Lecture 22 - S. pneumoniae Vaccination Flashcards
What receptors do neutrophils have?
- FcR
* CR (complement receptors)
What receptors do neutrophils have?
- FcR
* CR (complement receptors)
What is the function of NETS?
Contain bacteria at the site of infection
What is the makeup of a NET?
- DNA
- Histoproteins
- Granule contents
What is the name for the production of NETS?
NETosis
What are cathelicidins?
Antimicrobial proteins in a neutrophil
Describe what is important about colonial selectin
Only the B lymphocyte that has the specific TCR appropriate for the antigen will be selected
Then expansion occurs
Describe the concentration of antibody in the blood over time
- Before immunisation: none
- First immunisation: rapid increase, then decline to a low number
- Interim: low number (memory)
- Second immunisation: more antibody made, more quickly
What is the central principle of vaccination?
Vaccination will be the first exposure
When we are exposed to the antigen again, the immune response will be heightened and rapid
Describe the magnitude of e response the second time we are exposed to an antigen
- Greater magnitude
* More rapid response
Describe the differentiation of naive cells after exposure to antigen:
• first immunisation
• second immunisation
First: naive differentiates into:
• memory
• effector
Second:
• memory cells differentiate into many more effector cells
Which diseases are caused by S. pneumoniae
• Pneumonia
- Septicaemia
- Meningitis
- Otitis media
Why vaccinate against TB?
- Most important pathogen for children under 5
- Debilitating and permanent sequelae
- Disease occurs in the healthy as well as the immuno compromised
What is the primary site of replication of S. pneumonia
Nasopharynx
What we need to know when making a vaccine?
- Pathogenesis of bacterium
- Nature of immune response which will give protection (B cell, CD4+, CD8+, IgA?)
- Ensuring response to antigen is immunogenic, not pathogenic
To where does S. pneumonia disseminate?
Ears
Lungs
Blood
Meninges
What does the S. pneumoniae vaccine need to protect?
How do we do this?
IgG: • Blood • Meninges IgA: • Mucosa
What are the virulence factors of S. pneumonia?
- Adhesins
- Pneumolysin
- Capsule (critical for virulence)
Describe the functions of pneumolysin
- cilia inhibition
- cytotoxic to alveolar / endothelial cells
- triggers C’ cascade
What are the innate immune functions that allow us to recover from infection?
Phagocytes
Spleen
PRRs (TLR2, NOD2)
Why is the capsule virulent?
- Allows the bacterium to survive in the blood
- Masks underlying structures
- Reduces efficiency of phagocytosis
What are the adaptive immune responses that lead to recovery from infection
Antibodies against capsule
–> opsonisation
Why is the spleen important in recovery?
Spleen receives antigens from the blood
It is thus a major site of:
• antibody production
• removal of old cells
• removal of antigens
What happens to people without spleens?
Suffer from overwhelming infections, due to lack of antigen and immune complex removal
Describe how immune complexes are removed from the blood
- In tissue, circulation:
• Red blood cells have C3bR which bind complement in the immune complexes
RBCs + Immune Complexes circulate to spleen
- In spleen:
• Splenic macrophages express C3bR and FcR
• Endocytosis of complexes; removal
What will the ideal prophylactic vaccine induce?
IgA (mucosa)
IgG (meninges and blood)
What will an ideal theraputic vaccine induce?
Innate and adaptive responses:
• splenic macrophages
• antibody against capsule
Describe the first pneumococcal vaccine
- Whole killed vaccine
- Sir Almroth Wright
- South African miners
- Success questioned
How was the whole killed vaccine improved upon?
The whole killed vaccine elicited undesirable reactions
They extracted just capsular antigens
Describe the vaccine in 1983
Pneumococcal polysaccharide vaccine
• just capsular polysaccharide antigens
Vaccine contains 23 of the most common serotypes
80% of infection prevented
Describe the structure of a native antigen
T cell determinant
B cell determinant
Describe the effects of vaccination with capsular antigens (1983)
Adults:
• 80% effective in immunocompetent
• Short lived response (no memory)
Elderly, Children, immunocompromised:
• Variable / poor response
How are B cells activated to produce antibodies
- Take up, process antigen, present on MHC II
- Th cell activated by macrophage
- Th cell activates B cell with presentation of antigen, costimulation and cytokines
- B cell makes antibodies
What is required for isotype switching and high affinity antibodies?
T cell help
–> presentation of antigen on MHC II
What does T cell help bring about
Memory
High affinity antibody
Isotype switching
Can we launch an immune response against polysaccharide at all?
Yes
Describe how B cells respond to polysaccharide
- Repetitive antigens
- Cross linking to receptors on B cells
- B cells activated
NB not T cell help
What is produced by B cells that are activated by polysaccharide?
IgM
A little IgG
Why are highly repetitive polysaccharides required?
Only repetitive sugars can cross link on the B cell receptors
Cross linking is required for activation
Compare the type of molecule in T cell dependent and T cell independent antigen
TD: protein
TI: polysaccharide, lipids, nucleic acids
Compare repeating epitopes in T cell dependent and T cell independent antigen
TD: no
TI: yes
Compare response in infants in T cell dependent and T cell independent antigen
Explain this
TD: yes
TI: no
In infants, the immune system has not yet developed to be able to response to TI antigen
Compare isotype switching in T cell dependent and T cell independent antigen
TD: yes
TI: no (some IgG)
Compare antibody affinity in T cell dependent and T cell independent antigen
TD: high
TI: low
Compare memory in T cell dependent and T cell independent antigens
TD: yes
TI: no
How do we change our antigens so that the vaccine is more effective?
Chemically connect a protein antigen to a polysaccharide antigen
Perform conjugation, because
T cell reacts to protein
B cells react to polysaccharide
What is the connection of TD and TI called?
Conjugation
What does a B cell do to a conjugate antigen?
What is the significance of this?
BCR recognises polysaccharides
Takes it up whole thing up
Presents the protein on MHC II
Now, Th cells can recognise this B cell
–> isotype switching, affinity, memory
What is the antigen specificity of the antibodies?
The capsular polysaccharide
Because the initial B cell receptor recognised the polysaccharide
What is the specificity of the T cell receptor?
The protein from the conjugated antigen
When were conjugated vaccines first licensed in Australia?
Which proteins are used?
2001
By 2005, on the national vaccination program
Tetanus toxoid or diphtheria toxoid
How many serotypes in the new generation conjugate S. pneumoniae vaccine?
Heptavalent - 7 serotypes
Now, 13
What are the pros and cons of conjugate S. pneumoniae vaccine?
Pros:
- response in children
Cons:
- expensive
What is the result of the conjugate vaccine?
Children:
72% efficacy against IPD
Adults:
Reduced incidence of pneumonia –> if children don’t have it, their parents won’t
New disease, serotype 19A:
From serotypes that aren’t in the vaccine, esp. 19A
What is serotype replacement?
Give an example
This is when a non-vaccinated serotype starts to cause the majority of infections
For example:
19A infection rate has increased since vaccination was brought in, because it was not in the vaccine
Describe the effect of the vaccine on under 2s from 2001 to 2006
Dramatic decrease in IPD
Indigenous communities: still have a higher rate of infection than other groups
Why was there also a decrease in IPD in elderly when the children were infected?
The children were no longer transmitting the bacteria to their grandparents
HERD IMMUNITY
What is herd immunity?
This is when vaccinating one group has effects on another group
What happened to incidence of IPD due to non 7vPCV serotypes after vaccination?
Increase in incidence
Due to serotype replacement
Why did the vaccine elicit such a poor response?
The vaccine contained only polysaccharide, not protein.
Since there was no antigen presented on MHC, no T cells were activated.
Low affinity antibodies, no isotype switching, no memory
WHat are some possibilities of new vaccines?
1/ Less antigenic variation
- pneumolysin
2/ Protein antigens
How is it that B cells can be helped by T cells that recognise an internal part of the antigen?
B cells take up the antigen, degrade it and express the internal antigen on their MHC II.
Th cells recognise this with their TCR
What does H. influenzae cause in children?
Meningitis
Describe the mode of action of the Hib vaccine
(vaccine against H. influenzae type b)
• Conjugate vaccine: polysaccharide antigen + toxoid protein
• BCR binds polysaccharide
• TCT recognises toxoid protein
• B cell present toxoid on BCR –> T cell help
• high affinity, isotype switching, memory
What have been the outcomes in the community since the use of the Hib conjugate vaccine?
Big decrease in incidence of childhood H. influenzae infection
What is the protein that is conjugated onto the polysaccharide antigens?
A toxoid:
• Diphtheria
• Tetanus
