Vaccines and vaccine development

Question 1

What is passive immunisation and give examples

Answer 1

Immunity conferred without active host response on behalf of recipient.
Preparations of antibodies taken from hyper-immune donors, either human or animal.
E.g. immunoglobulin replacement in antibody deficiency
-> VZV prophylaxis during exposure in pregnancy,
anti-toxin therapies e.g. snake anti-serum.
Protection is temporary.

Question 2

What is active immunisation?

Answer 2

Immunity conferred in recipient following generation of adaptive immune response.
Stimulates adaptive immune response without causing clinically-apparent infection.

Question 3

How do most vaccines work?

Answer 3

By generating long-lasting, high-affinity IgG antibody response which are sufficient to prevent primary infection. strong CD4 T cell response is a pre-requisite

Question 4

What is found in a vaccine?

Answer 4

Antigen -> to stimulate antigen-specific T + B cell response.
Adjuvants -> immune potentiators to increase immunogenicity of vaccine.
‘Excipients’ -> various diluents + additives for vaccine integrity.

Question 5

How are active vaccines classified?

Answer 5

On basis of antigen:

Active vaccines -> subunit / whole organism -> live attenuated / inactivated.

Question 6

How are live attenuated vaccines used and give examples

Answer 6

Live but attenuated organisms. prolonged culture ex vivo in non-physiological conditions which selects variants that adapted to live in culture.
variants are viable in vivo but can’t cause disease.
Measles, mumps, rubella, polio (Sabin), BCG, cholera,
zoster, VZV, live influenza.

Question 7

What are the pros and cons of live vaccines?

Answer 7

Replication within host, so produces effective + durable responses.
For viral vaccines intracellular infection leads to good CD8 response.
Repeated boosting not required.
In some diseases, may get secondary protection of unvaccinated individuals who are infected with live-attenuated vaccine strain e.g. polio.
Storage problems, short shelf-life.
May revert to wild type.
E.g. vaccine associated poliomyelitis.
Immunocompromised recipients may develop clinical disease.

Question 8

What is the primary infection and viral reactivation of varicella zoster?

Answer 8

Primary infection -> chickenpox
Cellular + humoral immunity provide lifelong protection, but viruses establishes permanent infection of sensory ganglia.
Viral reactivation -> zoster.
Esp elderly, debilitating + may cause long-term neuropathic pain.

Question 9

How does the varicella zoster vaccine work?

Answer 9

Live-attenuated VZV -> induction of anti-VZV antibodies.

Attenuated virus establishes infection of sensory ganglia, but subsequent zoster is probably rare.

Question 10

Why is the varicella zoster vaccine presently not on the UK schedule?

Answer 10

Schedule is crowded + controversial
Safety concerns based on evidence from other countries -> ‘disease shift’ to unvaccinated adults where VZV is less well tolerated, increase in zoster – probably reduced immune boosting in adults.

Question 11

How does the zoster vaccination work?

Answer 11

Similar VZV preparation used for primary disease, but much higher dose.
Boosts memory T cell responses to VZV.
In over 60s, 50% reduction in zoster incidence after vaccination compared to controls, reduced severity + complications amongst vaccinated cases.

Question 12

What is poliomyelitis?

Answer 12

Enterovirus establishes infection in oropharynx + GI tract -> alimentary phase.
Spreads to Peyers patches -> disseminated via lymphatics.
Haematogenous spread -> viraemia phase.
1% develop neurological phase -> replication in motor neurones in spinal cord, brainstem + motor cortex -> denervation + flaccid paralysis.

Question 13

Outline the properties of Sabin oral polio vaccine (OPV)

Answer 13

Live-attenuated.
Viable virus can be recovered from stool after immunisation.
Highly effective, establishes some protection in non-immunised population.
1 in 750 000 vaccine-associated paralytic polio.

Question 14

Outline the properties of Salk injected polio vaccine (IPV)

Answer 14

Inactivated.
Effective, but herd immunity inferior.
OPV better suited to endemic areas, where benefits of higher efficacy outweigh risks of vaccine-associated paralysis.

Question 15

How does MTB affect the body?

Answer 15

During primary infection, MTB establishes infection within phago-lysosomes of macrophages.
Macrophages present TB antigen to MTB-specific CD4 T cells, which secrete IFN-g –> activates macrophages to encase TB in granuloma.
May be visible as calcified lesion on plain CXR -> Ghon focus.
Most TB -> re-activation of primary infection.

Question 16

What are the properties of the TB vaccination?

Answer 16

BCG, produced by Mycobacterium bovis.
Increases Th1 (IFN-g) cell responses to M bovis -> protecting against MTB.
Intradermal injection.
80% effective in preventing disseminated TB / TB meningitis in children. little / no effect on pulmonary TB

Question 17

How are killed (inactivated) vaccines used and give examples

Answer 17

Entire organism. physical / chemical methods used to destroy viability -> formaldehyde.
Stimulates B cells, taken up by APCs to stimulate antigen-specific CD4 T cells.
Probably elicit minimal CD8 response, as vaccine can’t undergo intracellular replication.
Responses less robust compared to live-attenuated vaccines.
Hep A, influenza.

Question 18

What are the pros and cons of killed vaccines?

Answer 18

No potential for reversion, safe for immunocompromised
stable in storage.
Weaker response than live vaccines + no CD8 response:
Responses less durable -> generally boosters required.
Higher uptake generally required to achieve herd immunity.

Question 19

Protective antibody responses for influenza are largely directed against which molecules and what is antigenic shift and drift?

Answer 19

Haemagglutinin (H) + neuramidase (N) surface antigens.
Natural antigenic ‘drift’ each year -> protective immune response from previous years may not be protective.
Major antigenic ‘shift’ -> virus recombines with animal influenza strain e.g. ‘Spanish’ Influenza.

Question 20

What are subunit vaccines?

Answer 20

Only critical part of organism.
Components may be -> purified from organism or
generated by recombinant techniques.
Protection depends on eliciting CD4 + antibody responses.

Question 21

How do subunit vaccines - toxoids work?

Answer 21

Toxin-producing bacteria -> Corynebacterium diphtheriae, Clostridium tetani, Bordatella pertussis.
Toxins chemically detoxified to ‘toxoids’.
Retain immunogenicity.
Stimulates antibody response -> neutralises toxin.

Question 22

How can tetanus be treated?

Answer 22

Pre-formed high-affinity IgG antibodies neutralise
toxin molecules in circulation -> immune complexes
removed via spleen.
Anti-toxin given in established cases -> passive immunisation.

Question 23

How do subunit vaccines - polysaccharide capsules work?

Answer 23

Thick polysaccharide coats of Streptococcus pneumoniae + Neisseria meningitidis make them resistant to phagocytosis.
Vaccines formed of purified polysaccharide coats, induce IgG antibodies that improve opsonisation.
Suboptimal as polysaccharides are weakly immunogenic -> no peptide so no T cell response, stimulate small population of T-independent B cells.
Latest vaccines utilise vaccine conjugation to boost responses -> protein carrier attached to polysaccharide antigen.

Question 24

What is vaccine conjugation?

Answer 24

Naive B cell expressing surface IgM recognises polysaccharide antigen which is internalised with protein conjugate. 
Conjugate processed in class II pathway. naive B cell presents peptides from conjugate to helper T cell with correct receptor.
T cell helps B cell to perform affinity maturation, but antibody is specific for polysaccharide + not for protein conjugate.

Question 25

What is recombinant protein subunit vaccine and give examples

Answer 25

Proteins expressed in lower organisms purified to produce vaccine -> hep B surface antigen, HPV vaccine.
Increasingly employed in vaccine development.

Question 26

How does the human papilloma virus vaccination work?

Answer 26

HPV subtypes 16 + 18 infection -> cervical carcinoma.
Vaccine development problematic as HPV is difficult to culture.
Subunit vaccines are ‘empty virus particles’ that prevent primary infection
Quadravalent vaccine covers additional HPV strains -genital warts, penile cancer.

Question 27

What are the pros and cons of subunit vaccines?

Answer 27

Extremely safe
Work well where primary infection may be prevented by antibody response.
When virus can’t easily be cultured -> HPV / Hep B.
Weaker immune responses –> boosting often needed + response rate varies.

Question 28

What are adjuvants and give examples

Answer 28

Boost immune response to antigen + responses to subunit vaccines.
E.g. alum, lipopolysaccharide.
Binds to PRRs on APCs.
Enhances co-stimulation + cytokine secretion -> robust T / B cell response.
Novel adjuvants -> TLR ligands e.g. CPG repeats.