Viral Vaccines

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Viral Vaccines
Immunisation the most generally applicable
method of preventing infectious
disease. Vaccinate to administer, as a single
or multiple dose, a nonpathogenic antigen (intact
virus or virion subunit) to an animal or human
such that the immune system of the individual
responds by producing antibodies (humoral
immunity) and in some cases, cell-mediated
immunity directed against one, several, or all
viral antigens. Eradication of
smallpox Eradication of polio in Europe
2002 Sebastião Salgado
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What are the parameters necessary for the
eradication of a virus?

• The virus must have no alternative hosts
• Infection (or vaccination) must produce lifelong
  immunity

from Flint et al. (2000) Principles of Virology
ASM Press
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Approaches to Vaccine Design

• 3 general categories
• Attenuated viruses
• Inactivated (killed) viruses
• Purified viral components (subunit vaccines)

• Requirements of an effective vaccine
• Safety
• Induction of protective immune response
• Practical issues

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Live attenuated virus vaccines
from Flint et al. (2000) Principles of Virology
ASM Press

• Successful live attenuated vaccines are effective
  for 3 reasons
• The attenuated viruses replicate to some extent
  in the host
• The attenuated viruses have a reduced capacity
  to spread from the site of replication
• The attenuated viruses cause mild or inapparent
  disease.

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adapted from Flint et al. (2000) Principles of
Virology ASM Press
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• Delivery of live attenuated viruses
• Injection (e.g. measles-mumps-rubella vaccine)
• Oral (e.g. poliovirus, rotavirus, adenovirus
  vaccines)
• Nasal spray (respiratory viruses)

• Potential problems
• Virus shedding and infection of unvaccinated
  individuals
• Arisal of revertants due to compensatory
  mutations
• Difficulty in prediction of behaviour in
  individuals and the population
• elimination before induction of protective
  response
• infection of new niches in host
• initiation of atypical infections (e.g.
  triggering Guillain-Barré syndrome)
• Ensuring purity and sterility

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Recombinant DNA approaches to attenuation
from Flint et al. (2000) Principles of Virology
ASM Press
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Inactivated (killed) Virus Vaccines

• Chemical inactivation
• formalin - traditionally used now being
  supplanted by
• b-propiolactone, ethylenimines
• nonionic detergent-disruption

• Advantages
• non-infectious
• relatively uncomplicated and inexpensive to
  produce
• killed virus more easily stored than live-virus
  vaccines
• Disadvantages
• Injection of large amounts necessary to elicit
  antibody response
• Vaccine must be injected (no oral delivery)
• Multiple rounds of immunisation required
• Vaccination does not result in complete immunity

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Subunit vaccines (synthetic vaccines)

• Recombinant DNA methods
• Clone appropriate viral genes into
  nonpathogenic host to produce immunogenic
  protein.
• Example Hepatitis B subunit vaccine (HBsAg)
• Advantages
• no contamination of vaccine with original virus
  (nontoxic, nonallergenic)
• inexpensive production of viral proteins in
  quantity
• feasible even if virus cannot be cultured
• Disadvantages
• lack of sufficient immune response
• IgA response rarely stimulated
• requires adjuvant

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• Synthetic peptides (20 amino acids in length)
• Identification of immunogenic viral protein
• Cloning and sequencing of gene encoding this
  protein
• Synthesis of short peptides corresponding to
  sections in sequence
• Test for immune response
• Advantages extremely safe, well-defined
• Disadvantages expensive weak and short-lived
  antibody response requires adjuvant
  single-epitope vaccine will readily select mutants

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New Vaccine Technology
Viral vaccines DNA vaccines

• Viral vectors
• Use nonpathogenic virus to immunise host against
  a pathogenic virus.
• Merges subunit vaccine and live attenuated virus
  technologies.
• Provides benefit of viral infection with
  respect to the immune response without the
  pathogenesis associated with the virulent virus.
• Vaccinia virus smallpox eradication continued
  use as viral vector
• Problems
• host is immunised against viral vector as well
  as the vaccine antigen subsequent uses of vector
  may result in weak/no response, or an
  immunopathological response.
• Immunocompromised individuals may be infected
  within the vaccinated population with adverse
  consequences.

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Construction of a recombinant vaccinia virus
expressing the influenza virus HA gene
from Flint et al. (2000) Principles of Virology
ASM Press
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DNA vaccines
from Flint et al. (2000) Principles of Virology
ASM Press
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Methods for enhancing immunogenicity

• Adjuvants
• When mixed with killed viruses or subunit
  vaccines, produce a more robust acquired immune
  response that requires less antigen.
• Adjuvants work in at least 3 ways
• by presentation of antigen as particles
• by localisation of antigen to the site of
  inoculation
• by direct stimulation of the immune response

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Immune-stimulating complexes (ISCOMs) as peptide
delivery vehicles