Immunology of Vaccines

1
Immunology of Vaccines

• It is important to understand the immune
  mechanism that delivers protection
• This understanding guides the design of more
  effective vaccines

2
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

3
Adaptive immune response- review
4
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

5
Primary response to a vaccinemost current
vaccines induce protective antibodies
6
Secondary response to an infection primed by
vaccine
7
Primary secondary antibody responsesvaccination
infection
8
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)

9
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

10
Development of immunity in infants

• Infants 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.

11
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.

12
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

13
Understanding of the stages of the immune
response will assist design of vaccines

• We will look at these stages
• 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

14
Initiation of immune response- danger signal

• An antigen must be recognised as foreign i.e. a
  danger signal
• 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
• Antigen processing
• Migration of cells to lymph nodes
• Maturation of dendritic cells

15
Initiation of immune response- danger signal
16
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

17
Initiation of immune responsemigration
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

18
Example of DC maturation in measles infection
19
Two aspects important for vaccine design

• Need for the danger signal to initiate immune
  response
• Whole micro-organism may deliver the right
  signals but sub-unit vaccines may be poorly
  immunogenic
• Adjuvants may be needed to increase danger
  signal
• The nature of the danger signal has an
  important impact on the type of immune response
  generated
• Adjuvants tend to drive a strong antibody
  response
• Need to better understand the signals that drive
  DCs
• Need to design for appropriate immune response

20
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

21
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

22
Strategies for future vaccines based on
understanding the immune response

• 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.
• 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

23
DNA vaccines generate antigen inside the cellDNA
plasmid vector vaccines carry the genetic
information encoding an antigen, The DNA
vaccine-derived protein antigen is degraded by
proteosomes into intracellular peptidesThese
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.
24
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

25
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

26
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)

27
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