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Host defence against infectious agents

basic review immunology

Host immunity:
a) Innate immunity:
First line of defence
not require exposure to the infectious agent
immediate (almost)
Mediated by monocytes and Polymorphonuclear neutrophils
b) Acquired immunity:
exposure to infectious agents
time to develop
Mediated mainly by lymphocytes (B and T cells)
Other cell types involved, for example monocytes and dendritic cells

-Vaccines can stimulate both immune responses, but primarily aimed at acquired immunity

Acquired immunity:
i) Humoral immunity:
Directly mediated by antibodies
Antibodies are produced by B lymphocytes
Plasma cells (terminally differentiated B lymphocytes) are the primary source of secreted immunoglobulins
ii) Cell Mediated Immunity:
Not primarily mediated by antibodies
Mediated by B-lymphocytes and NK cells
Indirectly other cell types may play a role, such as macrophages


Immunity to Bacterial Infections

Role of antibody 3

Role of cell-mediated immunity 2


Role of antibody:
o Toxin neutralization
o complement binding – antibody mediated bactericidal activity
o opsonin promoting phagocytosis – antibody mediated bactericidal activity

Role of cell-mediated immunity:
o for eliminating intracellular bacteria
o Interaction of the reactive T lymphocytes and the macrophages is key to clearance of infection

***protection combo of humoral and cell mediated immunity


Properties of a good vaccine 6

• Stimulates an effective immune response
• Is safe and does not cause adverse reactions
• Is inexpensive to manufacture and distribute
• Is stable
• Is easy to administer
• Should be simple for both manufacturer and regulatory authorities to control


Direct Protection:

herd immunity
endemic state

Direct protection: preventing disease spread from one person to another directly, aims to help individual
e.g. meningitis by meningococcus
-Meningococcus passed from person to person, cannot exist outside body

Herd immunity: protecting pop. by preventing cycle of meningococcus from occurring --> protecting more people (specially susceptible) in general
endemic state: balance between transmissibility of the infectious agents and level of immunity in the population


Vaccine safety and efficacy are assessed by clinical trials

1) 2

2) 2

3) 3

Phase 1 trials:
o Primarily for safety, also assess immunogenicity
o small numbers of healthy volunteers

Phase 2 trials:
o Primarily for assessing immune response, also expand safety database
o Typically all grps likely use vaccine

Phase 3 trials:
o Mass protection studies, usually placebo controlled and double bind trials (determine vaccine efficacy)
o provide statistically conclusive data for license
o Require good disease surveillance, thru case ascertainment & defined endpoint


Vaccine Efficacy


=1- (Attack Rate in Vaccinated Group)/(Attack Rate in unvaccinated group)



herd effect

vaccine coverage needed to achieve herd effect = (1-1/R0)/effectiveness

herd effect =1- (Attack Rate in unvaccinated post-intro of vaccine)/(Attack Rate in unvaccinated pre-intro of vaccine)

Vaccine formulations:
1) Antigen – stimulate immune response to target disease:
Live attenuated organisms
Killed whole organisms
Purified component vaccines
Polysaccharide conjugates
2) Adjuvant – enhance & modulate immune response
3) Excipients – buffer, salts, saccharides, proteins to maintain pH, osmolarity & stability of vaccine. Also preservatives


Paediatric Vaccines

2 mths

3 mths

4 mths

1 yr

3/4 yrs +

2 mths
-pneumococcal conjugate

3 mths

4 mths
-pneumococcal conjugate

1 yr
-pneumococcal conjugate
-HiB + MenC booster

3/4 yrs +
-Pre-primary school – DTaP-IPV booster, MMR booster
-Live attenuated influenza vaccine
-Girls 12-13 yrs HPV vaccine
-2nd education, the dT-IPV booster and the Men ACWY


DT component of DTaP:
o caused
o 4: (2)

aP component of DTaP:
o caused
o characteristic
o Recovery
o old vaccine 4
o -->

Components of Bordetella pertussis associated with virulence
-attachment of... 3
-toxins 5
-acellular vaccines 3

DT component of DTaP:
o Tetanus and diphtheria toxoids (chemical inactivation of bacterial exotoxins)
o Simple to produce, Relatively pure, Safe, High protective efficacy: (v. immunogenic, appropriate immune response, i.e. toxin neutralizing antibodies block activity)

AP component of DTaP:
o whooping cough - Bordetella pertussis infecting ciliated epithelial & releasing toxins
o characteristic convulsive cough
o Recovery coincides with antibody production
o old vaccine involved using whole cell, high efficacy rate, but associated with a number of adverse side-effects, such as: anaphylaxis, prolonged crying, febrile seizures, acute encephalopathy
o --> acellular/component vaccine

Components of Bordetella pertussis associated with virulence
-Attachment of ciliated epithelium:
o Filamentous hemagglutinin (FHA)
o Fimbriae
o Pertactin
-Adherence and complement resistance
o Pertussis toxin (PT)
o Adenylate cyclase
o Tracheal cytotoxin
o Heat labile toxin
o Endotoxin
-acellular vaccines:
o Multicomponent (bi-,tri- and pentavalent formulations)
o PT, FHA, pertactin, fimbrial antigens 2 and 3
o Safe and efficacious



-H aemophilus influenza type b --> meningitis and septicemia in young
-Bacterial surface covered by a polyribosyl-ribitol phosphate capsule
-Polysaccharides are poorly immunogenic
-conjugate vaccine


Paediatric combination vaccines

e.g. Pediacel and Infanrix
• Antigens include:
o Tetanus toxoid
o Diptheria toxoid
o Pertussis components:
Pertussis toxoid
Filaemtos hemagglutinin
Fimbriae types 2 and 3
o Hib PRP conjugate
o Inactivated polio virus types 1,2 and 3
• Adjuvant: Aluminum phosphate


Conjugate Vaccines:
-components 3
-effective - 3
-form: 3

e.g. 5+1

-carbohydrates which are chemically linked to immunogenic protein
-overcome the drawbacks of plain polysaccharide vaccines by making them T cell dependent --> form memory cells
-sophisticated technology; v. expensive
-Highly purified components: purified saccharide and carrier proteins, such as tetanus toxoid, diphtheria toxoid, v. safe, simple for license and control
-V. effective when humoral immunity is required – long-lived, boost-able immunity. reduce carriage (herd immunity)
o Random activation of high molecular weight or partly size reduced polysaccharides
o Degradation of the polysaccharide to form active functional groups at both terminals
o Degradation of the polysaccharide to form active functional group at only one terminal
-molecular structure of vaccine depends on chemistry for conjugation and the ratio of saccharide to conjugate

o Hib vaccine – polyribosyl ribitol phosphate (PRP) conjugated to CRM197 or tetanus toxoid
o Pneumococcal conjugates – seven, 10 and 12-valent formulations
o MenC conjugates – α 2-9 linked polysialic acid conjugated to CRM197 or tetanus toxoid
o MenC + HiB booster – Menitorix
o Other conjugates – Meningococcal ACWY conjugates, which include GSK CRM conjugate Menveo and Pfizer TT conjugate Nimenrix
(In future may be conjugate vaccines to Group B streptococcal)


MenC vaccination
-reduction no.

-originally successful when rolled out; completely removing the serotype
-no. reduction in both vaccinated & unvaccinated group – herd immunity
-booster doses (Men ACWY, due to the rise of Men) given to teenagers, as grp most at risk


Pneumococcal disease
-sig cause of 3
-vaccines 2

-Streptococcus pneumoniae is significant cause of meningitis + septicemia + mucosal infections worldwide
-90+ serotypes determined by capsular polysaccharides
-antibiotic resistance being associated with some serotypes
o Pneumovax II – 23-valent plain (unconjugated) polysaccharide vaccine
o Prevenar 7,13 and synflorix are conjugate vaccines


New vaccines against group B meningococcal disease

-meningococcus is one of a small number of gram -ve species that normally bleb off outer vesicles of outer membrane, which have all the protein antigens usually associated with the OM
• Just like the outer membrane, they consist of lipopolysaccharides and proteins
• Vaccine is made by extracting the MNVs by detergent to reduce the LPS content and thereby make them less reactogenic
• These vaccines are more complex than other purified component vaccines
• Even with very careful manufacture, the antigen profile and the LPS content can vary from batch to batch
• In the era of genome sequencing data, an alternative approach to identifying vaccine candidates is first to identify potential candidate antigens on computers
• The candidates are then over-expressed in a suitable expression system
• Novartis has used this method to identify 3 possible meningococcal antigens:
o Factor H binding protein
o Neisseria adhesin
o Heparin binding protein
• Sequence analysis of their proteins has concluded that they are less variable than PorA, and it is hoped that a vaccine based on these antigens would be broadly cross-protective against diverse meningococcal strains