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Year 2 - T3 Theme 1 > L7 Vaccines and vaccine development > Flashcards

L7 Vaccines and vaccine development Flashcards

1
Q

What is immunisation

A
  • Is an artificial process by which an individual is rendered immune
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2
Q

Types of immunisation

A

Passive immunisation - no immune response in recipient

Active immunisation (vaccination) - recipient develops a protective adaptive immune response

  • One of the cheapest and most effective methods of improving survival and reducing morbidity
  • Estimated reduction in mortality worldwide 3 million/yr
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3
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
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4
Q

Examples of passive immunisation

A
  • Immunoglobulin replacement in antibody deficiency
  • VZV prophylaxis eg during exposure during pregnancy
  • Anti-toxin therapies eg snake anti-serum
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5
Q

Can VZV affect pregnancy

A
  • VZV during pregnancy can cause fetal complications
  • In case of exposure, women should contact their GP
  • Urgent VZV serology is available when required
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6
Q

What is active immunisation

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
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7
Q

Active immunisation - gen principles 1

A
  • To be effective, vaccines need to be administered to targeted cohorts in advance of exposure to the pathogen of interest
  • Vaccination of sufficient numbers impacts the transmission dynamic so that even unimmunised individuals are at low risk (called herd immunity)
  • As vaccines are given to healthy individuals, the risk-to-benefit ratio requires that vaccines meet high safety standards
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8
Q

Active immunisation - gen principles 2

A
  • Most vaccines work by generating a long-wasting, high-affinity IgG antibody response
  • These antibodies are sufficient to prevent primary infection
  • A strong CD4 T cell response is a pre-requisite for this
  • The most effective vaccines are for diseases where natural exposure results in protective immunity
  • ‘Problem’ diseases are generally those where the immune system cannot eliminate infection or generate long-lasting protective immunity during natural infection (eg common cold, MTB, HIV, malaria)
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9
Q

What goes into a vaccine

A

Antigen - to stimulate an antigen-specific T and B cell response

Adjuvants - Immune potentiators to increase the immunogenicity of the vaccine

‘Excipients’ - various diluents and additives required for vaccine integrity

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10
Q

Classification of active vaccines on the basis of the antigen

A

Active vaccines – whole organism + subunit

Whole organism – live-attenuated + inactivated (killed)

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11
Q

Examples of subunits

A
  • Toxoids
  • Capsular polysaccharides
  • Conjugated polysaccharide
  • Recombinant subunit
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12
Q

Features of live-attenuated vaccines

A
  • Prolonged culture ex vivo in non-physiological conditions
  • This selects variants that are adapted to live in culture
  • These variants are viable in vivo but are no longer able to cause disease
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13
Q

Examples of live-attenuated vaccines

A
  • Measles
  • Mumps
  • Rubella
  • Polio (sabin)
  • BCG
  • Cholera
  • Zoster
  • VZV (not routinely used for primary prevention in UK at present)
  • Live influenza (not routinely used in UK at present)
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14
Q

Pros of live vaccines

A
  • Replication within host, therefore produces highly effective and durable responses
  • In case of viral vaccine, 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 the live-attenuated vaccine strain eg polio
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15
Q

Cons of live vaccines

A
  • Storage problems, short shelf-life
  • May revert to wild type (eg vaccine associated poliomyelitis: around 1 in 750 000 recipients)
  • Immunocompromised recipients may develop clinical disease
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16
Q

Features of varicella-zoster vaccine

A
  • Primary infection - chickenpox
  • Cellular and humoral immunity provide lifelong protection, but viruses establishes permanent infection of sensory ganglia
  • Viral reactivation = zoster
  • Particularly elderly, fairly debilitating and may cause long-term neuropathic pain
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17
Q

How does the varicella-zoster vaccine work

A
  • Live-attenuated VZV, works by induction of anti-VZV antibodies
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18
Q

How effective is the varicella-zoster vaccine

A
  • 95% effective at preventing chickenpox
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19
Q

Is it possible for a subsequent zoster after a varicella-zoster vaccine

A
  • Attenuated virus does establish infection of sensory ganglia, but subsequent zoster is probably rare
  • 3-5% mild post-vaccination varicella infection
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20
Q

Why is the varicella-zoster vaccine not on UK schedule at the moment

A

VZV is a fairly benign childhood infection
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
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21
Q

Link between zoster, immunity and ageing

A
  • The incidence of zoster increases with age, in parallel with declining cell-mediated immune responses to zoster
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22
Q

Preparation of zoster vaccination

A
  • Similar VZV preparation, 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
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23
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
24
Q

Features of sabin oral polio vaccine (OPV)

A

OPV - live attenuated

  • Viable virus can be recovered from stool after immunisation
  • Highly effective, and also establishes some protection in non-immunised population
  • 1 in 750 000 vaccine-associated paralytic polio
25
Q

Features of salk injected polio vaccine (IPV)

A

IPV - inactivated

  • Effective, but herd immunity inferior
  • OPV better suited to endemic areas, where benefits of higher efficacy outweigh risks of vaccine-associated paralysis (UK switched to IPV in 2004)
26
Q

Features of TB

A
  • 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 - this activates macrophages to encase TB in granuloma
  • May be visible as a calcified lesion on plain CXR (ghon focus)
  • Most TB thought to be re-activation of this primary infection
27
Q

Features of TB vaccination

A
  • Only licensed product is BCG
  • Produced by repeat passage of a non-tuberculus mycobacterium: mycobacterium bovis
  • Aims to increase Th1 (IFN-g) cell responses to M bovis, thereby conferring protection against MTB
28
Q

how is a TB vaccination given

A
  • By intradermal injection
29
Q

How effective is the TB vaccination

A
  • 80% effective in preventing disseminated TB/TB meningitis in children; little or no effect on pulmonary TB
30
Q

Features of killed (inactivated) vaccines

A
  • Entire organism used, but physical or chemical methods used to destroy viability (eg formaldehyde)
  • 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
31
Q

Examples of killed(inactivated) vaccines

A
  • Hepatitis A

- Influenza (standard vaccine - live-attenuated also available but not routinely used)

32
Q

Pros of killed vaccines

A
  • No potential for reversion
  • Safe for immunocompromised
  • Stable in storage
33
Q

Cons of killed vaccines

A
  • Mainly CD4/antibody response
  • Responses less durable than live vaccines(generally boosters required)
  • Higher uptake generally required to achieve herd immunity
34
Q

Structure of influenza virus

A
  • The internal antigens (matrix and RNP) are the type-specific proteins and are used to determine whether a particular virus is A, B, or C
  • The external antigens (hemagglutinin and neuraminidase) are subtype and strain-specific antigens of influenza A virus (H1N1, H2N2, H3N2)
35
Q

What are protective antibody responses largely directed against

A
  • Protective antibody responses largely directed against haemagglutinin and neuramidase, and probably mostly work by blocking entry to cells, blocking release of new virions from infected cells and promoting ADCC
36
Q

Difficulties of influenza vaccination

A
  • Target antigens prone to mutation (antigenic drift) causing seasonal variation (therefore vaccine produced annually based on predictions)
  • CDC provide candidate virus strains to manufacturer, injected into fertilised hens eggs and virus then harvested (inactivated for standard vaccine)
  • More major changes (antigenic shift) occur when viral strains recombine - eg with animal strain, causing pandemic influenza
37
Q

Features of subunit vaccines

A
  • 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
38
Q

Examples of toxoids

A

Many examples relate to toxin-producing bacteria

  • Corynebacterium diphtheriae
  • Clostridium tetani
  • Bordatella pertussis
39
Q

What are toxoids

A
  • Toxins are chemically detoxified to ‘toxoids’
  • Retain immunogenicity
  • Work by stimulating antibody response; antibodies then neutralise the toxin
40
Q

Response to tetanus toxins

A
  • 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)
41
Q

Features of subunit vaccines: polysaccharide capsules

A
  • Thick polysaccharide coats of strep. penumoniae and neisseria meningitidis make them resistant to phagocytosis
  • Vaccines for these organisms formed of purified polysaccharide coats
42
Q

Aim of vaccines formed of purified polysaccharide coats

A
  • Aim to induce IgG antibodies that improve opsonisation
  • Suboptimal as polysaccharides are weakly immunogenic (no protein/peptide, so no T cell response, stimulate a small population of T-independent B cells)
  • Latest vaccines utilise vaccine conjugation to boost responses: protein carrier attached to polysaccharide antigen
43
Q

What is vaccine conjugation

A
  • 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
44
Q

Features of recombinant protein subunit vaccine

A
  • Knowledge of key immunogenic proteins required
  • Proteins expressed in lower organisms
  • Purified to produce vaccine(Hep B surface antigen, HPV vaccine)
  • This approach is increasingly employed in vaccine development
45
Q

Major HPV subtypes linked to cervical carcinoma

A
  • HPV subtypes 16 and 18 infection major causal factor in cervical carcinoma
46
Q

Why is HPV vaccine development difficult

A
  • HPV is difficult to culture
47
Q

What are subunit vaccines

A

Empty virus particles that prevent primary infection

48
Q

What is a quadravalent vaccine

A
  • Covers additional HPV strains (genital warts, penile cancer)
49
Q

Pros of subunit vaccines

A
  • Extremely safe
  • 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
50
Q

Cons of subunit vaccines

A
  • Development requires detailed knowledge of virology, pathogenesis and immunology
  • Specialised and expensive production
  • Weaker immune responses (boosting often needed and response rate varies)
51
Q

Function of adjuvants

A
  • Boost immune response to the antigen

- Widely used, but mechanism understood only relatively recently

52
Q

Examples of adjuvants

A
  • Alum

- Lipopolysaccharide

53
Q

How do adjuvants work

A
  • Work by binding to pattern-recognition receptors on antigen presenting cells which 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
54
Q

Examples of novel adjuvants

A
  • Toll-like receptor ligands eg CPG repeats
55
Q

Novel approaches: DNA vaccines

A
  • Plasmid DNA that encodes vaccine antigen of interest applied; taken up by cells, transcribed and translated
  • Elicits host immune response
  • Mainly performed in mice models
  • Poorly immunogenic to date in human trials
56
Q

Novel approaches: viral vector

A
  • Benign virus that can be easily grown in culture engineered to carry genes encoding immunogenic antigens
  • Altered virus used as a live-attenuated vaccine
  • Use restricted to animals to date

Year 2 - T3 Theme 1 (15 decks)

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