Vaccine adjuvants

Question 1

why are adjuvants required

Answer 1

• Increase magnitude of immune response.
• Increase duration of protective immunity.
• Lower doses of vaccine required.
• Allow the immune response to be modified.

Question 2

Types of adjuvants

Answer 2

• Depot effects
• Delivery vehicles
• Immune stimulators (modifiers).

Or all of the above - combination.

Question 3

depot effects

Answer 3

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

Question 4

Aluminium salts

Answer 4

Depot effect. Widely used example. Forms a mesh-like gel matrix to which the antigen becomes absorbed and disociates slowly. “Absorbed” vaccines.

Question 5

Liposomes

Answer 5

antigen is encapsulated in a double lipid bilayer shell which degrades over time.
Depot effect.

Question 6

How do gel-like matrix in aluminum salts bind antigen?

Answer 6

Electrostatic Attraction - Aluminium salt is charged and antigen has opposite charge.
Ligand Exchange - exchange of hydroxyl groups for phosphate groups on the polysaccharide/protein

Question 7

Delivery vehicles

Answer 7

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

Question 8

particle delivery system using particles

Answer 8

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

Question 9

Delivery vehicle - using liposomes

Answer 9

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.

Question 10

Immune stimulators (modifiers)

Answer 10

Adjuvent activates elements of the innate immuen system to modify the response. Release cytokines to then lead to an adaptive response.

Question 11

What molecules activate the innate immune system (microorganisms)

Answer 11

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).

Question 12

LPS

Answer 12

lipopolysaccharide (found in Gram -ve bacteria cell wall) - anchored by lipid A anchor. Recognised by TLR4.

Question 13

TLR pathway

Answer 13

Dimerisation causes a signaling pathway down one of two routes (MyD88 or TRIF) to produce cytokines, chemokines and interferons –> shape adaptive response.

Question 14

MD2

Answer 14

Lipid A anchor of LPS binds to MD2 of TLR

Question 15

Toll agonists

Answer 15

promote maturation of DC which activates them to present antigen and initiate CD4 and CD8 responses

Question 16

Sepsis

Answer 16

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)

Question 17

Adjuvant vs toxicity

Answer 17

Modify LPS to get rid of toxicity but maintain adjuvant properties. Removal of phosphate group gives monophosphoryl lipid A (MPLA).

Question 18

MPLA in vaccines

Answer 18

MPLA + QS21 in shingles (lysosomes). MPLA + aluminium salts for HPV

Question 19

Why is MPLA not toxic

Answer 19

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.