IMI7: Immune memory and vaccination Flashcards
(99 cards)
1
Q
What did the German scientist Emil von Behring and the Japanese physician Shibasaburo Kitasato discover in 1890?
A
that the transfer of serum from a mouse immunised against tetanus to a non-immunised mouse could completely protect the latter from a normally fatal challenge with virulent tetanus bacteria.
2
Q
What did Emil von Behring and the Shibasaburo Kitasato’s observation support?
A
Paul Ehrich’s model of humoral factors being the critical mediators of immunity, and is relatively short-lived. .
3
Q
What did subsequent adoptive transfer experiments show? (where various sets of cells from immunised mice are transferred to immunologically naive mice)
A
That certain subsets of B and T lymphocytes are the key elements in the potentially life-long immunity that we develop after infection or vaccination.
4
Q
What is the primary role of B cells in immunity?
A
the development and production of high affinity specific antibodies.
5
Q
Why do B cells need to have the ability to develop and produce high affinity specific antibodies?
A
To be pre-armed against re-infection, the body needs both an abundance of antibodies in the body fluids (be it blood, lymphatics or mucosal surfaces), and cells that can accelerate the production of more antibody when a re-infection occurs. For any given antibody, these two jobs are done by different B cell subsets.
6
Q
Where are high affinity antibodies produced?
A
Germinal centre of the secondary lymphoid organs
7
Q
What are the two cell types that emerge from the germinal centre reaction?
A
Effector B cells that make antibodies
The resting cell that is ready to respond next time
8
Q
What is the effector B cells that make antibodies called?
A
Plasma cell
9
Q
What is the resting cell that is ready to respond next time called?
A
Memory B cell
10
Q
What is the quickest response that the adaptive immune system can provide? Why?
A
Having sufficient levels of antibody when a pathogen invades - If the antibody can intercept the pathogen before it gets a chance to properly invade or proliferate, then the infection will be stopped before it even begins.
11
Q
What is opsonisation?
A
Marking a pathogen for phagocytosis
12
Q
What is complement fixation?
A
Promoting the rupture of membranes
13
Q
What is neutralisation?
A
Preventing the successful invasion of cells by the pathogen
14
Q
The antibodies in our body fluids are produced mainly by what? Where do they take up residence?
A
long-lived plasma cells
in our bone marrow and mucosal tissues (gut, lung)
15
Q
Despite being a _____ _______ cell type, long lived plasma cells appear to be able to survive extremely long periods of time.
A
terminally differentiated
16
Q
Why do long-lived plasma cells survive a very long time?
A
In part, because they express very low levels of the B cell receptor (BCR), which means they are not easily activated when encountering antigen. thus the long-lived cells do not boost body-wide antibody production, but rather are responsible for maintaining a baseline of antibody production in the long term.
17
Q
What are long-lived plasma cells responsible for?
A
maintaining a baseline of antibody production in the long term.
18
Q
Early in the response, many of these memory cells will retain what type of immunoglobulin production, having not class-switched?
A
IgM
19
Q
Later in the response, the majority of memory cells leaving the germinal centre will have class switched to what? depending on what? What has happened to the affinity?
A
IgG, IgA or IgE, depending on the nature of the signals provoked by the pathogen. These will also have Ig with a higher affinity for the target.
20
Q
What kind of metabolic rates do memory B cells have?
A
low
21
Q
Do naive or memory B cells have a faster rate of response to a pathogen?
A
memory B cells
22
Q
Why do memory B cells respond more quickly to pathogens than naïve B cells?
A
In part because they have more of the activating receptors such as CD40, CD80 and CD86 on their surface. They are also more sensitive to stimulation by PAMPs.
23
Q
What restrictions to proliferation and activation do naïve and memory B cells have in common?
A
They require T cell help, BCR binding and an innate signal (through cytokine signals and/or sensing of PAMPs) to trigger their activation and proliferation.
24
Q
When B cells are activated what happens to them?
A
Some of these cells then differentiate into plasma cells to produce antibodies, while others – particularly the lower affinity IgM subset – will migrate to the germinal centre to undergo further affinity maturation.
25
Why would a memory B cell, which has already undergone affinity maturation, return to the germinal centre for more?
To adapt to pathogens mutating – particularly to antigenic drift:
- It keeps diverse Igs with low affinity as memory B cells, making it more likely that some of those will still be able to recognise a modestly mutated antigen.
- This will then act as a basis for producing new high affinity immunoglobulins against this modified strain of pathogen, protecting against a wider variety of virus strains.
26
Once a pathogen has been defeated, what happens to the amount of antigen present?
It reduces
27
What does the reduction of antigen in the blood do to B cell production?
It first triggers more of the cells to leave the germinal centre as plasma cells, some of which will migrate to the local mucosal niche or the bone marrow, to become long lived plasma cells.
28
Once the pathogen has been defeated what happens to the remaining cells in the germinal centre?
Most of the remaining cells in the germinal centre will stop proliferating and die, so there is space in the lymph node for a new germinal centre to form around the next batch of antigen to arrive.
29
What controls which memory B cells and plasma cells remain as the long-lived memory?
This is not yet known
30
Why are memory B cells easy to identify?
Most B cells undergo modification of their Ig genes (through somatic hypermutation and often class switching) after encountering antigens, and before committing to become memory B cells.
31
Why are T cells that have encountered an antigen previously less easily defined?
since their TCR remains unchanged. Nevertheless, the body wants more ready access to those T cells whose TCR has already recognised antigen, thereby proving itself to be potentially useful in future.
32
What are the subsets of memory T cells defined based on?
Their locations in the body and their cytokine, receptor and metabolic profiles -> These properties will give them different roles in subsequent immune responses.
33
Do naïve T cells or memory T cells respond more readily in response to their TCR being presented with antigen. ?
Memory T cells
| All of the memory T cells are relatively long-lived.
34
How do the different subsets of memory T cells relate to each other?
It is still not fully understood but there appear to be subsets that are more pluripotent (i.e. more able to give rise to many different cell types) or closer to terminal differentiation than others.
35
What are T stem cell memory cells?
TSCM cells are memory cells that are capable of differentiation into the various other types of memory T cell. This subset was discovered in mice, but its existence in humans has not yet been proved. It may be that this type of cell is the origin of the other types, which may be constantly replenished in the blood.
36
What are central memory T cells?
TCM cells are found in both secondary lymphoid tissue and in the circulation. They are the most long-lived T cell type, and secrete relatively few cytokines at rest. They can give rise to both TEM and TRM cells. It is this subset that is most likely activated for helper functions in the lymphoid tissues (eg helping B cells refine their antibodies). This location allows them to be rapidly activated when peripheral dendritic cells arrive in lymph nodes with antigen that their TCR can detect.
37
What are effector memory T cells?
TEM cells are memory cells are found in tissues or in the circulation. They lack receptors that would drive them to relocate to the secondary lymphoid organs (eg lymph nodes). They will respond to APCs (CD4+ memory) or infected/cancerous cells (CD8+ memory) in the blood or tissues.
38
What are effector T cells?
These are the T cells that we have largely spoken about previously, the T cells that are activated and get out and do the job of detecting presented antigen, either to provide help (CD4+) or kill offending cells (CD8+). Memory cells can change into effector cells in response to stimulation. It is not clear whether they can return to a memory state once they have changed. It is thought that a CD4 memory T cell can become any one of the various subsets of cells (TH1, TH2, TH17, Treg etc) that are effector T cells. This will depend on the nature of the response and the cytokine environment.
39
What are resident memory T cells?
TRM cells that are present in tissues, in a position to respond locally to an invasion of a pathogen. They tend to be more mobile – actively patrolling tissues – and more metabolically active (and as a result perhaps more short lived) than other memory cell subsets. As a result these are likely to be the first to come across antigen at a site of infection
40
Describe the diagram depicting the different subtypes of T cells, with increasing antigen exposure
naïve T cell -> TSCM cell -> TCM cell -> TEM cell <=> TEFF cell -> death
Naïve T cell -> TSCM cell -> TCM cell } all of these work in lymphoid tissues (-> TRM cell)
TEM cell <=> TEFF cell} both act in peripheral tissues and differentiate into TRM cell (this also comes from lymphoid tissues)
41
Why do memory T cells not have predefined roles?
Because the CD4 or CD8 status of the T cells is largely defined by whether their TCR recognises peptides on Class I or Class II MHC molecules, memory cells also retain this property: a CD8 memory T cell will always reactivate into a cytotoxic T cell. E.g. it cannot, become a CD4+ T cell.
42
Why is the CD4 subset (which can have a variety of helper functions) not a predefined property of the memory cell?
A CD4 memory cell has the potential to become a TH1 cell or a Treg, and this is solely dependent on the signals (cytokines, PAMPs, etc) that it encounters when its TCR is activated by an antigen.
43
Once you have established memory to a pathogen, how are subsequent responses improved?
1) Antibodies from long-lived plasma cells secreted into your circulation and lymph, diffuse into the spaces between cells in the tissues. And in the case of an IgA response the antibodies are also secreted onto the mucosal surfaces of the body.
2) Once antibodies are secreted they will all be able to directly act against the pathogen. This will allow opsonisation and complement fixation of infectious agents, and perhaps neutralisation, particularly of non-enveloped viruses which can be eliminated by TRIM21 even with a small amount of antibody binding.
3) The basal levels of antibodies in our extracellular spaces will stave off small scale invasions, which means that a more concerted attack will need a more active and dedicated response. Here the cellular memory will be important.
4) Memory B cells need to be activated to differentiate into plasma cells to produce more antibodies, or cytotoxic T cells (TC) need to be activated to identify infected cells. Both of these processes usually also require T helper (TH) cells.
44
While the response could start in the tissues, it is most likely that a strong response would come only once what happens?
The antigen has been transported to the large collections of immune cells in the secondary lymphoid tissues.
45
Why does activation of the cellular adaptive response take longer to mobilise than the humoral immune response? (for secondary infection)
Because it needs to bring T helper (TH) and B cells together, and because it may also need the specific cells to proliferate into a decent fighting force and to differentiate into effector cells (particularly plasma cells),
46
During secondary infection, how long does humoral response take compared to during a primary immune response?
The response will often reach a potent level within a day or two, in contrast to the 4-7 days more typical of a primary immune response.
47
During the primary response what is the first stage of the response graph? Explain it.
Lag phase:
Before the immune system can produce large amounts of specific antibodies, a lot has to happen. Both T cells and B cells with receptors specific for he antigen must proliferate, and then somatic hypermutation and clonal selection of the B cells for high affinity Ig takes place in the germinal centre. This can take 4-7 days or more to generate decent quantities of high affinity antibodies. As a result, there is a lag in the antibody response. If the pathogen is not controlled by the innate immunity, this period is characterised by increase in the amount of pathogen
48
Following the lag phase what occurs?
Antibody response:
At last the B cells have been selected to make high affinity antibodies and they can differentiate into plasma cells that provide antibody at the site of infection and into the wider body fluids. This will rise while the B cells are stimulated by antigen, but stop rising when the infection is cleared.
49
What response occurs following antibody response phase?
Peak antibody level:
New antibodies are no longer being produced, because antibodies have a half life of around 2-4 weeks, there will be a period after the infection has been resolved when the antibodies have reached their peak amount
50
Following peak antibody level what is the next phase of the response graph?
Primary response is over:
At the end of the primary response, the level of antibodies against antigen A fall to a steady level. This level is higher than it was before the first challenge, and the antibodies will probably have higher affinity and avidity. These new high affinity antibodies are continually produced by long lived plasma cells. Over a very long time (varies on a case by case basis) the level of specific antibody will slowly fall if the person does not encounter the antigen again.
There has been no change in levels of antibodies against antigen B, because the B cells have not yet encountered it
51
On the response graph, what is the first phase of secondary infection response?
Rapid secondary response:
The production of antibodies against antigen A is triggered by the activation of memory B cells and their differentiation into plasma cells that secrete antibodies. This process is supported by the activation of T helper cells specific for peptides from antigen A. Note the much shorter lag (1-2 days) that it takes before antibody levels increase.
52
On the response graph, what is the second phase of secondary infection response, following rapid secondary response?
Long term antibody levels:
The long term resting antibody levels (not shown on the graph) may be higher after the secondary antigen exposure than they were after the primary response finished. This probably depends on how effective the primary response was. Repeated stimulation by a pathogen is likely to maintain higher antibody levels than a one-off challenge.
53
If you are simultaneously infected with a pathogen for the first time that shares T cell epitopes with a pathogen you have previously been infected with, what will be the difference in the primary response?
the naive B cell response may be helped to develop a little bit more quickly by having larger number of specific memory T helper cells ready to go. However, since antibody maturation is the slowest part of the process, it is unlikely to make a big difference.
54
During a memory response, which of the following cells produce factors that can directly damage an invading pathogen?
cytotoxic T cell
Plasma cell
The cells that actually do all the dirty work are mainly the same in a memory response as a primary response. The effector cells (CD8+ T cells or plasma cells) are producing the adaptive response, although resident memory and effector memory CD8+ T cells may also be able to combat pathogens directly without first differentiating into effector cells. CD4+ T cells play a support role for these effectors (and for innate cells), so do not directly combat the pathogens.
55
The memory response to an infection is usually ______ and ______ than the primary adaptive immune response.
larger
| more rapid
56
During an extracellular bacterial infection, why is the CD8+ response not relevant?
As the TCR on CD8+ T cells can only respond to MHC class I-presented peptides, which have an intracellular origin.
57
When was the first documented vaccine? What for?
1768/1769, cowpox
| Edward Jenner
58
When did the WHO use attenuated animal poxvirus to vaccinate around the world for small pox?
1960
Last reported case of smallpox was 1973
1980 smallpox was declared eradicated from the planet
59
Roughly how many lives does immunisation save every year?
2.5 million: from diseases such as diphtheria, tetanus, pertussis and measles
60
What is the purpose of vaccines?
to establish an adaptive immune response as memory against a pathogen before you catch it in the wild.
61
What can vaccination can be undertaken against?
viruses (e.g. flu, polio, measles, mumps),
bacteria (e.g. meningitis)
or their toxins (e.g. diphtheria toxin, tetanus toxin).
62
What are live attenuated vaccines?
Versions of the pathogen with reduced virulence; They can infect and spread in the person, but don’t cause disease (but can cause problems in the immunosuppressed).
63
What are inactivated vaccines?
whole pathogens that have been chemically wrecked, so they cannot infect cells or replicate. They are therefore only presented to the extracellular immune system.
64
What are subunit vaccines?
consist only of a part derived from a pathogen or antigen. For example, bacterial surface proteins or viral glycoproteins, pillin proteins or toxins. Subunit vaccines are very safe but may require booster vaccinations (that means repeated vaccinations to build up the immune responses to an adequate protective level).
65
What are toxoid vaccines?
(to promote immunity to a bacterial toxin) use a chemically disabled form of the purified toxin. These vaccines protect against the harmful consequences of the infection, but do not establish immunity to the bacterium, just the symptoms it causes.
66
```
Which of the following responses:
1) Cytotoxic T-cell lymphocyte (CTL)
2) Helper T cell
3) Antibody / B cell
Will be elicited by:
a) live attenuated
b) inactivated
c) subunit
d) toxoid
e) DNA
VACCINES
```
a) live attenuated 1,2,3
b) inactivated 2,3
c) subunit 2 maybe, 3
d) toxoid 2 maybe, 3
e) DNA 1, 2&3 maybe
67
Describe the poliomyelitis virus
Poliomyelitis (polio) is caused by polio virus, an enterovirus, a single stranded RNA (ssRNA) virus that infects the gut.
Polio virus spreads easily, and can cause permanent muscle weakness in around 0.5% of cases, either at the time of infection, or developing years later.
68
How are live attenuated vaccines made?
classically the pathogen is grown and adapted to an environment different from what was normal for the virus.
69
Give an example of a live attenuated vaccine being produced
The resulting virus was able to grow in the gut of vaccinated people, but did not cause disease, and it appears unable to infect the nervous system.
70
Why does the inactivated polio vaccine not generate a cytotoxic T cell response?
It is unable to replicate and amplify itself in the person
71
Why does the inactivated polio vaccine not prevent poliovirus infection of the gut?
because it is delivered into the muscle, the primary immune response is to produce specific IgG, but not IgA. As a result, this vaccine is effective at preventing disease, but does not prevent poliovirus infection in the gut.
72
As one of the forms of polio virus is live, and sanitation in conflict associated regions is poor, what happened as a result of the polio vaccine?
it is able to continue to circulate. Worse, by circulating in people, the virus has reversed some of its attenuating mutations, meaning that the vaccine-derived polio has evolved to again be able to cause disease.
73
What are the difficulties with erasing polio completely?
if the vaccine strain is still circulating, then it has the potential to spread into unvaccinated youngsters. The obvious solution is to switch to the IPV, but this is both much more expensive to manufacture and deliver, and may not even be able to prevent the circulation of polio, because it fails to induce gut immunity.
74
What was added to vaccines to promote a stronger response? (as purification of vaccines lead to weaker, short lived immune responses)
Adjuvants
75
What did added adjuvants to vaccines assume?
| What was wrong with this assumption?
correlate of protection
simply generating an antibody response against an antigen from a pathogen is not always protective: those antibodies may not be the element of memory that prevents infection or disease, or the antibodies induced do not actually neutralise the pathogen.
76
What are good adjuvants are thought to work by?
some combination of prolonging the time that antigen survives to stimulate immunity and triggering the innate (PRR) responses of innate immunity.
77
What are the benefits are risks of inactivated viruses?
- The chemical inactivation needs to be stringent enough to kill any chance of a live pathogen surviving, but too much chemical modification runs the risk of changing the antigen so much that antibodies against it will not recognise the undamaged antigen.
- However, if produced and stored correctly, the vaccine should contain all the PAMPs and antigens to produce a decent antibody response, but not a cellular effector (ie CTL) response.
- Growing virus at scale is a logistically challenging process
78
Why are subunit vaccines challenging to engineer with the correct correlates of protection?
- Making the surface protein so that it is correctly folded, and has the right post-translational modifications (e.g. glycosylation) is a challenge.
- Additional strategies are needed to identify a suitable adjuvant for the vaccine, so that the antigen is directed to an immune response, and not a tolerising one. And it requires that antibodies against that subunit correlate with protection from infection or disease: this approach will not work if the CD8+ T cell response is essential for protection.
79
Describe how nucleic acid vaccines work
DNA (or RNA) molecules are made that encode the antigen, and these molecules are delivered to cells. In the cells, the DNA is transcribed and translated into protein, which will be expressed on the cell membrane, while peptides will be presented by MHC class I, to allow both antibody and CTL responses to be induced. Most of the DNA/RNA will never makes it to be translated in the cells, and this will act as a PAMP to provide help for antigen presentation from the innate response. Often the DNA is engineered with increased frequencies of CpG dinucleotides to help trigger an innate response from TLR9.
80
What is a disadvantage of nucleic acid vaccines?
However, these vaccines still show limited immunogenicity, and need multiple administrations, or combination with a subunit vaccine to get effective immunity.
81
Discuss conjugate vaccines
What are they?
How do they work?
Some potential antigens are very poorly immunogenic, but if an immune response against them was raised, it would be protective. This is particularly true of non-protein antigens, such as bacterial surface polysaccharides that are joined to lipids (lipopolysaccharide – LPS).
Conjugate vaccines join a non-immunogenic antigen to a protein, so that it becomes more easily identified by the immune system. This approach has revolutionised the production of anti-bacterial vaccines in recent years.
82
Discuss nanoparticle vaccines
A recent adaptation of subunit vaccines is to engineer them into a more virus-like form. This can use either an artificial bead, lipid droplet or can rely on the ability of (some) virus capsids to assemble spontaneously from their component parts.
Different types have different properties, but having a small and repeating profile better resembles a pathogen surface, and may enhance antibody production through T-independent mechanisms. The human papilloma virus vaccine is made from its capsid protein, which self-assembles into a virus-like particle.
83
The proportion of people in the population that need to be immune to stop the disease from spreading depends on what?
how easily the virus can spread.
84
What does the reproduction number mean? (R0)
The average number of times an infected individual transmits their pathogen to a new person
85
Why do viruses recently spread from animals tend to have a lower R0?
They do not spread as easily in humans
86
Why would viruses from animals get an increasing R0 over time?
zoonotic viruses evolve and adapt to their new host
87
How can you reduce the R0?
Environmental factors can alter this number: practising safe sex, or antiretroviral treatment can reduce the R0 of HIV to almost zero. Hygiene control measures, such as changes in how bodies were handled during the West African Ebola outbreak reduced the R0 of Ebola virus, helping to control the 2014-2015 Ebola pandemic. Having a vaccinated population also reduces the effective R0 of a virus, by limiting the number of vulnerable contacts to whom the virus can spread.
88
If the R0 is reduced and sustained below 1, then what will happen?
the infection will not sustain continued spread, and the infection will burn out.
89
Having a level of immunity that means an infection cannot spread indefinitely is called what?
herd immunity
90
What % immunity rate was required to prevent the spread of smallpox?
80-85%
91
What % immunity rate was required to prevent the spread of measles?
90%
92
By not increasing herd immunity, what happens to the venerable members of society?
we place vulnerable ones, such as cancer patients receiving chemotherapy and individuals with compromised immune systems, at risk of contracting potentially lethal diseases.
93
What system is in place to reduce vaccine complications and to catch them early?
Vaccine Adverse Events Reporting system
94
If you have been bitten by a snake, will a vaccine be helpful then?
No, as toxins tend to work more quickly than an adaptive response can develop, so vaccination is probably not helpful.
95
Following a snake bite, what can be administered instead of a vaccine?
Patient can be injected with an antibody against the toxin (anti-toxin) to neutralise it. This is called passive immunisation.
96
Give an example of passive immunisation in nature
The transplacental passage of IgG from mother to foetus and acquisition of IgA during breastfeeding are natural examples of passive immunisation.
97
Give some examples of passive immunisation against different antigens
1) Tetanus infection: anti-tetanus toxin antibodies in patients where immunisation is incomplete or absent;
2) Botulism: anti-botulinum toxin antibodies allows post-exposure prophylaxis;
3) Snake bites, jellyfish sting: anti-venom antibodies prevent receptor binding and help clearance of the toxin;
4) Rabies infection: anti-rabies virus polyclonal/monoclonal antibodies used to reduce/prevent infection after a bite
5) Emerging infectious diseases: serum from recovered patients given to patients or contacts to reduce illness or prevent spread of disease
98
While it can transiently protect against pathogen infection, passive immunisation is not a form of vaccination.
Why?
The fact is that these antibodies do not last long in the circulation, so they cannot induce long term immunity, which leaves people vulnerable to re-infection on another bite.
99
T or F:
One disadvantage of DNA vaccines is that they do not generate immunologic memory.
Explain your answer
False
The aim of DNA vaccines is to allow prolonged exposure to antigen just like a real infection. Thus, the likelihood that they will generate both B and T cell memory is high, so long as there are sufficient co-stimulatory signals.
