7. vaccines Flashcards
define immunisation
an artificial process by which an individual is rendered immune
define passive immunity
no immune response in recipient
active immunisation
(vaccination)
recipient develops protective adaptive immune response
historical background: variolation
variola (smallpox virus)
fluid harvested from pustules of recovering individuals
documented from 1000AD globally
historical background: Jenner
1796: fluid from cowpox lesions to protect against smallpox
first documented use of live-attenuated vaccine
= birth of modern immunisation
passive immunity
immunity conferred without active host response on behalf of recipient
protection is temporary
what are passive vaccines?
preparations of antibodies taken from hyperimmune donors
examples of passive vaccines
immunoglobulin replacement in antibody deficiency
VZV prophylaxis, eg during exposure during pregnancy
anti-toxin therapies, eg snake anti-serum
VZV exposure during pregnancy
can cause foetal complications
pregnant women should contact GP if exposed
active immunity
immunity conferred in recipient following generation of adaptive immune response
general principle = stimulate adaptive immune response without causing clinically apparent infection
what is herd immunity?
vaccination of sufficient numbers impact transmission dynamic, so even unimmunised individuals are low risk
general principles of immunisation
given to healthy individuals prior to pathogen exposure
generate long lasting, high affinity IgG antibody response
strong CD4 T cell response is prerequisite
what goes into a vaccine?
antigen
adjuvants
excipients
what are adjuvants?
immune potentiators to increase the immunogenicity of the vaccine
what are excipients?
various diluents and additives required for vaccine integrity
which vaccines are most effective?
those for disease where natural exposure results in protective immunity
classifications of active vaccines
live-attenuated
inactivated (killed)
subunit
how are live-attenuated vaccines created?
prolonged culture ex vivo in non physiological conditions
selected variants adapted to live in culture
variants are viable in vivo, but no longer able to cause disease
examples of live-attenuated vaccines
measles mumps rubella polio BCG cholera zoster VZV live influenza
pros of live-attenuated vaccines
replication within hot, produces highly effective and durable response
in viral vaccine, intracellular infection leads to good CD8 response
repeated boosting not required
in some disease, may get secondary protection of unvaccinated individuals
cons of live-attenuated vaccines
storage problems, short half life
may revert to wild type
immunocompromised recipients may develop clinical disease
varicella zoster vaccine
primary infection = chickenpox
cellular and humeral immunity provide lifelong protection
viral reaction = zoster
particularly elderly, fairly debilitating, may cause long term neuropathic pain
vzv features
live attenuated
95% effective at preventing chickenpox
attenuated virus does establish infection of sensory ganglia
not on UK schedule
zoster vaccination
similar to vzv preparation, much higher dose
aims to boost memory t cell responses to vzv
reduces severity and zoster incidence in elderly
poliomyelitis
enterovirus establishes infection in oropharynx and GI tract (alimentary phase)
spreads to peyers patches, disseminated via lymphatics
haematogenous spread (viraemia phase)
1% patients develop neurological phase: replication in motor neurone in spinal cord, brainstem and motor cortex
polio vaccines
sabin and salk
sabin oral polio vaccine
live attenuated
viable virus recovered from stool after immunisation
highly effective - some protection in non-immunised population
1/7500000 vaccine associated paralytic polio
salk infected polio vaccine
inactivated
effective, but herd immunity inferior
used where risk of contraction is less
less risk
what happens during tuberculosis infection?
during primary infection, MTB establishes infection within phase-lysosomes of macrophages
macrophages present TB antigen to MTB specific CD4 t cells
secrete IFN-g
activated macrophages encase TB in granuloma
TB vaccination
only licensed product is BCG
produced by repeat passage of non-tuberculous mycobacterium
aims to increase Th1 cell responses to M bovis - conferring protection against MTB
given by intradermal infection
80% effective in preventing disseminated tb/tb meningitis in children
little effect on pulmonary tb
killed vaccines
entire organism used, but physical/chemical methods destroy viability
stimulates b cells, taken up by antigen-presenting cells to stimulate antigen specific cd4 cells
minimal cd8 response?
responses are less robust than live attenuated
killed vaccines examples
hepatitis A
influenza
pros of killed vaccines
no potential for reversion
safe for immunocompromised
stable in storage
cons of killed vaccines
mainly cd4/antibody response
responses less durable than live responses - boosters required
higher uptake generally required for herd immunity
influenza virus structure
internal antigens = type specific proteins (matrix, RNP), used to determine particular virus, ie A, B or C external antigens (haemagglutinin and neuraminidase) , subtype and strain specific antigens of influenza A
difficulties of influenza vaccination
target antigens are prone to mutation (antigenic drift) - seasonal variation
CDC provide candidate virus strains to manufacture, infected into fertilised hen eggs then virus is harvested
major changes can occur when viral strains recombine
subunit vaccines
uses only critical part of the organism
components may be: purified from organism, generated by recombinant techniques
protection depends on eliciting CD4 and antibody responses
toxoids
relate to toxin-producing bacteria
eg Clostridium tetani, Bordatella pertussis
toxins are chemically detoxified to form toxoids
retain immunogenicity
stimulate antibody response, antibodies neutralise toxin
tetanus immunity
performed by high affinity IgG antibodies - neutralise toxin molecules in circulation
immune complexes are removed in spleen
anti-toxin can be given in established cases (passive immunisation)
polysaccharide capsules
eg Streptococcus pneumonia, Neisseria meningitidis
thick polysaccharide coats make them resistant to phagocytosis
polysaccharide capsule vaccinations
made from purified polysaccharide coats
aim to induce IgG antibodies to improve opsonisation
suboptimal - polysaccharides are weakly immunogenic
stimulate small population of t-independent t cells (no t cell response)
vaccine conjugation
naïve b cell expressing surface IgM recognises polysaccharide antigen - internalised with protein conjugate
conjugate processed in class II pathway
naïve b cells present peptides from conjugate to Th cell
t cell helps b cell perform affinity maturation
antibody = specific for polysaccharide not protein conjugate
recombinant protein subunit vaccine
proteins expressed in lower organisms
purified to produce vaccine
hep B surface antigen, hpv vaccine
hpv vaccine
hpv subtypes 16 and 18 = major causal factor in cervical carcinoma
vaccine development = problematic as hpv difficult to culture
subunit vaccines are ‘empty virus particles’, prevent primary infection
quadravalent vaccine cover 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 virus cannot be cultured, eg hpv, hep B
cons of subunit vaccines
development required detailed knowledge of virology, pathogenesis and immunology
specialised and expensive production
weaker immune responses - boosting often required
adjuvants
widely used, mechanism poorly understood
eg. alum lipopolysaccharide bind to prrs on apcs - enhances costimulation and cytokine secretion
important field for development
novel adjuvants = tlr ligands, eg CPG repeats
novel approaches to vaccines
dna vaccines
viral vector
DNA vaccines
plasma DNA encodes vaccine antigen of interest applied
taken up by cells, transcribed and translated
elicits host immune response
mainly performed in mice models
poorly immunogenic in human trials
viral vector
benign virus can be easily grown in culture engineered to carry genes encoding immunogenic antigens
watered virus used as live attenuated vaccine
use restricted to animals to date
