Lecture 10 Vaccines

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Lecture 10Vaccines Antimicrobials

• Aims
• To be aware of the different types of vaccines
  used to combat human infections
• To understand the advantages disadvantages of
  each type
• To be aware of how vaccines are made and gain
  knowledge of some important vaccines
• To become aware of the range of antimicrobials
  available
• To understand how resistance or sensitivity to an
  antimicrobial may be determined

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A vaccine defined

• A vaccine is generally a biological substance
  which can be used to illicit an immune response
  in a host which may be protective in the event
  that the host is subsequently exposed to the
  virulent (disease causing) form of the infectious
  agent

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Vaccine types

• 2 main types
• Live attenuated
• Inert
• We will look later at how an immune response can
  be generated by vaccines (immunology section)

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Live attenuated vaccines

• Can use live agents of either
• Weak or weakened strains of virulent agent
• Eg Sabine polio vaccine
• Or
• Closely related species which provide cross
  protection
• Eg cow pox against small pox

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Inert vaccines

• Includes
• Killed or inactivated eg Salk against polio
• Recombinant eg HBV
• Fractionated eg HBVsAg from chronic carriers
• Newer forms of DNA vaccines

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Inert v live vaccines

• Inert no chance of reversion eg 1106 polio
• Inert less immunogenic- may need frequent
  boosters
• eg natural HBV following recovery gives almost
  lifelng protection cw vaccine lt10years in many
  cases

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Manufacture of vaccines

• In the past main method by killing whole microbe
• Generally used formalin
• Problem was changes caused by formalin to
  important microbial structures
• Current methods use rec expression
• Live vaccines usually attenuated- have advantage
  of few side effects and generally effective

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Problems with vaccines

• Measles vaccine has been associated with SSPE
  (s/acute slerosing panencephalomelitis)
• If this SSPE problem had been recognized in 1960s
  under the current guidelines, it would require
  SSPE testing- for which there is currently no
  known marker

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Problems with vaccines

• Polio (Sabin) about 11,000,000 doses revert to
  neurovirulence
• Unlikely under current regulations that the
  vaccine would be licenced because would need to
  demonstrate genetic stability-3rd world
  implications for this cheap oral vaccine

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Problems with vaccines

• Influenza vaccine In 1976 US govt funded 200M
  program to vaccinate entire population against
  Flu A
• Program abandoned after 40M doses because
  11,000,000 doses appeared to be associated with
  Guillain-Barr syndrome (not seen since,but
  litigations still running at about 1billion)

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Introduction to making a rec vaccine

• Several important steps are needed
• Determine epitopes (antigenic detrminants)
• Clone into a manufacturing cell eg yeast
• Need to illicit appropriate (protective) and long
  term immune response (longevity)
• Advantages of subunit or rec vaccines include QC
  easier, safe, lttoxicity, stability can be
  tested,may be only way for problem agents eg HIV

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What is an epitope?
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What is an Antibody? (immunoglobulin)
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How do antibodies attach to antigens (epitopes)?
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Examples of current vaccines

• HBV HBsAg rec vaccine grown in yeast
• Rubella (ssRNA virus) currently use live
  attenuated strain(Cendehill or RA/27/3)
• S.pneumoniae capsular polysaccharide extract of
  bacterium (subunit vaccine) used in trauma
  patients especially asplenic

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Introduction to antimicrobials

• A/microbials have selective toxicity
• Antibiotics
• Antibiotics are naturally produced (bacteria and
  fungi) or synthetically modified chemicals
• Interfere with metabolism of target bacteria eg
  cell wall, protein, DNA synthesis

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Factors affecting antibiotic efficacy

• Concentration of active form
• Binding to protein
• Half life
• Mechanism of excretion
• Ability to perfuse into target eg CSF

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Problems with antibiotics

• Toxicity (some for external use only, others
  accumulate)
• Anaphylaxis
• Resistance
• Limited spectrum-is this a problem?
• Oral/parenteral limits

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Working out which antibiotic?

• MIC minimal inhibitory dose
• eg 20µg/mL
• MBC minimal bacteriocidal dose
• eg 10µg/mL

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Antibiotic resistance

• Can arise by
• Selection pressure (high use picks for survivors)
• The R can be effected by
• The bacterium becoming
• Impermiable to a/biotic
• Alteration of target site
• Change of target pathways
• Producing enzymes to destroy antibiotic
• Genetic transfer-conjugation, transduction,
  transformation,

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Examples of antibiotic groups

• Betalactams (penicillins)-target cell wall
• Oral and parenteral forms
• Depending on type, can have restricted or broad
  spectrum of activity G/G-, G
• Subject to
• Betalactamases
• Permiability changes
• Adsorption site changes
• Bacterium must have cell wall
• Eg penicillin G, amoxicillin, cephalosporins

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The betalactam ring of penicillins
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Examples contin...

• Aminoglycosides (aa attached to aminocylitol)
• Inhibit protein synthesis
• Effective against wide range G- (can affect G)
• No absorbed orally
• Can be toxic if accumulated
• Eg gentamicin

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Examples contin...

• Chloramphenicol produced synthetically
• Bacteriostatic not bacteriocidal
• Good CSF infusion
• Broad spectrum
• Can affect bone marrow also lead to fatal
  aplastic anaemia
• Oral and parenteral
• Inhibits protein synthesis

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Antibiotics contin...

• Metronidazole (flagyl)
• Main antibiotic for anaerobic infections
• effective against protozoa eg Giardia
• Produces toxic metabolites with low redox
  potential

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Target sites for antibiotics
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Antivirals

• Amantidine (oral and parenteral)
• Antiflu, useful in first 24-48hrs
• Can be toxic
• Acyclovir (oral /parenteral)
• Anti HSV
• Gangicyclovir more useful against VZV
• Zidovudine (AZT) anti HIV
• Tribovarin HSV and some RNA viruses

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Antifungals

• Azoles imidazole or trizole ring
• Block fungal metabolic pathways
• Topical and systemic
• Eg fluconazole, micanazole, clotrimoxazole
• Polyenes
• Major drug for systemic fungal infection
• Toxicity problems
• Eg amphotericin B