines
- target cancer-specific antigens
4) Cell coupling
-- “Bispecific molecules” (mAb)
-- e.g., Blinatumomab (“Blincyto”)
 B-cell leukemia
-- mAb Fabs against CD3 & CD19
Immunotherapy
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Types of Cancer Immunotherapy,
con’t
5) Cell Therapy
May involve Infusion of :
A. Hematopoietic stem cells from either
umbilical cord blood, peripheral blood, or bone
marrow cells
-- commonly used for leukemia, etc
B. Dendritic cells
C. T cells or NK cells treated in vitro
to recognize and kill cancer cells directly.
-- engineer to produce Anti- tAG TCR
Immunotherapy
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