1. Vaccination & Immunotherapy
Chapter 14
Also see on-line Influenza resource at
The Parents' Guide to Childhood Immunizations
Immunotherapy:
Using Immune system to fight disease
Vaccination is most familiar
Self-Test
Questions:
Intro: both
A: 1 – 5, 7, 8
B: 1 - 8
C - G: all
Disease Virus
Small pox variola
Cow pox vaccinia
Chicken pox varicella
Vaccination & Immunotherapy

2. Vaccination & Immunotherapy
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
Vaccination & Immunotherapy

3. Vaccination & Immunotherapy
What are different types of immunization?
Active Immunization
-- innoculation with antigens
-- activation of immune response
-- immunological memory
Passive Immunization
-- direct transfer of antibodies
-- no immunological memory
Vaccination & Immunotherapy

4. Vaccination & Immunotherapy
Passive Immunization is used to prevent Fetal Erythroblastosis
-- Rh is another blood cell antigen
Vaccination & Immunotherapy

5. Vaccination & Immunotherapy
How are active immunization vaccines made?
Dead (inactivated) pathogens
IPV – Inactivated polio vaccine – ‘Salk’ vaccine
[old pertussis of DPT -- Bordetella pertussis]
Live (active) attenuated pathogens
MMR – measles, mumps, rubella viruses
OVP -- oral polio vaccine – ‘Sabin’ vaccine
Subunit / Peptide components
HepB (HBsAG) -- Hepititis B surface antigen
Flu – purified HA & NA antigens
HiB – Haemophilus influenzae type B
PCV – pneumococcal conjugate vaccine
Toxoids
DTaP -- diphtheria, tetanus toxoids
[ + “acellular pertussis” molecular component]
Egg cultured virus
Attenuating live vaccines
Cell cultured virus
Vaccination & Immunotherapy

6. Vaccination & Immunotherapy
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
better cell-mediated response
reversion -- Sabin polio (Types 1 & 2)
infection in immunodeficient patients
less stable
Molecular components
No living pathogen present
very stable
fewer epitopes
weaker cell mediated response
Adequate & Appropriate immune response
Diversity of peptides (whole organisms better than molecules)
Type of immune response: generate antibodies, and B- and T- memory cells
-- live attenuated the best for cell mediated (infect cells; MHC-I presentation)
-- but depends upon what is needed
-- Influenza virus: neutralizing Ab is key to control
-- short incubation period (<2 days); mem cell activation to slow
-- taken every year (virus mutates; new vaccine produced each year)
-- Polio virus: has a incubation period >3 days
-- time for activation of mem cells; long-term immunity possible
Salk vs Sabin polio vaccines
Jonas Salk (inactivated) vaccine (1955) applied through a shot
-- through a serious of boosters, high serum Ab generated
Albert Sabin oral vaccine: in 1961; replaced use of Salk in U.S.
-- more effective (almost 100%); easy to administer (oral) but less stable (refrigerated)
-- establishes an infection (at least transient)
-- generates intestinal and serum immunity (& humoral & cell mediated)
-- i.e., neutralizing IgA (passes through M-cells);
In general, attenuated vaccines
-- higher yield of memory cells -- requires fewer boosters,
-- but have higher reversion rate (1 in 2.4 million doses for Sabin)
-- less stable
Improved inactivated virus (Salk) now available
-- CDC recommended vaccination schedule includes both types
Salk (twice) then Sabin, (to reduce risk of polio from Sabin)
Adverse reactions a possible for any vaccine
old pertussis vaccine (attenuated bacterium) part of DPT
-- bacterial toxin: caused occasional encephalitis, brain damage & death
-- growing resistance to its use
new vaccine (DTaP) (acellular)
-- molecular component; equally effective, no side effects
old Hepatitis-B vaccine: virus purified from human blood & killed
-- sometimes was infected with other viruses
new HBaAG vaccine: molecular component; through genetic engineering
-- no risk of infection
Vaccine type
Example reactions
Vaccines from Chicken eggs and cell cultures
Allergic reactions
Contaminating pathogens
Vaccines with Preservatives
Live attenuated
Susceptibility during preganncy and among immunodepressed
Dead whole cell
Contamination with toxins
Vaccination & Immunotherapy

7. Vaccination & Immunotherapy
Vaccination scheduling optimizes immune system response
Age is important
Similar vaccines combined
MMR
DPaT
Boosters build immunity
Many other vaccines for special needs
TB, anthrax, plague, yellow fever, etc
Vaccination & Immunotherapy

8. Vaccination & Immunotherapy
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
Vaccination & Immunotherapy

9. History of vaccine success
Anti-vaccine campaigns are misguided
-- preservatives do not pose health issues
-- failure to vaccinate creates greater risk
Vaccine efficacy
= percent protected
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]
History of vaccine success
Cases per Year Decrease
before in in Cases
(average) per Year
Diphtheria 175, %
Measles 503, %
Mumps 152, %
Polio (paralytic) 16, %
Rubella 47, %
Smallpox 48, %
Tetanus 1, %
Vaccination & Immunotherapy

10. Vaccination & Immunotherapy
Why do we need to get an Influenza vaccine every year?
Genetic material
 8 short RNA molecules
2 key surface antigens
Hemaglutinin -- HA
Neuraminidase – NA
Different forms are numbered
1,2,3  “N1H2”, “N2H3”, etc.
Influenza can infect animals
-- birds, pigs, etc
-- are the viral “reservoir”
H & N antigens change types periodically
Minor genetic changes  seasonal flu
Major genetic changes  pandemic flu ??
Vaccination & Immunotherapy

11. Vaccination & Immunotherapy
Types of flu vaccines
Some contain . . .
1) inactivated whole viruses
-- Salk-like vaccine
2) purified HA & NA antigens
-- injected
3) live attenuated viruses
-- Flu-mist, nasal spray
-- only 46% effective
-- not recommended
Capacity only ~ 300 x 106 doses
Vaccination & Immunotherapy

12. Vaccination & Immunotherapy
Seasonal ‘Flu’
~36K deaths
~200,000 hospitalizations
Why is Flu seasonal?:
social interactions
environmental conditions
Spread of new forms
H and N change slightly annually
-- slightly different forms of viruses
-- different “mixes” of forms
= “Antigenic drift”
-- minor mutations in H and N genes
One recent vaccines contained
A -- New Caledonia/20/99 (H1N1)
A -- Wisconsin/67/2005 (H3N2)
B -- Malaysia/2506/2004
Vaccination & Immunotherapy

13. Vaccination & Immunotherapy
Pandemic Influenza
Genetic segments can recombine
Naturally in a host animal
-- “Antigenic-Shift”
-- DNA segments recombine
-- in animal hosts
Challenges to control
Vaccine development time
Production capacity
Distribution
Economics
Vaccination & Immunotherapy

14. Vaccination & Immunotherapy
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
Vaccination & Immunotherapy

15. Vaccination & Immunotherapy
Modern Immunotherapy
Direct activation/repression of immune cells
& cell subpopulations
-- autoimmune disease
-- transplant rejection
-- cancer
Long history: “Coley’s Toxins”
Now at advent of Cancer Immunotherapy
-- highly specific targeting
Vaccination & Immunotherapy

16. Vaccination & Immunotherapy
Conventional cancer treatments attempt to kill the cancerous cells
Radiotherapy
-- focuses radioisotope radiation on cancers
-- can miss secondary tumors
Chemotherapy
-- cell division inhibitors
-- cause dividing cells to die
-- not very specific
Vaccination & Immunotherapy

17. Vaccination & Immunotherapy
Our immune system can also kill cancerous cells
-- Why are cancerous cells perceived as being “foreign”?
Cancer immune
response
Vaccination & Immunotherapy

18. Vaccination & Immunotherapy
Immune attack is a cyclic process
which are
engulfed by
Professional
Antigen-Presenting
Cells . . .
4. Activated T-cells then
enter circulation . . .
and infiltrate tumors located any where in body.
and trigger apoptosis of the cancer cells
which then
travel to 2O
lymphoid organs and
activate T-cells
6. T-killer cells recognize “foreign” antigens on tumor cells . . .
1. Cancer cells produce & release foreign antigens . . .
Vaccination & Immunotherapy

19. Vaccination & Immunotherapy
Cancers can evade
immune system attack
Unrecognized cancer
antigens
-- T-cells do not respond
No/reduced MHC
Proteins that block
Immune system
Vaccination & Immunotherapy

20. Vaccination & Immunotherapy
Types of Cancer Immunotherapy,
1) Cell Therapy
May involve Infusion of :
A. Hematopoietic stem cells
-- commonly used for leukemia, etc
B. Dendritic cells
C. T cells or NK cells
-- engineer to produce Anti- tAG TCR
Vaccination & Immunotherapy

21. Vaccination & Immunotherapy
Types of Cancer Immunotherapies, cont.
2) Cancer vaccines
- target cancer-specific antigens
3) Cell coupling molecules
-- “Bispecific molecules” (mAb)
-- e.g., Blinatumomab (“Blincyto”)
 B-cell leukemia
-- coupled Fabs against CD3 & CD19
4) Cell activating/repressing molecules -- e.g., Rituximab:
-- mAb against CD-20 (Ca++ channel?)
-- triggers B-cell destruction
Checkpoint inhibitors
-- very important class of treatments
Vaccination & Immunotherapy

22. Vaccination & Immunotherapy
As you know, many different proteins participate in activation of T-cells
-- form an “Immune synapse”
These proteins may…
-- be needed for T-cell
activation
-- suppress T-cells
Called “Checkpoint Regulators”
Suppressive proteins often compromise the immune response to cancer
Vaccination & Immunotherapy

23. Two checkpoint regulators are particularly important to cancer immune evasion
T-cell express CTLA-4 to suppress eventually immune responses
Tumor cells can express PD-1L to block apoptosis
Vaccination & Immunotherapy

24. Vaccination & Immunotherapy
Modern immunotherapies help the immune system circumvent checkpoints
T-cell transfer therapy Monoclonal antibodies
-- retrain/stimulate cells checkpoint blockers
Vaccination & Immunotherapy

25. Vaccination & Immunotherapy
Ipilimumab binds
to CTLA-4
Examples of checkpoint blocking immunotherapies
Nivolumab binds to PD-1
CTLA4 is a regulator
Of T-cell activation
Vaccination & Immunotherapy

26. Vaccination & Immunotherapy
Immunotherapies are not without some side effects
-- Create an “unleashed” immune system
… and are very expensive
Vaccination & Immunotherapy