Vaccines and Vaccine Development Flashcards
(54 cards)
1
Q
Define Immunisation
- different forms
A
an artificial process by which an individual is rendered immuneTerm includes:
– Passive immunisation – no immune response in the recipient
– Active immunisation (vaccination) – recipient develops a protective adaptive immune response
2
Q
What is Passive Immunisation?
A
- Immunity conferred without an active host response on behalf of recipient
- Passive vaccines are preparations of antibodies taken from hyper-immune donors, either human or animal
- protection is temporary
- can be used to make anti-toxins
3
Q
What is the disadvantage of using Horse serum to make diptheria anti-toxins?
A
- The proteins on horse antibodies induce anti-antibodies
- Following this between a week and 10 days after inoculation the antibodies will form complexes with the horse immunoglobulin and inactivate it
- The complexes can be deposited and cause secondary immune complex disease
- Horse antitoxin is more rabidly eliminated than human antitoxin - half-life of human IgG is ~20days vs 5days horse
- Repeat administration of horse anti-serum can cause severe anaphylactic shock
4
Q
What are clinical symptoms of Immune Complex disease?
A
chills, fever, rash, urticaria, arthritis, and glomerulonephritis.
these usually present them selves 7-10 days after coming into contact with the offensive antigen
5
Q
Give examples of Passive Immunisation in vaccines
- effect
A
- Immunoglobulin replacement in antibody deficiency
- taken from donors
- VZV prophylaxis eg during exposure during pregnancy
- Anti-toxin therapies eg snake anti-serum
- Diphteria anti-toxin using anti-toxins form horses infected with it
- protection is temporary
6
Q
How would the following presentation of Vassilis zoster zirus (VZV) in pregnancy be managed
- Definite history of previous chickenpox
- No history of chickenpox or unsure
- No history of chickenpox, or unsure
A
- Definite history of previous chickenpox
- not indicated in the blood after VZV serology
- reassure patients
- not indicated in the blood after VZV serology
- No history of chickenpox or unsure
- VZV IgG positive
- reassure patient
- VZV IgG positive
- No history of chickenpox, or unsure
- VZV IgG negative or equivocal
- administer VZV immunoglobulin to protect against primary infection
- VZV IgG negative or equivocal
7
Q
What is Active Immunization (vaccination)
A
- Immunity conferred in recipient following the generation of an adaptive immune response
- General principle is to stimulate an adaptive immune response without causing clinically apparent infection
8
Q
What are important requirements for vaccines?
A
- safe to use and not cause the disease they aim to prevent
- must have minimal side effects
- must be long lasting
- easy to store and transport
- as cheap as possible
9
Q
What are general principles of vaccines?
A
- adminstered to target cohorts in advance of exposure to pathogen
- enough people need to be vaccinated to reach heard immunity
- vaccines are given to healthy people so risk to benefit ratio requires vaccines to have high safety standards
- most vaccines work by generating a long-lasting, high-affinity IgG antibody response
- strong CD4 T cell response is important for this
- ‘problem’ diseases are generally those where the immune system cannot eliminate infection or generate long-lasting protective immunity during natural infection
- MTB, HIV,malaria
10
Q
What goes into vaccines?
(3)
A
- Antigen: To stimulate an antigen-specific T and B cell response
-
Adjuvants: Immune potentiators to increase the immunogenicity of the vaccine
- most act on toll-like receptors
- ‘Excipients’: Various diluents and additives required for vaccine integrity
11
Q
How are active vaccines classified in terms of the antigen?
A
12
Q
What are live attenuated vaccines?
- how are they formed?
A
- Live but attenuated organisms used
- attenuated –> reduced
- Achieved by prolonged culture ex vivo in non-physiological conditions
- This selects variants that are adapted to live in a culture
- These variants are viable in vivo but are no longer able to cause disease in humans
13
Q
Give examples of Live-attenuated vaccines
(4/7)
A
- Measles, Mumps, Rubella (MMR)
- Polio (Sabin)
- BCG
- Cholera
- Zoster
- VZV (not routinely used for primary prevention in UK at present)
- Live influenza (not main product in UK at present)
14
Q
What are the Pros of live attenuated vaccines?
A
- Replication within-host, therefore produces highly effective and durable responses
- In the case of viral vaccine, intracellular infection leads to a good CD8 response
- Repeated boosting not required
- In some diseases, may get secondary protection of unvaccinated individuals, who are infected with the live-attenuated vaccine strain eg polio
15
Q
What are the Cons of live vaccines?
A
- Storage problems, short shelf-life
- needs a cold chain
- May revert to wild type
- Eg vaccine-associated poliomyelitis: around 1 in 750 000 recipients
- Immunocompromised recipients may develop clinical disease
16
Q
Give an overview of the Varicella-Zoster Virus
A
- Primary infection = chickenpox
- Cellular and humoral immunity provide lifelong protection, but viruses establish permanent infection of sensory ganglia –>
- Viral reactivation=zoster
- Particularly elderly, fairly debilitating and may cause long-term neuropathic pain
17
Q
Give an overview of the Varicella-Zoster Vaccine
- how does it work
- efficacy in the UK
A
- Live-attenuated VZV, works by induction of anti-VZV antibodies
- 95% effective at preventing chickenpox
- Attenuated virus does establish the infection of sensory ganglia, but subsequent zoster is probably rare
- 3-5% mild post-vaccination varicella infection
- Not on UK schedule at present, because:
- VZV is a fairly benign childhood infection
- ?Schedule is already crowded and controversial
- Safety concerns based on evidence from other countries
- ‘Disease shift’ to unvaccinated adults, in whom VZV is less well tolerated
- Increase in zoster – probably reduced immune-boosting in adults
18
Q
Give an overview of Zoster infection and age
A
- The incidence of zoster increases with age, in parallel with declining cell-mediated immune responses to zoster
19
Q
Explain the Zoster vaccination
- type of vaccine
- effect and use
A
- Similar VZV preparation to that used for primary disease, but much higher dose
- Aims to boost memory T cell responses to VZV
- In over 60s, 50% reduction in zoster incidence after vaccination compared to controls; reduced severity and complications amongst vaccinated cases
20
Q
What is Poliomyelitis
A
- Enterovirus establishes infection in oropharynx and GI tract (alimentary phase)
- Spreads to peyers patches then disseminated via lymphatics
- Haematogenous spread (viremia phase)
- 1% of patients develop neurological phase: replication in motor neurones in spinal cord, brainstem and motor cortex, leading to denervation and flaccid paralysis
21
Q
What are the two Polio vaccines?
- what type of vaccines are they
- efficacy?
A
-
Sabin oral polio vaccine (OPV) = live-attenuated
- Viable virus can be recovered from stool after immunisation
- Highly effective, and also establishes some protection in the non-immunised population
- 1 in 750 000 vaccine-associated paralytic polio
- better suited to endemic areas where benefits of higher efficacy outweigh risk of vaccine-associated paralysis
-
Salk injected polio vaccine (IPV) = inactivated
- Effective, but herd immunity inferior
- better suited in lower prevalence areas (UK switched in 2004)
22
Q
Explain the Tuberculosis infection
A
- During primary infection, MTB establishes infection within phagolysosomes of macrophages.
- Macrophages present TB antigen to MTB-specific CD4 T cells, which secrete IFN-g
- this activates macrophages to encase TB in the granuloma.
- It may be visible as a calcified lesion on plain CXR (Ghon focus)
- Most TB thought to be re-activation of this primary infection
23
Q
What is the TB vaccination?
- type of vaccine
- administration
- efficacy
A
- Only licensed product is BCG (bacille Calmette-Guerin)
- Produced by repeat passage of a non-tuberculous mycobacterium: Mycobacterium Bovis
- gives an attenuated vaccine
- Aims to increase Th1 (IFN-g) cell responses to M bovis, thereby conferring protection against MTB
- Given by intradermal injection –> scar
- 80% effective in preventing disseminated TB/ TB meningitis in children; little or no effect on pulmonary TB in adults
24
Q
What are Killed (Inactivated) vaccines?
- how are they formed
- action, overall efficacy
A
- Entire organism used, but physical or chemical methods used to destroy viability (eg formaldehyde)
- also preserves the immunogenicity of the organism
- Stimulates B cells, and taken up by antigen-presenting cells to stimulate antigen-specific CD4 T cells
- Probably elicit minimal CD8 response, as the vaccine cannot undergo intracellular replication
- Responses less robust compared to live-attenuated vaccines
25
What are examples of Killed vaccines?
* Hepatitis A
* Influenza (standard vaccine – live-attenuated also available but not routinely used)
* Pertussis
* typhoid
26
What are Pros of Killed vaccines?
* No potential for reversion
* Safe for immunocompromised
* Stable in storage (formaldehyde)
27
What are Cons of Killed vaccines?
* Weaker responses compared to live vaccines, and no CD8 response, therefore
* Responses less durable than live vaccines
* Generally, boosters required
* Higher uptake generally required to achieve herd immunity
28
Give an overview of the Influenza virus
* Seasonal viral illness
* Protective antibody responses largely directed against **haemagglutinin (H) and neuramidase (N) surface antigens**
* Natural antigenic ‘drift’ each year means that protective immune response from previous years may not be protective
* Major antigenic ‘shift’ when virus recombines with animal influenza strain – eg ‘Spanish’ Influenza (1918), H1N1 (2009)
29
What is the approach to producing Influenza vaccines?
* As immune responses are not durable, CDC attempts to predict likely dominant viruses for next season
* Candidate viruses grown in hens eggs and distributed to manufacturers
* Killed vaccine is standard UK approach
* Live vaccine also available (nasal spray)
* Success varies from year to year
30
What are Subunit vaccines?
- different types (3)
* Uses only a critical part of the organism
* Components may be:
* purified from the organism or
* generated by recombinant techniques
* Protection depends on eliciting CD4 and antibody responses
- Toxoids, Polysaccharide capsules, Recombinant protein subunit vaccines
31
What are Toxoid Subunit vaccines?
- examples
- how do they work
* Many examples relate to toxin-producing bacteria
* Corynebacterium diphtheria
* Clostridium tetani
* Bordatella pertussis (whopping cough)
* Toxins are taken and chemically detoxified to ‘toxoids’
* Retain immunogenicity
* Work by stimulating antibody response; antibodies then neutralise the toxin
32
What is the vaccine used for tetanus?
* Subunit toxoid vaccine
* you can still get infected with tetanus but the effect neuromuscular effect isn't there
* Pre-formed high-affinity IgG antibodies can neutralise the toxin molecules in the circulation;
* the immune complexes are then removed via the spleen
* Anti-toxin can also be given in established cases (passive immunisation)
33
What are Polysaccharide capsules Subunit vaccines?
- which two infections is this used in?
* Thick polysaccharide coats of ***Streptococcus pneumoniae*** and ***Neisseria meningitidis*** make them resistant to phagocytosis
* Vaccines for these organisms formed of purified polysaccharide coats
* Vaccines formed of purified polysaccharide coats; aim to _induce IgG antibodies that improve opsonisation_
* Suboptimal as polysaccharides are weakly immunogenic:
* No protein/ peptide, so no T cell response
* they can stimulate a small population of T-independent B cells
* Latest vaccines utilise _vaccine conjugation_ to boost responses: protein carrier attached to polysaccharide antigen
34
Explain Vaccine Conjugation
* Naive B cell expressing surface IgM recognises polysaccharide antigen.
* Antigen is internalised together with the protein conjugate
* Conjugate is processed in the class II pathway.
* Naive B cell presents peptides from the conjugate to a helper T cell with the correct receptor.
* T cell helps the B cell to perform affinity maturation, but antibody is specific for the polysaccharide and not for the protein conjugate
35
What is Recombinant protein Subunit vaccines?
- vaccines produced?
* The key immunogenic protein is required
* the protein is then expressed in lower organisms
* then purified to produce the vaccine
* Hep B surface antigen
* HPV vaccine
36
Explain the development Human Papillomavirus Vaccination
- what does the vaccine protect against?
* HPV subtypes 16 and 18 infection major causal factor in cervical carcinoma
* vaccine protects against this
* Vaccine development problematic as HPV is difficult to culture so they used
* Subunit vaccines are **‘empty virus particles**’ that prevent primary infection
* _viral particles which only have the capsid protein_
* Quadrivalent vaccine covers additional HPV strains (genital warts, penile cancer)
37
What are the Pros of Subunit vaccines?
* Extremely safe as only parts of the organism is present
* Work well where primary infection may be prevented by an antibody response
* Works when the virus cannot easily be cultured eg HPV and Hep B
38
What are the cons of Subunit vaccines?
* Development requires detailed knowledge of virology, pathogenesis and immunology
* Specialised and expensive production
* Weaker immune responses – boosting often needed and response rate varies
39
Give three Adjuvant categories, examples of the adjuvants.
* Mineral salts → Aluminum hydroxide
* Micro-fluidised detergents; emulsions, saponins → MF59, AS03
* Toll-Like-Receptor agonists → CpG Flagellin
* in clinical trials CpG in Hep B vaccines induces B-cell and dendritic cell proliferation and differentiation, production of IL-6 and IFN-∝
40
What are Adjuvants?
* Boost immune response to the antigen
* Eg alum, lipopolysaccharide
* Work by **_binding to pattern-recognition receptors on antigen-presenting cells_**
* This _enhances co-stimulation and cytokine secretion, which ensures a robust T/ B cell response_
* Important field for development in order to improve responses to subunit vaccines
* Novel adjuvants are toll-like receptor ligands eg _CpG repeats_
41
How is Intracellular mRNa stability achieved?
* A specially modified Nucleotide positioned at the 5’ end (Cap)
* A poly (A) tail (length)
* The composition and structure of the 3’ untranslated regions (3’UTR)
42
Explain mRNA vaccines
- how are they formed
- how do they work
* For mRNA vaccines, they create a sequence generated which codes for critical pathogen antigens
* Delivered via vector
* eg lipid nanoparticles OR
* ex vivo (harvest circulating monocytes then return to the recipient)
* Sequence translated by host cells to produce encoded antigens, which then stimulates host immune response
43
What are the technical challenges of mRNA vaccines?
- solutions?
* **Preventing degradation of mRNA** – solution was lipid nanoparticle delivery
* polyethylene glycol (PEG)- used to encapsulate the mRNA and protect it against destruction
* **Inflammatory response caused by mRNA** – solution was modifying nucleosides to reduce the inflammatory potential but still being able to create the protein of intrest
44
What is ‘Trained immunity’?
* describes the ‘epigenetic reprogramming’ of innate immune cells
* Gene expression is regulated by epigenetic mechanisms such as histone protein modification, DNA methylation, and different types of RNAs that interfere with gene expression or mRNA translation. **Infections/vaccinations can change the epigenetic programme**
45
What are the Positives of mRNA vaccines?
* Can be produced more rapidly; can be easily **modifiable; is standardized and gives an improved response speed** in emerging outbreaks
* Safety: no **pathogen particles or inactivated pathogen, non-infectious,** not integrated into host genome, **RNA strand degraded once protein is made**
* Efficacy: reliable immune response, well-tolerated by healthy individuals, few side effects
46
Explain Viral vectors
- challenges
* Benign virus that can be easily grown in culture engineered to carry genes encoding immunogenic antigens
* Altered virus used as a _live-attenuated vaccine_ or a _non-replicating viral vaccine_
_Challenges_
* Pre-existing immunity to viral vector
* Immune responses to viral vector may affect later use
47
What is the routine childhood immunization schedule in the UK
* they start at _eight weeks_ old with vaccines against → Diptheria, tetanus, pertussis (whooping cough), polio, Haemophilus type b and hep B (thigh), minungococcal B () , Rotavirus gastroenteritis (by mouth)
* 12 weeks then 16 weeks repeat of Td/IPV, 1 years old. 3 years 4 months old, 12 to 13 HPV, 14 years old tetanus and diptheria and polio
48
What would a pike protein against COVID-19 entail?
* The SARS-CoV-2 **spike protein** can bind to **ACE-2** (angiotensin converting enzyme-2) and **Nrp-1** (Neuropilin-1) both of which are located **at the cell surface**.
* Regeneron Pharmaceuticals have developed an apparently effective **antibody cocktail** from recovered patients and humanised mice containing antibodies **that recognise different parts of the receptor binding domain** in a **non-competitive fashion** and abrogate binding.
* If only one antibody or antibodies competing for binding are given, novel spike protein mutations occur rapidly. Non-competitive antibodies, if given together, appear to prevent novel spike mutants. This is why a cocktail is used.
49
What is the effect of therapeutic antibodies on COVID-19?
* therapeutic B-cells antibodies recognising the spike protein are administered to individuals to prevent serious disease courses
* treatment with REGN-COV2 resulted in statistically significant reduction in the time-weighted average daily change from baseline in viral load
50
How does the Pfizer/Biontech COVID-19 virus work?
**BNT162b2** contains RNA that encodes an optimized **SARS-CoV-2 full-length spike protein** antigen
51
How does the Oxford/Astra Zeneca COVID-19 virus work?
**BNT162b2** contains RNA that encodes an optimized **SARS-CoV-2 full-length spike protein** antigen
52
How does the Moderna COVID-19 virus work?
**BNT162b2** contains RNA that encodes an optimized **SARS-CoV-2 full-length spike protein** antigen
53
What is herd immunity/ and how is it achieved?
* when an infection is no longer effectively transmitted across a population because too many individuals are immune
* this requires a certain percentage of the population to be immune and depend on how many others typically get infected by one case (**R0**)
* in the case of COVID-19 the R needs to be less than 1
54
What major side effect is attributed to the swine flue vaccine?
* explain the incidence and cause?
* Narcolepsy
* severe sleep disruption, loss of concentration, social difficulties, and complete loss of muscle control (cataplexy) in severe cases
* 1 in 55,000 pandemrix jabs induced narcolepsy when given to 6 million people in the UK in 2009/10
* this occurrence rate would not have been picked up when testing for safety of the adjuvant/the vaccine
* This was attributed to **AS03** an adjuvant used in some GSK vaccines
