L8 - Vaccines & vaccine development COPY

Question 1

DEFINITIONS

i) what is immunisation?
ii) what is passive immunisation? give an example
iii) what is active immunisation? give an example
iv) what is the estimated reduction in mortality worldwide per year?

Answer 1

i) artificial process by which an individual is rendered immune
ii) passive - doesnt require an immune response in the recipient eg giving pre formed antibods from another person
iii) active - recipient devleops a protective adaptive immune response eg vaccination
iv) 3 million/yr reduction

Question 2

PASSIVE IMMUNISATION

i) what is immunity confered without?
ii) what are passive vaccines? who are they taken from?
iii) give three examples of passive vaccines
iv) is protection temporary or permanent?

Answer 2

i) immunity without an active host response

ii) passive vaccines are preparations of antbodies
- taken from hyperimmune donors (strongly exposed and have a high level of antibodies) - human or animal

iii) Ig replacement in antibody deficiency
- VZV prophylaxis eg during pregnancy
- Anti-toxin therapies eg snake anti serum (inject antibodies to snake venom)

iv) protection is temporary > eventually all donated ab will be used up

Question 3

VZV EXPOSURE DURING PREGNANCY

i) if an individual has definite history of chickenpox - are bloods indicated? what action should be taken
ii) if indiv has no hx of chickenpox or unsure - what should be done?
iii) what antibody would an individual have if they have been exposed to VZV?
iv) what should be done if a) they have the VZV Ig? b) they dont have the VZV Ig?
v) what can VZV cause during pregnancy?

Answer 3

i) bloods not indicated - reassure
ii) no hx or unsure > do an urgent blood test
iii) individual would have VZV IgG antibody

iv) if VZV IgG is present then they have immunity > reassure
- if VZV igG is negative then give VZV IgG as an injection

v) VZV can cause fetal complications during pregnancy if the mother is not immune

Question 4

ACTIVE IMMUNISATION

i) what response is generated after administration?
ii) what is the general principle underlying active immunisation?
iii) who do vaccines need to be given to and what time to be effective?
iv) what is herd immunity?
v) what is required to be met given that vaccines are usually given to healthy individuals?

Answer 4

i) adaptive immune response
ii) stimulate an adaptive immune response without causing clinically apparent infection
iii) need to be given to targeted cohorts in advance of exposure
iv) herd imm - vaccination of sufficient numbers to impact transmission so even unimmunised individuals are at low risk
v) risk to benefit ratio needs to be low

Question 5

ANTIBODY RESPONSE OF ACTIVE IMMUNISATION

i) what do most vaccines generate? what is this sufficient to prevent? what is a pre requisite for this?
ii) which type of diseases are vaccines most effective for?
iii) what makes diseases a ‘problem’ for vaccination? give three examples

Answer 5

i) generate long lasting high affinity IgG response
- sufficient to prevent primary infection
- strong CD4 T cell response is required for this to allow activation of memory B cells

ii) vaccines are most effective for diseases where natural exposure results in protective immunity
iii) problem diseases are those where imm system cant eliminate the infection or generate long lasting immunity during natural infection eg malaria, HIV, MTB

Question 6

WHAT MAKES UP A VACCINE?

i) what is the main component? what does this do?
ii) what is added to increase immunogenicity of the vaccine? what receptors does this mostly work on?
iii) what is required for vaccine integrity?

Answer 6

i) main component is antigen which stimulates antigen specific T and B cell response
ii) adjuvants are immune potentiators that increase immunogenicity > work on TLRs
iii) excipients are req for vaccine integrity (dilulents/additives)

Question 7

CLASSIFICATION OF ACTIVE VACCINES

i) what are active vaccines classified on the basis of?
ii) what are the two types of whole organism vaccine? explain each
iii) what is a subunit vaccine? give two examples

Answer 7

i) classified on basis of antigen

ii) whole organism = live attenuated or inactivated
- live > organism is alove but altered to have low pathogenicity so it doesnt cause disease
- inactivated > organism present but dead and cant replicate

iii) subunit vacc > only the critical part of the patho is included
- toxoids, capsular polysacc, mRNA, virus like particles

Question 8

LIVE ATTENUATED VACCINES

i) how are they cultured? in what conditions? what does this allow?
ii) give four examples
iii) give four advantages
iv) which vaccine may confer secondary protection to non imm individuals?
v) give three disadvantages

Answer 8

i) prolonged culture ex vivo in non physiol conditions
- allows selection of variants that are adapted to live in culture which will be viable in vivo but no longer cause disease

ii) MMR, polio, BCG, cholera, zoster, VZV

iii) organism replicated in host so produces an effective response
- if viral > intracell infection gives a good CD8 response
- repeated boosting not required
- may get secondary protection of non vac individuals eg comes out in poo

iv) polio
v) storage problems, short shelf life, may revert back to WT and cause disease, immunocompromised people may develop the clinical disease

Question 9

VARICELLA ZOSTER

i) what is the primary infection?
ii) what type of immunity provides lifelong protection? however, where does the virus establish permanent infection?
iii) what is the virus reactivated as?
iv) which group are most vulnerable to reactivation? what may it cause long term?

Answer 9

i) chickenpox

ii) cellular and humoral immunity > lifelong protection
- permanently resides in sensory ganglia

iii) virus reactivated as zoster

iv) elderly
- can cause long term neuropathic pain

Question 10

VARICELLA ZOSTER VACCINE

i) what type of vaccine is it? how does it induce immunity?
ii) what does it aim to prevent? how effective is it at doing this?
iii) is infection established in the sensory ganglia? what % get mild post vacc infection
iv) give three reasons its not given in the UK currently
v) what does exposure to zoster do in adults that hava already been exposed?

Answer 10

i) live attenuated vaccine that induces anti VZV antibodies
ii) aims to prevent primary chickenpox > 95% effective

iii) yes infection is estab in sensory ganglia
3-5% get mild post vacc infection

iv) not given in UK as VZV is fairly benign childhood infec
- already crowded vaccination scheduke
- safety concerns of disease shift to unvacc adults who tolerate it less well

v) gives them an immune boost

Question 11

ZOSTER VACCINE AND AGEING

i) how does incidence of zoster change with age? how does immune response to zoster change with age?
ii) what is an explanation for this?
iii) why may zoster vaccine be given to elderly?
iv) how does the zoster vaccine compare to VZV? what does it aim to do?
v) what % reduction was seen in over 60s post zoster vaccination?
vi) what was seen in CD4 T cell response to VZV virus in people that recieved zoster vaccine?

Answer 11

i) incidence increases with age and immune repsonse declines
ii) T and B cells that gave original protection are getting old
iii) zoster vaccine can boost response in elderly

iv) zoster is similar to VZV but higher dose
- aims to boost memory T cell response to VZV

v) 50% reduction
vi) increased CD4 T cell response to VZV virus post vacc

Question 12

POLIOMYELITIS

i) what type of virus is it? what are the three phases of infection?
ii) where does it spread to before reaching the blood?
iii) give three neurological things that can happen? what % of patients develop this?

Answer 12

i) enterovirus
- alimentary phase > oropharynx and GI
- viremia phase > blood
- neurological phase

ii) spreads to peyers patches then lymphatics

iii) replication in motor neurons of spinal cord, brainstem and motor cortex
- denervation
- flaccid paralysis

Question 13

POLIO VACCINE - SALK VS SABIN

i) what type of vaccine is the sabin oral polio vaccine? where can it be recovered from after immunisation?
ii) how effective is the sabin vaccine? can it establish secondary protection? what is the rate of vacc assoc paralytic polio?
iii) what type of vaccine is the salk injected vaccine? how effective is it? is it good at establishing herd immunity?
iv) what type of areas is the oral polio vacc suited to? why?
v) what does the UK use? why?

Answer 13

i) oral - live attenuated
- can be recovered from stool post immunisation

ii) very effective, can estab secondary protection and low rates of vacc assoc paralysis
iii) injected vaccine is inactivated, effective but herd immunity is inferior to oral
iv) oral vacc is suited to endemic areas where benefits of higher efficacy outweight risk of paralysis
v) UK uses injected as low prevalence area and dont need as much immunity (lower risks)

Question 14

TUBERCULOSIS

i) where does mycobac TB establish infection during primary infection?
ii) which T cells are TB antigens presented to? what do they then secrete? what does this activate?
iii) what makes up the outside and inside of a granuloma? what may this be seen as on CXR?
iv) what is most TB thought to be?

Answer 14

i) phagolysosomes of macrophages

ii) macrophages present antigen to CD4 T cells
- T cells secrete IFN gamma > activates macrophages to encase TB in a granuloma

iii) ouside T cells and inside multi nucleated giant cells
- seen as calcified lesion in CXR

iv) most TB is thought to be reactivation of primary infection

Question 15

TB VACCINATION

i) what is the only licensed product? what bacteria is it made from?
ii) what cell responses does it aim to increase? to which bacteria?
iii) how is it administered? how effective is it in preventing dissem TB/TB meningitis in children?
iv) what effect does it have on pulmonary TB in adults?

Answer 15

i) BCG
- produced by repeated passage of a non TB mycobac = mycobacterium bovis

ii) aims to increase TH1 (IFN gamma) cell response to M bovis > therefore conferring protect against MTB as they share some epitopes

iii) admin by intra dermal injection
- 80% effective in prev dissem TB/TB meningitis in children

iv) little/no effect on pulmonary TB in adults

Question 16

KILLED (INACTIVATED) VACCINATION

i) what is used?
ii) which cells does it stimulate initially? which T cells does it activate?
iii) how much of a CD8 response does it elicit? why?
iv) how are responses compared to live attenuated vaccines?
v) give two examples
vi) give two adv and two disadv

Answer 16

i) entire organism used but phys or chemical methods used to destroy viability eg formaldehyde
ii) stimulates B cells then CD4 T cells
iii) minimal CD8 response as the vaccine cant undergo cellular replication (it is dead)
iv) responses less robust compared to live vaccs
v) hep A and influenza

vi) adv > no potential for reversion, safe if immunocomp
disadv > weaker response (low CD8) therefore less durable,
req booster
higher uptake to achieve herd immunity

Question 17

INFLUENZA

i) which surface antigens are protective antibody responses directed against? (2)
ii) what does antigenic drift each year mean for immunity?
iii) what happens in antigenic shift? give two examples
iv) how are flu vaccines developed? where are they grown before distrib to manufacturers?
v) what is the standard form? what form is the live vaccine availible in?

Answer 17

i) protective antibody response against haemagglutinin and neuramidase surface antigens
ii) antigenic drift means immune response from previous years may not always be effective
iii) antigenic shift > virus recombines with an animal influenza strain eg spanish flu/H1N1

iv) based on prediction of likely dominant viruses that year
- viruses grown in hens eggs and distrib to manufacturers to produce the vaccine

v) standard form is killed vaccine
- live vaccine is nasal spray

Question 18

SUBUNIT VACCINES

i) what does it use?
ii) where can components be from? (2)
iii) what does protection depend on?
iv) give three adv and three disadv of subunit vaccines

Answer 18

i) uses only the critical part of the organism
ii) components purified from organism, gen by recomb techniques or mRNA that codes for it
iii) protection depends on eliciting a CD4 antibody response
iv) adv - very safe, work well where primary infec can be prevented by antibody response, work when virus cant easily be cultured eg HPV

disadv > dev requires detailed knowledge of organism,
specialised and expensive production
weaker immune responses and boosters normally needed

Question 19

SUBUNIT VACCINES - TOXOIDS

i) what is a toxoid?
ii) what are clinical conditions due to in diseases targeted by these vaccines? give two examples
iii) how does the toxoid elicit an immune response?
iv) what does the toxoid stimulate? what then happens?

Answer 19

i) chemically detoxified toxins - they are no longer toxic

ii) clin conditions not due to the bacteria itself but due to the toxin the bacteria produces
- clostridium tetani and bordatella pertussis

iii) toxoid retains immunogenicity so elicits an immune respon
iv) toxoid stimulates an antibody response then antibodies neutralise the toxin

Question 20

TETANUS

i) what type of neurons does tetanus bind?
ii) what can be given to neutralise the toxin molelcules in the circulation? where are immune complexes then removed?
iii) what can be given in established cases? what type of immunisation is this?

Answer 20

i) binds inhibitory neurons and blocks them

ii) can give pre formed high affinity IgG antibodies which neutralise the toxin molecules in the circulation
- immune complexes are then removed by the spleen

iii) anti toxin can be given > passive immunity

Question 21

SUBUNIT VACCINES: POLYSACCHARIDE CAPSULES

i) give examples of two pathogens that have thick polysaccharide coats? what does this make them?
ii) what are vaccines for these organisms made of? what do they aim to induce?
iii) is there a T cell response? is there a B cell response?
iv) what can be used to boost responses?

Answer 21

i) strep pneumoniae and neisseria meningitidis
- thick polysacc coat makes them resistant to phagocytosis

ii) vaccines are made of purified polysacc coats which aim to induce IgG antibodies that improve opsonisation

iii) no T cell response as no protein
- small pop of T indepdent B cells are stimulated in the spleen

iv) can use vaccine conjugation to boost response
- protein carrier attached to polysacch antigen

Question 22

VACCINE CONJUGATION

i) what does the polysaccharide have to be coupled to for recognition?
ii) what surface Ig does a naive B cell express? what happens when it contacts a polysacc antigen?
iii) which class pathway is the antigen processed in? what is displayed on the B cell surface? which T cell can recognise this?
iv) what does the B cell undergo after contacting the T cell? what is the antibody specific for?

Answer 22

i) protein

ii) naive B cell expresses IgM
- contacts antigen and the conjugate is internalised

iii) processed through MHC class II pathway
- B cell present peptide from the conjugate on surface
- recog by CD4 T cell with correct receptor

iv) B cell undergoes affinity maturation
- antibody is specific for the polysaccharide and not the protein conjugate

Question 23

RECOMBINANT PROTEIN SUBUNIT VACCINES

i) knowledge of what is required?
ii) which type of organisms are these proteins expressed in? how are they used to produce a vaccine
iii) give two examples of these vaccines?

Answer 23

i) knowledge of key immunogenic proteins is req
ii) proteins expressed in lower organisms then purified to produce a vaccine
iii) Hepatitis B surface antigen, HPV vaccine

Question 24

HPV VACCINATION

i) which are the two HPV subtypes that cause cervical carcinoma?
ii) why is vaccine development for HPV difficult?
iii) what type of vaccine is used? what does it contain?
iv) what vaccine covers multiple HPV strains?

Answer 24

i) subtype 16 and 18
ii) HPV is difficult to culture
iii) subunit vaccines using empty virus particles that have the capsid only
iv) quadravalent vaccine covers multiple strains

Question 25

ADJUVANTS

i) what do they do?
ii) give two examples of adjuvants used?
iii) how do they work? what do they enhance?
iv) which type of vaccines are they especially important in?
v) give an example of a novel adjuvant

Answer 25

i) boost immune response to the antigen
ii) alum and lipopolysaccharide

iii) work by binding pattern recognition receptors on APCs
- this enhances co-stimulation and cytokine secretion which ensures a robust T and B cell response

iv) important to improve responses from subunit vaccines
v) novel adjuvant = TLR ligands eg CPG repeats

Question 26

mRNA VACCINES

i) what do sequences in the vaccine code for?
ii) how are they delivered? give two ways
iii) what happens once they are introduced into the host?
iv) give two technical challenges faced and how these may be overcome
v) give an advantage

Answer 26

i) code for critical pathogen antigens eg spike prot in COVID

ii) delivery by vector eg lipid nanoparticle (stops degred)
- or ex vivo - harvest circulating monocytes, transfect then return to recipient

iii) the sequence is then translated by host cells and produces the encoded antigen > stimulates host immune response

iv) challenges - preventing degreg of mRNA (use nanoparticle)
- inflamm response to mRNA > modify nucleosides

v) rapidly available and modifiable

Question 27

mRNA VACCINES MECHANISM

i) what response do they strongly elicit?
ii) once delivered to cell - what is it taken up into? what then happens in the cell (3)
iii) what allows recognition by T cells?

Answer 27

i) strong T cell response but not necessarily antibodies

ii) delivered in nanoparticle > taken into endosome
- attaches to rubosome and produces viral antigen
- processed by proteosome > ER to be loaded onto MHC

iii) loading onto MHC on cell surf of APC > recog by T cells

Question 28

NOVEL APPROACHES: VIRAL VECTOR

i) what type of virus is used? what can it carry?
ii) give a challenge
iii) how many viral vectors does the russian COVID vaccine use?

Answer 28

i) benign inactivated virus that can carry genes encoding immunogenic antigens
ii) challenges are pre exisiting immunity to viral vector
iii) two - one for priming and one for boosting