12. Trends in Vaccinology 1 Flashcards
1
Q
What is a vaccine?
A
A biological preparation that helps the immune system to defend against a specific pathogen
2
Q
What is an active vaccination?
A
- An active vaccination involves giving antigens from the target pathogen to the population to protect patients.
- The protection comes from their own immune system.
- This includes live pathogen, inactivated pathogen, subunits of pathogen and genetic material from the pathogen.
3
Q
What is passive vaccination?
A
- Passive vaccination gives protection from infection without stimulating the person’s immune system.
- This includes giving monoclonal antibodies.
4
Q
What is immunisation?
A
- The process of inducing immunity in an individual against a specific pathogen or disease.
- Vaccines are the primary tool for achieving immunisation
- This can be active or passive.
5
Q
What is an antigen?
A
- A molecule or part of a pathogen that triggers an immune response
- In the context of vaccines antigens are the key components that the immune system recognise.
6
Q
What is immunity?
A
- The ability of the immune system to protect the body from infection or disease.
- Vaccines aim to establish immunity without causing the actual disease.
7
Q
What is herd immunity?
A
- It occurs when a sufficiently high percentage of a population becomes immune to a disease through vaccination or previous infection.
- This reduces the likelihood of disease transmission and protects those who cannot be vaccinated.
8
Q
How effective is vaccination?
A
- They are the most effective public health tool after clean water.
- Vaccines prevent 2-3 million deaths every year.
- Vaccines have had much larger effects on some diseases then others.
9
Q
What can vaccines lead to?
A
disease eradication
10
Q
Why do antibiotics not lead to disease eradication?
A
due to resistance
11
Q
Why can vaccination lead to disease eradiction?
A
- Vaccines have longevity and create long lasting protection from disease.
- Escape or resistance to vaccines is rare.
12
Q
What disease has been eradicated by vaccination?
A
Small pox
13
Q
What diseases are close to eradication due to vaccination?
A
- Poliovirus
- (measles was very close to eradication in the 2000s but not so much now)
14
Q
How do vaccines work?
A
- The vaccine is injected or given. Usually through an intramuscular injection.
- The vaccine contains the antigen in some form.
- This antigen is then taken up by antigen presenting cells like dendritic cells.
- APCs present the antigen in MHC to the rest of the immune system and activate T cells.
- CD4 T cells stimulate their partner B cells to produce antibodies and generate immune memory.
- CD8 T cells are activated and have direct effector functions on the pathogen/vaccine.
15
Q
What is the vaccine development timeline?
A
1789: natural vaccination for smallpox using cowpox.
1881: Engineered live attenuated whole organism vaccines.
1896: Killed whole organism vaccines.
1923: Toxoid vaccines
1970: Subunit vaccines
1986: Virus like particles
1987: protein conjugate vaccines.
Reverse vaccinology
2019/2020: adaptable platforms like RNA vaccines and viral vectors.
16
Q
What are examples of engineered live attenuated whole organism vaccines?
A
- Anthrax
- Measles
- BCG
- Influenza (LAIV)
17
Q
What are examples of killed whole organism vaccines?
A
- Typhoid
- Polio
- Influenza
- Pertussis
18
Q
What are toxoid vaccines?
A
- It was determined that some microorganisms produce 1 virulence factors that is critical for disease.
- These can be specifically vaccinated against.
- You don’t need sterilising immunity you just need protection against the toxin.
19
Q
What are examples of toxoid vaccines?
A
- Tetanus
- Diphtheria
20
Q
What are subunit and virus-like particle vaccines used for?
A
To display and facilitate the entry of the antigen into immune cells
21
Q
What are examples of subunit vaccines?
A
- Anthrax
- Pertussis
- HepB
22
Q
What is an example of a virus like particle vaccine?
A
HPV
23
Q
What are conjugate vaccines?
A
- A vaccine for a polysaccharide antigen that has been attached to a protein antigen.
- This is done to induce a good immunogenic response.
- This is especially important in young children as they produce a T cell-independent antibody response.
24
Q
What is an example of a protein conjugate vaccine?
A
- Pneumococcus
- H.influenzae type B
25
Why are conjugate protein vaccines used?
Because polysaccharides are generally not very immunogenic when in a vaccine.
26
What is the process of reverse vaccinology?
1. The pathogen is identified.
2. The pathogen is sequenced.
3. The immunodominant conserved antigens are identified.
4. A vaccine is designed for these antigens.
5. This is rational vaccine design.
27
What vaccine was created using reverse vaccinology?
1. Meningococcal B
2. This is because you couldn’t give the whole polysaccharide capsule due to CNS reactivity.
28
Which vaccine platform is the best?
1. Different vaccine platforms are more appropriate for different situations and different pathogens.
2. The newer vaccine platforms are not always better then the older methods.
29
Which vaccine seems to give the best long-lasting immunity?
1. Conjugate protein vaccines
2. This is because the polysaccharide and protein combo is very immunogenic.
30
What are the benefits and drawbacks of RNA vaccines?
1. Good for dealing with outbreaks.
2. Quick production and quick control of disease.
3. There are some side effects
4. They are generally not great at blocking transmission.
5. The durability of these vaccines is still untested and debated.
31
What is the main advantage of reverse vaccinology?
You can use it to create a vaccine when you don’t know the antigen and cannot give the whole microorganism.
32
What is the main advantage of live attenuated vaccines?
They produce good indirect effects.
33
What phases are in the current UK vaccination schedule?
1. Maternal vaccines.
2. Infant vaccines.
3. Childhood vaccines.
4. Adolescent vaccines.
34
What is maternal vaccination used for?
1. To protect young infants from pathogens from the 1st day of life.
2. This includes influenza, Pertussis and RSV.
35
What is infant vaccination used for?
1. To protect infants against invasive pathogens that exploit immature infant immunity.
2. These are usually bacterial infections that cause diarrhoea.
36
What is childhood vaccination used for?
1. To protect children against severe complications of mostly viral infections.
2. To boost immunity from previous infant vaccinations.
3. To protect children as maternal immunity wanes.
37
What is adolescent vaccination used for?
1. To protect against cervical cancer (HPV) and meningitis.
2. To boost immunity from previous vaccination.
38
How does maternal vaccination protect infants?
1. The vaccines induce an immune response in the mother.
2. The antibodies produced can be passed to the foetus through the placenta and the infant through the breast milk.
3. It also protects the mother.
4. Breast milk contains high levels of secretory IgA.
39
What do indirect effects of vaccines result in?
Herd immunity
40
How do indirect effects of vaccines cause herd immunity?
1. Vaccines work directly by protecting the person vaccinated but have wider effects on the population level.
2. This is because vaccinated people are less likely to transmit the infection.
3. This helps to protect the wider population.
4. This means that disease cannot spread in a population with a high percentage of vaccinated population.
5. This helps to protect people that can't/won't get vaccinated or respond poorly to the vaccine.
6. Most vaccines for diseases with human to human transmission work this way.
7. This population protection is called herd immunity.
41
What vaccine provides a good example for indirect effects on the population?
MenC vaccine
42
How has the epidemiology of MenC changed due to indirect effects of the vaccine?
1. The MenC vaccine is a conjugate protein vaccine.
2. Before the vaccine, paediatric patients had lots of MenC.
3. The MenC vaccine was given babies and teenagers.
4. The vaccines massively reduced the incidence of MenC in under 20s.
5. It also caused a reduction of MenC incidence in over 20s despite them never being vaccinated.
6. This is the indirect effect of MenC.
7. This worked as you were vaccinating the main transmitters of the disease.
43
Why are 3 sets of primary immunisations given?
1. Young infants need more help to fight infection and they are more set up for tolerance.
2. We don’t really know if 2 or 3 doses should be given but we know 1 is not enough.
44
Why is the measles vaccine given at 12 months?
1. Transplacental antibodies wane from 6-12 months.
2. If you have measles maternal antibodies this can actually neutralise the vaccine.
3. So the effect and protection from the vaccine it mitigated.
4. So the vaccine is given once most maternal antibodies have waned.
45
Why is the measles vaccine given earlier then 12 months in some places?
1. In countries with low uptake of the measles vaccine, it is offered at around 8 months.
2. This is because the low uptake means the risk of infection is bigger then the risk of of reduced effectiveness from the vaccine.
3. Also based on environment
46
Why is MenC now only given at 12 months?
1. Due to the indirect effects of the MenC vaccine on the population.
2. Circulating disease has reduced and infections are rarer.
3. The population's nasopharynx microbiome has been altered by the vaccine.
47
What is the R number of measles?
12-18
48
What is the R number?
How many people a person with an infection will infect
49
Why are we experiencing regular epidemics of measles across Europe?
1. It is a very infectious and clinically relevant disease.
2. The measles vaccine has had limited uptake due to controversy surrounding the MMR vaccine.
3. The majority of children infected with measles are unvaccinated.
4. Vaccinated children can still get measles but it is attenuated and very mild.
5. Only around 75-80% of children are getting both doses of the vaccine.
50
What are the solutions to reduce measles infections in Europe?
1. A mass vaccination campaign
2. Combating misinformation about MMR vaccine. This is tricky.
3. Focusing on migrant health.
51
Why is focusing on migrant health important to combat a rise in measles?
1. They often come from countries with non-functional healthcare systems so are not vaccinated.
2. They are communities that are a hot bed for measles.
52
What is the perfect vaccine?
1. It addresses a clinically important problem.
2. It is effective at reducing the target disease.
3. It has predictable on-target effects against the pathogen.
4. It provides durable protection.
5. It reduces transmission.
6. It is well tolerated.
7. It has no unpredictable off-target effects.
8. Little to no side effects
9. It has some non-specific effects.
10. It has indirect effects.
11. It is acceptable to the public.
12. Cheap to manufacture
13. Easy to administer (single dose).
14. Thermostable for ease of transport.
15. For a pathogen with established correlates of protection.
53
What are the steps in vaccine development?
1. Clinical research to understand the effects of the pathogen on the population and what is protecting us.
2. Research for understanding of the pathogen and correlates of protection.
3. Research for understanding the antigen and most suitable delivery platform.
4. After all this work and a bit of luck you might get a candidate vaccine.
5. Then you need to try and manufacture the vaccine under good manufacture process.
6. Test for safety and immune correlates in mice.
7. Then clinical trials and licensing.
8. Thousands and thousands of vaccines don’t make it through development. (steps 2-6)
54
Why were the SARS-CoV-2 vaccines able to be developed so quickly?
1. If the pandemic was years earlier then it would have been worse.
2. The technology used for the SARS-CoV-2 vaccines had been proven and was ready for use.
3. The vaccine was made as soon as the sequence data was made available. Then was tested in mice.
4. Everything else stopped and all efforts were concentrated on this.
5. Everything happened at the right time and place.
55
How do you know a vaccine works?
1. Phase 3 trials are used to look at the efficacy of the vaccine.
2. Phase 1 and 2 trials measure efficacy through correlates of protection.
56
What are the limitations of phase 3 trials?
1. They are very expensive.
2. You need to have a high enough incidence of infection to know the effect of the vaccine.
3. These are tricky for rare and serious infection
57
What are correlates of protection?
Something you can measure in the blood that correlates to clinical protection from infection
58
How are correlates of protection determined?
1. The only good way to determine this is failed phase 3 trials.
2. You compare vaccinated and unvaccinated populations that got the infection.
3. You then see what the difference is in the blood between the populations.
59
What are the limitations of correlates of protection?
1. Blood is the really the only sample we can take so this is the only thing you can measure.
2. Reproducibility is important so the assays determining the correlates need to be cheap and standardised.
3. There is just a general lack of data on what protects us.
60
What is the most common correlate of protection?
Serum antibody levels against the pathogen/antigen.
61
What are some ways to measure immune correlates of protection?
1. Binding antibodies like in S. pneumoniae ELISAs.
2. Neutralisation of virus like in RSV
3. Bactericidal assays like in N. meningitidis.
4. Haemagglutinin assays like in influenza
62
What are bactericidal assays?
1. Using different dilutions of serum and incubation with the bacteria.
2. See the concentration that can kill 50% of the bacteria.
63
Do all pathogens have the same correlates of protection?
1. Different pathogens in different scenarios can have different correlates of protection.
2. The actual correlate measured can also vary.
64
What is the future of determining correlates of protection?
1. Lab advances mainly in standardisation, communication and robotics.
2. Using AI to measure and compare all the data collected and examine it in an unbiased way. (systems biology)
3. Using human challenge models to study the immune response
65
What is malaria?
1. Caused by Plasmodium parasites.
2. Causes ~400,000 deaths per year and mostly children.
3. They have very complex lifecycles.
66
What are the challenges of developing a malaria vaccine?
1. Attenuated or killed parasites didn’t make a good vaccine.
2. Immune evasion
3. The antigens the pathogen expresses change a lot depending on the stage of the parasite lifecycle.
67
How long has malaria vaccine development taken?
30 years of research
68
What was the 1st malaria vaccine?
1. A virus-like particle that displayed P.falciparum circumsporozoite protein.
2. Use a HBV scaffold.
3. It targets the pre-erythrocytic stage of malaria.
4. Only had 32% efficacy against severe malaria but wanes rapidly
5. But it's better than nothing.
69
How was the 1st malaria vaccine improved to make the 2nd malaria vaccine?
1. Used a yeast expression system to increase the circumsporozoite protein expression.
2. Apart from increased expression it is the exact same vaccine.
3. It was a lot cheaper, easy to manufacture and more thermostable.
4. Has 77% efficacy
5. It is durable for at least 2 years.
6. 3 doses
70
What is the main disadvantage of the new malaria vaccine?
1. It required 3 doses.
2. Need to vaccinate 40 million children.
3. Most vaccines are made in India but they don’t have malaria
4. So you need to get enough vaccine to the right place.
71
What is RSV?
1. Respiratory syncytial virus.
2. It causes severe respiratory disease in babies and the elderly.
72
What were the problems with the inactivated whole virion RSV vaccine?
1. The virus targets the F protein that is important for virus entry.
2. The F protein exists in 2 conformations.
3. Pre F is when the protein is unbound and its native conformation.
4. Post F is when it is bound to the host cell and allows viral entry.
5. If you vaccinate and generate antibodies against post F you facilitate entry into the cell.
6. This was causes the problems for the vaccine.
73
What did they need to do the RSV F protein in order to make a vaccine?
1. The structure of F protein is unstable and changes between Pre F and post F.
2. They needed to stabilise the structure and keep it in the PreF conformation.
3. This was done and a new vaccines created.
74
What are the new RSV vaccines?
1. Monoclonal antibodies directed at preF. This can be given to babies.
2. Protein subunit vaccines. This is given to elderly and pregnant people.
3. Live attenuated and mRNA vaccines are in trials
75
Why did the UK choose to give the RSV protein subunit vaccine instead of monoclonal antibodies?
1. They were one of the only countries to do this.
2. It is easier to give a mum a vaccine then a baby.
3. Making monoclonal antibodies is very expensive.
76
What can the route of vaccine delivery impact?
The immune response:
1. Magnitude
2. Quality
3. Location
77
What is the live attenuated influenza vaccine?
1. A mucosally delivered vaccine through a nasal spray.
2. It is a seasonal vaccine given annually to children 2-18 years old.
78
Why is the live attenuated influenza vaccine given to children?
1. Elderly people need protecting from flu.
2. The most common way they get flu is from children and their grandchildren.
3. You can't really give them the inactivated vaccine for this purpose as it is not very transmission blocking.
4. So made a non invasive vaccine that prevents transmission.
5. It has good indirect effects and protects the population.
79
How does the live attenuated influenza vaccine prevent transmission?
1. It is delivered mucosally.
2. It induces high titres of mucosal immune responses.
3. It protects the children but they are not really the problem.
80
What are vaccination schedules are determined by?
1. Basic immunological principles.
2. How vaccines were licensed
3. Implementation factors.
81
What could make you reduce the number of vaccine doses?
1. As the epidemiology changes
2. to save money
3. To save doses.
82
What are vaccines licensed on?
their ability to induce an immune response, not on their ability to reduce transmission.
83
What is a large problem that affects all vaccines?
The systemic inequity of where you live.
84
What are non-specific effects of vaccines?
1. Some live vaccines are associated with a reduction in all mortality not just to the disease it vaccinates against.
2. It trains that innate immune system to fight a variety of infections.
