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Prevention and Control of Virus Disease


From Flint et al Principles of Virology ASM Press. Measles in Faroe Islands - 18th century ... From killing, crippling or disfiguring 10% of the entire human ... – PowerPoint PPT presentation

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Title: Prevention and Control of Virus Disease

Prevention and Control of Virus Disease
  • Vaccination
  • Tues 11/11/2003

Vaccines the proven best defense against viruses
  • Smallpox
  • Poliovirus
  • Influenza
  • Measles
  • Hepatitis B
  • Ebola
  • Rabies
  • RSV

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
The immune system and vaccines
B cells T cells
The vaccine is a source of virus-specific antigen
From Nathanson. Viral Pathogenesis
  • From killing, crippling or disfiguring 10 of the
    entire human population, smallpox has now been
  • 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

  • Edward Jenner (1749-1823)
  • Jenners insight was to realize that cowpox (a
    related bovine virus) might confer immunity to
  • 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
  • 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
  • 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
  • When stimulated immune cells are used adoptive
  • 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

  • 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
  • Other important features --
  • 1) stability, 2) ease of administration, 3) cost

Vaccine success stories
Indigenous wild poliovirus
  • Smallpox -- eradicated (1979)
  • Poliovirus -- almost eradicated

From Nathanson Fine Science 296 269 (2002)
  • 20,000 paralytic cases/yr in 1950s, 2000-3000

From Strauss Strauss, Viruses and Human
Disease Academic Press
Live attenuated virus vaccines
  • The basis of the polio vaccine
  • Virulent viruses may become attenuated by growing
  • A) in different host cells
  • B) at different temperature

From Flint et al Principles of Virology ASM Press
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
  • 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

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
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
  • Biological properties indistinguishable from wild

From Kew et al Science 296 356 (2002)
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

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
  • 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)

Comparison of live and killed vaccines
From Flint et al Principles of Virology ASM Press
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

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//

  • 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
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
  • 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
  • By direct stimulation of the immune response
  • Killed mycobacterium/mineral oil is used in
    animals (Freunds), alum is used in humans

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
  • 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

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

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

From Flint et al Principles of Virology ASM Press
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.

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

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

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