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The Immune System and
How Vaccination Works
Rosalind Hollingsworth PhD
Therapeutic Team Leader, Specialist Care
Medical Department
Agenda
•
Overview of the immune system
•
How vaccination works
The Immune System
(Aim: Recognise pathogen, eliminate it!)
The ‘castle wall’
Exterior Defenses
Innate Immunity
The ‘soldiers’
Adaptive Immunity
Exterior Defences
• Skin
• Lysozyme
• Mucosal surfaces
Cilia
pH
MacNeil. Progress and opportunities for tissue-engineered skin. Nature 2007;445: 874-880
Innate Immunity
Phagocytes
Monocytes
Macrophages
Polymorphonuclear
neutrophils
Source: MSN Encarta
Dennis Krunkel/CNRI/Phototake NYC
Phagocytosis in Action
Adaptive Immunity
•
•
•
Lymphocytes
2 main categories
T lymphocytes
B lymphocytes
Derived from bone marrow stem cells
T cells develop in the thymus
B cells develop in the bone marrow
Lymphocytes
•
B lymphocytes produce antibody
•
T lymphocytes – 3 main groups:
Control B lymphocytes and antibody production
Seek and destroy virus-infected cells
Assist phagocytic cells
•
‘Key’ features:
• Specific antigen recognition
• Memory
B Lymphocytes
Bind specific antigen on
surface receptors
Divide and
differentiate into
plasma cells
Produce large amounts
of soluble receptor antibody
http://www.nature.com/nature/journal/v421/n6921/fig_tab/nature01409_F1.html
Antibodies (Immunoglobulins)
Antibody
Types
Description
IgA
2
Mucosal areas, such as gut,
respiratory tract, urogenital tract.
Prevents colonisation. Also found in
saliva, breast milk and tears.
IgD
1
Antigen receptor on B cells that
have not been exposed to antigen.
Function not well defined.
IgE
1
Binds to allergens to trigger
histamine release from mast cells
involved in allergy. Also protects
against parasitic worms.
IgG
4
Provides the majority of antibodybased immunity from invading
pathogens.
IgM
1
Eliminates pathogens in the early
stages of B cell mediated immunity
before there is sufficient IgG.
T Lymphocytes
•
T-helper cells (TH cells)
Interact with mononuclear phagocytes
Interact with B cells
•
T-cytotoxic cells (TC cells)
• Kill virus-infected cells
T Lymphocytes
Adaptive Immunity – T cells
CYTOTOXIC
Cytotoxins
T
HELPER
Th
Fas
Ligand
cytokines
Th
CD40
cytokines
CD40
CD40L
CD40L
Fas
Virus infected cell
Macrophage
Adapted from: Immunobiology 5th Edition, Janeway, Travers, Walport, Shlomchik.
New York and London, Garland Science 2001
Antigen specific B cell
Adaptive Immunity – Primary
and Secondary Responses
IgG
IgM/IgG
IgM/IgG
Taken from HPA National Immunisation Standards Slides
http://www.hpa.org.uk/infections/topics_az/vaccination/slides.htm
Agenda
•
Overview of the immune system
•
How vaccination works
Immune Response to a Vaccine
• Ideal vaccine - induce a similar or greater
protective immune response as seen following
natural infection
• Stimulate antigen presenting cells to engage
all aspects of immune response
• Activate T and B cells to produce specific
effector cells
• Provide long-term protection through
persistence of response and immunological
memory
Immune Response to a Vaccine
Immunisation
Challenge
Immune
response
Protective
threshold
Duration
Immune Response to a Vaccine
• Example: Pneumococcal vaccination
• Encapsulated bacteria
• Protection correlates with production of
anti-capsular polysaccharide antibody
• Two types of vaccine:
Streptococcus pneumoniae
Plain polysaccharide (T independent)
Polysaccharide conjugated to protein
carrier (T dependent)
Source: Carr J. CDC Public Health Image Library http://www.phil.cdc.gov/phil
Immune response to a vaccine – Pneumococcal
polysaccharide immunisation in adults
5
Immunisation
4
3
Antibody
Concentration
2
1
0
0
1
12
36
months
Ag
B
B
B
B
B
B
B
B
B
Data adapted from Sankilampi et al J. Infect. Dis 1997:176:1100-1104
B
B
Immune response to a vaccine – Pneumococcal
polysaccharide-protein conjugate vaccine responses in
children
14
antibody concentration (ug/mL)
12
Post 2 doses
10
8
Booster
6
4
2
0
Pre-Primary
Post Primary
Pre-Boost
Post-Boost
Ag
DC
Th
B
B
B
Th B
B
B
B
B
Ag
DC
Th
B B
B
B B B
B
B
B
B
B B
B
B
Goldblatt et al Pediatr Infect Dis J 2006 25: 312–319
Th B
Th B Th B
Th B
B
B
Immune response to a vaccine –
schedule of doses
• 2, 3, 4 month schedule designed to give protection to infants as
early as possible
• One month gap:
full response
secondary response
minimises potential for immune interference
• Schedule may not be optimal for conjugate vaccines
• Older infants respond better than younger infants
• Interruption of immunisation series does not necessarily mean
re-start the programme (Refer to Green Book
recommendations)
Immune response to a vaccine –
Vaccine Failures
• Primary failure – lack of an initial response to the
vaccine which means the individual remains
susceptible
• Secondary failure – occurrence of disease despite an
initial “protective” response to immunisation,
correlates with waning immunity
• A compromised immune system due to an
underlying medical condition may lead to vaccine
failure
Department of Health “Immunisation Against Infectious Disease (The Green Book). Chapter 1 – Immunity and how
vaccines work P4. Available online at:
http://www.dh.gov.uk/en/Publichealth/Healthprotection/Immunisation/Greenbook/DH_4097254
Immune response to a vaccine –
Vaccine Failure
Immunisation
Challenge
Immune
response
Protective
threshold
Primary Vaccine
failure
Duration
Secondary
Vaccine
failure
Active Immunisation – Live
Vaccines
• Attenuated strains to ensure not pathogenic
• Need to replicate to induce immune response
Advantages
Disadvantages
Mimics natural infection
Potential to revert to virulent strain
Strong local and systemic responses
Susceptible to interference with
ongoing immune responses or passive
antibodies
One dose usually sufficient to induce
long-lasting protection
Contraindicated in immunosuppressed
individuals
Stability issues
Potential for contamination
Taken from HPA National Immunisation Standards Slides
http://www.hpa.org.uk/infections/topics_az/vaccination/slides.htm
Active Immunisation –
Inactivated Vaccines
• Suspensions of killed intact organisms – e.g.
whole cell pertussis vaccine
• Acellular and sub-unit vaccines – contain one or
a few of the components (antigens) of the
pathogen
e.g acellular pertussis vaccine – contains 2-5
antigens of pertussis bacterium
Taken from HPA National Immunisation Standards Slides
http://www.hpa.org.uk/infections/topics_az/vaccination/slides.htm
Active Immunisation - Inactivated
Vaccines
Advantages
Disadvantages
No potential for return to
virulence
Most require more than one
dose
Not susceptible to
interference from ongoing
immune
responses/infections
Shorter duration of
immunity
Good stability
Local reactions common
Constituents clearly defined
– less chance of
contamination
Adjuvants required
Taken from HPA National Immunisation Standards Slides
http://www.hpa.org.uk/infections/topics_az/vaccination/slides.htm
Additional Vaccine Components
Component
Purpose
Example
Adjuvants
enhance the immune response to a vaccine
aluminium salts
Preservatives
prevent bacterial or fungal contamination
of vaccine
thiomersal
Additives
stabilise vaccines from adverse conditions
such as freeze-drying or heat, thereby
maintaining a vaccine’s potency
gelatine
Residuals from
manufacturing
process
Inactivating agents
Antibiotics - prevent bacterial
contamination during manufacturing
process
Egg proteins- some vaccine viruses are
grown in chick embryo cells
formaldehyde
neomycin, streptomycin,
polymyxin B
influenza, yellow fever
HepB vaccine
Source: HPA minimum slide set for Core Curriculum for Immunisation Training
Inactivated Vaccines – Conjugated Vaccines
• Vaccines based on the capsular polysaccharide of
bacteria poorly immunogenic in young children
• The polysaccharide is bound (conjugated) to a protein
carrier (eg diphtheria or tetanus toxoid) which enables
the immune system of infants and young children to
respond
Conjugation
Each saccharide is
chemically activated
Conjugation to carrier
protein
Combination Vaccines
• Allows reduction in number of injections
• Allows greater number of vaccines to be given at
one time
• Studies required to ensure safety and
immunogenicity matches that of the individual
vaccines
Immunisation Schedule as of 20th April 2009
Age
Vaccines
2 months
DTaP/IPV/Hib + PCV7
3 months
DTaP/IPV/Hib + MenC
4 months
DTaP/IPV/Hib + PCV7+ MenC
12 months
MenC/Hib
13 months
MMR+PCV7
3 years 4 months – 5 years
DTaP/IPV or dTaP/IPV + MMR
Girls aged 12-13 years
HPV
13 – 18 years
Td/IPV
Adapted from: Immunisation against Infectious Diseases, The Green Book.
Available at: http://www.dh.gov.uk/en/Publichealth/Healthprotection/Immunisation/Greenbook/DH_4097254
Summary
• Vaccination is the best known and the most successful
application of immunological processes to human
health
• The ability of lymphocytes to develop memory is
fundamental to this success
Prevenar – Prescribing
Considerations
• Prevenar is contraindicated inpatients with a history of hypersensitivity to the active
substances, to any of the excipients, or to diphtheria toxoid.
• Prevenar will not protect against other Streptococcus pneumoniae serotypes than
those included in the vaccine nor other micro-organisms.
• The use of Prevenar does not replace the use of 23-valent pneumococcal
polysaccharide vaccines in children 24 months of age with conditions placing them
at higher risk for invasive disease due to Streptococcus pneumoniae. The interval
between Prevenar and the 23-valent pneumococcal polysaccharide vaccine should
not be less than 8 weeks.
• As with other vaccines, the administration of Prevenar should be postponed in
subjects suffering from acute moderate or severe febrile illness.
• Prevenar should be administered intra-muscularly.
• It is not recommended to administer Prevenar intramuscularly to infants or children
with thrombocytopenia or other coagulation disorders. Please refer to official
guidance for the administration of vaccines to children with these conditions.
• Different injectable vaccines should always be given at different injection sites.
• Common and very common adverse events include injection site reactions,
drowsiness, fever, irritability, restless sleep, vomiting, diarrhoea, and decreased
appetite.
Prevenar – Abbreviated Prescribing Information
Prevenar*
Pneumococcal saccharide conjugated vaccine, adsorbed
Presentation: Each 0.5ml dose of Prevenar contains 2 micrograms of each of the following saccharide serotypes: 4, 9V, 14, 18C, 19F, 23F and 4 micrograms of
saccharide serotype 6B. Each saccharide is conjugated to the CRM197 carrier protein and adsorbed on aluminium phosphate.
Indications: Immunisation against disease (including sepsis, meningitis, pneumonia, bacteraemia and acute otitis media) caused by Streptococcus pneumoniae
serotypes 4, 6B, 9V, 14, 18C, 19F and 23F in infants and children from 2 months up to 5 years of age.
Dosage and Administration: The immunisation schedules for Prevenar should be based on official recommendations.
For intramuscular injection.
Infants 2-6 months: Three doses, the first dose usually given at 2 months of age and with an interval of at least 1 month between doses. A fourth dose is
recommended in the second year of life. Alternatively, when Prevenar is given as part of a routine infant immunisation programme, a two-dose schedule
may be considered. The first dose may be given from the age of 2 months with a second dose at least 2 months later and a third (booster) dose at 11 – 15
months of age.
Infants 7-11 months: Two doses with at least a 1 month interval between doses. A third dose is recommended in the second year of life.
Children 12-23 months: Two doses with at least a 2 month interval between doses.
Children 24 months-5 years: one single dose.
The need for a booster dose after these immunisation schedules has not been established.
Contra-indications: Hypersensitivity to any component of the vaccine or to diphtheria toxoid.
Warnings and Precautions: Do not administer intravenously. Appropriate treatment must be available in case of anaphylaxis. The potential risk of apnoea and
the need for respiratory monitoring for 48-72 hours should be considered when administering the primary immunisation series to very premature infants
(born ≤ 28 weeks of gestation) and particularly for those with a previous history of respiratory immaturity. Impaired immune responsiveness may affect
antibody levels. Prevenar does not replace 23-valent polysaccharide vaccine in at risk children  24 months of age. Children  24 months of age at high
risk, previously immunised with Prevenar should receive 23-valent pneumococcal polysaccharide vaccine whenever recommended. Prophylactic
antipyretics recommended when vaccinating children with history of seizure disorders, or when vaccinating simultaneously with whole cell pertussis
vaccines. Delay vaccination in acute moderate or severe febrile illness. The immunogenicity of Prevenar has been demonstrated in infants with sickle cell
disease. Safety and immunogenicity data are not yet available for children in other specific high-risk groups for invasive pneumococcal disease.
Side Effects: Very common: Decreased appetite, vomiting, diarrhoea, injection site reactions (e.g. erythema, induration/swelling, pain/tenderness), fever equal
to or over 38 °C, irritability, crying, drowsiness, restless sleep. Common: Injection site swelling/induration and erythema larger than 2.4cm, tenderness
interfering with movement, fever over 39 °C. Uncommon: rash/urticaria. Rare: Seizures including febrile seizures, hypotonic hyporesponsive episode,
injection site hypersensitivity reactions (e.g. dermatitis, pruritus, urticaria), hypersensitivity reactions including face oedema, angioneurotic oedema,
dyspnoea, bronchospasm, anaphylactic/anaphylactoid reaction including shock. Very rare: Lymphadenopathy localised to the region of the injection site,
erythema multiforme.
Legal Category: POM Package Quantities: Pack of 1 single-dose pre-filled syringe (with separate needle) or pack of 10 single-dose pre-filled syringes
Cost: Single-dose pre-filled syringe (with separate needle) pack of 1: £34.50. Single-dose pre-filled syringe pack of 10: £345.00
Marketing Authorisation Numbers: Single-dose pre-filled syringe (with separate needle) pack of 1:EU/1/00/167/006, single-dose pre-filled syringe pack of 10:
EU/1/001/167/004 Marketing Authorisation Holder: Wyeth-Lederle Vaccines S.A., Rue du Bosquet 15,B-1348 Louvain-la-Neuve, Belgium
For full prescribing information and details of other side effects see Summary of Product Characteristics
Full prescribing information is available on request from: Wyeth Pharmaceuticals, Huntercombe Lane South, Taplow, Maidenhead, Berkshire, UK, SL6
0PH. Telephone: 0845 367 0098
Date of Prescribing Information: 06Jan09 Date of Preparation: 10Feb09 Code no. ZAPI104 Doc ID: 51558 *Trade mark