Prevention and Control of Virus Disease

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Prevention and Control of Virus Disease

• Vaccination
• Tues 11/11/2003

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Vaccines the proven best defense against viruses

• Smallpox
• Poliovirus
• Influenza
• Measles
• Hepatitis B
• Ebola
• Rabies
• RSV

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Vaccine basics

• Attenuated vaccines
• Inactivated (killed) vaccines
• Subunit vaccines (purified viral components)

Vaccines stimulate immune memory
From Flint et al Principles of Virology
ASM Press
Measles in Faroe Islands - 18th century
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The immune system and vaccines
B cells T cells
The vaccine is a source of virus-specific antigen
From Nathanson. Viral Pathogenesis
Lippincott-Raven
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Smallpox

• From killing, crippling or disfiguring 10 of the
  entire human population, smallpox has now been
  eradicated
  
• Chinese and Indian physicians in the 11th century
  introduced pus from smallpox lesions into healthy
  individuals in the hope of introducing only mild
  disease and protection. In 18th century England,
  dried crusts of lesions were rubbed into the cuts
  of healthy people (variolation)
• These practices were very dangerous and often
  lead to full disease
  

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• Edward Jenner (1749-1823)
• Jenners insight was to realize that cowpox (a
  related bovine virus) might confer immunity to
  smallpox.
  
• Jenner introduced cowpox lesions into a healthy
  boy (1796), and then deliberately infected the
  boy with smallpox (vaccination). The boy survived
  with localized cowpox lesions at the site of
  infection.

• Louis Pasteur - 100 years later
• The vaccine for Rabies virus
• Deliberate, experimental production and control
  of the vaccine
  
• Serial passage of an infectious virus in rabbit
  spinal cord
  

The next vaccines (yellow fever and influenza)
did not appear until the 1930s
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• Vaccines usually give active immunization
• a modified form of the virus
• But they can give passive immunization
• The products of an immune response (e.g.
  antibodies) -- pooled human sera or immune
  globulin
  
• When stimulated immune cells are used adoptive
  transfer
  
• This is a short-term, emergency strategy
• The Dustin Hoffman approach
• Vaccines must be safe
• No presence of infectious virus
• No reversion to virulence
• No contamination
• But the use of any vaccine is not without some
  risk
  

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• Herd immunity
• To achieve success in preventing disease in a
  population, not every individual must be
  vaccinated - generally 80-95 is sufficient
  
• This reduces the virus load in the population
  such that the infection is not sustained
  
• In the case of smallpox, vaccination rates as low
  as 50 have led to eradication in some countries
  
• An outbred population will always have a varied
  response to vaccination
  
• Age and health of the individual
• Weak immune responses can select vaccine escape
  mutants
  
• Other important features --
• 1) stability, 2) ease of administration, 3) cost

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Vaccine success stories
Indigenous wild poliovirus

• Smallpox -- eradicated (1979)
• Poliovirus -- almost eradicated

From Nathanson Fine Science 296 269 (2002)
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Poliovirus

• 20,000 paralytic cases/yr in 1950s, 2000-3000
  deaths

From Strauss Strauss, Viruses and Human
Disease Academic Press
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Live attenuated virus vaccines

• The basis of the polio vaccine
• Virulent viruses may become attenuated by growing
  them
  
• A) in different host cells
• B) at different temperature

From Flint et al Principles of Virology ASM Press
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Attenuated poliovirus vaccines

• Sabin (live attenuated, or OPV) poliovirus
  vaccine consists of 3 serotypes of the virus,
  developed in 1961

From Flint et al Principles of Virology ASM Press
Mutations affect mRNA translation and virus
assembly
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• This type of virus attenuation is seemingly
  undirected, or blind
  
• But they work and are widely used , because
• The viruses replicate to some extent in the host
• The authentic immune response is elicited
• The virus will amplify somewhat,
• They have a reduced ability to spread, but can
  spread (vaccination of unvaccinated neighbors)
  
• They cause mild or inapparent disease

• Delivery is by syringe or mouth (good for
  enteric viruses) or by aerosol
  
• Delivery is usually easy
• The vaccine is often stable
• They are relatively cheap to produce
• The polio vaccine is currently 8c a dose

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Problems with attenuated viruses

• Reversion to wild-type
• Vaccine-derived polioviruses (VDPVs) - highly
  enterotropic and spread to non-immune subjects
  

From Flint et al Principles of Virology ASM Press
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Complications of vaccine strategies

• Outbreak of paralytic poliomyelitis in Dominican
  Republic during 2000-2001
  
• All patients were unvaccinated or incompletely
  vaccinated children in areas with low vaccine
  coverage (7-40)

• Outbreak associated with type 1 OPV strain
  originating with a single OPV dose given in
  1998-1999
  
• Biological properties indistinguishable from wild
  type

From Kew et al Science 296 356 (2002)
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Killed poliovirus vaccines

• The original (Salk) poliovirus vaccine was
  killed, developed in 1955
  
• It was very safe, it induces high levels of
  circulating antibody, but little mucosal immunity
  - hence stops paralysis, but not necessarily
  virus spread in the GI tract. Injected.
• Supeceded by the Sabin OPV vaccine
• The Salk vaccine is still used in the USA today
  in babies
  
• It is far less effective at preventing polio
  outbreaks and would never work in a disease
  eradication program

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Inactivated or killed vaccines

• The natural pathogenic virus is produced in
  quantity and inactivated by chemical or physical
  procedures - to eliminate infectivity without
  affecting antigenicity
• e.g formalin, Triton X-100
• These vaccines are uncomplicated and relatively
  inexpensive
  
• Theoretically they are very safe (assuming
  inactivation is good)
  
• The influenza vaccine is a killed virus, 75
  million doses, virus is grown in embryonated
  chicken eggs
  
• Can be whole virus (formalin inactivated) or a
  detergent soluble fraction (a subunit vaccine ?)
  
• Equivalent to 15 µg HA
• Must be given every year
• A mixture of 3 strains (A/H1N1, A/H3N2 and B)

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Comparison of live and killed vaccines
From Flint et al Principles of Virology ASM Press
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Cold-adapted virus vaccines

• For respiratory infections, viruses can be
  selected that replicate only in the upper
  respiratory tract (limited disease outcome)
  rather than the lower respiratory tract
• This is based on the relative temperatures of the
  two sites
  
• Viruses are selected able to infect at 32-34C,
  but not 37C
  
• Mutations arise in almost all gene segments
• Used fairly extensively for influenza virus - in
  the former Soviet Union

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A new influenza vaccine

• In the 1960s cold adapted vaccines were
  developed by John Maassab at the Univ. of
  Michigan, selected for growth at 25C
  
• In 2003, these viruses were approved by the FDA,
  for individuals aged 5-50
  
• No injection, can be given by a pharmacist (or
  even in the home)
  
• Cost x2 higher that the standard killed vaccine
• Aimed mainly at school-age children
• rtsp//umtv-live.rs.itd.umich.edu/sph/maassab2.rm

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MMR

• A highly successful vaccine
• Protects against measles, mumps and rubella

• Recent problems, due to (unfounded) link to
  autism and inflammatory bowel disease
  
• Some areas of Europe have vaccine coverage of
  young children down to 60
  
• Outbreaks of measles, with deaths of unvaccinated
  children have occurred (Dublin, Ireland 2003)

Measles can kill 12500 of those infected
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Designer attenuated vaccines

• Deliberate attenuation
• e.g. deletion mutants with exceedingly low
  probability of reversion to virulence
  

From Flint et al Principles of Virology
ASM Press
From Flint et al Principles of Virology ASM Press
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Adjuvants

• Killed viruses are often not very immunogenic
• Adjuvants are immunostimulatory substances that
  help early immune recognition
  
• By presentation of antigen as particles
• By localization of the antigen to the site of
  inoculation
  
• By direct stimulation of the immune response
• Killed mycobacterium/mineral oil is used in
  animals (Freunds), alum is used in humans

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Subunit vaccines

• A purified subset of viral proteins
• e.g. Hepatitis B virus surface antigen (HbSAg)
• Produced in yeast (S. cerevisiae)
• -spontaneously assembles into a virus-like
  particle
  
• Synthetic peptides (20aa)
• Taken up and presented with MHC class II
• Foot and mouth disease virus

• In general, subunit vaccines are expensive,
  difficult to produce, and give poor responses
  
• But, they are very safe, and can be used for
  unculturable viruses

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Rabies vaccine

• Killed rabies vaccine (in humans) is an example
  of post-exposure vaccination, used in combination
  with immune globulin therapy
  
• Smallpox vaccine can also be used after exposure
• Ring vaccination

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Viral vectors

• Vaccinia virus
• Recombinant viruses can be engineered to express
  one of more foreign virus gene products - rabies
  vaccine in animals
  
• Vesicular stomatitis virus (VSV)
• Level of protein expression can be controlled by
  the location in the genome - possible use for
  HIV-1 - expression of gp120
  

From Flint et al Principles of Virology ASM
Press

From Flint et al Principles of Virology ASM Press
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DNA vaccines

• Not a viral protein, but a DNA plasmid encoding a
  viral gene
  
• Delivered by injection or gene-gun
• Somehow the DNA gets into cells and expressed
• Gives good MHC I presentation
• Often combined with cytokine genes as immune
  response promoters (adjuvants)
  
• e.g new HIV gp120/IL-2 DNA vaccine
• Other examples
• Influenza vaccine - NP DNA (stimulates T cells)
• The van Gogh experiment - a rabbit was injected
  with a DNA vaccine in the ear and the ear cut off
  at various time post injection. Antibodies were
  produced even if the ear was cut off after a few
  minutes. The DNA is rapidly moving to other sites.

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Ebola vaccine

• Ebola DNA vaccine
• - gp DNA/Adenovirus booster
• Complex immunization strategy (6 months), but
  good response
  

• New vaccine is just the gp expressed by
  adenovirus - very fast response (can be used for
  ring vaccination)
  
• However, response is much weaker than original
  vaccine (but does protect)
  
• Also, 45 of the US population has immunity to
  adenovirus and might be resistant to the Ebola
  vaccine
  

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Notable vaccine failures

• HIV
• RSV (Respiratory syncytial virus)
• A common cause of pediatric hospitalization -
  very young children (
  
• In the early 1960s, a formalin-inactivated
  vaccine was tested
  
• This failed to give any protection
• But also gave exaggerated clinical response upon
  subsequent RSV infection - with highly increased
  rates of hospitalization (80 vs. 5) and two
  deaths in clinical trials
• There is still no effective RSV vaccine
• Current therapy is based on passive immunization

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Viral vaccines registered in the United States
From Flint et al Principles of Virology ASM Press
New 5-in-1 vaccines are now available
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Further reading Chapter 19 of Flint
Topley and Wilsons Microbiology and Microbial
Infections Vol1Virology Chapter 45
Nathanson Viral Pathogenesis Chapter 16