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What is immunisation?

Immunisation is an artificial process by which an individual is rendered immune


Passive and active immunisation

Passive immunisation – no immune response in recipient
Active immunisation (vaccination) – recipient develops a protective adaptive immune response


Effects of immunisation

One of the cheapest and most effective methods of improving survival and reducing morbidity
Estimated reduction in mortality worldwide 3 million/ yr



Variola =smallpox virus
For variolation, fluid harvested from pustules of recovering individuals and injected under skin of recipient
Crude method of obtaining an ‘inactivated’ vaccine
Documented practice in Far East, Middle East and South Asia from 1000AD
Limited use in UK (1700s)



Used fluid from cowpox lesions to protect against smallpox infection in 1796; recipient was James Phipps, aged 8

Subsequently experimented with several other children, including his own infant son; published findings in 1798

The first documented use of a live-attenuated vaccine and the birth of modern immunisation


Passive immunisation

Immunity conferred without an active host response on behalf of recipient
Passive vaccines are preparations of antibodies taken from hyper-immune donors, either human or animal
Immunoglobulin replacement in antibody deficiency
VZV prophylaxis eg during exposure during pregnancy
Anti-toxin therapies eg snake anti-serum
Protection is temporary


VZV exposure during pregnancy

VZV during pregnancy can cause fetal complications. In case of exposure, women should contact their GP, Midwife or Virology Dept. Urgent VZV serology is available when required


Active immunisation (vaccination)

Immunity conferred in recipient following the generation of an adaptive immune response
General principle is to stimulate an adaptive immune response without causing clinically-apparent infection


Herd immunity

To be effective, vaccines need to be administered to targeted cohorts in advance of exposure to the pathogen of interest
Vaccination of sufficient numbers impacts the transmission dynamic so that even unimmunised individuals are at low risk – called herd immunity
As vaccines are given to healthy individuals, the risk-to-benefit ratio requires that vaccines meet high safety standards


What prevents the primary infection

Most vaccines work by generating a long-lasting, high-affinity IgG antibody response
These antibodies are sufficient to prevent primary infection
A strong CD4 T cell response is a pre-requisite for this
The most effective vaccines are for diseases where natural exposure results in protective immunity
‘Problem’ diseases are generally those where the immune system cannot eliminate infection or generate long-lasting protective immunity during natural infection
Eg common cold, MTB, HIV, malaria


What goes into a vaccine?

To stimulate an antigen-specific T and B cell response

Immune potentiators to increase the immunogenicity of the vaccine

Various diluents and additives required for vaccine integrity


Classifications of active vaccines

Depends on basis of antigen:
Whole organism - live attenuated or inactivated

Subunit - toxoids, capsular polysaccharides, conjugated polysaccharides, recombinant subunit


Live attenuated vaccines

Live but attenuated organisms used
Prolonged culture ex vivo in non-physiological conditions
This selects variants that are adapted to live in culture
These variants are viable in vivo but are no longer able to cause disease
Polio (Sabin)
VZV (not routinely used for primary prevention in UK at present)
Live influenza (not routinely used in UK at present)


Pros and cons of live vaccines

Replication within host, therefore produces highly effective and durable responses
In case of viral vaccine, intracellular infection leads to good CD8 response
Repeated boosting not required
In some diseases, may get secondary protection of unvaccinated individuals, who are infected with the live-attenuated vaccine strain eg polio

Storage problems, short shelf-life
May revert to wild type
Eg vaccine associated poliomyelitis: around 1 in 750 000 recipients
Immunocompromised recipients may develop clinical disease


Varicella-zoster vaccine

Primary infection = chickenpox
Cellular and humoral immunity provide lifelong protection, but viruses establishes permanent infection of sensory ganglia
Viral reactivation=zoster
Particularly elderly, fairly debilitating and may cause long-term neuropathic pain

Live-attenuated VZV, works by induction of anti-VZV antibodies
95% effective at preventing chickenpox
Attenuated virus does establish infection of sensory ganglia, but subsequent zoster is probably rare
3-5% mild post-vaccination varicella infection
Not on UK schedule at present, because:
VZV is a fairly benign childhood infection
Safety concerns based on evidence from other countries
‘Disease shift’ to unvaccinated adults, in whom VZV is less well tolerated
Increase in zoster – probably reduced immune boosting in adults


Zoster, immunity and aging

The incidence of zoster increases with age, in parallel with declining cell-mediated immune responses to zoster


Zoster vaccine

Similar VZV preparation, but much higher dose
Aims to boost memory T cell responses to VZV
In over 60s, 50% reduction in zoster incidence after vaccination compared to controls; reduced severity and complications amongst vaccinated cases



Enterovirus establishes infection in oropharynx and GI tract (alimentary phase)
Spreads to peyers patches then disseminated via lymphatics
Haematogenous spread (viremia phase)
1% of patients develop neurological phase: replication in motor neurones in spinal cord, brainstem and motor cortex, leading to denervation and flaccid paralysis


Sabin polio

Sabin oral polio vaccine (OPV) = live-attenuated
Viable virus can be recovered from stool after immunisation
Highly effective, and also establishes some protection in non-immunised population
1 in 750 000 vaccine-associated paralytic polio


Salk polio

Salk injected polio vaccine (IPV) = inactivated
Effective, but herd immunity inferior
OPV better suited to endemic areas, where benefits of higher efficacy outweigh risks of vaccine-associated paralysis. UK switched to IPV in 2004



During primary infection, MTB establishes infection within phago-lysosomes of macrophages. Macrophages present TB antigen to MTB-specific CD4 T cells, which secrete IFN-g – this activates macrophages to encase TB in granuloma.

May be visible as a calcified lesion on plain CXR (Ghon focus)

Most TB thought to be re-activation of this primary infection


TB vaccination

Only licensed product is BCG (bacille Calmette-Guerin)
Produced by repeat passage of a non-tuberculus mycobacterium: Mycobacterium bovis
Aims to increase Th1 (IFN-g) cell responses to M bovis, thereby conferring protection against MTB
Given by intradermal injection
80% effective in preventing disseminated TB/ TB meningitis in children; little or no effect on pulmonary TB


Killed (inactivated)

Entire organism used, but physical or chemical methods used to destroy viability (eg formaldehyde)
Stimulates B cells, and taken up by antigen-presenting cells to stimulate antigen-specific CD4 T cells
Probably elicit minimal CD8 response, as the vaccine cannot undergo intracellular replication
Responses less robust compared to live-attenuated vaccines
Hepatitis A
Influenza (standard vaccine – live-attenuated also available but not routinely used)


Pros and cons of killed vaccines

No potential for reversion
Safe for immunocompromised
Stable in storage

Mainly CD4/ antibody response
Responses less durable then live vaccines
Generally boosters required
Higher uptake generally required to achieve herd immunity


What do influenza vaccines target?

Protective antibody responses largely directed against Haemagglutinin and Neuramidase, and probably mostly work by blocking entry to cells, blocking release of new virions from infected cells and promoting ADCC


Difficulties of influenza vaccination

Target antigens prone to mutation (antigenic drift) causing seasonal variation – therefore vaccine produced annually based on predictions

CDC provide candidate virus strains to manufacturer; injected into fertilised hens eggs and virus then harvested (inactivated for standard vaccine)

More major changes (antigenic shift) occur when viral strains recombine – eg with animal strain, causing pandemic influenza


Subunit vaccines

Uses only a critical part of the organism
Components may be:
purified from the organism or
generated by recombinant techniques
Protection depends on eliciting CD4 and antibody responses


Subunit vaccines: toxoids

Many examples relate to toxin-producing bacteria
Corynebacterium diphtheriae
Clostridium tetani
Bordatella pertussis
Toxins are chemically detoxified to ‘toxoids’
Retain immunogenicity
Work by stimulating antibody response; antibodies then neutralise the toxin


Tetanus vaccine

Pre-formed high-affinity IgG antibodies can neutralise the
toxin molecules in the circulation; the immune complexes
are then removed via the spleen

Anti-toxin can also be given in established cases (passive immunisation)


Subunit vaccines: polysaccharide capsules

Thick polysaccharide coats of Streptococcus pneumoniae and Neisseria meningitidis make them resistant to phagocytosis
Vaccines for these organisms formed of purified polysaccharide coats
Vaccines formed of purified polysaccharide coats; aim to induce IgG antibodies that improve opsonisation
Suboptimal as polysaccharides are weakly immunogenic:
No protein/ peptide, so no T cell response
Stimulate a small population of T-independent B cells
Latest vaccines utilise vaccine conjugation to boost responses: protein carrier attached to polysaccharide antigen