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204: Theme 1 - Immunology > Vaccines and Vaccine Development > Flashcards

Vaccines and Vaccine Development Flashcards

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

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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
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3
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
  • protection is temporary
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4
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
  • No history of chickenpox or unsure
    • VZV IgG positive
      • reassure patient
  • No history of chickenpox, or unsure
    • VZV IgG negative or equivocal
      • administer VZV immunoglobulin to protect against primary infection
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5
Q

What is Activ Immunisation (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
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6
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
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7
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
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8
Q

How are active vaccines classified in terms of the antigen?

A
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9
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
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10
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)
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11
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
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12
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
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13
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
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14
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
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15
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
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16
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
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17
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
18
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)
19
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
20
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
21
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
22
Q

What are examples of Killed vaccines?

A
  • Hepatitis A
  • Influenza (standard vaccine – live-attenuated also available but not routinely used)
23
Q

What are Pros of Killed vaccines?

A
  • No potential for reversion
  • Safe for immunocompromised
  • Stable in storage (formaldehyde)
24
Q

What are Cons of Killed vaccines?

A
  • 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
25
Q

Give an overview of the Influenza virus

A
  • 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)
26
Q

What is the approach to producing Influenza vaccines?

A
  • 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
27
Q

What are Subunit vaccines?

  • different types (3)
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
  • Toxoids, Polysaccharide capsules, Recombinant protein subunit vaccines
28
Q

What are Toxoid Subunit vaccines?

  • examples
  • how do they work
A
  • 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
29
Q

What is the vaccine used for tetanus?

A
  • 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)
30
Q

What are Polysaccharide capsules Subunit vaccines?

  • which two infections is this used in?
A
  • 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
31
Q

Explain 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
32
Q

What is Recombinant protein Subunit vaccines?

  • vaccines produced?
A
  • 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
33
Q

Explain the development Human Papillomavirus Vaccination

  • what does the vaccine protect against?
A
  • 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)
34
Q

What are the Pros of Subunit vaccines?

A
  • 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
35
Q

What are the 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
36
Q

What are Adjuvants?

A
  • 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
37
Q

Explain mRNA vaccines

  • how are they formed
  • how do they work
A
  • 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
38
Q

What are the technical challenges of mRNA vaccines?

  • solutions?
A
  • 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
39
Q

What are the Positives of mRNA vaccines?

A
  • Potentially rapidly available and modifiable;
  • Relatively quick and easy to produce and adapt once facility established
40
Q

Explain Viral vectors

  • challenges
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 or a non-replicating viral vaccine

Challenges

  • Pre-existing immunity to viral vector
  • Immune responses to viral vector may affect later use

204: Theme 1 - Immunology (13 decks)

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