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Classical Vaccines

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The word vaccination, which is derived from vacca, the Latin word for cow. Edward Jenner. ... The arm of Sarah Nelmes, a dairy maid, who had contracted cowpox. ... – PowerPoint PPT presentation

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Title: Classical Vaccines


1
Classical Vaccines
Ole Lund
2
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

3
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.

4
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).
5
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

6
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

7
Effectiveness of vaccines
1958 start of small pox eradication program
8
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

9
RD Productivity is Down Because of Increased
Costs and Decreased Success Rates
NME New Molecule entries
Industry RD Expense (Billions)
No. of NME Approvals
1
Source PhRMA, FDA, Lehman Brothers
10
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
11
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
12
Human Vaccines against pathogens
Immunological Bioinformatics, The MIT press.
13
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

14
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)

15
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

16
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.

17
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

18
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
19
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

20
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)

21
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

22
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.

23
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
24
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.
25
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

26
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
27
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
28
Trends
  • From
  • Whole live and killed organisms
  • Problems
  • Adverse effects
  • Production
  • To
  • Subunit vaccines
  • Genetic vaccines
  • Challenges
  • Enhance immunogenecity
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