Transcript Document

Immunology of
Vaccines
It is important to
understand the immune
mechanism that delivers
protection
This understanding
guides the design of more
effective vaccines
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Overview of the Immune Response
 When a microbe enters the body the immune system
responds in an attempt to eliminate the infectious agent.
 Innate immune system relies on immediate recognition of
antigenic structures common to many micro-organisms (pathogen
associated molecular patterns /PAMPS)
 Adaptive immune response made up of T & B lymphocytes that
have unique receptors specific to microbial antigens, take time to
respond
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Adaptive immune
response
- review
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Goal of Vaccination
 To generate and sustain the number of antigen specific B & T cells
against a particular pathogen / antigen sufficient to provide protection.
 Most of the successful vaccines are against small organisms (viruses &
bacteria)
 Microorganisms have evolved complex defense mechanisms that
interfere with the immune response. Some of these are
 Molecular mimicry
 Interference with antigen processing
 Prevention of apoptosis of infected cells
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Primary
response to a
vaccine
most current
vaccines induce
protective
antibodies
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Secondary
response to
an infection
primed by
vaccine
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Primary & secondary antibody responses
vaccination & infection
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1. Properties of an ideal vaccine
(easy to define, difficult to achieve)
 Give life-long immunity (the
vaccine illustrated at left is
required yearly)
 Broadly protective against
all variants of organism
 Prevent disease
transmission
 Rapidly induce immunity
 Effective in all subjects (the
old & very young)
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2. Properties of an ideal vaccine
(easy to define, difficult to achieve)
 Transmit maternal
protection to the foetus
 Require few
immunisations to induce
protection
 Not need to be administered
by injection (oral, intranasal,
transcutaneous)
 Stable, cheap & safe
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Development of
immunity in infants
 Infant’s immune system is relatively complete at birth.
 IgG antibodies received from mother are important for the protection of
the infant while the infant is developing its own repertoire of antibodies.
 Passive transient protection by IgA against many common illnesses is
also provided to the infant in breast milk.
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What happens in a natural infection to produce immunity?
 To develop a vaccine to we must first consider what happens in a
natural infection to produce protective immunity - these are called “the
correlates of protection”
 An effective vaccine against intracellular pathogens should only induce
effector mechanisms ultimately leading to the destruction of the
parasites.
 The vaccine should not trigger components of the immune response
favoring the survival of the parasites.
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Four types of
traditional
vaccines
 Killed microorganisms - these are previously virulent micro-organisms that
have been killed with chemicals or heat.
 Live, attenuated microorganisms - live micro-organisms that have been
cultivated under conditions that disable their virulent properties. They typically
provoke more durable immunological responses and are the preferred type for
healthy adults.
 Toxoids - inactivated toxic compounds from micro-organisms in cases where
these toxins (rather than the micro-organism itself) cause illness.
 Subunit - A fragment of a microorganism can create an immune response.
Example is the subunit vaccine against HBV that is composed of only the
surface proteins of the virus which are produced in yeast
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Understanding of the stages of the immune
response will assist design of vaccines

We will look at these stages
1.
2.
3.
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Initiation of immune response
Development of immunological memory
Deciding on appropriate immune response
for protective vaccine
Current challenge is to achieve strong
immunogenicity without increasing the
incidence of adverse events to vaccines
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Initiation of immune response- danger signal

An antigen must be recognised as foreign i.e. a danger signal
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Binding through pattern recognition receptors (e.g. Tolls)
Tissue damage
Initial recognition is likely by dendritic cells & tissue resident
macrophages in non-lymphoid tissue
Activation of dendritic cells is crucial in initiation of a primary immune
response
Uptake of antigen initiates:
1.
2.
3.
Antigen processing
Migration of cells to lymph nodes
Maturation of dendritic cells
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Initiation of immune response- danger signal
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Initiation of immune
response- antigen
processing
 Antigens entering cells by endocytosis (such as bacteria) are broken
down in lysosomal vesicles
 Peptides are loaded into MHC II molecules for transport to the cell
surface
 Antigens synthesised in the cell (such as viruses) are broken down to
peptides by proteasomes and transported to rough endoplasmic
reticulum for loading into MHC I molecules and transport to cell surface
 Thus surface expression of MHC molecules increases
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Initiation of immune
response
migration & maturation of
DCs
 Antigen presenting dendritic cells migrate from the tissues
to the draining lymph nodes.
 The migration is controlled by chemokines & receptors
 Dendritic cells mature to display more of the surface
molecules needed for interaction with T cells
 CD40, B7 deliver co-stimulatory signals to T cell activation
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Example of DC maturation in measles infection
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Two aspects important for
vaccine design
1. Need for the “danger signal” to initiate immune response
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Whole micro-organism may deliver the right signals but sub-unit
vaccines may be poorly immunogenic
Adjuvants may be needed to increase “danger signal”
2. The nature of the “danger signal” has an important impact
on the type of immune response generated
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Adjuvants tend to drive a strong antibody response
Need to better understand the signals that drive DCs
Need to design for appropriate immune response
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Development of immunological memory
 Almost all vaccines have the
objective of long-lasting protective
immunity (not certain how to
achieve this)
 Memory populations of cells have
encountered antigen and changed
phenotype as a result of stimulation
 Phenotypically defined memory cells
are shown to divide more rapidly than
naïve cells
 There are constraints on the duration
of memory
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Constraints on immunological memory
 T lymphocyte clones can only undergo a limited number of
cell divisions, then they become senescent
 Absence of re-exposure to antigen may limit duration of immunological
memory
 There is constraint of space in the space in the memory pool. Every time a
new antigen is encountered, expansion occurs and other cells must die to
provide space in the memory pool.
 If initial stimulation is large - memory persists longer
 If antigen persists - memory cells may also persist
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Strategies for future vaccines based on
understanding the immune response
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Most of the present generation of vaccines depend principally on
generating high titres of antibody (Th2 bias)
Natural protection against many organisms is Th1(cell mediated),
especially for intracellular parasites
Cellular vaccines are being designed to induce Th1 and cytotoxic
responses.
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These require MHC I stimulation via intracellular antigen.
One effective way of doing this is through the use of live vectors vaccines that
infect cells and introduce antigen to the cytoplasm.
DNA vaccines also can generate antigen inside cells
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DNA vaccines generate
antigen inside the cell
DNA plasmid vector vaccines carry the
genetic information encoding an
antigen,
The DNA vaccine-derived protein antigen
is degraded by proteosomes into
intracellular peptides
These vaccine derived-peptides binds
MHC class I molecules
Peptide antigen/MHC I complexes are
presented on the cell surface binding
cytotoxic CD 8+ lymphocytes, and
inducing a cell-mediated immune
response.
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Factors Determining
Vaccine Efficacy
 Successful immunization requires
 Activation
 Replication
 Differentiation
 of T and B lymphocytes leading to the generation of memory cells.
 Many vaccines require multiple immunisations to maintain
effective immunity
 Live infection induces a greater frequency of antigen-specific
cells than immunisation with attenuated or sub-unit vaccines
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Vaccination strategies
 The best way to confer immune resistance to a pathogen is
to mimic the pathogens without causing disease or to
devise formulations which mimic its characteristics
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1. Properties of an ideal vaccine (review)
1. Give life-long immunity
2. Broadly protective against all variants of organism
3. Prevent disease transmission
4. Rapidly induce immunity
5. Effective in all subjects (the old & very young)
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2. Properties of an ideal vaccine (review)
6. Transmit maternal protection to the foetus
7. Require few immunisations to induce protection
8. Not need to be administered by injection (oral, intranasal,
transcutaneous)
9. Stable, cheap & safe
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