Vaccines and vaccine development Flashcards by Holly O'Flanagan

Immunisation

An artificial process by which an individual is rendered immune

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Historical background: variolation

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

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Historical background: Jenner

used fluid from cowpox lesions to protect against smallpox infections in 1796; recipient was James Phipps aged 8

First documented use of live attenuated vaccine and the birth of modern immunisation

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Passive immunisation

Immunity conferred without an active host response on behalf of recipient

Passive vaccines are preparations of antibodies taken from hyperimmune donors, either human or animal

Protection is temporary

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VZV exposure during pregnancy

Can cause fetal complications

In case of exposure, women should contact their GP, midwife or virology dept

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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

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Most vaccines work by

Generating long lasting, high affinity IgG antibody response

Antibodies sufficient to prevent primary infection

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What goes into a vaccine?

Antigen
- to stimulate an antigen specific T and B cell response

Adjuvants
- immune potentiators to increase the immunogenicity of the vaccine

Excipients
- various diluents and additives required for vaccine integrity

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Live attenuated vaccines

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

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Pros 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

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Cons of live vaccines

Storage problems, short shelf life

May revert to wild type

Immunocompromised recipients may develop clinical disease

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Varicella zoster vaccine

Primary infection= chicken pox

Cellular and humoral immunity provide lifelong protection, but virus establishes permanent infection of sensory ganglia

Viral reactivation= zoster

Particularly elderly, fairly debilitating and may cause long term neuropathic pain

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Zoster vaccination

Similar VZV preparation, but much higher dose

Aims to boost memory T cell responses to VZV

In over 60s, 50% reduciton in zoster incidence after vaccination compared to controls, reduced severity and complications amongst vaccinated cases

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Poliomyelitis

Enterovirus establishes infection in oropharynx and GI tract

Spreads to peyers patches then disseminated via lymphatics

Haematogenous spread

1% of patients develop neurological phase: replication in motor neurones in spinal cord, brainstem and motor cortex, leading to denervation and flaccid paralysis

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Sabin oral polio vaccine

Live attenuated

Viable virus can be recovered from stool after immunisation

Highly effective, and also establishes some protection in non-immunised population

1 in 750000 vaccine associated paralytic polio

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Salk injected polio vaccine

Inactivated

Effective but herd immunity inferior

Tuberculosis

During primary infection, MTB establishes infection within phago-lysosome of macrophages

Macrophages present TB antigen to MTB specific CD4 T cells which secrete IFN-g

Activates macrophages to encase TB granuloma

May be visible as a calcified lesion on plain CXR

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

TB vaccination

Only licensed product is BCG

Produced by repeat passage of a non-tuberculus mycobacterium

Aims to increase Th1 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

Stimulate 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

Pros of killed vaccines

No potential for reversion

Sage for immunocompromised

Stable in storage

Cons of killed vaccines

Mainly DC4/ antibody response

Responses less durable than live vaccines

Higher uptake generally required to achieve herd immunity

Structure of the influenza virus

Internal antigens are type specific proteins and are used to dteremine whether a particular virus is A, B or C

External antigens are subtype and strain specific antigens of influenza A virus: H1N1, H2N2 and H3N2

Difficulties of influenza vaccination

Target antigens prone to mutation 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

More major changes occur when viral strains recombine

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 Toxins are chemically detoxified to toxoids Retain immunogenicity Work by stimulating antibody response, antibodies then neutralise the toxin

Tetanus

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 polysacchardies coats; aim to induce IgG antibodies that improve posonisation Suboptimal as polysacchardies are weakly immunogenic Latest vaccines utilise vaccine conjugation to boost responses: protein carrier attached to polysaccharide antigen

Vaccine conjugation

Naive B cell expressing surface IgM recognises polysaccharide antigen Antigen is internalised together with the protein conjugate Conjugate is processed in the class II pathway Naive B cell presents peptides from the conjugate to a helper T cell with the correct receptor T cell helps the B cell to perform affinity maturation, but antibody is specific for the polysaccharide and not for the protein conjugate

Recombinant protein subunit vaccine

Knowledge of key immunogenic proteins required Proteins expressed in lower organisms Purified to produce vaccine - hepatitis B surface antigen - HPV vaccine This approach is increasingly employed in vaccine development

Human papilloma virus vaccination

HPV subtypes 16 and 18 major causal factor in cervical carcinoma Vaccine development problematic as HPV is difficult to culture Subunit vaccines are 'empty virus particles' that prevent primary infection Quadravalent vaccine covers additional HPV strains (genital warts, penile cancer)

Pros of subunit vaccines

Extremely safe Work well where primary infection may be prevented by an antibody response Works when the virus cannot easily be cultured e.g. HPV and hep B

Cons of subunit vaccines

Development requires detailed knowledge of virology, pathogenesis and immunology Specialised and expensive production Weaker immune responses- boosting often needed and response rate varies

Adjuvants

Boost immune response to the antigen Widely used, but mechanism understood only relatively recently E.g. alum, lipopolysaccharide Work by binding to pattern recognition receptors on antigen presenting cells - this enhances co-stimulation and cytokine secretion, which ensures a robust T/B cell response Important field for development in order to improve responses to subunit vaccines Novel adjuvants are toll like receptor ligands e.g. CPG repeats

Novel approaches: DNA vaccines

Plasmid DNA that encodes vaccine antigen of interest applied; taken up by cells, transcribed and translated Elicits host immune response Mainly performed in mice models Poorly immunogenic to date in human trials

Novel approaches: viral vector

Benign virus that can be easily grown in culture engineered to carry genes encoding immunogenic antigens Altered virus used as a live attenuated vaccine Use restricted to animals to date