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Ab formation
Hallmarks
of the
Immune Response
• Self/Non-self Discrimination
• Memory
• Specificity
Fate of the Immunogen
– Equilibrium phase
– Catabolic decay phase
– Immune elimination phase
• Clearance after 2o exposure
– More rapid onset of immune
elimination phase
Amount of Circulating Ag (%)
• Clearance after 1o exposure
Equilibrium Phase
100
75
50
Catabolic
Decay Phase
Immune
Elimination
Phase
25
2
4 6 8 10 12
Days after Injection
Kinetics of the Ab Response
T-dependent Ag; 1o Response
LAG
LOG
PLATEAU
DECLINE
Ab Titer
• Lag phase
• Log phase
• Plateau phase
• Decline phase
Ag
Days After Immunization
Kinetics of the Ab Response
• Lag phase
• Log phase
• Plateau phase
• Decline phase
Ab Titer
T-dependent Ag; 2o Response
1o Ag
2o Ag
* Specificity
Days After Immunization
Qualitative Ab Changes during
1o and 2o Responses
• Class variation
Total
Ab
IgG Ab
IgM
Ab
– 2o - IgG, IgA or IgE
Ab Titer
– 1o - IgM
1o Ag
2o Ag
Days After Immunization
Qualitative Ab Changes during
1o and 2o Responses
• Class variation
• Affinity
Maturation
Low Dose
AffInIty
– Affinity
IgG Ab
IgM Ab
1o Ag
2o Ag
High Dose
Days After Immunization
Qualitative Ab Changes during
1o and 2o Responses
• Class variation
• Affinity
– Clonal selection
High Ag Concentration
1010
109
108
107
106
105
Moderate
Affinity Ab
– Somatic mutation
Low Ag Concentration
1010
107
109
106
108
105
High
Affinity Ab
Qualitative Ab Changes during
1o and 2o Responses
• Class variation
• Affinity
• Avidity
• Cross reactivity
Affinity of Ab for Ag
Early
Immunizing
Ag
Cross
reactive Ag
6
10
+
3
10
-
Late
9
10
++
6
10
+
Cellular Events in 1o Response to
T-dependent Ags
• Lag
– Clonal selection
• Log
– IgM
– Class switching
• Stationary
• Decline
• Memory Cell Pool
1o Ag
IgM
IgG
Memory Cells
Cellular Events in 2o Response to
T-dependent Ags
• Lag phase
– Virgin cells
– Memory cells
Virgin B cell
• Log phase
IgG
– Pool size
– IgG, IgA or IgE
• Stationary
• Decline
– Sustained
production
IgM
Memory
Pool
Memory
Cells
IgG
Memory
Cells
Memory T cells
• T Cells
– Virgin cells
– Memory cells
Virgin cell
• Th cells
Th
Th
– Cytokines
• Long Term
Memory
Memory
Pool
Memory
Cells
Th
Memory
Cells
Kinetics of Ab Response to
T-independent Ags
Ab Titer
• 4 Phases
• IgM
antibody
• No
secondary
response
IgM Ab
1o Ag
2o Ag
Days After Immunization
Class Switching
L
• DNA
rearrangement
– Antigen
dependent
– Switch site
– Same VDJ
– TH cytokines

VDJ
S
P

1
 
3
S
S

2
S

4

1

S
S
S

2
S
DNA
DNA Rearrangement

L VDJ
P
L VDJ


S
L VDJ
 
1
2
S
S
DNA

RNA
Primary Transcript IgM
or IgD
Primary Transcript
IgE
Membrane vs Secreted Ig
Polyadenylation Sites
• Differential
pre-mRNA
processing
– Membrane
exons
– Alternate
polyA sites
– Same VDJ
region used
H3 H4
M
M
DNA
H3 H4
H3 H4
M
M
AAAA
H3 H4
AAAA Primary
Transcript
H3 H4MM
AAAA
Secreted
AAAA
Membrane
Bound
mRNA
Milestones in immunization
3000BC
 Evidence
of sniffing
powdered small pox
crust in Egypt
2000BC
 Sniffing
of small
pox crust in China
1500BC
 Turks
introduce
variolation
1700AD
Introduction
of
variolation in England
and later in the US
17
Introduction of variolation
The wife of the British Ambassador in
Turkey, in March 1717 wrote, following
the variolation of her son, to a friend in
England: “The small pox, so fatal, so general
amongst us, is entirely harmless here
by the invention of ingrafting….I am
patriot enough to bring this invention into
fashion in England.
18
Milestones in immunization
1780AD

Edward Jenner discovers small
pox vaccine
19
Edward Jenner
Discovery of small pox vaccine
20
Edward Jenner
Among patients awaiting small pox vaccination
21
Modern era of the vaccine
1885
Rabies vaccine
(Pasteur)
1920s
Diphtheria and
Tetanus
1934
Pertussis
1955
Salk polio
22
Modern era of the vaccine
1960s
Mumps measles
and rubella virus
Sabin polio
1990s
Hepatitis and
varicella
1985
Haemophilus
 2000
Human Papillomavirus
(HPV)
23
Pre- & post-vaccine incidence of
common preventable diseases
24
Different modes of acquiring
immunity
Immunity
Natural
resistance
Passive
Acquired
Active
Artificial Natural Artificial Natural
25
Passive Immunity
Natural
Artificial
Placental
transfer of IgG
Antibodies or
immunoglobulins
Colostral
transfer of IgA
Immune cells
26
Passive Immunization
disease
diphtheria, tetanus
antibody
source
human, horse
indication
prophylaxis, therapy
vericella zoster
human
immunodeficiencies
gas gangrene,
botulism, snake bite,
scorpion sting
horse
post-exposure
rabies,
human
post-exposure
human
prophylaxis
hypogammaglobulinemia
27
Advantages and Disadvantages
of Passive Immunization
Advantages
Disadvantages
no long term
protection
immediate
protection
serum sickness
risk of hepatitis
and Aids
graft vs. host
disease (cell
graft only)
28
Active Immunization
Natural
Artificial
Attenuated
organisms
killed organisms
exposure to subclinical infections
subcellular
fragments
toxins
others
29
Live Attenuated Vaccines
polio*
hepatitis A
not used in std. schedule
standard 2006
measles, mumps
& rubella
yellow fever
Varicella zoster
children with no
history of chicken pox
Military and travelers
Influenza
selected age group
(5-49)
tuberculosis
not used in this
country
30
Killed Whole-Organism Vaccines
Q fever
polio
influenza
elderly and at risk
rabies
post
exposure
population at risk
typhoid, cholera, plague
epidemics and travelers
pertussis
replaced by the
acellular vaccine
31
Microbial Fragment Vaccines
Bordetella. Pertussis
virulence factor protein
Haemophilus influenzae B
protein conjugated polysaccharide
Streptococcus pneumoniae
Polysaccharide mixture
Neisseria meningitidis
polysaccharide
32
Microbial Fragment Vaccines
Clostridium tetani (tetanus)
inactivated toxin (toxoid)
Corynebacterium diphtheriae
inactivated toxin (toxoid)
Vibrio cholerae
toxin subunits
Hepatitis B virus
cloned in yeast
33
Modification of Toxin to Toxoid
Toxin
Toxoid
chemical
modification
toxin moiety
antigenic determinants
34
Future Vaccines
anti-Idiotype Vaccine
DNA
Immuno-dominant peptide
35
anti-Idiotype Vaccine
36
Antiidiotype antibody in tolerance
Antiidiotype antibody
production
Antiidiotype mediated
tolerance
37
Adjuvants
Adjuvant type
Human use
• Salts:
• Al(OH)3; AlPO4;
CaPO4
• Be(OH)2
• Mineral oils without
bacteria
• Bacteria in Mineral oils
(Mycobacteria,
Nocardia)
Mode of action
Yes
Yes
No
Slow release of antigen;
TLR interaction and
cytokine induction
No
Slow release of antigen
Yes
No
Slow release of antigen
TLR interaction and
cytokine induction
38
Adjuvants
Adjuvant type
• Bacteria:
• Bordetella pertussis
• Mycobacterium bovis
(BCG and others)
Human use
Yes
No
TLR interaction and
cytokine induction
No
TLR interaction and
cytokine induction
• Bacterial products:
• Myramyl peptides
• Synthetic polymers:
• Liposomes
• ISCOM
• Poly-lactate
Mode of action
No
Slow release of antigen
39
Adjuvants
Adjuvant type
Human use
• Poly-nucleotides:
• CpG
No*
TLR interaction and
cytokine induction
No*
Activation of T and B
cells and APC
• Cytokines:
• IL-1, IL-2, IL-12,
IFN-γ, etc.
Mode of action
*Used in experimental immunotherapy of human
malignancies
40
Recommended Childhood
Immunization Schedule
Recommended age range
Catch-up immunization
Certainigh risk groups
41
MMWR, 55: Jan 5, 2007
Recommended Immunization
Schedule for Ages 7-18
Recommended age range
Catch-up immunization
Certain high risk groups
MMWR, 55: Jan 5, 2007
42
Adverse Events Occurring
Within 48 Hours DTP of Vaccination
Event
Frequency
local
redness, swelling, pain
1 in 2-3 doses
systemic: Mild/moderate
fever, drowsiness, fretfulness
vomiting
anorexia
1 in 2-3 doses
1 in 5-15 doses
systemic: more serious
persistent crying, fever
collapse, convulsions
acute encephalopathy
permanent neurological deficit
1 in 100-300 doses
1 in 1750 doses
1 in 100,000 doses
1 in 300,000 doses
44