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

vaccine

most 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

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.

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 stages1. Initiation of immune response2. Development of immunological memory3. 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: 1. Antigen processing2. Migration of cells to lymph nodes3. 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 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

18

Example of DC maturation in measles infection

19

Two aspects important for vaccine design

1. 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”

2. 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 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.

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