Classical Vaccines

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Classical Vaccines
Ole Lund
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Vaccination

• Vaccination
• Administration of a substance to a person with
  the purpose of preventing a disease
• Traditionally composed of a killed or weakened
  micro organism
• Vaccination works by creating a type of immune
  response that enables the memory cells to later
  respond to a similar organism before it can cause
  disease

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Early History of Vaccination

• Pioneered India and China in the 17th century
• The tradition of vaccination may have originated
  in India in AD 1000
• Powdered scabs from people infected with
  smallpox was used to protect against the disease
• Smallpox was responsible for 8 to 20 of all
  deaths in several European countries in the 18th
  century
• In 1721 Lady Mary Wortley Montagu brought the
  knowledge of these techniques from Constantinople
  (now Istanbul) to England
• Two to three percent of the smallpox vaccinees,
  however, died from the vaccination itself
• Benjamin Jesty and, later, Edward Jenner could
  show that vaccination with the less dangerous
  cowpox could protect against infection with
  smallpox
• The word vaccination, which is derived from
  vacca, the Latin word for cow.

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Edward Jenner. Vaccine trials
The arm of Sarah Nelmes, a dairy maid, who had
contracted cowpox. Jenner used material from her
arm to vaccinate an eight year old boy, James
Phipps. (1798).
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Early History of Vaccination II

• In 1879 Louis Pasteur showed that chicken
  cholera weakened by growing it in the laboratory
  could protect against infection with more
  virulent strains
• 1881 he showed in a public experiment at
  Pouilly-Le-Fort that his anthrax vaccine was
  efficient in protecting sheep, a goat, and cows.
• In 1885 Pasteur developed a vaccine against
  rabies based on a live attenuated virus
• A year later Edmund Salmon and Theobald Smith
  developed a (heat) killed cholera vaccine.
• Over the next 20 years killed typhoid and plague
  vaccines were developed
• In 1927 the bacille Calmette-Guérin (BCG
  vaccine) against tuberculosis was developed

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Vaccination since WW II

• Cell cultures
• Ability to grow cells from higher organisms such
  as vertebrates in the laboratory
• Easier to develop new vaccines
• The number of pathogens for which vaccines can
  be made have almost doubled.
• Many vaccines were grown in chicken embryo cells
  (from eggs), and even today many vaccines such as
  the influenza vaccine, are still produced in eggs
• Alternatives are being investigated

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Effectiveness of vaccines
1958 start of small pox eradication program
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Vaccines Today

• Vaccines have been made for only 34 of the more
  than 400 known pathogens that are harmful to man
  (lt10).
• Immunization saves the lives of 3 million
  children each year, but that 2 million more lives
  could be saved if existing vaccines were applied
  on a full-scale worldwide
• Many vaccine products of today are short lived
• Maintained cool and last lt 1 year
• The cost for developing new vaccine is estimated
  to be close to 500 million us ,
• and the time span from development to the vaccine
  marked is between 10 and 30 years

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RD Productivity is Down Because of Increased
Costs and Decreased Success Rates
NME New Molecule entries
Industry RD Expense (Billions)
No. of NME Approvals
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Source PhRMA, FDA, Lehman Brothers
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Example Live Influenza VaccineThe First 36 years
FDA VRBPAC Review - 2
John Maassab describes cold adapted influenza
viruses
Aviron formed
Four-year efficacy study
FDA VRBPAC Review - 1
First human studies
Licensure 6/17/03
First FluMisttm trial
1967
1985
1989
1995
1976
2003
Johnson 1963 - 69
Nixon 1969 - 74
Ford 1974 - 77
Carter 1977 - 81
Reagan 1981 - 89
Bush 1989 - 93
Clinton 1993 - 01
Bush, W 2001-
William C. Gruber, M.D. VP, Global Clinical
Research Wyeth Vaccines Research June 17, 2005
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Live Influenza Vaccine FluMist

• Development Time 1967-2003 ( 36 years)
• Development Costs gtgt 1 Billion (3 companies)
• Price 45/dose
• Launched 2003/04 season
• Projected sales gt50M doses
• Manufactured in 03 5M doses in 1st season
• Sold in 03/04 lt1M doses
• Impact on public health yet to be determined

William C. Gruber, M.D. VP, Global Clinical
Research Wyeth Vaccines Research June 17, 2005
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Human Vaccines against pathogens
Immunological Bioinformatics, The MIT press.
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Categories of Vaccines

• Live vaccines
• Are able to replicate in the host
• Attenuated (weakened) so they do not cause
  disease
• Subunit vaccines
• Part of organism
• Genetic Vaccines
• Part of genes from organism

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Live Vaccines

• Characteristics
• Able to replicate in the host
• Attenuated (weakened) so they do not cause
  disease
• Advantages
• Induce a broad immune response (cellular and
  humoral)
• Low doses of vaccine are normally sufficient
• Long-lasting protection are often induced
• Disadvantages
• May cause adverse reactions
• May be transmitted from person to person
• Cannot repeat vaccination (boost)

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Subunit Vaccines

• Definition Vaccine composed of a purified
  antigenic determinant that is separated from the
  virulent organism.
• Advantages
• Relatively easy to produce (not live)
• Create a better-tolerated vaccine that is free
  from whole microorganism cells
• The vaccine may be purified
• Selecting one or a few proteins which confer
  protection
• Disadvantages
• Induce little CTL
• Viral and bacterial proteins are not produced
  within cells

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Subunit Vaccines Polysaccharides

• Definition A vaccine containing purified
  capsular polysaccharide antigen from the most
  common infectious types of Streptococcus
  pneumoniae, used to immunize against
  pneumonococcal disease.
• Many bacteria have polysaccharides in their
  outer membrane
• Polysaccharide based vaccines
• Neisseria meningitidis
• Streptococcus pneumoniae
• Generate a T cell-independent response
• Inefficient in children younger than 2 years old
• Overcome by conjugating the polysaccharides to
  peptides
• Used in vaccines against Streptococcus
  pneumoniae and Haemophilus influenzae.

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Subunit Vaccines Toxoids

• Definition A substance that has been treated to
  destroy its toxic properties but that retains the
  capacity to stimulate production of antitoxins,
  used in immunization.
• Toxins
• Responsible for the pathogenesis of many
  bacteria
• Toxoids
• Inactivated toxins
• Toxoid based vaccines
• Bordetella pertussis
• Clostridium tetani
• Corynebacterium diphtheriae
• Inactivation
• Traditionally done by chemical means
• Altering the DNA sequences important to toxicity

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Subunit Vaccines Recombinant

• The hepatitis B virus (HBV) vaccine
• Originally based on the surface antigen purified
  from the blood of chronically infected
  individuals.
• Due to safety concerns, the HBV vaccine became
  the first to be produced using recombinant DNA
  technology (1986)
• Produced in bakers yeast (Saccharomyces
  cerevisiae)
• Virus-like particles (VLPs)
• Viral proteins that self-assemble to particles
  with the same size as the native virus.
• VLP is the basis of a promising new vaccine
  against human papilloma virus (HPV)
• Merck, In phase III

For more information se http//www.nci.nih.gov/nc
icancerbulletin/NCI_Cancer_Bulletin_041205/page5
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Genetic Vaccines

• Introduce DNA or RNA into the host
• Injected (Naked)
• Coated on gold particles
• Carried by viruses
• Vaccinia, adenovirus, or alphaviruses
• bacteria such as
• Salmonella typhi, Mycobacterium tuberculosis
• Advantages
• Easy to produce
• Induce cellular response
• Disadvantages
• Low response in 1st generation
• That is Does not work in primates

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Epitope based vaccines

• Advantages (Ishioka et al. 1999)
• More potent
• Better control
• Induce subdominant epitopes (e.g. against tumor
  antigens where there is tolerance against
  dominant epitopes)
• Target multiple conserved epitopes in rapidly
  mutating pathogens like HIV and Hepatitis C virus
  (HCV)
• Designed to break tolerance
• Overcome safety concerns associated with entire
  organisms or proteins
• Epitope-based vaccines have been shown to confer
  protection in animal models (Snyder et al.,
  2004, Rodriguez et al. 1998 and Sette and
  Sidney 1999)

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Passive Immunization

• Immunity acquired by the transfer of antibodies
  from another individual, as through injection or
  placental transfer to a fetus (The outbreak,
  Dustin Hoffman)
• Used in special cases against many pathogens
• Cytomegalovirus
• Hepatitis A and B viruses
• Measles
• Varicella
• Rubella
• Respiratory syncytial virus
• Rabies
• Clostridium tetani
• Varicella-zoster virus
• Vaccinia
• Clostridium botulinum
• Corynebacterium diphtheriae
• Hanta virus

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Therapeutic vaccines

• Vaccines to treat the patients that already have
  a disease
• Targets
• Tumors
• AIDS
• Allergies
• Autoimmune diseases
• Hepatitis B
• Tuberculosis
• Malaria
• Helicobacter pylori
• Concept
• suppress/boost existing immunity or induce immune
  responses.

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Cancer vaccines

• Break the tolerance of the immune system against
  tumors
• 3 types
• Whole tumor cells, peptides derived from tumor
  cells in vitro, or heat shock proteins prepared
  from autologous tumor cells
• Tumor-specific antigendefined vaccines
• Vaccines aiming to increase the amount of
  dendritic cells (DCs) that can initiate a
  long-lasting T cell response against tumors.
• Therapeutic cancer vaccines can induce antitumor
  immune responses in humans with cancer
• Antigenic variation is a major problem that
  therapeutic vaccines against cancer face
• Tools from genomics and bioinformatics may
  circumvent these problems

Se also http//cis.nci.nih.gov/fact/7_2.htm
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Allergy vaccines

• Increasing occurrence of allergies in
  industrialized countries
• The traditional approach is to vaccinate with
  small doses of purified allergen
• Second-generation vaccines are under development
  based on recombinant technology
• Genetically engineered Bet v 1 vaccine can reduce
  pollen-specific IgE memory response significantly
• Example of switching a wrong immune response to
  a less harmful one.

Figure by Thomas Blicher.
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Therapeutic Vaccines against Persistent Infections

• For example for preventing HIV-related disease
  progression
• Most of the first candidate HIV-1 vaccines were
  based entirely or partially on envelope proteins
  to boost neutralizing antibodies
• Envelope proteins are the most variable parts of
  the HIV genome. Vaccines composed of monomeric
  gp120 molecules induce antibodies that do not
  bind to trimeric gp120 on the surface of virions
• A number of recent vaccines are also designed to
  induce strong cell-mediated responses.
• Escapes from CTL responses are associated with
  disease progression and high viral loads
• Some CTL epitopes escape recognition quickly
  because they are not functionally constrained,
  others might need several compensatory mutations
  because they are in functionally or structurally
  constrained regions of HIV-1

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Vaccines Against Autoimmune Diseases

• Multiple sclerosis
• T cells specific for mylein basic protein (MBP)
  can cause inflammation of the central nervous
  system.
• The vaccine uses copolymer 1 (cop 1), a protein
  that highly resembles MBP. Cop 1 competes with
  MBP in binding to MHC class II molecules, but it
  is not effective in inducing a T cell response
• On the contrary, cop 1 can induce a suppressor T
  cell response specific for MBP, and this response
  helps diminish the symptoms of multiple sclerosis
• A vaccine based on the same mechanisms is
  developed for myasthenia gravis

More information http//www.ninds.nih.gov/disord
ers/multiple_sclerosis/detail_multiple_sclerosis.h
tm, http//www.ncbi.nlm.nih.gov/entrez/query.fcgi
?cmdRetrievedbpubmeddoptAbstractlist_uids12
667659query_hl4
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Vaccines Market

• The vaccine market has increased fivefold from
  1990 to 2000
• Annual sales of 6 billion euros
• Less than 2 of the total pharma market.
• Major producers (85 of the market)
• GlaxoSmithKline (GSK), Merck, Aventis Pasteur,
  Wyeth, Chiron
• Main products (gt50 of the market)
• Hepatitis B, flu, MMR (measles, mumps, and
  rubella) and DTP (diphtheria, tetanus, pertussis)
• 40 are produced in the United States and the
  rest is evenly split between Europe and the rest
  of the world Gréco, 2002
• It currently costs between 200 and 500 million US
  dollars to bring a new vaccine from the concept
  stage to market André, 2002

More information Gréco, 2002 André, 2002
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Trends

• From
• Whole live and killed organisms
• Problems
• Adverse effects
• Production
• To
• Subunit vaccines
• Genetic vaccines
• Challenges
• Enhance immunogenecity