Vaccinology - Vaccine formulations Flashcards
1
Q
Which types of vaccine are considered ‘classic’? (3)
A
Vaccines that are based on the modification of a wild-type pathogen
1. Live-attenuated vaccines
2. Inactivated vaccines
3. Subunit vaccines
2
Q
Which type of vaccine are considered ‘novel’? (5)
A
Vaccines that rely on recombinant DNA technologies
1. DNA vaccines
2. Vector-based vaccines
3. Virus-like particles
4. Antigen-loading of autologous DCs
5. RNA/mRNA vaccines
3
Q
What are examples of current live-attenuated vaccines? (5)
A
- Measles, mumps, rubella (MMR/BMR)
- Varicella zoster virus (VZV)
- Yellow fever (YFV)
- Influenza
- BCG
4
Q
Which two production strategies can be used to produce live attenuated vaccines?
A
- Taking an animal pathogen similar to the human pathogen to generate cross-protection
- Adapt the virus to conditions very dissimilar in humans, ensuring that it can no longer effectively replicate in humans
5
Q
What are requirements of animal viruses being used to induce cross-protectivity against human viruses? (2)
A
- It must generate strong cross-protection
- The animal pathogen must have some replication in humans to induce an immune response, but not so much that it causes disease
6
Q
What is an example of a succesful case of an animal virus being used to generate cross-protectivity against the human virus?
A
Cowpox being used for smallpox eradication
7
Q
What is an example of a virus that was passaged in conditions dissimilar to humans, making it unable to replicate efficiently in humans? Under which conditions was it adapted?
A
Rubella -> passaged in embryonated chicken eggs at reduced temperature
8
Q
What are the advantages of live attenuated vaccines? (2)
A
- Immune responses resemble natural immunity
- Often induce long-lasting protection after a single dose
9
Q
Why do live attenuated vaccines strongly mimic natural immunity?
A
Viral replication & antigen production within host cells leads to presentation on MHCI and MHCII, inducing a strong B- and T-cell (both CD4+ and CD8+) response
10
Q
What are the disadvantages of live attenuated vaccines? (3)
A
- Safety risk in immunocompromised
- Possibility to revert to wildtype
- Interference by maternal antibodies
11
Q
What are two reasons live attenuated vaccines cannot be given during the first few months of children’s life?
A
- Maternal antibodies neutralize the virus before it has a chance to trigger the immune system
- Immunodeficiencies have not always been diagnosed at a very young age -> live attenuated viruses could cause severe illness
12
Q
From how many months onwards are children typically vaccinated with live attenuated vaccines?
A
> 14 months
13
Q
What is the advantage of inactivated vaccines over live attenuated vaccines?
A
Infectivity & replication eliminated (no chance of spread or disease) while maintaining immunogenicity
14
Q
What are examples of current inactivated vaccines? (4)
A
- Influenza (being replaced by subunit vaccines)
- Polio
- Hepatitis A
- Bordetella pertussis
15
Q
What are strategies to inactivate a virus for vaccines? (3)
A
- Chemicals (formalin)
- Heat (mild)
- Radiation
16
Q
What are important characteristics for possible inactivation methods to produce an inactivated vaccine? (2)
A
- Antigenicity should be retained
- Immunogenicity should be retained
17
Q
What is the main advantage of inactivated vaccines?
A
Safety
18
Q
Why do inactivated vaccines induce poor CD8+ T-cell responses?
A
No endogenous production of proteins -> no presentation on MHCI
18
Q
What are the disadvantages of inactivated vaccines? (3)
A
- Usually multiple doses required
- Short-lasting immunity
- Poor induction of CD8+ T-cells
19
Q
In which settings is the lack of CD8+ T-cells induction by a vaccine problematic, and in which cases isn’t it?
A
Problematic in case of intracellular pathogens, but not a problem in case of extracellular pathogens
20
Q
What is an additional rare disadvantages of inactivated vaccines? In which virus families does it occur?
A
Risk of priming for advanced disease in paramyxoviruses & feline coronavirus
21
Q
What are the two manufacturing options to manufacture subunit vaccines? Are they both in use?
A
- Non-recombinant: fractionation of pathogen & purification of proteins
- Recombinant: express gene of interest in yeasts/bacteria/cells & purification of proteins
Nearly all subunit vaccines are produced using recombinant techniques
22
Q
What are examples of current subunit vaccines? (3)
A
- Influenza
- Hepatitis B (HBV)
- Tetanus
23
Q
Which antigens are typically used in subunit vaccines?
A
Capsid- or membrane proteins
24
What are the advantages of subunit vaccines? (3)
1. Safe
2. Selection of subunits facilitates a targeted immune response
3. Can be used as a marker vaccine to differentiate infected from vaccinated animals
25
What are disadvantages of subunit vaccines? (3)
1. Poorly immunogenic
2. Short-lasting immunity
3. Poor induction of CD8+ T-cell responses
26
Why do subunit vaccines induce poor CD8+ T-cell responses?
No endogenous production of proteins -> no presentation on MHCI
27
What are solutions for the poor immunogenicity of subunit vaccines? (2)
1. Multiple doses
2. Addition of adjuvants
28
What is DIVA?
Differentiating vaccinated from infected animals though analyzing their immune response -> if it is only specific to vaccine components, the animal was not infected
29
What is a virus-like particle?
Essentially a subunit vaccine, modified in such a way that the presentation of the subunits is virus-like -> virus-like capsid structure
30
By which mechanism do virus-like particles deliver antigens to cells?
They can infect cells, much like viruses can (they just lack the genetic material)
31
What are examples of virus-like particle vaccines? (3)
1. Hepatitis B virus (HBV)
2. Human papilloma virus (HPV)
3. Hepatitis E virus (HEV)
32
What are the advantages of virus-like particle vaccines? (4)
1. Safe
2. Structural similarity to viruses
3. Selection of subunit facilitates targeted immune response
4. Can be used as a marker vaccine to differentiate infected from vaccinated animals
33
What are disadvantages of virus-like particle vaccines? (4)
1. Poorly immunogenic
2. Short-lasting immunity
3. Poor induction of CD8+ T-cell responses
4. Pre-existing immunity to VLP vector
34
Why do virus-like particle vaccines induce poor CD8+ T-cell responses?
No endogenous production of proteins -> no presentation on MHCI
35
Why is pre-existing immunity to VLP-vectors a problem for virus-like particle vaccines?
Immunity to the vector could neutralize the particles before they have a change to deliver their antigens
36
In what configuration is the DNA in DNA vaccines stored?
Bacterial plasmid DNA
37
What is the mechanism of action of DNA vaccines?
DNA gets taken up by host cells and causes transient expression of encoded genes & proteins
38
True or false: DNA vaccines are currently used in humans
False; they have proven poorly immunogenic in humans
39
In which settings can DNA vaccines sometimes be effective in humans?
In heterologous prime-boost settings
40
In which settings have DNA vaccines proven to be effective on their own?
For vaccination of small laboratory animals
41
What is the major challenge of DNA vaccines?
Administration
42
What are currently explored administration methods for DNA vaccines? (4)
1. Gene gun
2. Microneedles
3. Gas injectors
4. In vivo electroporation
43
What is 'gene gun' administration?
Intradermal administration of DNA-coated gold particles
44
What are the advantages of DNA vaccines? (5)
1. Easy to produce
2. Induction of humoral immune responses
3. Induction of CD4+ and CD8+ responses
4. Very stable -> can be stored at room temperature
5. Can encompass large inserts
45
Why do DNA vaccines induce CD8+ T-cells?
They lead to endogenous production of antigens, which are presented on MHCI
46
What are disadvantages of DNA vacciness? (2)
1. Often poor protection
2. Perceived risk of genome integration by the public
47
Which two types of RNA vaccines can be distinguished?
1. Non-replicating mRNA
2. Viral-derived self-amplifying mRNA (SAM)
48
What is the configuration of RNA in non-replicating mRNA vaccines?
Replicates human mRNA: gene of interest, flanking untranslated regions, 5'-cap and poly(A)-tail
49
What is the configuration of RNA in viral-derived self-amplifying (SAM) mRNA vacciness?
Alphavirus mRNA structures added to region of interest, allowing for replication of mRNA
50
What is the advantage of viral-derived self-amplifying mRNA vaccines (SAM) over standard mRNA vaccines?
Large amount of antigen production from an extremely small dose of vaccine
51
How is RNA in RNA vaccines delivered intracellularly?
With lipid nanoparticles
52
What are the advantages of RNA vaccines? (5)
1. Safe
2. Good induction of cellular immune responses, including CD8+
3. Good induction of humoral immune response
4. Can be administered repeatedly without immunity to administration mechanism
5. Scalable
53
What is the main disadvantage of all RNA vaccines?
Stability -> require cold-chain
54
What are disadvantages specific to self-amplifying viral-mRNA (SAM) vaccines? (2)
1. Size constraints
2. dsRNA formation
55
Why is dsRNA formation in self-amplifying viral-mRNA (SAM) vaccines disadvantageous?
dsRNA = potent TLR trgger -> can cause side effects
Sidenote: this can also be beneficial to inuce a strong immune response
56
True or false: DC vaccines are currently being used to vaccinate against rare infectious diseases
False: DC vaccination is fully experimental
57
What is the process of DC vaccine manufacturing? (4)
1. Isolate PBMCs
2. Select monocytes & culture into DCs
3. Maturate DCs & expose them to antigen
4. Re-infuse loaded DCs
58
What are advantages of DC vaccines? (2)
1. Good induction of cellular immune responses, including CD8+
2. Individual, tailor-made vaccines
59
What is the main disadvantage of DC vaccines? Why? (2)
Individual, tailor-made vaccine
1. Labour-intensive
2. Expensive
60
What is a viral vector?
Tool used by molecular biologists to deliver genetic material into cells/hosts
61
What is a viral vector-based vaccine?
Use of vectors to carry selected genes from another pathogen for immunization purposes
62
What is the immunological advantage of vector-based vaccines?
They form their own adjuvant & induce a natural type of immune response
63
For which disease are vector-based vaccines currently in use?
Covid-19 (Johnson & Johnson, University of Oxford-Astrazeneca)
64
For which disease are RNA vaccines currently in use?
Covid-19 (Moderna, Pfizer-BioNTech)
65
What are the advantages of vector-based vaccines? (4)
1. Safe
2. Intrinsic adjuvant
3. Induction of natural immunity, including CD8+
4. Can be used as marker vaccine to differentiate infected from vaccinated animals
66
What are the disadvantages of vector-based vaccines? (2)
1. Usually multiple doses required
2. Pre-existing immunity against the vector
67
What is the problem with repeated adminstration of vector-based vaccines?
Can lead to immunity against the vector, rather than the target of the vaccine
68
What is an adjuvant?
Pharmacologica/immunological agent that enhances the immune response to a vaccine
69
What are mechanisms of action of adjuvants? (4)
1. Antigen stabilization and/or delayed release
2. Enhanced antigen uptake in macrophages
3. Activation of co-stimulatory molecules
4. Improved delivery of antigens to the cytosol -> increased cross-presentation
70
What are examples of adjuvants? (6)
1. Aluminium salts
2. Mineral oils
3. Bacterial products
4. Detergents
5. ISCOMS
6. Cytokines
71
What are bacterial products that are frequently used as adjuvants? (2)
1. Pertussis
2. Freund's adjuvant
72
What is the disadvantage of using adenoviruses as a vector for vaccines?
Adenoviruses are common in humans -> there is a lot of pre-existing immunity against adenovirus
73
What are workarounds of the high pre-existing immunity to adenoviruses when using them as vaccine vectors? (2)
1. Picking a serotype taht is uncommon in humans
2. Use a non-human adenovirus
74
What are the currently approved SARS-CoV-2 vaccine platforms? (4)
1. Inactivated virus
2. mRNA
3. Viral vector
4. Protein subunit
75
Which SARS-CoV-2 vaccines make use of inactivated virus? (3)
1. Sinovac
2. Sinopharm
3. Bharat
76
Which SARS-CoV-2 vaccines make use of mRNA? (2)
1. Pfizer-BioNTech
2. Moderna
77
Which SARS-CoV-2 vaccines make use of viral vectors? (2)
1. University of Oxford-AstraZeneca
2. Johnson & Johnson
78
Which SARS-CoV-2 vaccine makes use of protein subunits?
Sputnik V
79
What is the common target antigen of all SARS-CoV-2 vaccines?
Spike protein
80
What is "vaccine effectiveness"? (definition)
Ability to protect an individual or population from an infectious disease
81
What is "vaccine efficacy"? (definition)
Protection offered by vaccines in ideal-world settings (=clinical trials)
82
When comparing mRNA and vector-based vaccines for SARS-CoV-2, which has higher efficacy?
mRNA has higher efficacy
83
How can the lower efficacy of vector-based SARS-CoV-2 (when compared to mRNA) be offset?
By boosting
84
Which groups of factors influence vaccine effectiveness? (5)
1. Host factors
2. Demographic factors
3. Vaccine access factors
4. Immune factors
5. Viral variant factors
85
Which host factors can positively/negatively/both affect vaccine effectiveness? (5)
Positively: previous infection
Negatively:
-Old age
-Immune compromised
-Underlying health conditions
Both: genetic polymorphisms
86
Which demographic factors can positively/negatively/both affect vaccine effectiveness? (4)
Positively:
-High levels of vaccine uptake
-High levels of herd immunity
Negatively:
-High levels of circulating virus
-Close proximity of people living together
87
Which vaccine access factors can positively/negatively/both affect vaccine effectiveness? (6)
Negatively:
-Limited access to vaccines
Both:
-Type of vaccine used
-Number of doses
-Timing between doses
-Heterologous prime-boost
-Cost-benefit decision by national vaccine bodies
88
Which immune factors can positively/negatively/both affect vaccine effectiveness? (3)
Positively:
-High antibody titres
-High quality of antibodies (neutralization)
Both: T-cell response
89
Which viral variant factors can positively/negatively/both affect vaccine effectiveness? (2)
Negatively:
-Antigenic mismatch with vaccine
-Increased transmissibility
90
What is "immunogenicity" of a vaccine? (definition)
The ability of a vaccine to stimulate an immune response to the vaccine product
91
Why are immunogenicity studies of vaccines important? (3)
1. Easy & high-throughput read-out in smaller numbers of patients (compared to clinical trials)
2. Improving vaccine formulations when the immune response is not as desired
3. Adaptation of vaccination policies
92
What is a correlate of protection? (definition)
Immune response a vaccine/natural infection needs to induce protection from the infectious disease in the future
93
What is the most frequent assay to test correlates of protection?
Neutralization assays using antibodies
94
What is the new strategy to study correlates of protection?
Establishing immune profiles of protection -> trying to correlate a broad set of immunological characteristics to protection against disease
95
Which immunological factors can be analysed to obtain immune profiles of protection? (8)
Humoral immunity:
1. Virus neutralization
2. Macrophage phagocytosis (Fc-mediated)
3. Neutrophil activation (Fc-mediated)
4. Complement deposition (Fc-mediated)
5. Antibody-dependent cellular cytotoxicity (Fc-mediated)
Cellular immunity:
6. CD4 T-cell regulation of the immune response
7. CD4 T-cell capacity to activate & induce class switch in B-cells
8. CD8 T-cell capacity to lyse virus-infected cells
96
True of false: the difference in antibody titres between mRNA and adeno-based SARS-CoV-2 vaccines directly correlates to the difference in efficacy
False: while the adeno-based vaccines had lower antibody titres, their efficacy was relatively comparable with mRNA-based vaccines
97
What are the differences between mRNA and adeno-based SARS-CoV-2 vaccines when it comes to:
1. Antibody titres
2. T-cell responses
Antibody titres: mRNA vaccines have higher titres & longer persistence of antibodies
T-cell responses: mRNA vaccines induce a higher number of spike-specific T-cells
98
Does the humoral or cellular response suffer more from antigenic variation of viruses?
Humoral response
99
Why does the humoral response suffer more from antigenic variation than cellular responses?
Antibodies recognize 3D structures -> more sensitive to antigenic variation
T-cell recognize nonamers/decamers -> less sensitive to antigenic variation
100
What is a possible solution to antigenic variation?
Bivalent vaccination -> include multiple variants in vaccines
101
What is the downside of bivalent vaccination?
Leads to a disproportionate boosting of the original vaccine, but does not lead to a substantial response to the new variant
102
What is a problem of the current method of measuring correlates of protection of vaccines?
They are measured in circulation -> not representative for location where pathogens are encountered
103
What is a strategy to induce local immune responses that is currently being explored for SARS-CoV-2?
Step 1: induce systemic immunity with intramuscular injectoin
Step 2: boost with mucosal vaccine to attract immune cells to pathogen entry sites
104
What is the advantage of heterologous prime-boosting for SARS-CoV-2?
Leads to superior boosting of antibody and T-cell responses compared with homologous boosting
105
Prior SARS-CoV-2 infection gives a [weaker/stronger] vaccination response
(Far) stronger
106
What is the influence of age on mRNA SARS-CoV-2 vaccines?
No strong influence
107
What is the influence of age on inactivated/adeno-based SARS-CoV-2 vaccines?
Less effective in elderly
