Vaccine adjuvants Flashcards
why are adjuvants required
- Increase magnitude of immune response.
- Increase duration of protective immunity.
- Lower doses of vaccine required.
- Allow the immune response to be modified.
Types of adjuvants
- Depot effects
- Delivery vehicles
- Immune stimulators (modifiers).
Or all of the above - combination.
depot effects
Antigen’s sequested at site of injection and maintained around this site until it becomes released over long period of time - long exposure to immune system.
2 types - protein encapsulated in…
- physical structure that breaks down slowly
- gel-like matrix that disocciates slowly
Aluminium salts
Depot effect. Widely used example. Forms a mesh-like gel matrix to which the antigen becomes absorbed and disociates slowly. “Absorbed” vaccines.
Liposomes
antigen is encapsulated in a double lipid bilayer shell which degrades over time.
Depot effect.
How do gel-like matrix in aluminum salts bind antigen?
Electrostatic Attraction - Aluminium salt is charged and antigen has opposite charge.
Ligand Exchange - exchange of hydroxyl groups for phosphate groups on the polysaccharide/protein
Delivery vehicles
Deliver the antigen to a specific immune cell e.g. APC. try to forcce the protein or polysaccharide through either MHCI - CD8 pathway of MHCII- CD4 pathway
particle delivery system using particles
Antigen/ vaccine attached to particles that are then taken up by APC - pushed towards MHCII pathway. Types of particles used: - Virus-like (hollow) - liposomes - Non-degradable nanoparticles - ISCOM - Polymeric nanoparticle
Delivery vehicle - using liposomes
Liposomes encapsulating antigenic particles. Liposomes have double bilayer which can fuse with the membrane of APC and release antigens directly into cytosol to promote activation of MHCI pathway to activate CD8 T cell response.
Immune stimulators (modifiers)
Adjuvent activates elements of the innate immuen system to modify the response. Release cytokines to then lead to an adaptive response.
What molecules activate the innate immune system (microorganisms)
Cell wall components (lipopolysaccharide (bacteria), peptidoglycan (gram +ve bacteria), phospholipomannans (fungi).
Nucleic acid (CpG motif DNA Ibacteria), ssRNA (virus), dsRNA (virus)
Conserved surface proteins (flagellin (bacteria))
conserved stress proteins (heat shock proteins (bacteria).
LPS
lipopolysaccharide (found in Gram -ve bacteria cell wall) - anchored by lipid A anchor. Recognised by TLR4.
TLR pathway
Dimerisation causes a signaling pathway down one of two routes (MyD88 or TRIF) to produce cytokines, chemokines and interferons –> shape adaptive response.
MD2
Lipid A anchor of LPS binds to MD2 of TLR
Toll agonists
promote maturation of DC which activates them to present antigen and initiate CD4 and CD8 responses
Sepsis
Over activation of innate immune system is a risk when using LPS as an adjuvant as it is a key mediator of sepsis. (overproduction of cytokines - cytokine storm - positive feedback loop)
Adjuvant vs toxicity
Modify LPS to get rid of toxicity but maintain adjuvant properties. Removal of phosphate group gives monophosphoryl lipid A (MPLA).
MPLA in vaccines
MPLA + QS21 in shingles (lysosomes). MPLA + aluminium salts for HPV
Why is MPLA not toxic
Cells treated with LPS either with toxic lipid A or MPLA. RNA transcripts of genes associated with MyD88 and TRIF pathways (e.g. IL-6 and IFN-g). Expression of genes associated witth MyD88 went down with MPLA , no effect with TRIF pathway genes. Suggested that signalling only occurs down TRIF pathway and it’s the cytokines that are in the MyD88 effects that are toxic.
