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IMMUNE RESPONSES
TO MICROBES AND VACCINES
DEVELOPMENT
Infectious diseases are among the
leading causes of death worldwide
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Innate Immunity to Extracellular
Bacteria
• Complement activation
• Activation of phagocytes and inflammation
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Adaptive Immunity to Extracellular
Bacteria
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Bacteria Can Evade Host Defense Mechanisms
at Several Different Stages
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multiple mechanisms used by Neisseria to evade
humoral immunity
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IMMUNITY TO INTRACELLULAR BACTERIA
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Mechanisms of Immune Evasion by
intercellular Bacteria
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Innate and adaptive immune responses against viruses
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Many Viruses Are Neutralized by
Antibodies
• influenza virus binds to sialic acid residues in cell
membrane glycoproteins and glycolipids
• rhinovirus binds to inter cellular adhesion molecules
(ICAMs)
• Epstein-Barr virus (EBV) binds to type 2 complement
receptors on B cells.
So
antibodies may block viral penetration
Fc-receptore –mediated phagocytosis
complement-activating antibody
lysis or C3b-receptore mediated phagocytosis
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Cell-Mediated Immunity Is Important
for Viral Control and Clearance
• Antibodies can not eliminate established
infection!!!
• NOW, cell-mediated immune mechanisms are
most important in host defense.
• CD8+ TC cells and CD4 TH1 cells
• cytokines, including IL-2, IFN-γ, and tumor necrosis
factor- α (TNF-α)
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Viruses Employ Several Different Strategies
to Evade Host Defense Mechanisms
• Hepatitis C virus (HCV)
• human immunodeficiency
Virus (HIV)
• Herpes simple virus (HSV)
• Polio virus
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Cytosolic receptors for PAMPs and DAMPs
HIV
Vaccinia
RIG-1-like receptors
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C3a
C3b
C3
Ba
C3
C3b
Alternative C5
convertase
Bb
C3bB
C3bBb
C3bBb3b
Alternative C3
convertase
Factor B
Bacterium
Factor D
Factor H
Properdin
HIV
Lysis
C5-C9
MAC
C5b
C5a
MEMBRANE
ATTACK
COMPLEX
C9
C8
(CD59)
C7
C5
C6
HIV and human CMV
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• An anti-inflammatory cytokine.
• An inhibitor of
and
.
• Negative feedback regulator.
• Inhibits production of
.
and ultimately
• Inhibits the expression of
on MQs and DCs.
and
Epstein-Barr virus (EBV) produce IL-10 like cytokine
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Innate and Adaptive Immunity to Fungi
• The principal mediators of innate immunity against
fungi are neutrophils and macrophages.
– TLRs and lectin-like receptors (dectins)
• Dendritic cells activated via this lectin receptor
produce TH17-inducing cytokines, such as IL-6 and
IL-23.
– The Th17 cells stimulate inflammation, and the recruited
neutrophils and monocytes destroy the fungi
• Cell-mediated immunity is the major mechanism of
adaptive immunity against fungal infections.
– CD4+ and CD8+ T cells cooperate to eliminate the yeast
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Mechanisms of Immune Evasion by
fungal
• Virulent strains of Cryptococcus neoformans
inhibit the production of cytokines such as
TNF and IL-12 by macrophages and stimulate
production of IL-10, thus inhibiting
macrophage activation.
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Immune Responses to Disease-Causing
Parasites
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Mechanisms of Immune Evasion by Parasites
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STRATEGIES FOR VACCINE DEVELOPMENT
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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
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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
efficacy
appropriate response
booster
safety
stability, cost
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Why are boosters needed?
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How effective are vaccines?
Vaccine “efficacy”
incidence among those administered
and
Is 100% efficacy necessary?
-- “herd immunity”
incidence among those not administered
-- e.g., 60% efficacy
-- depends upon population, age, etc
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]
Diphtheria
Hib (<5 yrs old)
Measles
Mumps
Pertussis
Polio (paralytic)
Rubella
Smallpox
Tetanus
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
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Decrease
in Cases
per Year
99.9%
98.8%
99.9%
99.9%
92.1%
100.0%
99.9%
100.0%
98.5%
Sources
CDC. Impact of vaccines universally recommended for children — United States,
1900-1998.
MMWR 8(12):243-8
CDC. Notice to Readers: Final 2003 Reports of Notifiable Diseases. MMWR
2004;53(30):687
Malaria vaccine trial
2011: 45 – 56%
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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
Subunit / Peptide components
Cell cultured virus
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
Toxoids
DTaP -- diphtheria, tetanus toxoids
[ + “acellular pertussis” molecular component]
Remember Adjuvants?
-- increase immune response
e.g., aluminum hydroxide
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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
infection in immuno-deficient patients
(malignancies, Receiving corticosteroids,
Radiation, pregnancy)
less stable
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
Molecular components
pros
No living pathogen present
very stable
cons
fewer epitopes
weaker cell mediated response
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Types of vaccines
Live
vaccines
Live
Killed
Attenuated Inactivated
vaccines
vaccines
Toxoids
Cellular fraction
vaccines
Recombinant
vaccines
•Small pox
variola
vaccine
•BCG
•Typhoid
oral
•Plague
•Oral polio
•Yellow
fever
•Measles
•Mumps
•Rubella
•Intranasal
Influenza
•Typhus
•Diphtheria
•Tetanus
•Meningococcal
polysaccharide
vaccine
•Pneumococcal
polysaccharide
vaccine
•Hepatitis B
polypeptide
vaccine
•Hepatitis B
vaccine
•Typhoid
•Cholera
•Pertussis
•Plague
•Rabies
•Salk polio
•Intramuscular
influenza
•Japanise
encephalitis
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New Vaccination Strategies
DNA vaccines
DNA for an AG injected
-- expressed in cells
Pros
Both arms respond
DNA is very stable
No pathogen involved
Cons
Still experimental
Limited epitopes
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The mechanism of action of DNA vaccines
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New Vaccination Strategies
Recombinant vectors
e.g., HIV genes in an Adenovirus vector
Pors
•Easily manufactured and often relatively
stable
•Cannot “revert” to recreate pathogen
Cons
• Poorly immunogenic
• Post-translational modifications
• Poor CTL response
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‫برنامه واکسیناسیون جدید در ایران (اجرا از آبان ‪)93‬‬
‫برنامه‬
‫واكسن‬
‫بدو تولد‬
‫ب ث ژ‪ ،‬هپاتيت ب‪ ،‬فلج اطفال خوراكي‬
‫‪ ۴ ،۲‬و ‪ ۶‬ماهگي‬
‫پنج گانه (سه گانه ‪ +‬هپاتيت ب ‪ +‬هموفيلوس انفلوانزای ‪ ، )B‬فلج اطفال خوراكي‪ ،‬فلج‬
‫اطفال تزریقی‬
‫‪ ۱۲‬ماهگي‬
‫‪MMR‬‬
‫‪ ۱۸‬ماهگي‬
‫يادآور اول سه گانه ‪ ،‬يادآور فلج اطفال خوراكي ‪MMR ،‬‬
‫‪ ۶‬سالگي‬
‫‪33‬‬
‫يادآور دوم سه گانه‪ ،‬يادآور فلج اطفال خوراكي‬