Vaccines and vaccine development Flashcards
Immunisation
An artificial process by which an individual is rendered immune
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
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
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
VZV exposure during pregnancy
Can cause fetal complications
In case of exposure, women should contact their GP, midwife or virology dept
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
Most vaccines work by
Generating long lasting, high affinity IgG antibody response
Antibodies sufficient to prevent primary infection
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
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
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
Cons of live vaccines
Storage problems, short shelf life
May revert to wild type
Immunocompromised recipients may develop clinical disease
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
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
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
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
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
